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Sample records for high-risk hla haplotypes

  1. Extended HLA-D region haplotype associated with celiac disease

    SciTech Connect

    Howell, M.D.; Smith, J.R.; Austin, R.K.; Kelleher, D.; Nepom, G.T.; Volk, B.; Kagnoff, M.F.

    1988-01-01

    Celiac disease has one of the strongest associations with HLA (human leukocyte antigen) class II markers of the known HLA-linked diseases. This association is primarily with the class II serologic specificities HLA-DR3 and -DQw2. The authors previously described a restriction fragment length polymorphism (RFLP) characterized by the presence of a 4.0-kilobase Rsa I fragment derived from an HLA class II ..beta..-chain gene, which distinguishes the class II HLA haplotype of celiac disease patients from those of many serologically matched controls. They now report the isolation of this ..beta..-chain gene from a bacteriophage genomic library constructed from the DNA of a celiac disease patient. Based on restriction mapping and differential hybridization with class II cDNA and oligonucleotide probes, this gene was identified as one encoding an HLA-DP ..beta..-chain. This celiac disease-associated HLA-DP ..beta..-chain gene was flanked by HLA-DP ..cap alpha..-chain genes and, therefore, was probably in its normal chromosomal location. The HLA-DP..cap alpha..-chain genes of celiac disease patients also were studied by RFLP analysis. Celiac disease is associated with a subset of HLA-DR3, -DQw2 haplotypes characterized by HLA-DP ..cap alpha..- and ..beta..-chain gene RFLPs. Within the celiac-disease patient population, the joint segregation of these HLA-DP genes with those encoding the serologic specificities HLA-DR3 and -DQw2 indicates: (i) that the class II HLA haplotype associated with celiac disease is extended throughout the entire HLA-D region, and (ii) that celiac-disease susceptibility genes may reside as far centromeric on this haplotype as the HLA-DP subregion.

  2. HLA Type Inference via Haplotypes Identical by Descent

    NASA Astrophysics Data System (ADS)

    Setty, Manu N.; Gusev, Alexander; Pe'Er, Itsik

    The Human Leukocyte Antigen (HLA) genes play a major role in adaptive immune response and are used to differentiate self antigens from non self ones. HLA genes are hyper variable with nearly every locus harboring over a dozen alleles. This variation plays an important role in susceptibility to multiple autoimmune diseases and needs to be matched on for organ transplantation. Unfortunately, HLA typing by serological methods is time consuming and expensive compared to high throughput Single Nucleotide Polymorphism (SNP) data. We present a new computational method to infer per-locus HLA types using shared segments Identical By Descent (IBD), inferred from SNP genotype data. IBD information is modeled as graph where shared haplotypes are explored among clusters of individuals with known and unknown HLA types to identify the latter. We analyze performance of the method in a previously typed subset of the HapMap population, achieving accuracy of 96% in HLA-A, 94% in HLA-B, 95% in HLA-C, 77% in HLA-DR1, 93% in HLA-DQA1 and 90% in HLA-DQB1 genes. We compare our method to a tag SNP based approach and demonstrate higher sensitivity and specificity. Our method demonstrates the power of using shared haplotype segments for large-scale imputation at the HLA locus.

  3. HLA class I antigen and HLA-A, -B, and -C haplotype frequencies in Uruguayans.

    PubMed

    Alvarez, Ines; Bengochea, Milka; Toledo, Roberto; Carretto, Elena; Hidalgo, Pedro C

    2006-08-01

    HLA class I antigens were determined for 959 unrelated Uruguayans. The predominant HLA alleles were A2, Cw4, and B35, and the most frequently observed two-loci haplotypes were A2-B44 and B35-Cw4. The most frequent three-loci HLA haplotype was A2-Cw5-B44. We compared the Uruguayan sample with similar data from other populations.

  4. Ancient haplotypes of the HLA Class II region.

    PubMed

    Raymond, Christopher K; Kas, Arnold; Paddock, Marcia; Qiu, Ruolan; Zhou, Yang; Subramanian, Sandhya; Chang, Jean; Palmieri, Anthony; Haugen, Eric; Kaul, Rajinder; Olson, Maynard V

    2005-09-01

    Allelic variation in codons that specify amino acids that line the peptide-binding pockets of HLA's Class II antigen-presenting proteins is superimposed on strikingly few deeply diverged haplotypes. These haplotypes appear to have been evolving almost independently for tens of millions of years. By complete resequencing of 20 haplotypes across the approximately 100-kbp region that spans the HLA-DQA1, -DQB1, and -DRB1 genes, we provide a detailed view of the way in which the genome structure at this locus has been shaped by the interplay of selection, gene-gene interaction, and recombination.

  5. TNFA Haplotype Genetic Testing Improves HLA in Estimating the Risk of Celiac Disease in Children

    PubMed Central

    Zambon, Carlo-Federico; Navaglia, Filippo; Greco, Eliana; Pelloso, Michela; Artuso, Serena; Padoan, Andrea; Pescarin, Matilde; Aita, Ada; Bozzato, Dania; Moz, Stefania; Cananzi, Mara; Guariso, Graziella; Plebani, Mario

    2015-01-01

    Background TNF-α and IFN-γ play a role in the development of mucosal damage in celiac disease (CD). Polymorphisms of TNFA and IFNG genes, as well as of the TNFRSF1A gene, encoding the TNF-α receptor 1, might underlie different inter-individual disease susceptibility over a common HLA risk background. The aims of this study were to ascertain whether five SNPs in the TNFA promoter (-1031T>C,-857C>T,-376G>A,-308G>A,-238G>A), sequence variants of the TNFRSF1A gene and IFNG +874A>T polymorphism are associated with CD in a HLA independent manner. Methods 511 children (244 CD, 267 controls) were genotyped for HLA, TNFA and INFG (Real Time PCR). TNFRSF1A variants were studied (DHPLC and sequence). Results Only the rare TNFA-1031C (OR=0.65, 95% CI:0.44-0.95), -857T (OR=0.42, 95% CI:0.27-0.65), -376A (OR=2.25, 95% CI:1.12-4.51) and -308A (OR=4.76, 95% CI:3.12-7.26) alleles were significantly associated with CD. One TNFRSF1A variant was identified (c.625+10A>G, rs1800693), but not associated with CD. The CD-correlated TNFA SNPs resulted in six haplotypes. Two haplotypes were control-associated (CCGG and TTGG) and three were CD-associated (CCAG, TCGA and CCGA). The seventeen inferred haplotype combinations were grouped (A to E) based on their frequencies among CD. Binary logistic regression analysis documented a strong association between CD and HLA (OR for intermediate risk haplotypes=178; 95% CI:24-1317; OR for high risk haplotypes=2752; 95% CI:287-26387), but also an HLA-independent correlation between CD and TNFA haplotype combination groups. The CD risk for patients carrying an intermediate risk HLA haplotype could be sub-stratified by TNFA haplotype combinations. Conclusion TNFA promoter haplotypes associate with CD independently from HLA. We suggest that their evaluation might enhance the accuracy in estimating the CD genetic risk. PMID:25915602

  6. Evidence for HLA class II susceptible and protective haplotypes for osteomyelitis in pediatric patients with sickle cell anemia.

    PubMed

    Al-Ola, K; Mahdi, N; Al-Subaie, A M; Ali, M E; Al-Absi, I K; Almawi, W Y

    2008-05-01

    We investigated the association of human leukocyte antigen (HLA) class II alleles and haplotypes with the pathogenesis of sickle cell anemia (SCA) osteomyelitis. SCA patients comprised 42 patients with osteomyelitis and 150 patients without osteomyelitis; HLA-DRB1* and HLA-DQB1* genotyping was performed by polymerase chain reaction-sequence-specific priming (SSP). DRB1*100101 (P value corrected for the number of different alleles tested, Pc=0.003) was positively associated with osteomyelitis. At the haplotype level, DRB1*100101-DQB1*050101 (Pc=0.001) was more prevalent among patients, while DRB1*030101-DQB1*0201 (Pc=0.020) and DRB1*040101-DQB1*0302 (Pc=0.039) were more prevalent among SCA controls, thereby conferring disease susceptibility or protection to these haplotypes, respectively. These results show that specific HLA haplotypes influence SCA osteomyelitis risk and that specific HLA types may serve as markers for identifying SCA patients at high risk for osteomyelitis.

  7. HLA DRB1*130101-DQB1*060101 haplotype is associated with acute chest syndrome in sickle cell anemia patients.

    PubMed

    Mahdi, N; Al-Subaie, A M; Al-Ola, K; Al-Irhayim, A Q; Ali, M E; Al-Irhayim, Z; Almawi, W Y

    2009-03-01

    We investigated the association of human leukocyte antigens (HLA) class II alleles and haplotypes with the pathogenesis of acute chest syndrome (ACS) in 186 sickle cell anemia (SCA) patients, of whom 58 had documented ACS (new pulmonary infiltrate, fever, and other associated clinical events) and 128 with a negative history of ACS, serving as controls. HLA DRB1* and -DQB1* genotyping was performed by polymerase chain reaction-sequence-specific priming. Of the DRB1* and DQB1* alleles analyzed, only DRB1*130101 (Pc < 0.001) was positively associated with ACS. DRB1*130101-DQB1*060101 haplotype was more prevalent among ACS patients (P = 0.018), thus conferring disease susceptibility. Specific HLA alleles and haplotypes may influence ACS risk in SCA patients, and specific HLA genotypes may be useful markers for identifying high-risk SCA ACS patients.

  8. HLA-DQA1 and HLA-DQB1 alleles and haplotypes in two Brazilian Indian tribes: evidence of conservative evolution of HLA-DQ.

    PubMed

    Sotomaior, V S; Faucz, F R; Schafhauser, C; Janzen-Dück, M; Boldt, A B; Petzl-Erler, M L

    1998-08-01

    Nucleotide sequence polymorphism of the HLA-DQA1 and HLA-DQB1 class II genes was analyzed in the Kaingang and Guarani Amerindians from southern Brazil using PCR sequence-specific oligonucleotide typing methods. Four different DQA1-DQB1 haplotypes were found: DQA1*0401-DQB1*0402 (associated with DRB1*0802, DRB1*08041, and DRB1*0807), DQA1*0501-DQB1*0301 (associated with DRB1*1602, DRB1*1413, and DRB1*1402), DQA1*03-DQB1*0302 (associated with DRB1*0404 and DRB1*0411), and DQA1*03-DQB1*03032 (associated with DRB1*09012). These HLA-DQA1 and HLA-DQB1 alleles and haplotypes are common in many other populations of all major ethnic groups. Alleles and haplotypes introduced into the populations by post-Columbian admixture were seen at low frequency both in the Kaingang (3.2%) and in the Guarani (3.8%). No novel HLA-DQA1 and HLA-DQB1 alleles have thus far been identified in Amerindians. This differs from previous results for HLA-DRB1, another class II locus presenting novel alleles (i.e., alleles not found in other ethnic groups and probably generated after migration of paleo-Indians to the Americas) in the Guarani and in other South American Indian populations. The distribution of the HLA-DQ alleles and haplotypes in Amerindians indicates a weaker diversifying selective pressure on the HLA-DQ genes compared with HLA-DRB1 and HLA-B. The more conservative evolution of HLA-DQA1 and HLA-DQB1 compared with HLA-DRB1 is strong evidence of (still not well-defined) functional differences of these class II genes.

  9. HLA-DRB and HLA-DQB Allele and Haplotype Frequencies in Iranian Patients with Recurrent Aphthous Stomatitis.

    PubMed

    Najafi, Shamsolmoulouk; Mohammadzadeh, Mahsa; Zare Bidoki, Alireza; Meighani, Ghasem; Aslani, Saeed; Mahmoudi, Mahdi; Rezaei, Nima

    Recurrent aphthous stomatitis (RAS) is known as the most common chronic disease of the oral cavity, which affects a range of 5-25% of the population. RAS appears to be associated with some human leukocyte antigen (HLA) class II alleles and haplotypes. This study attempts to survey the distribution of HLA-DRB and -DQB alleles among Iranian RAS patients and healthy controls. In order to evaluate the association of HLA-DR and DQ alleles and haplotypes, 54 patients with RAS and 100 unrelated healthy subjects as control group were investigated. Our data indicated that DRB1*13:17, DRB1*15:01, and DRB5*01 were significantly more frequent in RAS patients in comparison to controls. However, DRB3:01allele frequency was higher in the controls compared to the patients. The significantly frequent allele in the patients compared with the healthy subjects was HLA-DQB1*03:02. However, both HLA-DQB1*02:01 and HLA-DQB1*03:01 alleles were most frequent in the healthy individuals rather than the patients. The DRB*04/DQB1*03:01 and DRB*01:01/DQB1*02:01 haplotypes were significantly distributed in healthy subjects compared with patients. However, DRB*07:01/DQB1*03:02 haplotype was found to be significantly frequent in patients than controls. In respect of HLA genes, factors are involved in the incidence of RAS; various HLA-DRB and HLA-DQB1 alleles and the related haplotypes are suggested to be the three main RAS susceptibility factors in our population study.

  10. Class I HLA haplotypes form two schools that educate NK cells in different ways.

    PubMed

    Horowitz, Amir; Djaoud, Zakia; Nemat-Gorgani, Neda; Blokhuis, Jeroen; Hilton, Hugo G; Béziat, Vivien; Malmberg, Karl-Johan; Norman, Paul J; Guethlein, Lisbeth A; Parham, Peter

    2016-09-01

    Natural killer (NK) cells are lymphocytes having vital functions in innate and adaptive immunity, as well as placental reproduction. Controlling education and functional activity of human NK cells are various receptors that recognize HLA class I on the surface of tissue cells. Epitopes of polymorphic HLA-A,-B and -C are recognized by equally diverse killer cell immunoglobulin-like receptors (KIR). In addition, a peptide cleaved from the leader sequence of HLA-A,-B or -C must bind to HLA-E for it to become a ligand for the conserved CD94:NKG2A receptor. Methionine/threonine dimorphism at position -21 of the leader sequence divides HLA-B allotypes into a majority having -21T that do not supply HLA-E binding peptides and a minority having -21M, that do. Genetic analysis of human populations worldwide shows how haplotypes with -21M HLA-B rarely encode the KIR ligands: Bw4(+)HLA-B and C2(+)HLA-C KIR. Thus there are two fundamental forms of HLA haplotype: one preferentially supplying CD94:NKG2A ligands, the other preferentially supplying KIR ligands. -21 HLA-B dimorphism divides the human population into three groups: M/M, M/T and T/T. Mass cytometry and assays of immune function, shows how M/M and M/T individuals have CD94:NKG2A(+) NK cells which are better educated, phenotypically more diverse and functionally more potent than those in T/T individuals. Fundamental new insights are given to genetic control of NK cell immunity and the evolution that has limited the number of NK cell receptor ligands encoded by an HLA haplotype. These finding suggest new ways to dissect the numerous clinical associations with HLA class I.

  11. Class I HLA haplotypes form two schools that educate NK cells in different ways

    PubMed Central

    Horowitz, Amir; Djaoud, Zakia; Nemat-Gorgani, Neda; Blokhuis, Jeroen; Hilton, Hugo G.; Béziat, Vivien; Malmberg, Karl-Johan; Norman, Paul J.; Guethlein, Lisbeth A.; Parham, Peter

    2016-01-01

    Summary Natural killer (NK) cells are lymphocytes having vital functions in innate and adaptive immunity, as well as placental reproduction. Controlling education and functional activity of human NK cells are various receptors that recognize HLA class I on the surface of tissue cells. Epitopes of polymorphic HLA-A,-B and –C are recognized by equally diverse killer cell immunoglobulin-like receptors (KIR). In addition, a peptide cleaved from the leader sequence of HLA-A,-B or –C must bind to HLA-E for it to become a ligand for the conserved CD94:NKG2A receptor. Methionine/threonine dimorphism at position -21 of the leader sequence divides HLA-B allotypes into a majority having -21T that do not supply HLA-E binding peptides and a minority having -21M, that do. Genetic analysis of human populations worldwide shows how haplotypes with -21M HLA-B rarely encode the KIR ligands: Bw4+HLA-B and C2+HLA-C KIR. Thus there are two fundamental forms of HLA haplotype: one preferentially supplying CD94:NKG2A ligands, the other preferentially supplying KIR ligands. -21 HLA-B dimorphism divides the human population into three groups: M/M, M/T and T/T. Mass cytometry and assays of immune function, shows how M/M and M/T individuals have CD94:NKG2A+ NK cells which are better educated, phenotypically more diverse and functionally more potent than those in T/T individuals. Fundamental new insights are given to genetic control of NK cell immunity and the evolution that has limited the number of NK cell receptor ligands encoded by an HLA haplotype. These finding suggest new ways to dissect the numerous clinical associations with HLA class I. PMID:27868107

  12. HLA class II haplotypes distinctly associated with vaso-occlusion in children with sickle cell disease.

    PubMed

    Mahdi, Najat; Al-Ola, Khadija; Al-Subaie, Abeer M; Ali, Muhallab E; Al-Irhayim, Zaid; Al-Irhayim, A Qader; Almawi, Wassim Y

    2008-04-01

    We investigated the association of HLA class II alleles and haplotypes with sickle cell anemia vaso-occlusive crisis (VOC). DRB1*100101 was positively associated, while DRB1*140101, DRB1*150101, and DQB1*060101 were negatively associated, with VOC. Both susceptible (DRB1*100101-DQB1*050101) and protective (DRB1*110101-DQB1*030101 and DRB1*150101-DQB1*060101) haplotypes were identified, indicating that HLA class II haplotypes influence VOC risk.

  13. Haplotypes of the HLA-G 3’ Untranslated Region Respond to Endogenous Factors of HLA-G+ and HLA-G- Cell Lines Differentially

    PubMed Central

    Cagnin, Natalia F.; Sgorla de Almeida, Bibiana; Castelli, Erick C.; Carosella, Edgardo D.; Donadi, Eduardo A.; Moreau, Philippe

    2017-01-01

    The immune checkpoint HLA-G prevents maternal rejection of the fetus and contributes in cancer invasion and acceptance of allografts. The 5’ and 3’ regulatory regions of the HLA-G gene are polymorphic and balancing selection probably maintains this variability. It is proposed that nucleotide variations may affect the level of HLA-G expression. To investigate this issue we aimed to analyze how haplotypes of the 3’ untranslated region (3’UTR) with highest worldwide frequencies, namely UTR-1, UTR-2, UTR-3, UTR-4, UTR-5, UTR-18 and UTR-7, impact the expression of a luciferase reporter gene in vitro. Experiments performed with the HLA-G positive cell lines JEG-3 (choricarcinoma) and FON (melanoma), and with the HLA-G negative cell lines M8 (melanoma) and U251MG (glioblastoma) showed that the HLA-G 3’UTR polymorphism influences the response to endogenous cellular factors and may vary according to the cell type. UTR-5 and UTR-7 impact the activity of luciferase the most whereas UTR-2, UTR-3, UTR-4, and UTR-18 have intermediate impact, and UTR-1 has the lowest impact. These results corroborate the previous associations between amounts of plasma sHLA-G levels and 3’UTR haplotypes in healthy individuals and reinforce that 3’UTR typing may be a predictor of the genetic predisposition of an individual to express different levels of HLA-G. PMID:28045999

  14. Haplotypes of the HLA-G 3' Untranslated Region Respond to Endogenous Factors of HLA-G+ and HLA-G- Cell Lines Differentially.

    PubMed

    Poras, Isabelle; Yaghi, Layale; Martelli-Palomino, Gustavo; Mendes-Junior, Celso T; Muniz, Yara Costa Netto; Cagnin, Natalia F; Sgorla de Almeida, Bibiana; Castelli, Erick C; Carosella, Edgardo D; Donadi, Eduardo A; Moreau, Philippe

    2017-01-01

    The immune checkpoint HLA-G prevents maternal rejection of the fetus and contributes in cancer invasion and acceptance of allografts. The 5' and 3' regulatory regions of the HLA-G gene are polymorphic and balancing selection probably maintains this variability. It is proposed that nucleotide variations may affect the level of HLA-G expression. To investigate this issue we aimed to analyze how haplotypes of the 3' untranslated region (3'UTR) with highest worldwide frequencies, namely UTR-1, UTR-2, UTR-3, UTR-4, UTR-5, UTR-18 and UTR-7, impact the expression of a luciferase reporter gene in vitro. Experiments performed with the HLA-G positive cell lines JEG-3 (choricarcinoma) and FON (melanoma), and with the HLA-G negative cell lines M8 (melanoma) and U251MG (glioblastoma) showed that the HLA-G 3'UTR polymorphism influences the response to endogenous cellular factors and may vary according to the cell type. UTR-5 and UTR-7 impact the activity of luciferase the most whereas UTR-2, UTR-3, UTR-4, and UTR-18 have intermediate impact, and UTR-1 has the lowest impact. These results corroborate the previous associations between amounts of plasma sHLA-G levels and 3'UTR haplotypes in healthy individuals and reinforce that 3'UTR typing may be a predictor of the genetic predisposition of an individual to express different levels of HLA-G.

  15. Increased sharing of maternal HLA haplotypes among children exposed to diphenylhydantoin during pregnancy.

    PubMed Central

    Hodge, S E; Van Dyke, D C; Goldman, A S; Heide, F; Hill, R; Zmijewski, C M

    1988-01-01

    During investigation of HLA types among children exposed to diphenylhydantoin (DPH) in utero, we found no evidence of a distortion in haplotype sharing among affected sib pairs. Unexpectedly, however, we found a marked increase in the proportion of all sib pairs (not just affected ones) sharing maternal haplotypes. Among 14 two child families, 12 shared the maternal haplotype (expected would be seven); among families with more than two children the distortion was also pronounced. This finding, if verified in future studies, could indicate that something in the mothers, whether DPH use during pregnancy, or some genetic factor associated with seizures, or some effect of the seizures themselves, may be leading to non-random segregation of HLA haplotypes in their offspring. PMID:3225825

  16. Extended tumour necrosis factor/HLA-DR haplotypes and asthma in an Australian population sample

    PubMed Central

    Moffatt, M.; James, A.; Ryan, G.; Musk, A; Cookson, W.

    1999-01-01

    BACKGROUND—Tumour necrosis factor (TNF) is a potent pro-inflammatory cytokine which is prominent in asthmatic airways. TNF shows genetic variations in secretion which are linked to polymorphisms in the TNF gene complex and the surrounding major histocompatibility (MHC) locus. These polymorphisms do not seem to be themselves functionally important. In these circumstances, the identification of disease associated haplotypes (combination of alleles on individual chromosomes) may narrow the search for polymorphisms which alter gene function.
METHODS—TNF-308, LTαNcoI, and HLA-DRB1 polymorphisms were investigated for association with asthma, bronchial responsiveness, and medication use in 1004 subjects in 230 families from a general population sample.
RESULTS—The common LTαNcoI*1/TNF-308*2/HLA-DRB1*03 haplotype, which was present in 11% of unrelated individuals, was weakly associated with asthma (OR = 1.38, p = 0.016, corrected for familial correlation). The rarer LTαNcoI*1/TNF-308*2/HLA-DRB1*02 haplotype, which was found in 0.6% of unrelated subjects, was more strongly associated with asthma (OR = 6.68, p = 0.002). This haplotype also showed association with bronchial hyperresponsiveness (OR = 21.9, p =0.0000) and the use of inhaled or oral steroids (OR 8.0, p = 0.04).
CONCLUSIONS—The results of this study show only two extended TNF/HLA-DR haplotypes to be associated with asthma. The search for functional alleles responsible for an increased risk of asthma should concentrate on the LTαNcoI*1/TNF-308*2/HLA-DRB1*02 haplotype.

 PMID:10456966

  17. Very long haplotype tracts characterized at high resolution from HLA homozygous cell lines

    PubMed Central

    Norman, Paul J.; Norberg, Steve; Nemat-Gorgani, Neda; Royce, Thomas; Hollenbach, Jill A.; Won, Melissa Shults; Guethlein, Lisbeth A.; Gunderson, Kevin L.; Ronaghi, Mostafa; Parham, Peter

    2015-01-01

    The HLA region of chromosome 6 contains the most polymorphic genes in humans. Spanning ~5Mbp the densely packed region encompasses approximately 175 expressed genes including the highly polymorphic HLA class I and II loci. Most of the other genes and functional elements are also polymorphic, and many of them are directly implicated in immune function or immune-related disease. For these reasons this complex genomic region is subject to intense scrutiny by researchers with the common goal of aiding further understanding and diagnoses of multiple immune-related diseases and syndromes. To aid assay development and characterization of the classical loci, a panel of cell lines partially or fully homozygous for HLA class I and II was assembled over time by the International Histocompatibility Working Group (IHWG). Containing a minimum of 88 unique HLA haplotypes, we show this panel represents a significant proportion of European HLA allelic and haplotype diversity (60–95%). Using a high-density whole genome array that includes 13,331 HLA region SNPs, we analyzed 99 IHWG cells to map the coordinates of the homozygous tracts at a fine scale. The mean homozygous tract length within chromosome 6 from these individuals is 21Mbp. Within HLA the mean haplotype length is 4.3Mbp, and 65% of the cell lines were shown to be homozygous throughout the entire region. In addition, four cell lines are homozygous throughout the complex KIR region of chromosome 19 (~250kbp). The data we describe will provide a valuable resource for characterizing haplotypes, designing and refining imputation algorithms and developing assay controls. PMID:26198775

  18. Very long haplotype tracts characterized at high resolution from HLA homozygous cell lines.

    PubMed

    Norman, Paul J; Norberg, Steve J; Nemat-Gorgani, Neda; Royce, Thomas; Hollenbach, Jill A; Shults Won, Melissa; Guethlein, Lisbeth A; Gunderson, Kevin L; Ronaghi, Mostafa; Parham, Peter

    2015-09-01

    The HLA region of chromosome 6 contains the most polymorphic genes in humans. Spanning ~5 Mbp the densely packed region encompasses approximately 175 expressed genes including the highly polymorphic HLA class I and II loci. Most of the other genes and functional elements are also polymorphic, and many of them are directly implicated in immune function or immune-related disease. For these reasons, this complex genomic region is subject to intense scrutiny by researchers with the common goal of aiding further understanding and diagnoses of multiple immune-related diseases and syndromes. To aid assay development and characterization of the classical loci, a panel of cell lines partially or fully homozygous for HLA class I and II was assembled over time by the International Histocompatibility Working Group (IHWG). Containing a minimum of 88 unique HLA haplotypes, we show that this panel represents a significant proportion of European HLA allelic and haplotype diversity (60-95 %). Using a high-density whole genome array that includes 13,331 HLA region SNPs, we analyzed 99 IHWG cells to map the coordinates of the homozygous tracts at a fine scale. The mean homozygous tract length within chromosome 6 from these individuals is 21 Mbp. Within HLA, the mean haplotype length is 4.3 Mbp, and 65 % of the cell lines were shown to be homozygous throughout the entire region. In addition, four cell lines are homozygous throughout the complex KIR region of chromosome 19 (~250 kbp). The data we describe will provide a valuable resource for characterizing haplotypes, designing and refining imputation algorithms and developing assay controls.

  19. Genetic link between Asians and native Americans: evidence from HLA genes and haplotypes.

    PubMed

    Tokunaga, K; Ohashi, J; Bannai, M; Juji, T

    2001-09-01

    We have been studying polymorphisms of HLA class I and II genes in East Asians including Buryat in Siberia, Mongolian, Han Chinese, Man Chinese, Korean Chinese, South Korean, and Taiwan indigenous populations in collaboration with many Asian scientists. Regional populations in Japan, Hondo-Japanese, Ryukyuan, and Ainu, were also studied. HLA-A, -B, and -DRB1 gene frequencies were subjected to the correspondence analysis and calculation of DA distances. The correspondence analysis demonstrated several major clusters of human populations in the world. "Mongoloid" populations were highly diversified, in which several clusters such as Northeast Asians, Southeast Asians, Oceanians, and Native Americans were observed. Interestingly, an indigenous population in North Japan, Ainu, was placed relatively close to Native Americans in the correspondence analysis. Distribution of particular HLA-A, -B, -DRB1 alleles and haplotypes was also analyzed in relation to migration and dispersal routes of ancestral populations. A number of alleles and haplotypes showed characteristic patterns of regional distribution. For example, B39-HR5-DQ7 (B*3901-DRB1*1406-DQB1*0301) was shared by Ainu and Native Americans. A24-Cw8-B48 was commonly observed in Taiwan indigenous populations, Maori in New Zealand, Orochon in Northeast China, Inuit, and Tlingit. These findings further support the genetic link between East Asians and Native Americans. We have proposed that various ancestral populations in East Asia, marked by different HLA haplotypes, had migrated and dispersed through multiple routes. Moreover, relatively small genetic distances and the sharing of several HLA haplotypes between Ainu and Native Americans suggest that these populations are descendants of some Upper Paleolithic populations of East Asia.

  20. Extended HLA haplotypes in a Carib Amerindian population: the Yucpa of the Perija Range.

    PubMed

    Layrisse, Z; Guedez, Y; Domínguez, E; Paz, N; Montagnani, S; Matos, M; Herrera, F; Ogando, V; Balbas, O; Rodríguez-Larralde, A

    2001-09-01

    Eleven MHC loci haplotypes have been defined among a Carib speaking Amerindian population; the Yucpa, inhabiting the northern section of the Perija Range, on the limits between Colombia and Venezuela. This tribe has been known with the name of "Motilones mansos" and is located close to the Chibcha-Paeze speaking Bari or "Motilones bravos." Seventy-three full blooded Yucpa living at the villages of Aroy, Marewa, and Peraya, were selected using a genealogy previously collected by an anthropologist and tested for Bf-C4AB complement allotypes and by serology, high resolution PCR-SSO and SBT typing for HLA class 1 and class 2 alleles. Combinations of 6 HLA-A, 6 HLA-B, 5 HLA-C, 1 Bf, 3 C4AB, 3 DQA1, 3DQB1 and 2 DPA1 and 2 DPB1 alleles present in this population originate 17 different haplotypes, 3 of which represent 63% of the haplotypic constitution of the tribe. The presence of 13 individuals homozygous for 11-loci haplotypes corroborates the existence of the following allelic combinations: DRB1*0411 DQA1*03011 DQB1*0302 DPA1*01 DPB1*0402 with HLA-A*6801 C*0702 B*3909 BfS C4 32 (f = 0.3372) or with A*0204 C*0702 B*3905 (f = 0.1977) and a third haplotype which differs only in DRB1*0403 and A*2402 (f = 0.0930). The results demonstrate the isolation of the tribe and the existence of high frequencies of a reduced number of "Amerindian" ancestral and novel class 1 and class 2 alleles (B*1522, DRB1*0807) with significant linkage disequilibria. These results will be useful to test the hypothesis that differentiation of Amerindian tribal groups will have to rely on haplotypes and micropolymorphism rather than allelic lineage frequencies due to the uniformity shown thus far by the putative descendants of the original Paleo-Indians.

  1. Analysis of the adequate size of a cord blood bank and comparison of HLA haplotype distributions between four populations.

    PubMed

    Haimila, Katri; Penttilä, Antti; Arvola, Anne; Auvinen, Marja-Kaisa; Korhonen, Matti

    2013-02-01

    The number of units and especially the number of different HLA haplotypes present in a cord blood (CB) bank is a crucial determinant of its usefulness. We generated data relevant to the development of our national CB in Finland. The HLA haplotype distribution was examined between specific populations. We developed graphical ways of data presentation that enable easy visualization of differences. First, we estimated the optimal size of a CB bank for Finland and found that approximately 1700 units are needed to provide a 5/6 HLA-matched donor for 80% of Finnish patients. Secondly, we evaluated HLA haplotype distributions between four locations, Finland, Japan, Sweden and Belgium. Our results showed that the Japanese Tokyo Cord Blood Bank differs in both the frequency and distribution of haplotypes from the European banks. The European banks (Finnish Cord Blood Registry, The Swedish National Cord Blood Bank, and Marrow Donor Program-Belgium) have similar frequencies of common haplotypes, but 26% of the haplotypes in the Finnish CB bank are unique, which justifies the existence of a national bank. The tendency to a homogenous HLA haplotype distribution in banks underlines the need for targeting recruitment at the poorly represented minority populations.

  2. [Haplotype and linkage analysis of HLA-I classical genes in Chinese Han population].

    PubMed

    Yuan, Fang; Sun, Yu-Ying; Luo, Yuan; Liang, Fei; Liu, Nan; Jin, Li; Liu, Jin-Feng; Liu, Shu-Guang; Xi, Yong-Zhi

    2007-10-01

    The aim of this study was to investigate the parameters of gene frequencies, haplotype frequencies and linkage disequilibrium of HLA-A, -B, -Cw in HLA classical I loci for Chinese Han population. HLA-A, HLA-B and HLA-Cw loci were genotyped in 1014 unrelated China people using low resolution PCR-SSP typing method, and their genetic parameters were analyzed by statistic methods. The results indicated that among all the detected HLA-I genes, A*02 (0.33), A*11 (0.24), B*15 (0.14), B*13 (0.13), Cw*03 (0.25) and Cw*07 (0.18) were the popular gene groups distributing in Chinese Han population, and A*02-B*46 (0.071), A*11-B*15 (0.051), A*02-Cw*01 (0.084), A*11-Cw*03 (0.079), B*46-Cw*01 (0.095) and B*13-Cw*03 (0.071) were the predominant haplotypes in Han population. Additionally, A*02-B*46, A*30-B*13, A*30-Cw*06, A*02-Cw*01, B*46-Cw*01 and B*58-Cw*03 were statistically significant with strong linkage disequilibrium. While A*02-B*15, A*02-B*40, A*24-Cw*03, A*02-Cw*03 and A*31-Cw*03 were in low linkage disequilibrium, among them A*24-Cw*03 appeared frequently in HLA recombination events. In addition, A*02-B*46-Cw*01 (0.075), A*30-B*13-Cw*06 (0.046), A*11-B*13-Cw*03 (0.045), A*33-B*58-Cw*03 (0.044), A*11-B*15-Cw*08 (0.027), A*02-B*38-Cw*07 (0.023) and A*11-B*40-Cw*07 (0.022) were the main extended haplotypes in Han population. In conclusions, this study investigated systematically the genetic polymorphism features of Chinese Han population, which may provide useful genetic parameters for researches in colonial evolution, clinical transplantation and disease susceptibility.

  3. HLA in Jaidukama: an Amerindian secluded Colombian population with new haplotypes and Asian and Pacific-shared alleles.

    PubMed

    Martinez-Laso, J; Montoya, F; Areces, C; Moscoso, J; Silvera, C; Rey, D; Parga-Lozano, C; Gomez-Prieto, P; Enriquez de Salamanca, M; Arnaiz-Villena, A

    2011-08-01

    America first inhabitants and peopling are still debated. In order to increase knowledge about these questions, we have aimed to detect HLA genes of an Amerindian secluded community: Jaidukama, who lives in North Colombia Equatorial forest. HLA genotyping and extended haplotype calculations were carried out in 39 healthy individuals belonging to 13 families. HLA frequencies were compared to other Amerindians and worldwide populations by calculating genetic distances, relatedness dendrograms and correspondence analyses. Only four DRB1 alleles were found (*0404, *0407, *1402 and *1602); however a total of 17 Amerindian different extended class I-class II HLA haplotypes were directly counted from the family studies, nine of them were specific of Jaidukamas. Some of the alleles or group of alleles within an extended haplotype (i.e. DQB1-DRB1) were also found in Asians and Pacific Islanders, further supporting existence of Asian and Pacific gene flow with Amerindians or a common founder effect. It is further supported that HLA extended haplotypes vary faster than alleles in populations. It is concluded that this unique model of Amerindian secluded families study suggests that rapid HLA haplotype variation may be more important than allele variation for survival (starting immune responses). This work may also be useful for future transplant programs in the area.

  4. MHC-Linked Olfactory Receptor Loci Exhibit Polymorphism and Contribute to Extended HLA/OR-Haplotypes

    PubMed Central

    Ehlers, Anke; Beck, Stephan; Forbes, Simon A.; Trowsdale, John; Volz, Armin; Younger, Ruth; Ziegler, Andreas

    2000-01-01

    Clusters of olfactory receptor (OR) genes are found on most human chromosomes. They are one of the largest mammalian multigene families. Here, we report a systematic study of polymorphism of OR genes belonging to the largest fully sequenced OR cluster. The cluster contains 36 OR genes, of which two belong to the vomeronasal 1 (V1-OR) family. The cluster is divided into a major and a minor region at the telomeric end of the HLA complex on chromosome 6. These OR genes could be involved in MHC-related mate preferences. The polymorphism screen was carried out with 13 genes from the HLA-linked OR cluster and three genes from chromosomes 7, 17, and 19 as controls. Ten human cell lines, representing 18 different chromosome 6s, were analyzed. They were from various ethnic origins and exhibited different HLA haplotypes. All OR genes tested, including those not linked to the HLA complex, were polymorphic. These polymorphisms were dispersed along the coding region and resulted in up to seven alleles for a given OR gene. Three polymorphisms resulted either in stop codons (genes hs6M1-4P, hs6M1-17) or in a 16–bp deletion (gene hs6M1-19P), possibly leading to lack of ligand recognition by the respective receptors in the cell line donors. In total, 13 HLA-linked OR haplotypes could be defined. Therefore, allelic variation appears to be a general feature of human OR genes. [The sequence data reported in this paper have been submitted to EMBL under accession nos. AC006137, AC004178, AJ132194, AL022727, AL031983, AL035402, AL035542, Z98744, CAB55431, AL050339, AL035402, AL096770, AL133267, AL121944, Z98745, AL021808, and AL021807.] PMID:11116091

  5. Interaction between HLA-DRB1-DQB1 Haplotypes in Sardinian Multiple Sclerosis Population

    PubMed Central

    Cocco, Eleonora; Murru, Raffaele; Costa, Gianna; Kumar, Amit; Pieroni, Enrico; Melis, Cristina; Barberini, Luigi; Sardu, Claudia; Lorefice, Lorena; Fenu, Giuseppe; Frau, Jessica; Coghe, Giancarlo; Carboni, Nicola; Marrosu, Maria Giovanna

    2013-01-01

    We performed a case-control study in 2,555 multiple sclerosis (MS) Sardinian patients and 1,365 healthy ethnically matched controls, analyzing the interactions between HLA-DRB1-DQB1 haplotypes and defining a rank of genotypes conferring a variable degree of risk to the disease. Four haplotypes were found to confer susceptibility (*13∶03-*03∶01 OR = 3.3, Pc 5.1×10−5, *04∶05-*03∶01 OR = 2.1, Pc 9.7×10−8, *15∶01-*06∶02 OR = 2.0, Pc = 9.1×10−3, *03∶01-*02∶01 OR = 1.7 Pc = 7.9×10−22) and protection (*11, OR = 0.8, Pc = 2.7×10−2, *16∶01-*05∶02 OR = 0.6, Pc = 4.8×10−16, *14∶01-4-*05∶031 = OR = 0.5, Pc = 9.8×10−4 and *15∶02-*06∶01 OR = 0.4, Pc = 5.1×10−4). The relative predispositional effect method confirms all the positively associated haplotypes and showed that also *08 and *04 haplotypes confers susceptibility, while the *11 was excluded as protective haplotype. Genotypic ORs highlighted two typologies of interaction between haplotypes: i) a neutral interaction, in which the global risk is coherent with the sum of the single haplotype risks; ii) a negative interaction, in which the genotypic OR observed is lower than the sum of the OR of the two haplotypes. The phylogenic tree of the MS-associated DRB1 alleles found in Sardinian patients revealed a cluster represented by *14∶01, *04∶05, *13∶03, *08∶01 and *03∶01 alleles. Sequence alignment analysis showed that amino acids near pocket P4 and pocket P9 differentiated protective from predisposing alleles under investigation. Furthermore, molecular dynamics simulation performed on alleles revealed that position 70 is crucial in binding of MBP 85–99 peptide. All together, these data suggest that propensity to MS observed in Sardinian population carried by the various HLA-DRB1-DQB1 molecules can be due to functional peculiarity in the antigen presentation mechanisms. PMID:23593151

  6. Redundancy in Antigen-Presenting Function of the HLA-DR and -DQ Molecules in the Multiple Sclerosis-Associated HLA-DR2 Haplotype1

    PubMed Central

    Sospedra, Mireia; Muraro, Paolo A.; Stefanová, Irena; Zhao, Yingdong; Chung, Katherine; Li, Yili; Giulianotti, Marc; Simon, Richard; Mariuzza, Roy; Pinilla, Clemencia; Martin, Roland

    2009-01-01

    The three HLA class II alleles of the DR2 haplotype, DRB1*1501, DRB5*0101, and DQB1*0602, are in strong linkage disequilibrium and confer most of the genetic risk to multiple sclerosis. Functional redundancy in Ag presentation by these class II molecules would allow recognition by a single TCR of identical peptides with the different restriction elements, facilitating T cell activation and providing one explanation how a disease-associated HLA haplotype could be linked to a CD4+ T cell-mediated autoimmune disease. Using combinatorial peptide libraries and B cell lines expressing single HLA-DR/DQ molecules, we show that two of five in vivo-expanded and likely disease-relevant, cross-reactive cerebrospinal fluid-infiltrating T cell clones use multiple disease-associated HLA class II molecules as restriction elements. One of these T cell clones recognizes >30 identical foreign and human peptides using all DR and DQ molecules of the multiple sclerosis-associated DR2 haplotype. A T cell signaling machinery tuned for efficient responses to weak ligands together with structural features of the TCR-HLA/peptide complex result in this promiscuous HLA class II restriction. PMID:16424227

  7. Strong association between microsatellites and an HLA-B, DR haplotype (B18-DR3): Implication for microsatellite evolution

    SciTech Connect

    Crouau-Roy, B.; Bouzekri, N.; Clayton, J.

    1996-09-01

    The HLA haplotype B18-DR3 has a widespread geographical distribution, but has its greatest frequencies in Southern Europe, probably vestigial of the earliest populations of this region, particularly in the Pays Basque and Sardinia. This haplotype is of medical significance, being that most implicated as a factor of risk in insulin-dependent diabetes mellitus. In this study, the closely linked microsatellite markers (TNFa,b,c) in the region of the tumor necrosis factor (TNF) genes have been used in an attempt to subtype this haplotype in the two populations and/or in healthy and diabetic populations. A total of 79 HLA-B18-DR3 haplotypes were analyzed: 54 in Basques (12 from healthy individuals and 42 from diabetics or their first-degree relatives) and 25 in Sardinians (13 from healthy and 13 from diabetic individuals). The TNF haplotype a1-b5-c2 is completely associated with B18-DR3 in both populations. The homogeneity of the B18-DR3 haplotype in two ethnically pure populations implies stability in evolution, which suggest that the mutation rate of these microsatellite markers must be less than is usually assumed (i.e., {approximately} 5x10{sup {minus}6} per site per generation). Such markers should be powerful tools for studying genetic drift and admixture of populations, but it remains to be established whether this stability is a rule for all microsatellites in HLA haplotypes or whether or whether it is restricted to some microsatellites and/or some HLA haplotypes. The population genetics of those microsatellites associated with HLA B18-DR3 was also studied in a random sample of the Basque population. 44 refs., 3 tabs.

  8. HLA class II linkage disequilibrium and haplotype evolution in the Cayapa Indians of Ecuador.

    PubMed Central

    Trachtenberg, E A; Erlich, H A; Rickards, O; DeStefano, G F; Klitz, W

    1995-01-01

    DNA-based typing of the HLA class II loci in a sample of the Cayapa Indians of Ecuador reveals several lines of evidence that selection has operated to maintain and to diversify the existing level of polymorphism in the class II region. As has been noticed for other Native American groups, the overall level of polymorphism at the DRB1, DQA1, DQB1, and DPB1 loci is reduced relative to that found in other human populations. Nonetheless, the relative evenness in the distribution of allele frequencies at each of the four loci points to the role of balancing selection in the maintenance of the polymorphism. The DQA1 and DQB1 loci, in particular, have near-maximum departures from the neutrality model, which suggests that balancing selection has been especially strong in these cases. Several novel DQA1-DQB1 haplotypes and the discovery of a new DRB1 allele demonstrate an evolutionary tendency favoring the diversification of class II alleles and haplotypes. The recombination interval between the centromeric DPB1 locus and the other class II loci will, in the absence of other forces such as selection, reduce disequilibrium across this region. However, nearly all common alleles were found to be part of DR-DP haplotypes in strong disequilibrium, consistent with the recent action of selection acting on these haplotypes in the Cayapa. PMID:7668268

  9. HLA alleles and haplotypes among the Lakota Sioux: report of the ASHI minority workshops, part III.

    PubMed

    Leffell, Mary S; Fallin, M Daniele; Hildebrand, William H; Cavett, Joshua W; Iglehart, Brian A; Zachary, Andrea A

    2004-01-01

    Human leukocyte antigen (HLA) class I and II alleles were defined for 302 Lakota Sioux American Indians as part of the American Society for Histocompatibility and Immunogenetics coordinated studies on minority populations. The study group was comprised of adult volunteers from the Cheyenne River and Ogala Sioux tribes residing, respectively, on the Cheyenne River and Pine Ridge Reservations in South Dakota. Of the participants, 263 (87%) claimed full American Indian ancestry through both maternal and paternal grandparents. The study group included 25 nuclear families that were informative for genotyping. HLA phenotypes from 202 adults with no other known first-degree relative included in the study were used for calculation of allele and haplotype frequencies by maximum likelihood estimation. HLA-A, -B, and -Cw alleles were found to be in Hardy Weinberg equilibrium. Deviation from equilibrium was observed for DRB1 alleles (p=0.01), but could be attributed to the sample size and the occurrence of some genotypes with low expected frequencies. Polymorphism among the Sioux was limited with four to seven alleles comprising >80% of those observed at each locus. Several alleles were found at high frequency (0.05-0.30) among the Sioux that are also prevalent in other Native Americans and Alaska Natives, including: A*2402, *3101, and *0206; B*3501,*3901, *5101, and *2705; Cw*0702, *0404, and *03041; DRB1*0407, *0404, *1402, and *16021; and DQB1*0301, *0302, and *0402. DRB1*0811, which has been only previously described in Navajo and Tlingit Indians, was found to occur at a frequency of 0.119 among the Sioux. Two new alleles were defined among the Sioux: Cw*0204 and DRB1*040703, which were found in two and four individuals, respectively. In the haplotype analyses, significant linkage disequilibrium (p<0.00001) was seen in all pairwise comparisons of loci and numerous two and three locus haplotypes were found to have strong, positive linkage disequilibrium values. The two most

  10. HLA-A-B-C-DRB1-DQB1 phased haplotypes in 124 Nigerian families indicate extreme HLA diversity and low linkage disequilibrium in Central-West Africa.

    PubMed

    Testi, M; Battarra, M; Lucarelli, G; Isgro, A; Morrone, A; Akinyanju, O; Wakama, T; Nunes, J M; Andreani, M; Sanchez-Mazas, A

    2015-10-01

    The simultaneous typing of five-HLA loci at high resolution and the availability of pedigree data allowed us to characterize extended five-locus phased haplotypes in 124 Nigerian families and to compare the observed frequencies with those expected by an expectation-maximization algorithm for unphased data. Despite the occurrence of some frequent alleles at each locus (e.g. B*53:01, which is assumed to protect against Plasmodium falciparum), as many as 82% of the sampled individuals carry two unique five-locus haplotypes and only three extended haplotypes with frequency above 1% exhibit significant linkage disequilibrium. Although preliminary, these results reveal an extreme level of HLA diversity in the Nigerian population, which reflects both its multi-ethnic composition and the very ancient demographic history of African populations.

  11. HLA-DRB1-DQB1 Haplotypes Confer Susceptibility and Resistance to Multiple Sclerosis in Sardinia

    PubMed Central

    Cocco, Eleonora; Sardu, Claudia; Pieroni, Enrico; Valentini, Maria; Murru, Raffaele; Costa, Gianna; Tranquilli, Stefania; Frau, Jessica; Coghe, Giancarlo; Carboni, Nicola; Floris, Matteo; Contu, Paolo; Marrosu, Maria Giovanna

    2012-01-01

    Introduction Genetic predisposition to multiple sclerosis (MS) in Sardinia (Italy) has been associated with five DRB1*-DQB1* haplotypes of the human leukocyte antigen (HLA). Given the complexity of these associations, an in-depth re-analysis was performed with the specific aims of confirming the haplotype associations; establishing the independence of the associated haplotypes; and assessing patients' genotypic risk of developing MS. Methods and Results A transmission disequilibrium test (TDT) of the DRB1*-DQB1* haplotypes in 943 trio families, confirmed a higher than expected transmission rate (over-transmission) of the *13:03-*03:01 (OR = 2.9, P = 7.6×10−3), *04:05-*03:01 (OR = 2.4, P = 4.4×10−6) and *03:01-*02:01 (OR = 2.1, P = 1.0×10−15) haplotype. In contrast, the *16:01-*05:02 (OR = 0.5, P = 5.4×10−11) and the *15:02-*06:01 (OR = 0.3, P = 1.5×10−3) haplotypes exhibited a lower than expected transmission rate (under-transmission). The independence of the transmission of each positively and negatively associated haplotype was confirmed relative to all positively associated haplotypes, and to the negatively associated *16:01-*05:02 haplotype. In patients, carriage of two predisposing haplotypes, or of protective haplotypes, respectively increased or decreased the patient's risk of developing MS. The risk of MS followed a multiplicative model of genotypes, which was, in order of decreasing ORs: *04:05-*0301/*03:01-*02:01 (OR = 4.5); *03:01-*02:01/*03:01-*02:01 (OR = 4.1); and the *16:01-*05:02/*16:01-*0502 (OR = 0.2) genotypes. Analysis of DRB1 and DQB1 protein chain residues showed that the Val/Gly residue at position 86 of the DRB1 chain was the only difference between the protective *16:01- *15:02 alleles and the predisposing *15:01 one. Similarly, the Ala/Val residue at position 38 of the DQB1 chain differentiated the positively associated *06:02 allele and the negatively associated *05

  12. Mapping the genetic diversity of HLA haplotypes in the Japanese populations.

    PubMed

    Saw, Woei-Yuh; Liu, Xuanyao; Khor, Chiea-Chuen; Takeuchi, Fumihiko; Katsuya, Tomohiro; Kimura, Ryosuke; Nabika, Toru; Ohkubo, Takayoshi; Tabara, Yasuharu; Yamamoto, Ken; Yokota, Mitsuhiro; Teo, Yik-Ying; Kato, Norihiro

    2015-12-09

    Japan has often been viewed as an Asian country that possesses a genetically homogenous community. The basis for partitioning the country into prefectures has largely been geographical, although cultural and linguistic differences still exist between some of the districts/prefectures, especially between Okinawa and the mainland prefectures. The Major Histocompatibility Complex (MHC) region has consistently emerged as the most polymorphic region in the human genome, harbouring numerous biologically important variants; nevertheless the presence of population-specific long haplotypes hinders the imputation of SNPs and classical HLA alleles. Here, we examined the extent of genetic variation at the MHC between eight Japanese populations sampled from Okinawa, and six other prefectures located in or close to the mainland of Japan, specifically focusing at the haplotypes observed within each population, and what the impact of any variation has on imputation. Our results indicated that Okinawa was genetically farther to the mainland Japanese than were Gujarati Indians from Tamil Indians, while the mainland Japanese from six prefectures were more homogeneous than between northern and southern Han Chinese. The distribution of haplotypes across Japan was similar, although imputation was most accurate for Okinawa and several mainland prefectures when population-specific panels were used as reference.

  13. HLA-A, HLA-B, HLA-DRB1 allele and haplotype frequencies in 6384 umbilical cord blood units and transplantation matching and engraftment statistics in the Zhejiang cord blood bank of China.

    PubMed

    Wang, F; He, J; Chen, S; Qin, F; Dai, B; Zhang, W; Zhu, F M; Lv, H J

    2014-02-01

    Umbilical cord blood (UCB) is a widely accepted source of progenitor cells, and now, many cord blood banks were established. Here, we analysed the HLA-A, HLA-B and HLA-DRB1 allele and haplotype frequencies, HLA matching possibilities for searching potential donors and outcome of UCB transplantations in Zhejiang cord blood bank of China. A total of 6384 UCB units were characterized for 17 HLA-A, 30 HLA-B and 13 HLA-DRB1 alleles at the first field resolution level. Additionally, B*14, B*15 and B*40 were typed to the second field level. A total of 1372 distinct A-B-DRB1 haplotypes were identified. The frequencies of 7 haplotypes were more than 1%, and 439 haplotypes were <0.01%. A*02-B*46-DRB1*09, A*33-B*58-DRB1*03 and A*30-B*13-DRB1*07 were the most common haplotypes, with frequencies of 4.4%, 3.3%, and 2.9%, respectively. Linkage disequilibrium(LD) analysis showed that there were 83 A-B, 106 B-DRB1, 54 A-DRB1 haplotypes with positive LD, in which 51 A-B, 60 B-DRB1, 32 A-DRB1 haplotypes exhibited a significant LD (P < 0.05). In 682 search requests, 12.9%, 40.0% and 42.7% of patients were found to have 6 of 6, 5 of 6 and 4 of 6 HLA-A, HLA-B and HLA-DRB1 matching donors, respectively. A total of 30 UCB units were transplanted to 24 patients (3 patients not evaluated due to early death); 14 of 21 patients (66.7%) engrafted. This study reveals the HLA distribution and its transplantation application in the cord blood bank of Zhejiang province. These data can help to select potential UCB donors for transplantation and used to assess the scale of new cord blood banking endeavours.

  14. HLA Class I and Class II Alleles and Haplotypes Confirm the Berber Origin of the Present Day Tunisian Population

    PubMed Central

    Hajjej, Abdelhafidh; Almawi, Wassim Y.; Hattab, Lasmar; El-Gaaied, Amel; Hmida, Slama

    2015-01-01

    In view of its distinct geographical location and relatively small area, Tunisia witnessed the presence of many civilizations and ethnic groups throughout history, thereby questioning the origin of present-day Tunisian population. We investigated HLA class I and class II gene profiles in Tunisians, and compared this profile with those of Mediterranean and Sub-Sahara African populations. A total of 376 unrelated Tunisian individuals of both genders were genotyped for HLA class I (A, B) and class II (DRB1, DQB1), using reverse dot-blot hybridization (PCR-SSO) method. Statistical analysis was performed using Arlequin software. Phylogenetic trees were constructed by DISPAN software, and correspondence analysis was carried out by VISTA software. One hundred fifty-three HLA alleles were identified in the studied sample, which comprised 41, 50, 40 and 22 alleles at HLA-A,-B,-DRB1 and -DQB1 loci, respectively. The most frequent alleles were HLA-A*02:01 (16.76%), HLA-B*44:02/03 (17.82%), HLA-DRB1*07:01 (19.02%), and HLA-DQB1*03:01 (17.95%). Four-locus haplotype analysis identified HLA-A*02:01-B*50:01-DRB1*07:01-DQB1*02:02 (2.2%) as the common haplotype in Tunisians. Compared to other nearby populations, Tunisians appear to be genetically related to Western Mediterranean population, in particular North Africans and Berbers. In conclusion, HLA genotype results indicate that Tunisians are related to present-day North Africans, Berbers and to Iberians, but not to Eastern Arabs (Palestinians, Jordanians and Lebanese). This suggests that the genetic contribution of Arab invasion of 7th-11th century A.D. had little impact of the North African gene pool. PMID:26317228

  15. HLA class II variation in the Gila River Indian Community of Arizona: alleles, haplotypes, and a high frequency epitope at the HLA-DR locus.

    PubMed

    Williams, R C; McAuley, J E

    1992-01-01

    A genetic distribution for the HLA class II loci is described for 349 "full-blooded" Pima and Tohono O'odham Indians (Pimans) in the Gila River Indian Community. A high frequency epitope in the *DRw52 family was defined by reactions with 31 alloantisera, which we have designated *DR3X6. It segregates as a codominant allele at HLA-DR with alleles *DR2, *DR4, and *DRw8, and has the highest frequency yet reported for an HLA-DR specificity, 0.735. It forms a common haplotype with *DRw52 and *DQw3 that is a valuable marker for genetic admixture and anthropological studies. Phenotype and allele frequencies, and haplotype frequencies for two and three loci, are presented. Variation at these loci is highly restricted, the mean heterozygosity for HLA-DR and HLA-DQ being 0.361. The Pimans represent a contemporary model for the Paleo-Indians who first entered North America 20,000 to 40,000 years ago.

  16. PCR/oligonucleotide probe typing of HLA class II alleles in a Filipino population reveals an unusual distribution of HLA haplotypes.

    PubMed Central

    Bugawan, T. L.; Chang, J. D.; Klitz, W.; Erlich, H. A.

    1994-01-01

    We have analyzed the distribution of HLA class II alleles and haplotypes in a Filipino population by PCR amplification of the DRB1, DQB1, and DPB1 second-exon sequences from buccal swabs obtained from 124 family members and 53 unrelated individuals. The amplified DNA was typed by using nonradioactive sequence-specific oligonucleotide probes. Twenty-two different DRB1 alleles, including the novel Filipino *1105, and 46 different DRB1/DQB1 haplotypes, including the unusual DRB1*0405-DQB1*0503, were identified. An unusually high frequency (f = .383) of DPB1*0101, a rare allele in other Asian populations, was also observed. In addition, an unusual distribution of DRB1 alleles and haplotypes was seen in this population, with DR2 (f = .415) and DRB1*1502-DQB1*0502 (f = .233) present at high frequencies. This distribution of DRB1 alleles differs from the typical HLA population distribution, in which the allele frequencies are more evenly balanced. The distribution of HLA class II alleles and haplotypes in this Filipino population is different from that of other Asian and Pacific groups: of those populations studied to date; the Indonesian population is the most similar. DRB1*1502-DQB1*0502 was in strong linkage disequilibrium (D' = .41) with DPB1*0101 (f = .126, for the extended haplotype), which is consistent with selection for this DR, DQ, DP haplotype being responsible for the high frequency of these three class II alleles in this population. PMID:8304349

  17. Dominant sequences of human major histocompatibility complex conserved extended haplotypes from HLA-DQA2 to DAXX.

    PubMed

    Larsen, Charles E; Alford, Dennis R; Trautwein, Michael R; Jalloh, Yanoh K; Tarnacki, Jennifer L; Kunnenkeri, Sushruta K; Fici, Dolores A; Yunis, Edmond J; Awdeh, Zuheir L; Alper, Chester A

    2014-10-01

    We resequenced and phased 27 kb of DNA within 580 kb of the MHC class II region in 158 population chromosomes, most of which were conserved extended haplotypes (CEHs) of European descent or contained their centromeric fragments. We determined the single nucleotide polymorphism and deletion-insertion polymorphism alleles of the dominant sequences from HLA-DQA2 to DAXX for these CEHs. Nine of 13 CEHs remained sufficiently intact to possess a dominant sequence extending at least to DAXX, 230 kb centromeric to HLA-DPB1. We identified the regions centromeric to HLA-DQB1 within which single instances of eight "common" European MHC haplotypes previously sequenced by the MHC Haplotype Project (MHP) were representative of those dominant CEH sequences. Only two MHP haplotypes had a dominant CEH sequence throughout the centromeric and extended class II region and one MHP haplotype did not represent a known European CEH anywhere in the region. We identified the centromeric recombination transition points of other MHP sequences from CEH representation to non-representation. Several CEH pairs or groups shared sequence identity in small blocks but had significantly different (although still conserved for each separate CEH) sequences in surrounding regions. These patterns partly explain strong calculated linkage disequilibrium over only short (tens to hundreds of kilobases) distances in the context of a finite number of observed megabase-length CEHs comprising half a population's haplotypes. Our results provide a clearer picture of European CEH class II allelic structure and population haplotype architecture, improved regional CEH markers, and raise questions concerning regional recombination hotspots.

  18. HLA-DRB1 and -DRB3 allele frequencies and haplotypic associations in Koreans.

    PubMed

    Song, Eun Young; Park, Hyejin; Roh, Eun Youn; Park, Myoung Hee

    2004-03-01

    We have investigated the frequencies of human leukocyte antigen-DRB1 (HLA-DRB1) and -DRB3 alleles and DRB1-DRB3 haplotypic associations in 800 Koreans. DRB1 genotyping was done using polymerase chain reaction-sequence-specific oligonucleotide (PCR-SSO) and PCR-single strand conformation polymorphism (SSCP) methods. DRB3 genotyping was done on 447 samples carrying DRB3-associated DRB1 alleles (DRB1*03, *11, *12, *13, and *14) using PCR-SSCP method. The allele frequencies of DRB3*0101, DRB3*0202, and DRB3*0301 were 0.073, 0.136, and 0.120, respectively, and we found one case of a probable new allele (DRB3*01new, 0.001). DRB1-DRB3 haplotypes with frequency (HF) > 0.005 exhibited strong associations between DRB3*0101 and DRB1*1201, *1301, and *1403; between DRB3*0301 and DRB1*1202 and *1302; between DRB3*0202 and DRB1*0301, *1101, *1401, *1405, and *1406 alleles. Most of the DRB1 alleles with frequency > 0.005 were exclusively associated with particular DRB3 alleles with relative linkage disequilibrium values of 1.0, except for DRB1*1201, *1202 and *1301; the rare presence (HF < 0.005) of DRB3*0202 associations were observed for these DRB1 alleles. We also investigated and presented rare DRB1-DRB3 associations in additional 6000 Koreans. Comparison with other ethnic groups revealed that DRB1*0301 and *1301 related DRB1-DRB3 haplotypes vary among different populations, in that Koreans and other Asian populations show less diversity compared with Caucasoids or African Americans.

  19. HLA class I (A, B) and II (DR, DQ) gene and haplotype frequencies in blood donors from Wales.

    PubMed

    Darke, C; Guttridge, M G; Thompson, J; McNamara, S; Street, J; Thomas, M

    1998-01-01

    Accurate estimates of HLA-A, B, DR and DQ phenotype, gene and haplotype frequencies (HF) in the normal population are of importance in, for example, disease susceptibility studies, platelet transfusion support and transplantation. HLA population genetics studies have been performed on numerous groups, however, no major studies have been carried out on the population of Wales. As part of the validation process for our routine HLA-A and B typing by PCR using sequence-specific primers (PCR-SSP) we examined 1,798 normal, unrelated Caucasoid blood donors living in Wales and recruited onto the Welsh Bone Marrow Donor Registry (WBMDR). Typing was performed by serology (HLA-A, B) and PCR-SSP at low resolution (HLA-A, B, DR, DQ) resulting in a particularly rigorous level of HLA specificity assignment. Four discrepancies were found between the HLA-A and B serological and PCR-SSP specificity assignments: (1) two instances of HLA-A2 by serology were undetected by PCR-SSP and were a new HLA-A2 allele - A*0224; (2) one example of HLA-B*15 by PCR-SSP failed to react by serology, and remained undetectable by serology in subsequent samples, and (3) one example of HLA-B45 by serology was identified as HLA-B*5002 by PCR-SSP. Hardy-Weinberg and homozygosity analysis showed that the goodness-of-fit was excellent (p > 0.05), for both phenotype distribution and the number of homozygotes identified, for all four loci. The phenotype and gene frequencies for the 18 HLA-A, 34 -B, 15 -DR and 8 -DQ specificities identified and two- and three-locus HF, linkage disequilibrium and related values for HLA-A/B, B/DR, DR/DQ and HLA-A/B/DR and B/DR/DQ were essentially typical of a northern European population. HLA-A2, B44, DR4 and DQ2 were the highest frequency phenotypes and HLA-A2403, A34, A74, B42, B75, B2708, B48, B67 and B703 occurred once only. There were no examples of: A36, A43, A69, A80, B46, B54, B59, B73, B76, B77, B7801, B8101 or DR18 specificities. DR17, DQ2 and A1, B8, DR17 were the

  20. Allele Polymorphism and Haplotype Diversity of HLA-A, -B and -DRB1 Loci in Sequence-Based Typing for Chinese Uyghur Ethnic Group

    PubMed Central

    Shen, Chun-mei; Zhu, Bo-feng; Deng, Ya-jun; Ye, Shi-hui; Yan, Jiang-wei; Yang, Guang; Wang, Hong-dan; Qin, Hai-xia; Huang, Qi-zhao; Zhang, Jing-Jing

    2010-01-01

    Background Previous studies indicate that the frequency distributions of HLA alleles and haplotypes vary from one ethnic group to another or between the members of the same ethnic group living in different geographic areas. It is necessary and meaningful to study the high-resolution allelic and haplotypic distributions of HLA loci in different groups. Methodology/Principal Findings High-resolution HLA typing for the Uyghur ethnic minority group using polymerase chain reaction-sequence-based-typing method was first reported. HLA-A, -B and -DRB1 allelic distributions were determined in 104 unrelated healthy Uyghur individuals and haplotypic frequencies and linkage disequilibrium parameters for HLA loci were estimated using the maximum-likelihood method. A total of 35 HLA-A, 51 HLA-B and 33 HLA-DRB1 alleles were identified at the four-digit level in the population. High frequency alleles were HLA-A*1101 (13.46%), A*0201 (12.50%), A*0301 (10.10%); HLA-B*5101(8.17%), B*3501(6.73%), B*5001 (6.25%); HLA-DRB1*0701 (16.35%), DRB1*1501 (8.65%) and DRB1*0301 (7.69%). The two-locus haplotypes at the highest frequency were HLA-A*3001-B*1302 (2.88%), A*2402-B*5101 (2.86%); HLA-B*5001-DRB1*0701 (4.14%) and B*0702-DRB1*1501 (3.37%). The three-locus haplotype at the highest frequency was HLA-A*3001-B*1302-DRB1*0701(2.40%). Significantly high linkage disequilibrium was observed in six two-locus haplotypes, with their corresponding relative linkage disequilibrium parameters equal to 1. Neighbor-joining phylogenetic tree between the Uyghur group and other previously reported populations was constructed on the basis of standard genetic distances among the populations calculated using the four-digit sequence-level allelic frequencies at HLA-A, HLA-B and HLA-DRB1 loci. The phylogenetic analyses reveal that the Uyghur group belongs to the northwestern Chinese populations and is most closely related to the Xibe group, and then to Kirgiz, Hui, Mongolian and Northern Han. Conclusions

  1. Sex and age at diagnosis are correlated with the HLA-DR2, DQ6 haplotype in multiple sclerosis.

    PubMed

    Celius, E G; Harbo, H F; Egeland, T; Vartdal, F; Vandvik, B; Spurkiand, A

    2000-09-15

    The HLA-DR2, DQ6 (i.e., HLA-DRB1*1501, DQA1*0102, DQB1*0602) haplotype contributes to the risk of developing multiple sclerosis (MS) in Caucasoids of Northern European heritage. A correlation between the clinical expression of MS and the presence of HLA-DR2, DQ6 has, however, not convincingly been shown. In this study conventional bivariate analysis and logistic regression analysis were used to study the relationship between HLA-DR2, DQ6 and four disease variables in a cohort of 286 Norwegian MS patients from the Oslo area. Logistic regression analysis showed that HLA-DR2, DQ6 was significantly more frequent among female than male patients (P=0. 0251), and was negatively correlated with age at diagnosis regardless of sex (P=0.0254). No significant correlation was observed between HLA-DR2, DQ6 and type of disease (relapsing-remitting versus primary chronic progressive MS) or presence/absence of oligoclonal bands in the cerebrospinal fluid.

  2. An analysis of HLA-A, -B, and -DRB1 allele and haplotype frequencies of 21,918 residents living in Liaoning, China.

    PubMed

    Li, Xiao-Feng; Zhang, Xu; Chen, Yang; Zhang, Kun-Lian; Liu, Xiang-Jun; Li, Jian-Ping

    2014-01-01

    HLA-A, -B and -DRB1 allele frequencies and their haplotype frequencies in 21,918 Chinese residents living in Liaoning Province, who were registered as volunteer donors of China Marrow Donor Registry, were investigated. They are composed of 93.37% Han Chinese, 5.1% Manchus, 0.57% Mongols, 0.46% Hui persons, 0.29% Koreans and 0.14% Xibe ethnic group. In total eighteen different HLA-A alleles, forty-eight different HLA-B alleles and fourteen different HLA-DRB1 alleles have been identified. Their frequencies are in agreement with the Hardy-Weinberg equilibrium. For Han Chinese in Liaoning, 1,534 different HLA-A-B-DRB1 haplotypes were identified, with a frequency of higher than 0.01%. A*30-B*13-DRB1*07, A*02-B*46-DRB1*09 and A*02-B*13-DRB1*12 are the most frequent haplotypes among Liaoning Han. While Liaoning Han, Liaoning Manchu, Liaoning Mongol, Liaoning Hui and Liaoning Korean share the northern Han characteristic haplotypes, all minority ethnic groups with the exception of Liaoning Manchu have developed their own unique HLA profiles. This dataset characterizes the HLA allele and haplotype frequencies in the Liaoning area and suggests that it is different from those in other parts of China and ethnic groups, which implicates transplant donor searching strategies and studies on population genetics.

  3. Anonymous marker loci within 400 kb of HLA-A generate haplotypes in linkage disequilibrium with the hemochromatosis gene (HFE)

    SciTech Connect

    Yaouanq, J.; Perichon, M.; Treut, A.L.; Kahloun, A.E.; Mauvieux, V.; Blayau, M.; Jouanolle, A.M.; Chauvel, B.; Le Gall, J.Y.; David, V. )

    1994-02-01

    The hemochromatosis gene (HFE) maps to 6p21.3 and is less than 1 cM from the HLA class I gene; however, the precise physical location of the gene has remained elusive and controversial. The unambiguous identification of a crossover event within hemochromatosis families is very difficult; it is particularly hampered by the variability of the phenotypic expression as well as by the sex- and age-related penetrance of the disease. For these considerations, traditional linkage analysis could prove of limited value in further refining the extrapolated physical position of HFE. The authors therefore embarked upon a linkage-disequilibrium analysis of HFE and normal chromosomes for the Brittany population. In this report, 66 hemochromatosis families yielding 151 hemochromatosis chromosomes and 182 normal chromosomes were RFLP-typed with a battery of probes, including two newly derived polymorphic markers from the 6.7 and HLA-F loci located 150 and 250 kb telomeric to HLA-A, respectively. The results suggest a strong peak of existing linkage disequilibrium focused within the i82-to-6.7 interval (approximately 250 kb). The zone of linkage disequilibrium is flanked by the i97 locus, positioned 30 kb proximal to i82, and the HLA-F gene, found 250 kb distal to HLA-A, markers of which display no significant association with HFE. These data support the possibility that HFE resides within the 400-kb expanse of DNA between i97 and HLA-F. Alternatively, the very tight association of HLA-A3 and allele 1 of the 6.7 locus, both of which are comprised by the major ancestral or founder HFE haplotype in Brittany, supports the possibility that the disease gene may reside immediately telomeric to the 6.7 locus within the linkage-disequilibrium zone. Additionally, hemochromatosis haplotypes possessing HLA-A11 and the low-frequency HLA-F polymorphism (allele 2) are supportive of a separate founder chromosome containing a second, independently arising mutant allele. 69 refs., 1 fig., 5 tabs.

  4. HLA Class I and Class II Conserved Extended Haplotypes and Their Fragments or Blocks in Mexicans: Implications for the Study of Genetic Diversity in Admixed Populations

    PubMed Central

    Ohashi, Marina; Lebedeva, Tatiana; Acuña-Alonzo, Víctor; Yunis, María; Granados-Montiel, Julio; Cruz-Lagunas, Alfredo; Vargas-Alarcón, Gilberto; Rodríguez-Reyna, Tatiana S.; Fernandez-Viña, Marcelo; Granados, Julio; Yunis, Edmond J.

    2013-01-01

    Major histocompatibility complex (MHC) genes are highly polymorphic and informative in disease association, transplantation, and population genetics studies with particular importance in the understanding of human population diversity and evolution. The aim of this study was to describe the HLA diversity in Mexican admixed individuals. We studied the polymorphism of MHC class I (HLA-A, -B, -C), and class II (HLA-DRB1, -DQB1) genes using high-resolution sequence based typing (SBT) method and we structured the blocks and conserved extended haplotypes (CEHs) in 234 non-related admixed Mexican individuals (468 haplotypes) by a maximum likelihood method. We found that HLA blocks and CEHs are primarily from Amerindian and Caucasian origin, with smaller participation of African and recent Asian ancestry, demonstrating a great diversity of HLA blocks and CEHs in Mexicans from the central area of Mexico. We also analyzed the degree of admixture in this group using short tandem repeats (STRs) and HLA-B that correlated with the frequency of most probable ancestral HLA-C/−B and -DRB1/−DQB1 blocks and CEHs. Our results contribute to the analysis of the diversity and ancestral contribution of HLA class I and HLA class II alleles and haplotypes of Mexican admixed individuals from Mexico City. This work will help as a reference to improve future studies in Mexicans regarding allotransplantation, immune responses and disease associations. PMID:24086347

  5. Distribution of HLA-G extended haplotypes and one HLA-E polymorphism in a large-scale study of mother-child dyads with and without severe preeclampsia and eclampsia.

    PubMed

    Nilsson, L L; Djurisic, S; Andersen, A-M N; Melbye, M; Bjerre, D; Ferrero-Miliani, L; Hackmon, R; Geraghty, D E; Hviid, T V F

    2016-10-01

    The etiological pathways and pathogenesis of preeclampsia have rendered difficult to disentangle. Accumulating evidence points toward a maladapted maternal immune system, which may involve aberrant placental expression of immunomodulatory human leukocyte antigen (HLA) class Ib molecules during pregnancy. Several studies have shown aberrant or reduced expression of HLA-G in the placenta and in maternal blood in cases of preeclampsia compared with controls. Unlike classical HLA class Ia loci, the nonclassical HLA-G has limited polymorphic variants. Most nucleotide variations are clustered in the 5'-upstream regulatory region (5'URR) and 3'-untranslated regulatory region (3'UTR) of HLA-G and reflect a stringent expressional control. Based on genotyping and full gene sequencing of HLA-G in a large number of cases and controls (n > 900), the present study, which to our knowledge is the largest and most comprehensive performed, investigated the association between the HLA-G 14-bp ins/del (rs66554220) and HLA-E polymorphisms in mother and newborn dyads from pregnancies complicated by severe preeclampsia/eclampsia and from uncomplicated pregnancies. Furthermore, results from extended HLA-G haplotyping in the newborns are presented in order to assess whether a combined contribution of nucleotide variations spanning the 5'URR, coding region, and 3'UTR of HLA-G describes the genetic association with severe preeclampsia more closely. In contrast to earlier findings, the HLA-G 14-bp ins/del polymorphism was not associated with severe preeclampsia. Furthermore, the polymorphism (rs1264457) defining the two nonsynonymous HLA-E alleles, HLA-E*01:01:xx:xx and HLA-E*01:03:xx:xx, were not associated with severe preeclampsia. Finally, no specific HLA-G haplotypes were significantly associated with increased risk of developing severe preeclampsia/eclampsia.

  6. HLA-G variability and haplotypes detected by massively parallel sequencing procedures in the geographicaly distinct population samples of Brazil and Cyprus.

    PubMed

    Castelli, Erick C; Gerasimou, Petroula; Paz, Michelle A; Ramalho, Jaqueline; Porto, Iane O P; Lima, Thálitta H A; Souza, Andréia S; Veiga-Castelli, Luciana C; Collares, Cristhianna V A; Donadi, Eduardo A; Mendes-Junior, Celso T; Costeas, Paul

    2017-03-01

    The HLA-G molecule presents immunomodulatory properties that might inhibit immune responses when interacting with specific Natural Killer and T cell receptors, such as KIR2DL4, ILT2 and ILT4. Thus, HLA-G might influence the outcome of situations in which fine immune system modulation is required, such as autoimmune diseases, transplants, cancer and pregnancy. The majority of the studies regarding the HLA-G gene variability so far was restricted to a specific gene segment (i.e., promoter, coding or 3' untranslated region), and was performed by using Sanger sequencing and probabilistic models to infer haplotypes. Here we propose a massively parallel sequencing (NGS) with a bioinformatics strategy to evaluate the entire HLA-G regulatory and coding segments, with haplotypes inferred relying more on the straightforward haplotyping capabilities of NGS, and less on probabilistic models. Then, HLA-G variability was surveyed in two admixed population samples of distinct geographical regions and demographic backgrounds, Cyprus and Brazil. Most haplotypes (promoters, coding, 3'UTR and extended ones) were detected both in Brazil and Cyprus and were identical to the ones already described by probabilistic models, indicating that these haplotypes are quite old and may be present worldwide.

  7. Distributions of HLA-A and -B alleles and haplotypes in the Yi ethnic minority of Yunnan, China: relationship to other populations*

    PubMed Central

    Zhu, Bo-feng; Yang, Guang; Shen, Chun-mei; Qin, Hai-xia; Liu, Shun-zhi; Deng, Ya-jun; Fan, Shuan-liang; Deng, Li-bin; Chen, Feng; Zhang, Ping; Fang, Jie; Chen, Li-ping; Wang, Hong-dan; Wang, Zhen-yuan; Lucas, Rudolf

    2010-01-01

    Objective: To investigate the distributions of human leukocyte antigen (HLA)-A and -B alleles and HLA-A-B haplotypes in the Yi ethnic minority of the Yunnan Province, situated in southwestern China. Methods: DNA typing for HLA-A and -B loci was performed using the polymerase chain reaction-sequence-based typing (PCR-SBT) method on 114 randomly selected healthy individuals of the Yi population. The allelic frequencies of HLA-A and -B loci were calculated by direct counting and HLA-A-B haplotypes were estimated using the expectation maximization algorithm. Results: A total of 17 HLA-A and 38 HLA-B alleles were found in the Yi population. The most frequent alleles were A*2402 (32.46%), A*1101 (26.32%), and A*0203 (10.09%) at the HLA-A locus and B*4601 (12.28%), B*1525 (10.09%), B*4001 (8.77%), and B*3802 (7.89%) at the HLA-B locus. The predominant HLA-A-B haplotypes were A*2402-B*1525 (7.86%) and A*0203-B*3802 (5.64%), followed by A*1101-B*4001 (4.69%). Phylogenetic analysis indicates that the Yi population in the Honghe, Yunnan Province of China basically belongs to groups of southeastern Asian origin, but shares some characteristics with northeastern Asian groups. Conclusion: The present study may add to the understanding of HLA polymorphism in the Yi ethnic group that was poorly defined previously, and provide useful information for bone marrow transplantation, anthropological research, and forensic sciences as well as for disease-association studies. PMID:20104647

  8. Cord blood banks collect units with different HLA alleles and haplotypes to volunteer donor banks: a comparative report from Swiss Blood stem cells.

    PubMed

    Meyer-Monard, S; Passweg, J; Troeger, C; Eberhard, H-P; Roosnek, E; de Faveri, G Nicoloso; Chalandon, Y; Rovo, A; Kindler, V; Irion, O; Holzgreve, W; Gratwohl, A; Müller, C; Tichelli, A; Tiercy, J-M

    2009-05-01

    Allogeneic haematopoietic SCT is a standard therapy for many patients with haematological diseases. A major aim of public umbilical cord blood (UCB) banking is to establish an inventory with a large HLA diversity. Few studies have compared HLA diversity between UCB banks and volunteer unrelated donor (VUD) registries and examined whether UCB banks indeed collect more units with rare alleles and haplotypes. This study compares HLA-A/B/DRB1 allele frequencies and inferred A/B/DRB1-haplotypes in 1602 UCB units and 3093 VUD from two centres in distinct recruitment areas in Switzerland. The results show that the frequencies of HLA-DRB1 alleles as well as of the HLA-A/B/DRB1 haplotypes differ between UCB and VUD. Ten DRB1 alleles occurred at a 2- to 12-fold higher relative frequency in UCB than in VUD and 27 rare alleles were identified in UCB. Out of these 27 alleles, 15 were absent in the entire VUD data set of the national registry. This difference in allele frequencies was found only by intermediate/high-resolution typing. Targeted recruitment of UCB units from non-Caucasian donors could further increase HLA allele and haplotype diversity of available donors. Intermediate or high-resolution DNA typing is essential to identify rare alleles or allele groups.

  9. Selected class I and class II HLA alleles and haplotypes and risk of high-grade cervical intraepithelial neoplasia.

    PubMed

    Ades, Steven; Koushik, Anita; Duarte-Franco, Eliane; Mansour, Nabil; Arseneau, Jocelyne; Provencher, Diane; Gilbert, Lucy; Gotlieb, Walter; Ferenczy, Alex; Coutlée, François; Roger, Michel; Franco, Eduardo L

    2008-06-15

    Human leukocyte antigens (HLAs) present foreign antigens to the immune system and may be important determinants of cervical neoplasia. Previously published associations between HLA and cervical neoplasia exhibit considerable variation in findings. The biomarkers of cervical cancer risk (BCCR) case-control study addressed the role of specific HLA alleles as cofactors in the development of high-grade cervical intraepithelial neoplasia (HG-CIN) based on the most consistent evidence from published literature. Cases (N = 381) were women with histologically-confirmed HG-CIN attending colposcopy clinics and controls (N = 884) were women from outpatient clinics with normal cytological screening smears. Subjects were mainly of French-Canadian descent. Cervical specimens were tested for human papillomavirus (HPV) DNA and HLA genotypes by PGMY L1 consensus primer PCR and a PCR sequence-specific primer method, respectively. Unlike other studies, the DQB1*03 and DRB1*13 allele groups were not associated with risk of HG-CIN. The B7-DRB1*1501-DQB1*0602 haplotype was associated with a 41% overall reduction in HG-CIN risk (odds ratio [OR] = 0.59; 95% confidence interval [CI]: 0.36-0.96), and an 83% reduction in risk of HG-CIN among HPV 16 or HPV 18-positive subjects (OR = 0.17; 95%CI: 0.05-0.54). Paradoxically, however, the same haplotype was associated with HPV 16/18 infection risk among controls (OR = 8.44, 95%CI: 1.12-63.73). In conclusion, the B7-DRB1*1501-DQB1*0602 haplotype was protective against HG-CIN, especially in individuals infected with oncogenic HPV, but the mechanism of the association seems to involve multiple steps in the natural history of HPV and CIN.

  10. HLA gene and haplotype frequencies in Russians, Bashkirs and Tatars, living in the Chelyabinsk Region (Russian South Urals).

    PubMed

    Suslova, T A; Burmistrova, A L; Chernova, M S; Khromova, E B; Lupar, E I; Timofeeva, S V; Devald, I V; Vavilov, M N; Darke, C

    2012-10-01

    We have characterized the HLA-A, -B, -DRB1, -DQA1 and -DQB1 profiles of three major ethnic groups living in Chelyabinsk Region of Russian South Urals, viz., Russians (n = 207), Bashkirs (n = 146) and Tatars (n = 135). First field level typing was performed by PCR using sequence-specific primers. Estimates included carriage and gene frequencies, linkage disequilibrium and its significance and related values. Population comparisons were made between the allele family frequencies of the three populations and between these populations and 20 others using a dendrogram. Chelyabinsk Region Russians demonstrate all the features typical of a Caucasoid population, but also have some peculiarities. Together with Tatars, Russians have high frequencies of allele families and haplotypes characteristic of Finno-Ugric populations. This presupposes a Finno-Ugric impact on Russian and Tatar ethnogenesis. However, this was not apparent in Bashkirs, the first of the three populations to live in this territory, and implies admixture with populations of a Finno-Ugric origin with precursors of Russians and Tatars before they came to the South Urals. The Bashkirs appear close to Mongoloids in allele and haplotype distribution. However, Bashkirs cannot be labelled either as typical Mongoloids or as Caucasoids. Thus, Bashkirs possess some alleles and haplotypes frequent in Mongoloids, which supports the Turkic impact on Bashkir ethnogenesis, but also possess the AH 8.1 haplotype, which could evidence an ancient Caucasoid population that took part in their ethnic formation or of recent admixture with adjacent populations (Russians and Tatars). Bashkirs showed no features of populations with a substantial Finno-Ugric component, for example Chuvashes or Russian Saami. This disputes the commonly held belief of a Finno-Ugric origin for Bashkirs. Tatars appeared close to many European populations. However, they possessed some characteristics of Asiatic populations possibly reflecting a Mongoloid

  11. Mating in parents of type 1 diabetes families as a function of the HLA DR-DQ haplotype

    PubMed Central

    Kahles, H.; Kordonouri, O.; Ramos Lopez, E.; Walter, M.; Rosinger, S.; Boehm, B. O.; Badenhoop, K.; Seidl, C.; Ziegler, A.

    2009-01-01

    Aim The Major Histocompatibility Complex (MHC) region on chromosome 6p21 (IDDM1) contributes about half of the familial clustering of type 1 diabetes (T1D). Several studies have revealed that highly polymorphic genes within the MHC may associate with the mating choice. Our study should determine whether a specific mating effect is detectable in T1D families as a function of human leucocyte antigen (HLA) DR-DQ, which could contribute to disease susceptibility. Methods We analysed the parental HLA-DR genotypes in 829 diabetic families. The families derive from the Type 1 Diabetes Genetics Consortium (T1DGC) in addition to those of our own centre and the original UK, US and SCAND diabetic families. Results A total of 307 of 829 parental couples (37.0%) were matched for at least one known T1D risk haplotype (DR3 or DR4), which is significantly less than the expected 374.9 (45.2%), derived from population genotype frequencies (p < 0.0009). Parents share less susceptibility haplotypes and rather complement each other as both carry one different risk haplotype (DR3 or DR4). The number of such parental couples was significantly higher than expected (293 vs. 223.4; p < 0.0003). All non-transmitted DR haplotype pairs were also analysed. More often than expected, both parents did not transmit DR1 (94 vs. 59.1; p < 0.003) and DRy (y: not DR1, not DR3, not DR4; 63 vs. 30.3; p < 0.0005). In contrast, the parental non-transmitted pair of haplotypes DR1-DRy was observed to a far lesser extent than expected (26 vs. 84.7; p < 10−8). These observations were only made in multiplex families, whereas in simplex families, no deviation from the expected frequencies was observed. Conclusions Our data are consistent with the conclusion that genes in the HLA region may influence the mating choice in parents of T1D patients, thus contributing to familial clustering of T1D in multiplex families. This may indicate a different parental background of multiplex compared with simplex T1D families

  12. Evidence for high-risk haplotypes and (CGG)n expansion in fragile X syndrome in the Hellenic population of Greece and Cyprus

    SciTech Connect

    Syrrou, M.; Georgiou, I.; Pagoulatos, G.

    1996-07-12

    The expansion of the trinucleotide repeat (CGG){sub n} in successive generations through maternal meiosis is the cause of fragile X syndrome. Analysis of CA repeat polymorphisms flanking the FMR-1 gene provides evidence of a limited number of {open_quotes}founder{close_quotes} chromosomes and predisposing high-risk haplotypes related to the mutation. To investigate the origin of mutations in the fragile X syndrome in the Hellenic populations of Greece and Cyprus, we studied the alleles and haplotypes at DXS548 and FRAXAC2 loci of 16 independent fragile X and 70 normal control chromosomes. In addition, we studied 191 unrelated normal X chromosomes for the distribution and frequencies of CGG alleles. At DXS548, 6 alleles were found, 2 (194 and 196) of which were represented on fragile X chromosomes. At FRAXAC2, 6 alleles were found, 4 of which were present on fragile X chromosomes. Sixteen haplotypes were identified, but only 5 were present on fragile X chromosomes. The highest number of CGG repeats ({ge} 33) were associated with haplotypes 194-147, 194-151, 194-153, and 204-155. The data provide evidence for founder chromosomes and high-risk haplotypes in the Hellenic population. 20 refs., 3 figs., 2 tabs.

  13. High-resolution HLA haplotype frequencies of stem cell donors in Germany with foreign parentage: how can they be used to improve unrelated donor searches?

    PubMed

    Pingel, Julia; Solloch, Ute V; Hofmann, Jan A; Lange, Vinzenz; Ehninger, Gerhard; Schmidt, Alexander H

    2013-03-01

    In hematopoietic stem cell transplantation, human leukocyte antigens (HLA), usually HLA loci A, B, C, DRB1 and DQB1, are required to check histocompatibility between a potential donor and the recipient suffering from a malignant or non-malignant blood disease. As databases of potential unrelated donors are very heterogeneous with respect to typing resolution and number of typed loci, donor registries make use of haplotype frequency-based algorithms to provide matching probabilities for each potentially matching recipient/donor pair. However, it is well known that HLA allele and haplotype frequencies differ significantly between populations. We estimated high-resolution HLA-A, -B, -C, -DRB1 haplotype and allele frequencies of donors within DKMS German Bone Marrow Donor Center with parentage from 17 different countries: Turkey, Poland, Italy, Russian Federation, Croatia, Greece, Austria, Kazakhstan, France, The Netherlands, Republic of China, Romania, Portugal, USA, Spain, United Kingdom and Bosnia and Herzegovina. 5-locus haplotypes including HLA-DQB1 are presented for Turkey, Poland, Italy and Russian Federation. We calculated linkage disequilibria for each sample. Genetic distances between included countries could be shown to reflect geography. We further demonstrate how genetic differences between populations are reflected in matching probabilities of recipient/donor pairs and how they influence the search for unrelated donors as well as strategic donor center typings.

  14. The higher frequency of IgA deficiency among Swedish twins is not explained by HLA haplotypes.

    PubMed

    Frankowiack, M; Kovanen, R-M; Repasky, G A; Lim, C K; Song, C; Pedersen, N L; Hammarström, L

    2015-01-01

    Serum immunoglobulin A (IgA) concentrations were determined in 12 600 adult Swedish twins, applying a high-throughput reverse-phase protein microarray technique. The prevalence of IgA deficiency (IgAD) was found to be 1:241 in monozygotic (MZ) twins and 1:198 in dizygotic (DZ) twins. Hence, the prevalence in twins is markedly elevated as compared with the normal Swedish adult population (1:600). The twins did not show a difference in the frequency of HLA haplotypes in comparison with almost 40 000 healthy Swedish controls. As expected, the risk-conveying HLA alleles A*01, B*08 and DRB1*01 were overrepresented among the IgAD twins and were also associated with significantly lower mean serum IgA concentrations in the twin cohort. In contrast, significantly higher mean IgA concentrations were found among individuals carrying the protective HLA alleles B*07 and DRB1*15. Exome sequencing data from two MZ twin pairs discordant for the deficiency showed no differences between the siblings. Model fitting analyses derived a heritability of 35% and indicate that genetic influences are modestly important for IgAD. The probandwise concordance rates for IgAD were found to be 31% for MZ and 13% for DZ twins.

  15. Resistance/susceptibility to Echinococcus multilocularis infection and cytokine profile in humans. II. Influence of the HLA B8, DR3, DQ2 haplotype.

    PubMed

    Godot, V; Harraga, S; Beurton, I; Tiberghien, P; Sarciron, E; Gottstein, B; Vuitton, D A

    2000-09-01

    Differences have been shown between HLA characteristics of patients with different courses of alveolar echinococcosis (AE). Notably the HLA B8, DR3, DQ2 haplotype was associated with more severe forms of this granulomatous parasitic disease. We compared IL-10, IL-5, interferon-gamma (IFN-gamma) and tumour necrosis factor (TNF) secretion by peripheral blood mononuclear cells (PBMC) isolated from eight HLA-DR3+, DQ2+, B8+ AE patients and from 10 HLA-DR3-, DQ2-, B8- patients after non-specific mitogenic and specific Echinococcus multilocularis antigenic in vitro stimulation. PBMC from seven HLA-DR3+, DQ2+, B8+ healthy subjects and nine HLA-DR3-, DQ2-, B8- subjects were also studied as controls. PBMC from AE patients with HLA DR3+, DQ2+ haplotype secreted higher levels of IL-10 without any stimulation and after specific antigenic stimulation than did patients without this haplotype. Higher levels of IL-5 and IFN-gamma were also produced by these patients' PBMC after stimulation with non-purified parasitic antigenic preparations; however, the specific alkaline phosphatase antigen extracted from E. multilocularis induced only Th2-type cytokine secretion. A spontaneous secretion of TNF by HLA DR3+, DQ2+ B8+ AE patients was also found. These results suggest that HLA characteristics of the host can influence immune-mediated mechanisms, and thus the course of AE in humans; specific antigenic components of E. multilocularis could contribute to the preferential Th2-type cytokine production favoured by the genetic background of the host.

  16. Distribution of HLA-A, -B and -DRB1 Genes and Haplotypes in the Tujia Population Living in the Wufeng Region of Hubei Province, China

    PubMed Central

    Zhang, Li; Cheng, Dangxiao; Tao, Ning; Zhao, Min; Zhang, Fan; Yuan, Yulin; Qiu, Xiaoping

    2012-01-01

    Background The distribution of HLA alleles and haplotypes varies widely between different ethnic populations and geographic areas. Before any genetic marker can be used in a disease-associated study it is therefore essential to investigate allelic frequencies and establish a genetic database. Methodology/Principal Findings This is the first report of HLA typing in the Tujia group using the Luminex HLA-SSO method HLA–A, –B and -DRB1 allelic distributions were determined in 124 unrelated healthy Tujia individuals, and haplotypic frequencies and linkage disequilibrium parameters were estimated using the maximum-likelihood method. In total 10 alleles were detected at the HLA–A locus, 21 alleles at the HLA–B locus and 14 alleles at the HLA-DRB1 locus. The most frequently observed alleles in the HLA-I group were HLA–A*02 (35.48%), A*11 (28.23%), A*24 (15.73%); HLA–B*40 (25.00%), B*46 (16.13%), and B*15 (15.73%). Among HLA-DRB1 alleles, high frequencies of HLA-DRB1*09 (25.81%) were observed, followed by HLA-DRB1*15 (12.9%), and DRB1*12 (10.89%). The two-locus haplotypes at the highest frequency were A*02–B*46A (8.47%), followed by A*11–B*40 (7.66%), A*02–B*40 (8.87%), A*11–B*15 (6.45%), A*02–B*15 (6.05%), B*40–DRB1*09 (9.27%) and B*46–DRB1*09 (6.45%). The most common three-locus haplotypes found in the Tujia population were A*02–B*46–DRB1*09 (4.84%) and A*02–B*40–DRB1*09 (4.03%). Fourteen two-loci haplotypes had significant linkage disequilibrium. Construction of a neighbor-joining phylogenetic tree and principal component analysis using the allelic frequencies at HLA-A was performed to compare the Tujia group and twelve other previously reported populations. The Tujia population in the Wufeng of Hubei Province had the closest genetic relationship with the central Han population, and then to the Shui, the Miao, the southern Han and the northern Han ethnic groups. Conclusions/Significance These results will become a valuable source of data

  17. KIR and HLA Genotypes are Associated with Disease Progression and Survival following Autologous Hematopoietic Stem Cell Transplantation for High-Risk Neuroblastoma

    PubMed Central

    Venstrom, Jeffrey M.; Zheng, Junting; Noor, Nabila; Danis, Karen E.; Yeh, Alice W.; Cheung, Irene Y.; Dupont, Bo; O’Reilly, Richard J.; Cheung, Nai-Kong V.; Hsu, Katharine C.

    2009-01-01

    Purpose Natural killer (NK) cells exhibit cytotoxicity against neuroblastoma. Gene polymorphisms governing NK cell function, therefore, may influence prognosis. Two highly polymorphic genetic loci instrumental in determining NK cell responses encode the NK cell killer immunoglobulin-like receptors (KIR) and their class I human leukocyte antigen (HLA) ligands. We hypothesized that patients with a “missing ligand” KIR-HLA compound genotype may uniquely benefit from autologous hematopoietic stem cell transplantation (HSCT). Experimental Design 169 patients treated with autologous HSCT for stage 4 neuroblastoma underwent KIR and HLA genotyping. Patients were segregated according to presence or absence of HLA ligands for autologous inhibitory KIR. Univariate and multivariate analyses were performed for overall and progression-free survival. Results 64% of patients lacked one or more HLA ligands for inhibitory KIR. Patients lacking an HLA ligand had a 46% lower risk of death (HR 0.54; 95% CI, 0.35–0.85, P=.007) and a 34% lower risk of progression (HR 0.66; 95% CI, 0.44–1.0; P=.047) at 3 years compared with patients who possessed all ligands for his/her inhibitory KIR. Among all KIR-HLA combinations, 16 patients lacking the HLA-C1 ligand for KIR2DL2/2DL3 experienced the highest 3-year survival rate of 81% (95% CI: 64–100). Survival was more strongly associated with “missing ligand” than with tumor MYCN gene amplification. Conclusion KIR-HLA immunogenetics represents a novel prognostic marker for patients undergoing autologous HSCT for high-risk neuroblastoma. PMID:19934297

  18. The Privilege of Induction Avoidance and Calcineurin Inhibitors Withdrawal in 2 Haplotype HLA Matched White Kidney Transplantation

    PubMed Central

    Brifkani, Zaid; Brennan, Daniel C.; Lentine, Krista L.; Horwedel, Timothy A.; Malone, Andrew F.; Delos Santos, Rowena; Maw, Thin Thin; Alhamad, Tarek

    2017-01-01

    Background White recipients of 2-haplotype HLA-matched living kidney transplants are perceived to be of low immunologic risk. Little is known about the safety of induction avoidance and calcineurin inhibitor withdrawal in these patients. Methods We reviewed our experience at a single center and compared it to Organ Procurement and Transplantation Network (OPTN) registry data and only included 2-haplotype HLA-matched white living kidney transplants recipients between 2000 and 2013. Results There were 56 recipients in a single center (where no induction was given) and 2976 recipients in the OPTN. Among the OPTN recipients, 1285 received no induction, 903 basiliximab, 608 thymoglobulin, and 180 alemtuzumab. First-year acute rejection rates were similar after induction-free transplantation among the center and induced groups nationally. Compared with induction-free transplantation in the national data, there was no decrease in graft failure risk over 13 years with use of basiliximab (adjusted hazard ratio [aHR], 0.86; confidence interval [CI], 0.68-1.08), Thymoglobulin (aHR, 0.92; CI, 0.7-1.21) or alemtuzumab (aHR, 1.18; CI, 0.72-1.93). Among induction-free recipients at the center, calcineurin inhibitor withdrawal at 1 year (n = 27) did not significantly impact graft failure risk (HR,1.62; CI, 0.38-6.89). Conclusions This study may serve as a foundation for further studies to provide personalized, tailored, immunosuppression for this very low-risk population of kidney transplant patients. PMID:28361117

  19. A decrease in the estimated frequency of the extended HLA haplotype B18 CF130 DR3 DQw2 is common to non-insulin-dependent diabetes, juvenile rheumatoid arthritis, and Berger's disease.

    PubMed

    Regueiro, J R; Arnaiz-Villena, A; Vicario, J L; Martinez-Laso, J; Pacheco, A; Rivera-Guzman, J M

    1993-07-05

    Extended HLA haplotypes frequencies were estimated from the HLA, C2, Bf and C4 phenotypes of 74 patients with non-insulin-dependent diabetes (NIDD), 92 with juvenile rheumatoid arthritis (JRA), 44 with Berger's disease (BD), 83 with insulin-dependent diabetes (IDD), and 140 healthy controls. The extended HLA haplotype B18 CF130 DR3 DQw2, which is common (around 10% phenotype frequency) in healthy Spaniards and in other populations of paleo-North African origin, was found to be significantly less frequent in NIDD, JRA and BD, whereas its frequency was normal in IDD (although DR3 DQw2 haplotypes were increased in the latter disease). These data support the existence of a common HLA-linked pathogeneic mechanism in NIDD, JRA and BD, and point to a genetic difference between IDD and NIDD at the HLA level. This effect is readily detectable in our population because the uncommon BfF1 allele marks that haplotype instead of the more common BfS, which marks B8 CS01 DR3 DQw2 in other Caucasians. Our results support the hypothesis of strong selective pressures operating at the HLA level to preserve extended HLA haplotypes with advantageous gene sets from dilution by crossing-over. Imbalanced incomplete haplotypes may give rise to inappropriate T-cell repertoire selection in the thymus and/or antigen handling in the periphery, and be partly responsible for the pathogenesis of certain HLA-linked diseases (i.e. NIDD, JRA, and BD).

  20. In silico analysis of microRNAS targeting the HLA-G 3' untranslated region alleles and haplotypes.

    PubMed

    Castelli, Erick C; Moreau, Philippe; Oya e Chiromatzo, Alynne; Mendes-Junior, Celso Teixeira; Veiga-Castelli, Luciana C; Yaghi, Layale; Giuliatti, Silvana; Carosella, Edgardo D; Donadi, Eduardo Antonio

    2009-12-01

    It has been reported that microRNAs (miRNA) may have allele-specific targeting for the 3' untranslated region (3' UTR) of the HLA-G locus. In a previous study, we reported 11 3'UTR haplotypes encompassing the 14-bp insertion/deletion polymorphism and seven SNPs (+3003 T/C, +3010 C/G, +3027 C/A, +3035 C/T, +3142 C/G, +3187 A/G, and +3196 C/G), of which only the +3142 C/G SNP has been reported to influence the binding of miRNAs. Using bioinformatics analyses, we identified putative miRNA-binding sites considering the haplotypes encompassing these eight polymorphic sites, and we ranked the lowest free energies that could potentially lead to an mRNA degradation or translational repression. When a specific haplotype or a particular SNP was associated with a miRNA-binding site, we defined a free energy difference of 4 kcal/mol between alleles to classify them energetically distant. The best results were obtained for the miR-513a-5p, miR-518c*, miR-1262 and miR-92a-1*, miR-92a-2*, miR-661, miR-1224-5p, and miR-433 miRNAs, all influencing one or more of the +3003, +3010, +3027, and +3035 SNPs. The miR-2110, miR-93, miR-508-5p, miR-331-5p, miR-616, miR-513b, and miR-589* miRNAs targeted the 14-bp fragment region, and miR-148a, miR-19a*, miR-152, mir-148b, and miR-218-2 also influenced the +3142 C/G polymorphism. These results suggest that these miRNAs might play a relevant role on the HLA-G expression pattern.

  1. Definition of High-Risk Type 1 Diabetes HLA-DR and HLA-DQ Types Using Only Three Single Nucleotide Polymorphisms

    PubMed Central

    Nguyen, Cao; Varney, Michael D.; Harrison, Leonard C.; Morahan, Grant

    2013-01-01

    Evaluating risk of developing type 1 diabetes (T1D) depends on determining an individual’s HLA type, especially of the HLA DRB1 and DQB1 alleles. Individuals positive for HLA-DRB1*03 (DR3) or HLA-DRB1*04 (DR4) with DQB1*03:02 (DQ8) have the highest risk of developing T1D. Currently, HLA typing methods are relatively expensive and time consuming. We sought to determine the minimum number of single nucleotide polymorphisms (SNPs) that could rapidly define the HLA-DR types relevant to T1D, namely, DR3/4, DR3/3, DR4/4, DR3/X, DR4/X, and DRX/X (where X is neither DR3 nor DR4), and could distinguish the highest-risk DR4 type (DR4-DQ8) as well as the non-T1D–associated DR4-DQB1*03:01 type. We analyzed 19,035 SNPs of 10,579 subjects (7,405 from a discovery set and 3,174 from a validation set) from the Type 1 Diabetes Genetics Consortium and developed a novel machine learning method to select as few as three SNPs that could define the HLA-DR and HLA-DQ types accurately. The overall accuracy was 99.3%, area under curve was 0.997, true-positive rates were >0.99, and false-positive rates were <0.001. We confirmed the reliability of these SNPs by 10-fold cross-validation. Our approach predicts HLA-DR/DQ types relevant to T1D more accurately than existing methods and is rapid and cost-effective. PMID:23378606

  2. Association of HLA-A, B, DRB1* and DQB1* alleles and haplotypes in south Indian T2DM patients.

    PubMed

    Chinniah, Rathika; Vijayan, Murali; Sivanadham, Ramgopal; Ravi, Padma Malini; Panneerselvam, Dharmarajan; Karuppiah, Balakrishnan

    2016-10-30

    The genes of Human Leukocyte Antigen (HLA) system are implicated in the susceptibility of several diseases including Type 2 diabetes (T2DM). Therefore, we aimed to investigate the association of HLA alleles with T2DM in south India. A total of 344 patients (195 males; 149 females) and 309 controls (186 males; 123 females) were genotyped for HLA-DR/-DQ alleles. Based on predominant DR/DQ haplotypes, 222 patients and 222 age/sex matched controls were HLA-A/-B genotyped. HLA alleles were typed by PCR-SSP methods. Susceptible association was observed for the alleles A*33 (OR=13.8), A*01 (OR=3.69), A*02 (OR=2.91), B*07 (OR=4.12), DRB1*11 (OR=2.23), DRB1*04 (OR=1.51), DRB1*03 (OR=1.90) and DQB1*02 (OR=1.49). Protective association was observed for the alleles A*11 (OR=0.59), A*68 (OR=0.68), B*40 (OR=0.50), B*54 (OR=0.42), B*57 (OR=0.31), B*51 (OR=0.29) and DRB1*10 (OR=0.45). Gender stratified analysis too confirmed many of these associations. Predominant susceptible haplotypes were A*33-B*40 (OR=10.27), A*01-B*07 (OR=4.97), A*02-B*07 (OR=6.50), DRB1*03-DQB1*05 (OR=1.88), DRB1*03-DQB1*06 (OR=3.01), DRB1*04-DQB1*05 (2.63), A*01-B*07-DRB1*10 (OR=8.26) and A*11-B*35-DRB1*07 (OR=9.338). Haplotypes A*03-B*07 (OR=0.57; p<0.034) and DRB1*10-DQB1*05 (OR=0.57; p<0.033) were protectively associated. Further, a very strong susceptible association was documented for four-locus haplotypes such as A*11-B*40-DRB1*15-DQB1*06 (n=15; OR=16.01; p<0.001); A*01-B*07-DRB1*10-DQB1*05 (n=8; OR=8.26; p<0.043) and A*11-B*07-DRB1*07-DQB1*05 (n=8; OR=8.26; p<0.043). Thus, a number of HLA alleles and haplotypes showed susceptible and protective association(s) in T2DM patients from south India.

  3. A tug-of-war between tolerance and rejection - New evidence for 3'UTR HLA-G haplotypes influence in recurrent pregnancy loss.

    PubMed

    Michita, Rafael Tomoya; Zambra, Francis Maria Báo; Fraga, Lucas Rosa; Sanseverino, Maria Teresa Vieira; Callegari-Jacques, Sidia Maria; Vianna, Priscila; Chies, José Artur Bogo

    2016-10-01

    HLA-G is a molecule essential to the maintenance of the maternal-fetal interface tolerance, thus contributing to a healthy pregnancy. Here we investigate the role of HLA-G single nucleotide polymorphisms (SNPs) and whether a specific HLA-G haplotype influence or not recurrent pregnancy loss (RPL) risk. A total of 296 DNA samples from RPL (N=140) and controls (N=156) were evaluated. The HLA-G 3'UTR region was sequenced and eight major SNPs were evaluated (14pb insertion/deletion, +3003T/C, +3010C/G, +3027C/A, +3035C/T, +3142G/C, +3187A/G, +3196C/G). A high linkage disequilibrium (LD) among all pairs and a perfect LD between +3010C/G and +3142G/A (D'=1.0, r(2)=1.0) were observed. Our data showed an increased risk to +3010CC genotype carriers in comparison with control [odds ratio (OR) 2.05 95% confidence interval (CI) 1.05-4.00, p=0.035] and to a decreased risk of RPL in +3142CC genotype carriers (OR=0.49 95%CI 0.25-0.95, p=0.035) and +3187AG genotype carriers (OR=0.58 95%CI 0.35-0.94, p=0.029). A total of eight haplotypes were observed in the sample, being UTR-1 and UTR-2 the most represented. An association between UTR-1 haplotype carriers with a reduced risk of both RPL and secondary RPL was observed. Our results indicate that the HLA-G 3'UTR plays important roles in RPL and might be an important marker of susceptibility to this, and possible to other, pregnancy disorders.

  4. A rare ancestral HLA-DRB1(∗)15:01̃DQB1(∗)02:01 haplotype and its reversion in the same Western European family.

    PubMed

    Binder, Thomas M C; Kelsch, Reinhard; Wikner, Julia M; Aly, Lilian; Brendel, Cornelia; Alster, Ina; Kühnl, Peter; Finckh, Ulrich; Eiermann, Thomas H

    2015-03-01

    The HLA-DR and -DQ loci are close neighbors on chromosome 6 that are highly linked. Many common associations between HLA-DR and DQ-alleles are known, normally transmitted as HLA-DR̃DQ haplotypes from one generation to another. Reports of very recent genetic rearrangements between HLA-DR and -DQ are rarely found in the literature. In Europeans haplotypes containing DRB1(∗)15:01, DQB1(∗)02:01, and DQA1(∗)05:01 have not been reported before. We report the finding of the rare HLA haplotype A(∗)24:02̃C(∗)07:02̃B(∗)07:02̃MICA(∗)008:01̃DRB5(∗)01:01̃DRB1(∗)15:01̃DQA1(∗)05:01̃DQB1(∗)02:01̃DPB1(∗)04:01 in a German stem cell donor with East Frisian ancestry. Our observation suggests a rare ancestral recombination between the DR and DQ loci. In order to investigate this haplotype, we typed 50/74 members of the family encompassing four generations for HLA classes I and II by serological and molecular methods. The rare haplotype was identified in 12 heterozygous carriers. Furthermore, we identified and further characterized a putative crossing over event resulting in its reversion to a common haplotype.

  5. Analysis of HLA class II haplotypes in the Cayapa Indians of Ecuador: a novel DRB1 allele reveals evidence for convergent evolution and balancing selection at position 86.

    PubMed Central

    Titus-Trachtenberg, E. A.; Rickards, O.; De Stefano, G. F.; Erlich, H. A.

    1994-01-01

    PCR amplification, oligonucleotide probe typing, and sequencing were used to analyze the HLA class II loci (DRB1, DQA1, DQB1, and DPB1) of an isolated South Amerindian tribe. Here we report HLA class II variation, including the identification of a new DRB1 allele, several novel DR/DQ haplotypes, and an unusual distribution of DPB1 alleles, among the Cayapa Indians (N = 100) of Ecuador. A general reduction of HLA class II allelic variation in the Cayapa is consistent with a population bottle-neck during the colonization of the Americas. The new Cayapa DRB1 allele, DRB1*08042, which arose by a G-->T point mutation in the parental DRB1*0802, contains a novel Val codon (GTT) at position 86. The generation of DRB1*08042 (Val-86) from DRB1*0802 (Gly-86) in the Cayapa, by a different mechanism than the (GT-->TG) change in the creation of DRB1*08041 (Val-86) from DRB1*0802 in Africa, implicates selection in the convergent evolution of position 86 DR beta variants. The DRB1*08042 allele has not been found in > 1,800 Amerindian haplotypes and thus presumably arose after the Cayapa separated from other South American Amerindians. Selection pressure for increased haplotype diversity can be inferred in the generation and maintenance of three new DRB1*08042 haplotypes and several novel DR/DQ haplotypes in this population. The DPB1 allelic distribution in the Cayapa is also extraordinary, with two alleles, DPB1*1401, a very rare allele in North American Amerindian populations, and DPB1*0402, the most common Amerindian DPB1 allele, constituting 89% of the Cayapa DPB1.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8023844

  6. Estimation of the 6-digit level allele and haplotype frequencies of HLA-A, -B, and -C in Koreans using ambiguity-solving DNA typing.

    PubMed

    Jun, J-H; Hwang, K; Kim, S-K; Oh, H-B; Cho, M-C; Lee, K-J

    2014-09-01

    Because Korean society is fast becoming multi-ethnic, the determination of ambiguous human leukocyte antigen (HLA) types using HLA allele frequencies is becoming less applicable. In this study, we focused on the development of new technical methods to directly resolve the ambiguities arising from HLA genotyping. One hundred and fifty unrelated healthy Korean adults were included in this study. All alleles from each HLA locus were first divided into 2-4 groups, with each group amplified in a single PCR tube (multi-group-specific amplification, MGSA). To resolve phase ambiguities, some allele groups were also amplified separately in small group-specific amplification (SGSA) tubes. In order to then resolve incomplete sequence ambiguities, primers for MGSA and SGSA were initially designed to cover additional exons. If needed, a heterozygous ambiguity resolving primer (HARP) or sequence specific primer (SSP) was also used. When MGSA and SGSA methods were applied, the rate of phase ambiguity was greatly reduced to an average of 6% (1.3% in HLA-A, 15.7% in -B, and 2.0% in -C). Additional HARP and SSP methods could resolve all the phase ambiguities. Using our proposed method, we also detected three alleles that have not been previously reported in Korea, C*04:82, C*07:18, and C*08:22, and report 6-digit level HLA allele and haplotype frequencies among Koreans. In conclusion, the use of MGSA/SGSA for the initial amplification step is a cost-effective method facilitating timely and accurate reporting, given the continuing increase in the ethnic diversity of the Korean population. The MGSA described here can be applicable to various populations and thus could be shared by the majority of HLA typing laboratories. However, efforts to solve HLA ambiguity should continue, because SGSA, HARPs and SSPs would be specific to a particular population.

  7. Analysis of HLA genes and haplotypes in Ainu (from Hokkaido, northern Japan) supports the premise that they descent from Upper Paleolithic populations of East Asia.

    PubMed

    Bannai, M; Ohashi, J; Harihara, S; Takahashi, Y; Juji, T; Omoto, K; Tokunaga, K

    2000-02-01

    The Ainu people are assumed to be the descendants of pre-agricultural native populations of northern Japan, while the majority of population of present-day Japan (Hondo-Japanese) is considered to have descended mainly from post-neolithic migrants. Sequence-level polymorphisms of the HLA-class I (HLA-A and HLA-B) genes were investigated in DNA samples of 50 Ainu living in Hidaka district, Hokkaido. HLA-A*2402, A*0201, A*0206, A*2601, A*3101, B*1501, B*5101, B*3901, and B*3501 were observed at frequencies of more than 10% and most of these have previously been found in populations of not only Asians but also North and South American Indians. A*68012, which has not so far been detected in Hondo-Japanese, was found in the Ainu (3%). On the other hand, several alleles common in Hondo-Japanese, including HLA-A*3303, A*1101, B*4403, B*5201, B*5401, B*4601, and B*0702 were infrequent in Ainu (0-1%). Correspondence and neighbor-joining analyses of various populations based on HLA-A, -B and -DRB1 gene frequencies enabled distinction between Asian, Native South American, European, and African populations. The Ainu, as well as Tlingit (Na-Dene), were placed midway between other East Asians, including Hondo Japanese, and Native South Americans (Amerindians) in the correspondence analysis. Furthermore, several HLA-A-B and HLA-B-DR-DQ haplotypes common in the Ainu, are shared with some Native American populations. These observations strongly suggest a unique place for the Ainu as descendants of some Upper Paleolithic populations of East Asia, from whom some Native Americans may have descended.

  8. Languages, geography and HLA haplotypes in native American and Asian populations.

    PubMed Central

    Monsalve, M V; Helgason, A; Devine, D V

    1999-01-01

    A number of studies based on linguistic, dental and genetic data have proposed that the colonization of the New World took place in three separate waves of migration from North-East Asia. Recently, other studies have suggested that only one major migration occurred. It is the aim of this study to assess these opposing migration hypotheses using molecular-typed HLA class II alleles to compare the relationships between linguistic and genetic data in contemporary Native American populations. Our results suggest that gene flow and genetic drift have been important factors in shaping the genetic landscape of Native American populations. We report significant correlations between genetic and geographical distances in Native American and East Asian populations. In contrast, a less clear-cut relationship seems to exist between genetic distances and linguistic affiliation. In particular, the close genetic relationship of the neighbouring Na-Dene Athabaskans and Amerindian Salishans suggests that geography is the more important factor. Overall, our results are most congruent with the single migration model. PMID:10649635

  9. Patient HSP70-hom TG haplotype is associated with decreased transplant-related mortality and improved survival after sibling HLA-matched hematopoietic stem cell transplantation.

    PubMed

    Kim, Inho; Kim, Jin Hee; Rhee, Ji Young; Kim, Jin Won; Cho, Hyeon Jin; Cho, Eun-Young; Lee, Jong-Eun; Hong, Yun-Chul; Park, Sung Sup; Yoon, Sung-Soo; Park, Myoung Hee; Park, Seonyang; Kim, Byoung Kook

    2010-01-01

    Heat shock protein 70-hom (HSP70-hom) plays an important role in protein folding and immune responses. Therefore, HSP70-hom gene polymorphisms may act as important factors in predicting the prognosis of patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). To evaluate the role of HSP70-hom gene polymorphisms in the prognosis of patients receiving sibling human leukocyte antigen (HLA)-matched allogeneic HSCT, the HSP70-hom polymorphisms, T2437C and G2763A, were genotyped in 147 patients receiving sibling HLA-matched allogeneic HSCT. Individual diplotypes were estimated from genotype data of the two HSP70-hom polymorphisms using the expectation maximization algorithm. Patients with the 2763GG or GA genotype showed longer overall survival compared with those with the 2763AA genotype, and patients with a TG haplotype (TG/TA, TG/TG or TG/CG) also showed longer overall survival compared with those with a non-TG haplotype (TA/TA or TA/CG) (both G2763A genotype and diplotype, p<0.01). Moreover, the 2437TT genotype was found to be protective for treatment-related death compared with the 2437TC genotype, and a TG haplotype was found to be very protective for treatment-related death compared with a non-TG haplotype (T2437C genotype, p=0.04; and diplotype, p=0.02). Therefore, our results suggest that HSP70-hom polymorphisms play an important role in the prognosis of patients receiving sibling HLA-matched allogeneic HSCT.

  10. The Influence of the Autoimmunity-Associated Ancestral HLA Haplotype AH8.1 on the Human Gut Microbiota: A Cross-Sectional Study

    PubMed Central

    Qin, Bingcai; Anmarkrud, Jarl Andreas; Holm, Kristian; Franke, Andre; Lie, Benedicte A.; Karlsen, Tom H.

    2015-01-01

    Multiple immune-related genes are encoded in the HLA complex on chromosome 6p21. The 8.1 ancestral haplotype (AH8.1) include the classical HLA alleles HLA-B*08:01 and HLA-DRB1*03:01, and has been associated with a large number of autoimmune diseases, but the underlying mechanisms for this association are largely unknown. Given the recently established links between the gut microbiota and inflammatory diseases, we hypothesized that the AH8.1 influences the host gut microbial community composition. To study this further, healthy individuals were selected from the Norwegian Bone Marrow Donor Registry and categorized as either I. AH8.1 homozygote (n=34), II. AH8.1 heterozygote (n=38), III. Non AH8.1 heterozygote or IV. HLA-DRB1 homozygote but non AH8.1 (n=15). Bacterial DNA from stool samples were subjected to sequencing of the V3–V5 region of the 16S rRNA gene on the 454 Life Sciences platform and data analyzed using Mothur and QIIME. The results showed that the abundances of different taxa were highly variable within all pre-defined AH8.1 genotype groups. Using univariate non-parametric statistics, there were no differences regarding alpha or beta diversity between AH8.1 carriers (categories I and II) and non-carriers (categories III and IV), however four different taxa (Prevotellaceae, Clostridium XVIII, Coprococcus, Enterorhabdus) had nominally significant lower abundances in AH8.1 carriers than non-carriers. After including possible confounders in a multivariate linear regression, only the two latter genera remained significantly associated. In conclusion, the overall contribution of the AH8.1 haplotype to the variation in gut microbiota profile of stool in the present study was small. PMID:26207384

  11. Genome-wide Association Study Identifies HLA 8.1 Ancestral Haplotype Alleles as Major Genetic Risk Factors for Myositis Phenotypes

    PubMed Central

    Miller, Frederick W.; Chen, Wei; O’Hanlon, Terrance P.; Cooper, Robert G.; Vencovsky, Jiri; Rider, Lisa G.; Danko, Katalin; Wedderburn, Lucy R.; Lundberg, Ingrid E.; Pachman, Lauren M.; Reed, Ann M.; Ytterberg, Steven R.; Padyukov, Leonid; Selva-O’Callaghan, Albert; Radstake, Timothy R.; Isenberg, David A.; Chinoy, Hector; Ollier, William E.R.; Scheet, Paul; Peng, Bo; Lee, Annette; Byun, Jinyoung; Lamb, Janine A.; Gregersen, Peter K.; Amos, Christopher I.

    2016-01-01

    Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis; 473 juvenile dermatomyositis; 532 polymyositis; and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P < 5 × 10−8) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1haplotype comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations. PMID:26291516

  12. Accumulation of Pol Mutations Selected by HLA-B*52:01-C*12:02 Protective Haplotype-Restricted Cytotoxic T Lymphocytes Causes Low Plasma Viral Load Due to Low Viral Fitness of Mutant Viruses.

    PubMed

    Murakoshi, Hayato; Koyanagi, Madoka; Chikata, Takayuki; Rahman, Mohammad Arif; Kuse, Nozomi; Sakai, Keiko; Gatanaga, Hiroyuki; Oka, Shinichi; Takiguchi, Masafumi

    2017-02-15

    HLA-B*52:01-C*12:02, which is the most abundant haplotype in Japan, has a protective effect on disease progression in HIV-1-infected Japanese individuals, whereas HLA-B*57 and -B*27 protective alleles are very rare in Japan. A previous study on HLA-associated polymorphisms demonstrated that the number of HLA-B*52:01-associated mutations at four Pol positions was inversely correlated with plasma viral load (pVL) in HLA-B*52:01-negative individuals, suggesting that the transmission of HIV-1 with these mutations could modulate the pVL in the population. However, it remains unknown whether these mutations were selected by HLA-B*52:01-restricted CTLs and also reduced viral fitness. In this study, we identified two HLA-B*52:01-restricted and one HLA-C*12:02-restricted novel cytotoxic T-lymphocyte (CTL) epitopes in Pol. Analysis using CTLs specific for these three epitopes demonstrated that these CTLs failed to recognize mutant epitopes or more weakly recognized cells infected with mutant viruses than wild-type virus, supporting the idea that these mutations were selected by the HLA-B*52:01- or HLA-C*12:02-restricted T cells. We further showed that these mutations reduced viral fitness, although the effect of each mutation was weak. The present study demonstrated that the accumulation of these Pol mutations selected by HLA-B*52:01- or HLA-C*12:02-restricted CTLs impaired viral replication capacity and thus reduced the pVL. The fitness cost imposed by the mutations partially accounted for the effect of the HLA-B*52:01-C*12:02 haplotype on clinical outcome, together with the effect of HLA-B*52:01-restricted CTLs on viral replication, which had been previously demonstrated.

  13. HLA-DP is the cervical cancer susceptibility loci among women infected by high-risk human papillomavirus: potential implication for triage of human papillomavirus-positive women.

    PubMed

    Jia, Meiqun; Han, Jing; Hang, Dong; Jiang, Jie; Wang, Minjie; Wei, Baojun; Dai, Juncheng; Zhang, Kai; Guo, Lanwei; Qi, Jun; Ma, Hongxia; Shi, Jufang; Ren, Jiansong; Hu, Zhibin; Dai, Min; Li, Ni

    2016-06-01

    Given that only a small proportion of women infected by high-risk human papillomavirus (hrHPV) develop cervical cancer, it's important to identify biomarkers for distinguishing women with hrHPV positivity who might develop cervical cancer from the transient infections. In this study, we hypothesized that human leukocyte antigens (HLA) susceptibility alleles might contribute to cervical cancer risk among females infected by hrHPV, and interact with hrHPV types. A case-control study with 593 cervical cancer cases and 407 controls (all hrHPV positive) was conducted to evaluate the effect of eight HLA-related single-nucleotide polymorphisms (SNPs) and their interactions with hrHPV types on the risk of cervical cancer. Three HLA-DP SNPs (rs4282438, rs3117027, and rs3077) were found to be significantly associated with risk of cervical cancer (rs4282438: odds ratio (OR) = 0.72, 95 % confidence interval (CI) = 0.56-0.93; rs3117027: OR = 1.41, 95 % CI = 1.10-1.83; and rs3077: OR = 1.37, 95 % CI = 1.04-1.80) among women infected with hrHPV. An additive interaction between HPV16 and rs4282438 for cervical cancer risk was also found (P for interaction = 0.002). Compared with subjects carrying variant genotypes (GG/TG) and non-HPV16 infections, those carrying wild-type genotype (TT) of rs4282438 and HPV16 positive had a 5.22-fold increased risk of cervical cancer (95 % CI = 3.39-8.04). Our study supported that certain HLA-DP alleles in concert with HPV16 could have a predisposition for cervical cancer development, which may be translated for triage of hrHPV-positive women.

  14. Computer-based design of an HLA-haplotype and HIV-clade independent cytotoxic T-lymphocyte assay for monitoring HIV-specific immunity.

    PubMed Central

    Amicosante, Massimo; Gioia, Cristiana; Montesano, Carla; Casetti, Rita; Topino, Simone; D'Offizi, Gianpiero; Cappelli, Giulia; Ippolito, Giuseppe; Colizzi, Vittorio; Poccia, Fabrizio; Pucillo, Leopoldo P.

    2002-01-01

    BACKGROUND: Human immunodeficiency virus (HIV)- specific CD8-positive cytotoxic T-lymphocytes (CTL) play a key role in controlling HIV infection. Monitoring CTL response could be clinically relevant during structured therapy interruption (STI), HIV exposure, and vaccine trials. However, HLA patients' restriction and HIV variability limited the development of a CTL assay with broad specificity. MATERIALS AND METHODS: We designed an HLA-class I/HIV-1 clade independent assay for assessing HIV- specific CTL by using a computer-assisted selection ofthe CTL epitopes. Twenty-eight 15-mers were selected by peptide-binding motifs analysis using different databases (HIV-Immunology Database, SYFPEITHI, BIMAS). Altogether they putatively bind to more than 90% of HLA haplotypes in different populations, with an overall HIV-1 variability below 9%. The peptide pool was used as an antigen in an intracellular cytokine staining (ICS) assay for quantifying HIV-specific CTL response. RESULTS: The test can be performed using both fresh and cryopreserved peripheral blood mononuclear cells (PBMC), whereas GAG protein as antigen works only on fresh PBMC. A significantly higher CTL response with respect to HIV-negative controls was detected in all HIV-1 infected subjects of two groups of patients with different ethnicities (Caucasians and Africans) and coming from areas with different HIV-1 clade prevalences (clade B and A/G, respectively). In Caucasian patients, after month of STI, the number of HIV-1 specific CTL (2,896 +/- 2,780 IFN-gamma specific CD8 cells/ml) was significantly higher than that found at enrolment (2,125 +/- 4,426 IFN-gamma specific CD8 cells/ml, p< 0.05). CONCLUSIONS: These data indicate that this CTL assay is broadly specific and could represent a useful clinical tool for HIV immunodiagnostic independent of HLA-haplotype and HIV-clade variabilities. PMID:12606814

  15. Discovery of a novel HLA-B*51 variant, B*51:112, in a Taiwanese bone marrow donor and identification of the plausible HLA haplotype in association with B*51:112.

    PubMed

    Yang, K L; Lee, S K; Lin, P Y

    2012-10-01

    The sequence of B*51:112 is identical to the sequence of B*51:01:01 in exons 2, 3 and 4, except the nucleotides at positions 206 (C→A) and 213 (C→G). The nucleotide replacement caused one amino acid substitution at residue 45 (T→K). The plausible HLA-A, -B and -DRB1 haplotype in association with B*51:112 may be deduced as HLA-A*02-B*51:112-DRB1*12. The generation of B*51:112 was probably as the result of a DNA recombination event where B*40:01:01 acted as a sequence donor donating a segment of the DNA sequence to the recipient sequence B*51:01:01. The donor carrying B*51:112 was a Minna Taiwanese whose ancestor came to Taiwan from the southern region of China.

  16. Frequency distribution of HLA-antigens, genes and haplotypes in the migrant population of Magadan as a function of length of residence in the region.

    PubMed

    Pereverzeva, V V; Solovenchuk, L L

    1996-09-01

    Peculiarities of the frequency distribution of antigens, genes, and haplotypes at subloci A, B, and Cw of the HLA system in 1429 Slavic inhabitants of Magadan are presented in dependence on length of residence in extreme conditions. No significant differences were revealed with respect to frequency of genes and antigens in inhabitants with different lengths of residence in northeastern Russian conditions. Analysis of gamete associations shows that the revealed positive or negative associativity in some cases is characteristic for Caucasoids on the whole, but an associativity specific to inhabitants of Magadan was also established. Its character depends on the length of residence in extreme conditions.

  17. MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo

    PubMed Central

    Cavalli, Giulio; Hayashi, Masahiro; Jin, Ying; Yorgov, Daniel; Santorico, Stephanie A.; Holcomb, Cherie; Rastrou, Melinda; Erlich, Henry; Tengesdal, Isak W.; Dagna, Lorenzo; Neff, C. Preston; Palmer, Brent E.; Spritz, Richard A.; Dinarello, Charles A.

    2016-01-01

    Genetic risk for autoimmunity in HLA genes is most often attributed to structural specificity resulting in presentation of self-antigens. Autoimmune vitiligo is strongly associated with the MHC class II region. Here, we fine-map vitiligo MHC class II genetic risk to three SNPs only 47 bp apart, located within a predicted super-enhancer in an intergenic region between HLA-DRB1 and HLA-DQA1, localized by a genome-wide association study of 2,853 Caucasian vitiligo patients. The super-enhancer corresponds to an expression quantitative trait locus for expression of HLA-DR and HLA-DQ RNA; we observed elevated surface expression of HLA-DR (P = 0.008) and HLA-DQ (P = 0.02) on monocytes from healthy subjects homozygous for the high-risk SNP haplotype. Unexpectedly, pathogen-stimulated peripheral blood mononuclear cells from subjects homozygous for the high-risk super-enhancer haplotype exhibited greater increase in production of IFN-γ and IL-1β than cells from subjects homozygous for the low-risk haplotype. Specifically, production of IFN-γ on stimulation of dectin-1, mannose, and Toll-like receptors with Candida albicans and Staphylococcus epidermidis was 2.5- and 2.9-fold higher in high-risk subjects than in low-risk subjects, respectively (P = 0.007 and P = 0.01). Similarly, production of IL-1β was fivefold higher in high-risk subjects than in low-risk subjects (P = 0.02). Increased production of immunostimulatory cytokines in subjects carrying the high-risk haplotype may act as an “adjuvant” during the presentation of autoantigens, tying together genetic variation in the MHC with the development of autoimmunity. This study demonstrates that for risk of autoimmune vitiligo, expression level of HLA class II molecules is as or more important than antigen specificity. PMID:26787888

  18. Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes.

    PubMed

    Miller, F W; Chen, W; O'Hanlon, T P; Cooper, R G; Vencovsky, J; Rider, L G; Danko, K; Wedderburn, L R; Lundberg, I E; Pachman, L M; Reed, A M; Ytterberg, S R; Padyukov, L; Selva-O'Callaghan, A; Radstake, T R; Isenberg, D A; Chinoy, H; Ollier, W E R; Scheet, P; Peng, B; Lee, A; Byun, J; Lamb, J A; Gregersen, P K; Amos, C I

    2015-10-01

    Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P<5×10(-8)) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.

  19. HLA DRB1*DQB1* haplotype in HTLV-I-associated familial infective dermatitis may predict development of HTLV-I-associated myelopathy/tropical spastic paraparesis

    SciTech Connect

    LaGrenade, L.; Miller, W.; Pate, E.; Rodgers-Johnson, P.

    1996-01-02

    A possible causal association between infective dermatitis and HTLV-I infection was reported in 1990 and confirmed in 1992. We now report familial infective dermatitis (ID) occurring in a 26-year-old mother and her 9-year-old son. The mother was first diagnosed with ID in 1969 at the age of 2 years in Dermatology Unit at the University Hospital of the West Indies (U.H.W.I.) in Jamacia. The elder of her 2 sons was diagnosed with ID at the age of 3 years, also at U.H.W.I. Both mother and son are HTLV-I-seropositive. A second, younger son, currently age 2 years, is also HTLV-I-seropositive, but without clinical evidence of ID. Major histocompatibility complex (MHC), class II, human leucocyte antigen (HLA) genotyping documented a shared class II haplotype, DRB1*DQB1* (1101-0301), in the mother and her 2 sons. This same haplotype has been described among Japanese patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and has been associated with a possible pathologically heightened immune response to HTLV-I infection. The presence of this haplotype in these familial ID cases with clinical signs of HAM/TSP may have contributed to their risk for development of HAM/TSP. The unaffected, HTLV-I-seropositive, younger son requires close clinical follow-up. 20 refs., 1 fig., 1 tab.

  20. MICA genetic polymorphism and HLA-A,C,B,MICA and DRB1 haplotypic variation in a southern Chinese Han population: identification of two new MICA alleles, MICA*060 and MICA*062.

    PubMed

    Tian, Wei; Cai, JinHong; Liu, XueXiang

    2011-06-01

    In this study, 201 healthy, unrelated Han subjects in Hunan province, southern China, were investigated by sequence-based typing (SBT) for the allelic variation of the human major histocompatibility complex (MHC) class I chain-related gene A (MICA). Nineteen MICA alleles were observed, among which MICA*008:01 predominated with gene frequency of 30.35%. There was significant linkage disequilibrium (LD) of MICA*012:01 with HLA-B*54 and HLA-B*55, which was not observed in a northern Chinese Han population. Haplotype HLA-A*11-C*07-B60-MICA*008:01 (9.16%) was highly specific to this southern Chinese Han population. The most common five-locus haplotype in this population was HLA-A*02-C*01-B*46-MICA*010-DRB1*09 (8.73%). A new MICA allele, MICA*060, was identified on an HLA-A*02-C*01-B*55:02-DRB1*14 haplotype through extended family analysis. MICA*060 has probably arisen from MICA*012:01. Another new MICA allele, MICA*062, was identified by screening 1432 subjects using polymerase chain reaction-sequence-specific priming technology. MICA*062 has probably derived from MICA*010. Of particular interest is that MICA*062 was carried on an HLA-C*08-B*48:01-DRB1*14 haplotypic segment, as HLA-B*48 has been consistently shown to be primarily linked to MICA gene deletion in east Asian populations. Our results provide new insight into MICA genetic polymorphism in human populations. The findings reported here are of importance for future studies on the potential role of MICA in allogeneic organ transplantation and disease association in populations of Chinese ancestry.

  1. The DQB1 *03:02 HLA haplotype is associated with increased risk of chronic pain after inguinal hernia surgery and lumbar disc herniation.

    PubMed

    Dominguez, Cecilia A; Kalliomäki, Maija; Gunnarsson, Ulf; Moen, Aurora; Sandblom, Gabriel; Kockum, Ingrid; Lavant, Ewa; Olsson, Tomas; Nyberg, Fred; Rygh, Lars Jørgen; Røe, Cecilie; Gjerstad, Johannes; Gordh, Torsten; Piehl, Fredrik

    2013-03-01

    Neuropathic pain conditions are common after nerve injuries and are suggested to be regulated in part by genetic factors. We have previously demonstrated a strong genetic influence of the rat major histocompatibility complex on development of neuropathic pain behavior after peripheral nerve injury. In order to study if the corresponding human leukocyte antigen complex (HLA) also influences susceptibility to pain, we performed an association study in patients that had undergone surgery for inguinal hernia (n=189). One group had developed a chronic pain state following the surgical procedure, while the control group had undergone the same type of operation, without any persistent pain. HLA DRB1genotyping revealed a significantly increased proportion of patients in the pain group carrying DRB1*04 compared to patients in the pain-free group. Additional typing of the DQB1 gene further strengthened the association; carriers of the DQB1*03:02 allele together with DRB1*04 displayed an increased risk of postsurgery pain with an odds risk of 3.16 (1.61-6.22) compared to noncarriers. This finding was subsequently replicated in the clinical material of patients with lumbar disc herniation (n=258), where carriers of the DQB1*03:02 allele displayed a slower recovery and increased pain. In conclusion, we here for the first time demonstrate that there is an HLA-dependent risk of developing pain after surgery or lumbar disc herniation; mediated by the DRB1*04 - DQB1*03:02 haplotype. Further experimental and clinical studies are needed to fine-map the HLA effect and to address underlying mechanisms.

  2. Autoimmune vitiligo is associated with gain-of-function by a transcriptional regulator that elevates expression of HLA-A*02:01 in vivo.

    PubMed

    Hayashi, Masahiro; Jin, Ying; Yorgov, Daniel; Santorico, Stephanie A; Hagman, James; Ferrara, Tracey M; Jones, Kenneth L; Cavalli, Giulio; Dinarello, Charles A; Spritz, Richard A

    2016-02-02

    HLA-A is a class I major histocompatibility complex receptor that presents peptide antigens on the surface of most cells. Vitiligo, an autoimmune disease in which skin melanocytes are destroyed by cognate T cells, is associated with variation in the HLA-A gene; specifically HLA-A*02:01, which presents multiple vitiligo melanocyte autoantigens. Refined genetic mapping localizes vitiligo risk in the HLA-A region to an SNP haplotype ∼20-kb downstream, spanning an ENCODE element with many characteristics of a transcriptional enhancer. Convergent CTCF insulator sites flanking the HLA-A gene promoter and the predicted transcriptional regulator, with apparent interaction between these sites, suggests this element regulates the HLA-A promoter. Peripheral blood mononuclear cells from healthy subjects homozygous for the high-risk haplotype expressed 39% more HLA-A RNA than cells from subjects carrying nonhigh-risk haplotypes (P = 0.0048). Similarly, RNAseq analysis of 1,000 Genomes Project data showed more HLA-A mRNA expressed in subjects homozygous for the high-risk allele of lead SNP rs60131261 than subjects homozygous for the low-risk allele (P = 0.006). Reporter plasmid transfection and genomic run-on sequence analyses confirm that the HLA-A transcriptional regulator contains multiple bidirectional promoters, with greatest activity on the high-risk haplotype, although it does not behave as a classic enhancer. Vitiligo risk associated with the MHC class I region thus derives from combined quantitative and qualitative phenomena: a SNP haplotype in a transcriptional regulator that induces gain-of-function, elevating expression of HLA-A RNA in vivo, in strong linkage disequilibrium with an HLA-A allele that confers *02:01 specificity.

  3. Molecular Variation at the HLA-A, B, C, DRB1, DQA1, and DQB1 Loci in Full Heritage American Indians in Arizona: Private Haplotypes and Their Evolution

    PubMed Central

    Williams, Robert; Chen, Yao-Fong; Endres, Robert; Middleton, Derek; Trucco, Massimo; Knowler, William

    2009-01-01

    A sample of 492 full heritage, unrelated residents of the Gila River Indian Community (GRIC) of Arizona were characterized for their high resolution DNA alleles at the HLA-A, B, C, DRB1, DQA1, and DQB1 loci. Only 5 allelic categories are found at HLA-A, 10 at HLA-B, 8 at HLA-C and HLA-DR, and 4 at DQA1 and DQB1. There is little evidence for population structure at the 6 loci. Two “private” alleles, B*5102 and B*4005, that are found nearly exclusively in American Indian populations in the desert southwest and northern Mexico, are likely new mutations after the first inhabitation of the area, the evolution of which are reflected in the contemporary distribution of their respective haplotypes. DRB1*1402 has the highest reported frequency of any specificity at the DRB1 locus, 0.7461, and serves as a sensitive probe for locating related east Asian populations. The haplotypes in this population also exhibit a highly restricted distribution and strong genetic disequilibria, which has important implications for matching solid organ and bone marrow allografts. It is shown that, when one considers HLA-A-B-DRB1 homozygotes as allograft donors for all full heritage members of the GRIC, 50% of the community would find a non-mismatched organ within the homozygotes for the 6 most common haplotypes. This raises questions about transplantation policy and whether, in the presence of high frequency private alleles and a restricted number of haplotypes, the full heritage American Indian community of the desert southwest should act as its own pool of donors for its affected members. PMID:19845915

  4. No difference in the parental origin of susceptibility HLA class II haplotypes among Norwegian patients with insulin-dependent diabetes mellitus

    SciTech Connect

    Undlien, D.E.; Akselsen, H.E.; Thorsby, E.

    1995-12-01

    Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease affecting genetically susceptible individuals. A major part of the genetic risk is encoded by HLA class II genes. Strong susceptibility is conferred by the DRB1*04-DQA1*03-DQB1*0302 (hereafter called {open_quotes}DR4-DQ8{close_quotes}) and the DRBI*0301-DQA1*0501-DQB1*0201 (hereafter called {open_quotes}DR3-DQ2{close_quotes}) haplotypes, particularly when they occur together. In an interesting publication it suggests that IDDM patients inherit DR4 from their fathers and DR3 from their mothers more often than vice versa. This has also been suggested elsewhere. Several different mechanisms have been proposed to explain this observation, such as parental imprinting, fetal loss, and maternal effect associated with the presence of the DR3 antigen in the mother. Several studies have shown that children of fathers with IDDM have a higher risk of IDDM than do children of mothers with IDDM. If there is an effect of the parental origin of HLA class II-encoded IDDM susceptibility, this could potentially explain the difference. 19 refs., 2 tabs.

  5. Allorecognition of HLA-C Mismatches by CD8+ T Cells in Hematopoietic Stem Cell Transplantation Is a Complex Interplay between Mismatched Peptide-Binding Region Residues, HLA-C Expression, and HLA-DPB1 Disparities

    PubMed Central

    Bettens, Florence; Buhler, Stéphane; Tiercy, Jean-Marie

    2016-01-01

    occurring together with HLA-DPB1 incompatibilities, should be considered as high-risk MMs in unrelated HSCT. PMID:28018351

  6. Association of HLA-A and Non-Classical HLA Class I Alleles

    PubMed Central

    Carlini, Federico; Ferreira, Virginia; Buhler, Stéphane; Tous, Audrey; Eliaou, Jean-François; René, Céline; Chiaroni, Jacques; Picard, Christophe; Di Cristofaro, Julie

    2016-01-01

    The HLA-A locus is surrounded by HLA class Ib genes: HLA-E, HLA-H, HLA-G and HLA-F. HLA class Ib molecules are involved in immuno-modulation with a central role for HLA-G and HLA-E, an emerging role for HLA-F and a yet unknown function for HLA-H. Thus, the principal objective of this study was to describe the main allelic associations between HLA-A and HLA-H, -G, -F and -E. Therefore, HLA-A, -E, -G, -H and -F coding polymorphisms, as well as HLA-G UnTranslated Region haplotypes (referred to as HLA-G UTRs), were explored in 191 voluntary blood donors. Allelic frequencies, Global Linkage Disequilibrium (GLD), Linkage Disequilibrium (LD) for specific pairs of alleles and two-loci haplotype frequencies were estimated. We showed that HLA-A, HLA-H, HLA-F, HLA-G and HLA-G UTRs were all in highly significant pairwise GLD, in contrast to HLA-E. Moreover, HLA-A displayed restricted associations with HLA-G UTR and HLA-H. We also confirmed several associations that were previously found to have a negative impact on transplantation outcome. In summary, our results suggest complex functional and clinical implications of the HLA-A genetic region. PMID:27701438

  7. Recipient HLA-C Haplotypes and microRNA 148a/b Binding Sites Have No Impact on Allogeneic Hematopoietic Cell Transplantation Outcomes.

    PubMed

    Hoff, Gretchen A; Fischer, Johannes C; Hsu, Katharine; Cooley, Sarah; Miller, Jeffrey S; Wang, Tao; Haagenson, Michael; Spellman, Stephen; Lee, Stephanie J; Uhrberg, Markus; Venstrom, Jeffrey M; Verneris, Michael R

    2017-01-01

    Natural killer cells are important in graft-versus-leukemia responses after hematopoietic cell transplantation (HCT). A variety of surface receptors dictates natural killer cell function, including killer cell immunoglobulin-like receptor recognition of HLA-C. Previous single-center studies show that HLA-C epitopes, designated C1 and C2, were associated with allogeneic HCT outcomes; specifically, recipients homozygous for the C1 epitope (C1/C1) experienced a survival benefit. Additionally, mismatching at HLA-C was beneficial in recipients possessing at least 1 C2 allele, whereas the opposite was true for homozygous C1 (C1/C1) recipients where HLA-C mismatching resulted in worse outcomes. In this analysis we aimed to validate these findings in a large multicenter study. We also set out to determine whether surface expression of recipient HLA-C, determined by polymorphism in a microRNA (miR-148a/b) binding site within the 3'-region of the HLA-C transcript, was associated with transplant outcomes. In this large registry cohort, we were unable to confirm the prior findings regarding recipient HLA-C epitope status and outcome. Additionally, HLA-C surface expression (ie, surface density), as predicted by the miR-148a/b binding single nucleotide polymorphism, was also not with associated transplant outcomes. Collectively, neither HLA-C surface expression, as determined by miR-148a/b, nor recipient HLA-C epitopes (C1, C2) are associated with allogeneic HCT outcomes.

  8. Dengue fever virus and Japanese encephalitis virus synthetic peptides, with motifs to fit HLA class I haplotypes prevalent in human populations in endemic regions, can be used for application to skin Langerhans cells to prime antiviral CD8+ cytotoxic T cells (CTLs)--a novel approach to the protection of humans.

    PubMed

    Becker, Y

    1994-09-01

    Flaviviruses were reported to induce CD8+ cytotoxic T cells in infected individuals, indicating that nonapeptides, proteolytic cleavage products of the viral precursor protein, enter the endoplasmic reticulum in infected cells and interact with HLA class I molecules. The assembled HLA class I molecules are transported to the plasma membrane and prime CD8+ T cells. Current knowledge of the interaction of viral peptides with HLA molecules is reviewed. Based on this review, an idea is presented to use synthetic flavivirus peptides with an amino acid motif to fit with the HLA class I peptide binding group of HLA haplotypes prevalent in a given population in an endemic area. These synthetic viral peptides may be introduced into the human skin using a lotion containing the peptides ("Peplotion") together with substances capable of enhancing the penetration of these peptides into the skin to reach Langerhans cells. The peptide-treated Langerhans cells, professional antigen-presenting cells, may bind the synthetic viral peptides by their HLA class I peptide-binding grooves. Antigens carrying Langerhans cells are able to migrate and induce the cellular immune response in the lymph nodes. This approach to the priming of antiviral CD8+ cytotoxic T cells may provide cellular immune protection from flavivirus infection without inducing the humoral immune response, which can lead to the shock syndrome in Dengue fever patients. To be able to develop anti-Dengue virus synthetic peptides for populations with different HLA class I haplotypes, it is necessary to develop computational studies to design HLA class I Dengue virus synthetic peptides with motifs to fit the HLA haplotypes of the population living in an endemic region for Dengue fever. Experiments to study Dengue virus and Japanese encephalitis peptides vaccines and their effectiveness in protection against Dengue fever and Japanese encephalitis are needed. The development of human antiviral vaccines for application of viral

  9. Long-term follow-up of HLA-A2+ patients with high-risk, hormone-sensitive prostate cancer vaccinated with the prostate specific antigen peptide homologue (PSA146-154).

    PubMed

    Perambakam, Supriya; Xie, Hui; Edassery, Seby; Peace, David J

    2010-01-01

    Twenty-eight HLA-A2+ patients with high-risk, locally advanced or metastatic, hormone-sensitive prostate cancer were immunized with a peptide homologue of prostate-specific antigen, PSA146-154, between July 2002 and September 2004 and monitored for clinical and immune responses. Fifty percent of the patients developed strong PSA146-154-peptide-specific delayed-type hypersensitivity skin responses, tetramer and/or IFN-γ responses within one year. Thirteen patients had stable or declining serum levels of PSA one year post-vaccination. A decreased risk of biochemical progression was observed in patients who developed augmented tetramer responses at six months compared to pre-vaccination levels (P = .02). Thirteen patients have died while 15 patients remain alive with a mean overall survival of 60 months (95% CI, 51 to 68 months) per Kaplan-Meier analysis. A trend towards greater overall survival was detected in men with high-risk, hormone-sensitive CaP who developed specific T-cell immunity following vaccination with PSA146-154 peptide.

  10. Long-Term Follow-Up of HLA-A2+ Patients with High-Risk, Hormone-Sensitive Prostate Cancer Vaccinated with the Prostate Specific Antigen Peptide Homologue (PSA146-154)

    PubMed Central

    Perambakam, Supriya; Xie, Hui; Edassery, Seby; Peace, David J.

    2010-01-01

    Twenty-eight HLA-A2+ patients with high-risk, locally advanced or metastatic, hormone-sensitive prostate cancer were immunized with a peptide homologue of prostate-specific antigen, PSA146-154, between July 2002 and September 2004 and monitored for clinical and immune responses. Fifty percent of the patients developed strong PSA146-154-peptide-specific delayed-type hypersensitivity skin responses, tetramer and/or IFN-γ responses within one year. Thirteen patients had stable or declining serum levels of PSA one year post-vaccination. A decreased risk of biochemical progression was observed in patients who developed augmented tetramer responses at six months compared to pre-vaccination levels (P = .02). Thirteen patients have died while 15 patients remain alive with a mean overall survival of 60 months (95% CI, 51 to 68 months) per Kaplan-Meier analysis. A trend towards greater overall survival was detected in men with high-risk, hormone-sensitive CaP who developed specific T-cell immunity following vaccination with PSA146-154 peptide. PMID:21253471

  11. Extended major histocompatibility complex haplotypes in type I diabetes mellitus.

    PubMed Central

    Raum, D; Awdeh, Z; Yunis, E J; Alper, C A; Gabbay, K H

    1984-01-01

    We have studied major histocompatibility complex markers in Caucasian patients with type I diabetes mellitus and their families. The frequencies of extended haplotypes that were composed of specific HLA-B, HLA-DR, BF, C2, C4A, and C4B allelic combinations, which occurred more commonly than expected, were compared on random diabetic and normal chromosomes in the study families. We demonstrated that all of the previously recognized increases in HLA-B8, B18, B15, DR3, and perhaps DR4 could be ascribed to the increase among diabetic haplotypes of a few extended haplotypes: [HLA B8, DR3, SC01, GLO2]; [HLA-B18, DR3, F1C30]; [HLA-B15, DR4, SC33]; and [HLA-BW38, DR4, SC21]. In fact, HLA-DR3 on nonextended haplotypes was "protective", with a relative risk considerably less than 1.0. There was a paucity or absence among diabetic patients of several extended haplotypes of normal chromosomes, notably [HLA-B7, DR2, SC31] and [HLA-BW44, DR4, SC30]. The extended haplotype [HLA-BW38, DR4, SC21] is found only in Ashkenazi Jewish patients, which suggests that extended haplotypes mark specific mutations that arise in defined ethnic groups. The data show that no known MHC allele, including HLA-DR3 and possibly HLA-DR4, is per se a marker for or itself a susceptibility gene for type I diabetes. Rather, extended haplotypes, with relatively fixed alleles, are either carriers or noncarriers of susceptibility genes for this disease. Thus, the increased frequency (association) or the decreased frequency (protection) of individual MHC alleles is largely explainable by these extended haplotypes. PMID:6746903

  12. Haplotyping algorithms

    SciTech Connect

    Sobel, E.; Lange, K.; O`Connell, J.R.

    1996-12-31

    Haplotyping is the logical process of inferring gene flow in a pedigree based on phenotyping results at a small number of genetic loci. This paper formalizes the haplotyping problem and suggests four algorithms for haplotype reconstruction. These algorithms range from exhaustive enumeration of all haplotype vectors to combinatorial optimization by simulated annealing. Application of the algorithms to published genetic analyses shows that manual haplotyping is often erroneous. Haplotyping is employed in screening pedigrees for phenotyping errors and in positional cloning of disease genes from conserved haplotypes in population isolates. 26 refs., 6 figs., 3 tabs.

  13. Uncommon HLA alleles identified by hemizygous ultra-high Sanger sequencing: haplotype associations and reconsideration of their assignment in the Common and Well-Documented catalogue.

    PubMed

    Voorter, Christina E M; Groeneweg, Mathijs; Groeneveld, Lisette; Tilanus, Marcel G J

    2016-02-01

    Although the number of HLA alleles still increases, many of them have been reported being uncommon. This is partly due to lack of full length gene sequencing, especially for those alleles belonging to an allele ambiguity in which the first discovered allele has been assigned as the most frequent one. As members of the working group on Common and Well Documented (CWD) alleles and since we implemented full length group-specific sequencing as standard method routinely, we have investigated the presence of presumably rare alleles in our collection of HLA typing data. We identified 50 alleles, that were not previously encountered as Common or Well Documented. Sixteen of them should be added to the CWD catalogue, since we encountered them in 5 or more unrelated individuals. Another 11 could be added, based upon our results and the data present in the IMGT database and the rare allele section of the allele frequencies database. Furthermore, tight associations were observed between several different alleles even at the level of synonymous and non-coding sequences. In addition, in several cases the uncommon allele was found to be more frequent than its common counterpart.

  14. Standardized genotyping of HLA STR by CE as surrogate for HLA class I and II markers and for identification of HLA identical siblings.

    PubMed

    Dauber, Eva-Maria; Wenda, Sabine; Schwartz-Jungl, Elisabeth-Maria; Glock, Barbara; Mayr, Wolfgang R

    2016-03-01

    Linkage disequilibria (LD) between alleles and haplotypes of human leucocyte antigen, locus A (HLA) and STR loci located in the human major histocompatibility complex were analyzed in order to investigate whether or not HLA alleles and haplotypes are predictable by alleles or haplotypes of HLA STRs. Standardized genotyping of eight STR loci (D6S2972, D6S2906, D6S2691, D6S2678, D6S2792, D6S2789, D6S273, and DQIV) was performed by CE on 600 individuals from 150 Austrian Caucasoid families with known HLA-A,-B,-C and -DRB1 typing. From those, 576 full haplotypes of four HLA and eight STR loci were obtained. Haplotypes of two flanking STRs predicted HLA alleles and two-locus HLA haplotypes better than single STR alleles, except HLA-DRB1 alleles (92% were in LD with DQIV alleles only). A percentage of 65-86% of three and four-locus HLA haplotypes were in LD with haplotypes of three, four, and eight of their flanking STR loci including numerous clear-cut predictions (20-61%). All eight and a set of the four most informative STR loci D6S2972, D6S2678, D6S2792, and DQIV could identify all HLA identical and nonidentical siblings in 138 pairs of siblings. The results of this proof of concept study in Austrian Caucasoids show, that HLA STRs can aid the definition of HLA-A,-B,-C,-DRB1 haplotypes and the selection of sibling donors for stem cell transplantation.

  15. HLA Immune Function Genes in Autism

    PubMed Central

    Torres, Anthony R.; Westover, Jonna B.; Rosenspire, Allen J.

    2012-01-01

    The human leukocyte antigen (HLA) genes on chromosome 6 are instrumental in many innate and adaptive immune responses. The HLA genes/haplotypes can also be involved in immune dysfunction and autoimmune diseases. It is now becoming apparent that many of the non-antigen-presenting HLA genes make significant contributions to autoimmune diseases. Interestingly, it has been reported that autism subjects often have associations with HLA genes/haplotypes, suggesting an underlying dysregulation of the immune system mediated by HLA genes. Genetic studies have only succeeded in identifying autism-causing genes in a small number of subjects suggesting that the genome has not been adequately interrogated. Close examination of the HLA region in autism has been relatively ignored, largely due to extraordinary genetic complexity. It is our proposition that genetic polymorphisms in the HLA region, especially in the non-antigen-presenting regions, may be important in the etiology of autism in certain subjects. PMID:22928105

  16. HLA-DQ primarily confers protection and HLA-DR susceptibility in type I (Insulin-dependent) diabetes studied in population-based affected families and controls

    SciTech Connect

    Kockum, I. Univ. of Lund Karolinska Institute, Karolinska Hospital, Stockholm ); Wassmuth, R. ); Holmberg, E. ); Michelsen, B. ); Lernmark, A. Karolinska Institute, Karolinska Hospital, Stockholm )

    1993-07-01

    The association between HLA-DR and -DQ and insulin-dependent diabetes mellitus (IDDM) in a defined high-incidence area was analyzed in a total of 58 population-based patients, representing 77% of IDDM patients with age at onset below 16 years, and in 92 unrelated parents in control families without IDDM. HLA haplotypes were confirmed by analyzing first-degree relatives in both groups. Seven different methods were used to analyze risk: (1) odds ratio, (2) absolute risk, (3) haplotype relative risk, (4) transcomplementation relative risk, (5) relative predisposing effects, (6) stratification analysis, and (7) test of predisposing allele on haplotype. DQB1*0302 indicated somewhat higher risk than did DR4, while DR3 had a higher risk than DQB1*0201; however, the 95% confidence intervals of the risk estimates overlapped. The positive association between IDDM and the DQB1*0201-DQA1*0501-DR3 haplotype seems to be due to DR3 or to an unknown linked gene. More important, DQA1*0301 was present among 93% of the patients, and this allele in various transcomplementation combinations with DQBL alleles showed closer association to IDDM than did any other alleles. The strong negative association of the DQB1*0602 allele also in the presence of either DR4 or DQBI*0302 or both suggests that, in a high-risk population for IDDM, HLA-DQ primarily confers protection, perhaps by induction of tolerance. Consistent with known functions, HLA-DR may primarily confer susceptibility, perhaps by induction of autoreactive T lymphocytes. 67 refs., 3 figs., 9 tabs.

  17. Comparison of MHC Class I Risk Haplotypes in Thai and Caucasian Psoriatics Reveals Locus Heterogeneity at PSORS1

    PubMed Central

    Stuart, Philip E.; Nair, Rajan P.; Hiremagalore, Ravi; Kullavanijaya, Preya; Kullavanijaya, Prisana; Tejasvi, Trilokraj; Lim, Henry W.; Voorhees, John J.; Elder, James T.

    2010-01-01

    Earlier studies have shown that psoriasis in Japan and Thailand is associated with two different MHC haplotypes—those bearing HLA-Cw6 and those bearing HLA-Cw1 and HLA-B46. In an independent case-control sample from Thailand, we confirmed association of psoriasis with both haplotypes. No association was seen in Thai HLA-Cw1 haplotypes lacking HLA-B46, nor was HLA-Cw1 associated with psoriasis in a large Caucasian sample. To assess whether these risk haplotypes share a common origin, we sequenced genomic DNA from a Thai HLA-Cw1-B46 homozygote across the ~300 kb MHC risk interval, and compared it to sequence of a HLA-Cw6-B57 risk haplotype. Three small regions of homology were found, but these regions share equivalent sequence similarity with one or more clearly non-risk haplotypes, and they contain no polymorphism alleles unique to all risk haplotypes. Differences in psoriasis phenotype were also observed, including lower risk of disease, greater nail involvement, and later age at onset in HLA-Cw1-B46 carriers compared to HLA-Cw6 carriers. These findings suggest locus heterogeneity at PSORS1, the major psoriasis susceptibility locus in the MHC, with HLA-Cw6 imparting risk in both Caucasians and Asians, and an allele other than HLA-Cw1 on the HLA-Cw1-B46 haplotype acting as an additional risk variant in East Asians. PMID:20604894

  18. Polymorphisms of HLA genes in Western Javanese (Indonesia): close affinities to Southeast Asian populations.

    PubMed

    Yuliwulandari, R; Kashiwase, K; Nakajima, H; Uddin, J; Susmiarsih, T P; Sofro, A S M; Tokunaga, K

    2009-01-01

    Identification of human leukocyte antigen (HLA) antigens that are known as the highest polymorphic genes has become a valuable tool for tissue transplantation, platelet transfusion, disease susceptibility or resistance, and forensic and anthropological studies. In the present study, the allele and haplotype frequencies of HLA-A, HLA-B, and HLA-DRB1 were studied in 237 unrelated healthy Western Javanese (Indonesia) by the high-resolution polymerase chain reaction-Luminex method. A total of 18 A, 40 B, and 20 DRB1 alleles were identified. The most frequent HLA-A, -B, and -DRB1 alleles were HLA-A*2407 (21.6%), HLA-B*1502 (11.6%) and HLA-B*1513 (11.2%), and DRB1*1202 (37.8%), respectively. The most frequent two-locus haplotypes were HLA-A*2407-B*3505 (7%) and HLA-B*1513-DRB1*1202 (9.2%), and three-locus haplotypes were HLA-A*3401-B*1521-DRB1*150201 (4.6%), HLA-A*2407-B*3505-DRB1*1202 (4.3%), and HLA-A*330301-B*440302-DRB1*070101 (4.2%). HLA allele and haplotype frequencies in addition to phylogenetic tree and principal component analyses based on the four-digit sequence-level allele frequencies for HLA-A, HLA-B, and HLA-DRB1 showed that Western Javanese (Indonesia) was closest to Southeast Asian populations.

  19. Three new HLA-G alleles and their linkage disequilibria with HLA-A.

    PubMed

    Morales, P; Corell, A; Martínez-Laso, J; Martín-Villa, J M; Varela, P; Paz-Artal, E; Allende, L M; Arnaiz-Villena, A

    1993-01-01

    Three new allelic forms of the HLA-G DNA sequence (HLA-G*II, HLA-G*III, and HLA-G*IV) have been identified. With the HLA-G*I sequence (previously designated HLA 6.0) as a reference, HLA-G*II shows a silent (G-->A) mutation at the third base of codon 57, HLA-G*III bears a non-synonymous (A-->T), but conservative, (Thr-->Ser) substitution at the first base of codon 31, and HLA-G*IV shows two silent substitutions: (A-->T) at the third base of codon 107 and (G-->A) at the third base of codon 57. A rapid method of singling out each allele on genomic DNA has been developed by using polymerase chain reaction amplification followed by restriction endonuclease treatment. Also, more or less strong linkage disequilibria has been found between most HLA-A alleles and either HLA-G*I or *II, both being the most prevalent alleles in the population, with a genotypic frequency of 0.55 and 0.38, respectively; HLA-G*III is very rare and HLA-G*IV has a genotypic frequency of 0.07. An evolutive classification of HLA-A alleles results according to their association with either HLA-G*I or HLA-G*II, which does not correlate with the classical serological cross-reacting groups classification. The finding of a strong and selective A/G linkage disequilibria with most HLA-A alleles, together with the existence of less frequent random A/G associations, may suggest that there exist in different haplotypes true and varied A/G genetic distances (and not a recombinational hotspot). It may be inferred from preliminary data that in primates HLA-A/G haplotypes bearing G*II may have appeared later than those bearing G*I.

  20. HLA Haplotype Mismatch Transplants and Posttransplant Cyclophosphamide.

    PubMed

    Bacigalupo, Andrea; Sica, Simona

    2016-01-01

    The use of high dose posttransplant cyclophosphamide (PT-CY) introduced by the Baltimore group approximately 10 years ago has been rapidly adopted worldwide and is becoming a standard for patients undergoing unmanipulated haploidentical (HAPLO) transplants. PT-CY has been used following nonmyeloablative as well as myeloablative conditioning regimens, for bone marrow or peripheral blood grafts, for patients with malignant and nonmalignant disorders. Retrospective comparisons of HAPLO grafts with conventional sibling and unrelated donor grafts have been published and suggest comparable outcome. The current questions to be answered include the use of PT-CY for sibling and unrelated donors transplant, possibly in the context of prospective randomized trial.

  1. HLA Haplotype Mismatch Transplants and Posttransplant Cyclophosphamide

    PubMed Central

    Bacigalupo, Andrea; Sica, Simona

    2016-01-01

    The use of high dose posttransplant cyclophosphamide (PT-CY) introduced by the Baltimore group approximately 10 years ago has been rapidly adopted worldwide and is becoming a standard for patients undergoing unmanipulated haploidentical (HAPLO) transplants. PT-CY has been used following nonmyeloablative as well as myeloablative conditioning regimens, for bone marrow or peripheral blood grafts, for patients with malignant and nonmalignant disorders. Retrospective comparisons of HAPLO grafts with conventional sibling and unrelated donor grafts have been published and suggest comparable outcome. The current questions to be answered include the use of PT-CY for sibling and unrelated donors transplant, possibly in the context of prospective randomized trial. PMID:27143973

  2. HLA-A, HLA-B, and HLA-DRB1 allele distribution in a large Armenian population sample.

    PubMed

    Matevosyan, L; Chattopadhyay, S; Madelian, V; Avagyan, S; Nazaretyan, M; Hyussian, A; Vardapetyan, E; Arutunyan, R; Jordan, F

    2011-07-01

    Human leukocyte antigen (HLA)-A, HLA-B, and HLA-DRB1 gene frequencies were investigated in 4279 unrelated Armenian bone marrow donors. HLA alleles were defined by using PCR amplification with sequence specific primers (PCR-SSP) high- and low-resolution kits. The aim of this study was to examine the HLA diversity at the high-resolution level in a large Armenian population sample, and to compare HLA allele group distribution in Armenian subpopulations. The most frequently observed alleles in the HLA class I were HLA-A*0201, A*0101, A*2402, A*0301, HLA-B*5101, HLA-B*3501, and B*4901. Among DRB1 alleles, high frequencies of DRB1*1104 and DRB1*1501 were observed, followed by DRB1*1101 and DRB1*1401. The most common three-locus haplotype found in the Armenian population was A*33-B*14-DRB1*01, followed by A*03-B*35-DRB1*01. Our results show a similar distribution of alleles in Armenian subpopulations from different countries, and from different regions of the Republics of Armenia and Karabagh. The low level of genetic distances between subpopulations indicates a high level of population homogeneity, and the genetic distances between Armenians and other populations show Armenians as a distinct ethnic group relative to others, reflecting the fact that Armenians have been an 'isolated population' throughout centuries. This study is the first comprehensive investigation of HLA-allele group distribution in a subset of Armenian populations, and the first to provide HLA-allele and haplotype frequencies at a high-resolution level. It is a valuable reference for organ transplantation and for future studies of HLA-associated diseases in Armenian populations.

  3. Hematopoietic stem cell transplantation from alternative sources in adults with high-risk acute leukemia.

    PubMed

    Aversa, Franco; Reisner, Yair; Martelli, Massimo F

    2004-01-01

    Since 75% of patients with high-risk acute leukemia do not have a human leukocyte antigen (HLA)-identical sibling, alternative sources for hematopoietic stem cell transplantation (HSCT) are matched unrelated donors (MUD), unrelated umbilical cord blood (UD-UCB) and one HLA haplotype mismatched family members (haploidentical). The chance of finding a suitable donor in the international voluntary donor registries is limited by frequency of the HLA phenotype and the time required to identify the right donor from a potential panel, to establish eligibility and to harvest the cells. In adult MUD recipients, event-free survival ranges up to 50% and refers only to patients who undergo transplant, without taking into account those who do not find a donor. Umbilical cord blood offers the advantages of easy procurement, the absence of risks to donors, the reduced risk of transmitting infections, immediate availability of cryopreserved samples and acceptance of mismatches at two of the six antigens. Although UD-UCB transplantation is a viable option for children, it is seldom considered for adults. The great divergency between body weight and the number of hematopoietic cells in a standard cord blood unit, particularly if associated with a two-antigen mismatch, increases the risk of graft failure and delays hematopoietic reconstitution. Work on full-haplotype mismatched transplants has been proceeding for over 20 years. Originally, outcome in leukemia patients was disappointing because of high incidence of severe graft-vs.-host disease in T-replete transplants and high rejection rates in T-cell-depleted transplants. The breakthrough came with the use of a megadose of T-cell-depleted progenitor cells after a high-intensity conditioning regimen. Treating end-stage patients inevitably confounded clinical outcome in the early pilot studies. Today, high-risk acute leukemia patients are treated at less advanced stages of disease, receive a reasonably well tolerated conditioning

  4. HLA class I-mediated control of HIV-1 in the Japanese population, in which the protective HLA-B*57 and HLA-B*27 alleles are absent.

    PubMed

    Naruto, Takuya; Gatanaga, Hiroyuki; Nelson, George; Sakai, Keiko; Carrington, Mary; Oka, Shinichi; Takiguchi, Masafumi

    2012-10-01

    We investigated the effect of HLA class I alleles on clinical parameters for HIV-1 disease progression in the Japanese population, where two strongly protective alleles, HLA-B*57 and HLA-B*27, are virtually nonexistent. HLA-B alleles showed a dominant role, primarily through HLA-B*67:01 and the HLA-B*52:01-C*12:02 haplotype. Neither a rare-allele nor a heterozygote advantage was found, suggesting that the effect of HLA alleles in the Japanese population is either different from those observed in Africans and Caucasians or undetectable due to limited power.

  5. Human leukocyte antigen haplotype phasing by allele-specific enrichment with peptide nucleic acid probes

    PubMed Central

    Murphy, Nicholas M; Pouton, Colin W; Irving, Helen R

    2014-01-01

    Targeted capture of large fragments of genomic DNA that enrich for human leukocyte antigen (HLA) system haplotypes has utility in haematopoietic stem cell transplantation. Current methods of HLA matching are based on inference or familial studies of inheritance; and each approach has its own inherent limitations. We have designed and tested a probe–target-extraction method for capturing specific HLA haplotypes by hybridization of peptide nucleic acid (PNA) probes to alleles of the HLA-DRB1 gene. Short target fragments contained in plasmids were initially used to optimize the method followed by testing samples of genomic DNA from human subjects with preselected HLA haplotypes and obtained approximately 10% enrichment for the specific haplotype. When performed with high-molecular-weight genomic DNA, 99.0% versus 84.0% alignment match was obtained for the specific haplotype probed. The allele-specific target enrichment that we obtained can facilitate the elucidation of haplotypes between the 65 kb separating the HLA-DRB1 and the HLA-DQA1 genes, potentially spanning a total distance of at least 130 kb. Allele-specific target enrichment with PNA probes is a straightforward technique that has the capability to improve the resolution of DNA and whole genome sequencing technologies by allowing haplotyping of enriched DNA and crucially, retaining the DNA methylation profile. PMID:24936514

  6. Extended major histocompatibility complex haplotypes in patients with gluten-sensitive enteropathy.

    PubMed Central

    Alper, C A; Fleischnick, E; Awdeh, Z; Katz, A J; Yunis, E J

    1987-01-01

    We have studied major histocompatibility complex markers in randomly ascertained Caucasian patients with gluten-sensitive enteropathy and their families. The frequencies of extended haplotypes, defined as haplotypes of specific HLA-B, DR, BF, C2, C4A, and C4B allelic combinations, occurring more frequently than expected, were compared on patient chromosomes, on normal chromosomes from the study families, and on chromosomes from normal families. Over half of patient chromosomes consisted almost entirely of two extended haplotypes [HLA-B8, DR3, SC01] and [HLA-B44, DR7, FC31] which, with nonextended HLA-DR7, accounted for the previously observed HLA markers of this disease: HLA-B8, DR3, and DR7. There was no increase in HLA-DR3 on nonextended haplotypes or in other extended haplotypes with HLA-DR3 or DR7. The distribution of homozygotes and heterozygotes for HLA-DR3 and DR7 was consistent with recessive inheritance of the major histocompatibility complex-linked susceptibility gene for gluten-sensitive enteropathy. On the other hand, by odds ratio analysis and from the sum of DR3 and DR7 homozygotes compared with DR3/DR7 heterozygotes, there was an increase in heterozygotes and a decrease in homozygotes suggesting the presence of modifying phenomena. PMID:3793924

  7. Full-length cDNA nucleotide sequence of a serologically undetectable HLA-DQA1 allele: HLA-DQA1*"LA".

    PubMed

    Lardy, N M; Otting, N; van der Horst, A R; Bontrop, R E; de Waal, L P

    1997-10-01

    This study describes the characterization of a serological HLA-DQ"blank" specificity that segregates with the HLA-A2, -B7, -DR14, -DR52 haplotype. Although conventional serological typing techniques could not detect an HLA-DQ product on the haplotype positive for the HLA-DQ"blank" specificity, sequence-specific oligonucleotide (SSO) dot-blot analysis demonstrated the presence of the HLA-DQA1*01 and HLA-DQB1*05 alleles. Full-length cDNA nucleotide sequence analysis revealed that the HLA-DQB1 allele that segregated with the HLA-DQ"blank" specificity was identical to HLA-DQB1*05031. As for the HLA DQA1 allele, one nucleotide substitution distinguished the HLA-DQA1 "blank" allele from HLA-DQA1*0104. In exon 2 at nucleotide position 304 a C was substituted for a T (Arg-->Cys). Pending official recognition by the WHO Nomenclature Committee, this HLA-DQA1 "blank" allele is termed HLA-DQA1*"LA". Furthermore, it is postulated that the introduction of cysteine at amino acid position 102 abrogates the classical HLA-DQ1 specificity.

  8. Association of Polymorphisms in HLA Antigen Presentation-Related Genes with the Outcomes of HCV Infection

    PubMed Central

    Lu, Xiaomei; Xu, Yin; Wang, Jie; Zhang, Yun; Yu, Rongbin; Su, Jing

    2015-01-01

    Antigen-presentation genes play a vital role in the pathogenesis of HCV infection. However, the relationship of variants of these genes with spontaneous outcomes of HCV infection has not been fully investigated. To explore novel loci in the Chinese population, 34 tagging-SNPs in 9 candidate genes were genotyped for their associations with the outcomes of HCV infection. The distributions of different genotypes and haplotypes were compared among 773 HCV-negative controls, 246 subjects with HCV natural clearance, and 218 HCV persistent carriers recruited from hemodialysis patients and intravenous drug users. Our study implicated that TAP2, HLA-DOA, HLA-DOB, and tapasin loci were novel candidate regions for susceptibility to HCV infection and viral clearance in the Chinese population. Logistic regression analyses showed that TAP2 rs1800454 A (OR = 1.48, P = 0.002) and HLA-DOB rs2071469 G (OR = 1.23, P = 0.048) were significantly associated with increased susceptibility to establishment of HCV infection. However, high-risk behavior exposure and age were stronger predictors of HCV infection. Mutation of tapasin rs9277972 T (OR = 1.57, P =0.043) increased the risk of HCV chronicity, and HLA-DOA rs3128935 C (OR = 0.62, P = 0.019) increased the chance of viral resolution. With regards to the effect of rs3128925, interactions were found with high-risk behavior (P = 0.013) and age (P = 0.035). The risk effect of rs3128925 T for persistent HCV infection was higher in injecting drug users (vs. dialysis patients) and in subjects ≥ 40 years old (vs. < 40 years old). PMID:25874709

  9. Detecting local haplotype sharing and haplotype association

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A novel haplotype association method is presented, and its power is demonstrated. Relying on a statistical model for linkage disequilibrium (LD), the method first infers ancestral haplotypes and their loadings at each marker for each individual. The loadings are then used to quantify local haplotype...

  10. HLA-G coding region and 3'untranslated region (3'UTR) in two Chinese Han populations.

    PubMed

    Wang, Wen Yi; Tian, Wei; Liu, Xue Xiang; Li, Li Xin

    2016-08-01

    In this study, exons 2-4 and 3'untranslated region (3'UTR) of human leukocyte antigen (HLA)-G gene were investigated for 201 and 104 healthy unrelated Han samples recruited from Hunan Province, southern China and central Inner Mongolia Autonomous Region, northern China, respectively, using sequence-based typing and cloning methods. Totally 12 HLA-G alleles in the coding region, 9 variable sites in 3'UTR, 8 3'UTR haplotypes and 15 HLA-G extended haplotypes (EHs) incorporating the coding region and 3'UTR were observed. Very strong linkage disequilibrium (LD) was observed between HLA-A and HLA-G, and between HLA-G coding region and 3'UTR in each population (all global P=0.0000). Seven HLA-A-G haplotypes showed significant LD in both populations. Three HLA-G alleles in the coding region, 4 polymorphic sites in the 3'UTR, 3 3'UTR haplotypes and 4 HLA-G EHs differed significantly in their distributions between the 2 Chinese Han populations (all P≤0.0001). There was evidence for balancing selection acting on HLA-G 3'UTR positions +3010, +3142 and +3187 in the two populations. The NJ dendrograms demonstrated the existence of two basic HLA-G lineages and indicated that, HLA-G*01:01:01, the most common HLA-G allele, formed a separate lineage from other alleles. Our results shed new lights into HLA-G genetics among Chinese Han populations. The findings reported here are of importance for future studies related to post-transcriptional regulation of HLA-G allelic expression and the potential role of HLA-G in disease association in populations of Chinese ancestry.

  11. HLA Genes in Mayos Population from Northeast Mexico

    PubMed Central

    Arnaiz-Villena, A; Moscoso, J; Granados, J; Serrano-Vela, J.I; de la Peña, A.; Reguera, R; Ferri, A; Seclen, E; Izaguirre, R; Perez-Hernandez, N; Vargas-Alarcon, G

    2007-01-01

    HLA class I and class II alleles have been studied in 60 unrelated people belonging to Mayos ethnic group, which lives in the Mexican Pacific Sinaloa State. Mayos HLA profile was compared to other Amerindians and worldwide populations’ profile. A total of 14,896 chromosomes were used for comparisons. Genetic distances between populations, Neigbour-Joining dendrograms and correspondence analyses were performed to determine the genetic relationship among population. The new specific Mayo HLA haplotypes found are: HLA-A*02-B*35-DRB1*1406-DQB1*0301; HLA-A*02-B*48-DRB1*0404-DQB1*0302; HLA-A*24-B*51-DRB1*0407-DQB1*0302 and HLA-A*02-B*08-DRB1*0407-DQB1*0302. However, the typical Meso American HLADRB1*0407 represents a 40% of all DRB1 alleles. While common HLA characteristics are found in Amerindian distant ethnic groups, still new group specific HLA haplotypes are being found, suggesting that a common founder effect (i.e. high DRB1*0407) is noticed. Moreover, new HLA haplotypes are almost certainly appearing along time probably due to specific pathogen (?) selection for diversity. Mayo language is close to the Tarahumara one (another geographically close group); notwithstanding both groups are not genetically close according to our results, showing again the different evolution of genes and languages, which do not correlate. Finally, Sinaloa is one of the Mexican States in which more European genes are found. However, the results presented in this paper, where no European HLA genes are seen in Mayos, should have a bearing in establishing transplant programs and in HLA and disease studies. PMID:19412332

  12. A web resource for mining HLA associations with adverse drug reactions: HLA-ADR.

    PubMed

    Ghattaoraya, Gurpreet S; Dundar, Yenal; González-Galarza, Faviel F; Maia, Maria Helena Thomaz; Santos, Eduardo José Melo; da Silva, Andréa Luciana Soares; McCabe, Antony; Middleton, Derek; Alfirevic, Ana; Dickson, Rumona; Jones, Andrew R

    2016-01-01

    Human leukocyte antigens (HLA) are an important family of genes involved in the immune system. Their primary function is to allow the host immune system to be able to distinguish between self and non-self peptides-e.g. derived from invading pathogens. However, these genes have also been implicated in immune-mediated adverse drug reactions (ADRs), presenting a problem to patients, clinicians and pharmaceutical companies. We have previously developed the Allele Frequency Net Database (AFND) that captures the allelic and haplotype frequencies for these HLA genes across many healthy populations from around the world. Here, we report the development and release of the HLA-ADR database that captures data from publications where HLA alleles and haplotypes have been associated with ADRs (e.g. Stevens-Johnson Syndrome/toxic epidermal necrolysis and drug-induced liver injury). HLA-ADR was created by using data obtained through systematic review of the literature and semi-automated literature mining. The database also draws on data already present in AFND allowing users to compare and analyze allele frequencies in both ADR patients and healthy populations. The HLA-ADR database provides clinicians and researchers with a centralized resource from which to investigate immune-mediated ADRs.Database URL: http://www.allelefrequencies.net/hla-adr/.

  13. Computational Approaches to Facilitate Epitope-Based HLA Matching in Solid Organ Transplantation

    PubMed Central

    Wissing, Jeroen; Koppenaal, Dirk; Niemann, Matthias

    2017-01-01

    Epitope-based HLA matching has been emerged over the last few years as an improved method for HLA matching in solid organ transplantation. The epitope-based matching concept has been incorporated in both the PIRCHE-II and the HLAMatchmaker algorithm to find the most suitable donor for a recipient. For these algorithms, high-resolution HLA genotype data of both donor and recipient is required. Since high-resolution HLA genotype data is often not available, we developed a computational method which allows epitope-based HLA matching from serological split level HLA typing relying on HLA haplotype frequencies. To validate this method, we simulated a donor-recipient population for which PIRCHE-II and eplet values were calculated when using both high-resolution HLA genotype data and serological split level HLA typing. The majority of the serological split level HLA-determined ln(PIRCHE-II)/ln(eplet) values did not or only slightly deviate from the reference group of high-resolution HLA-determined ln(PIRCHE-II)/ln(eplet) values. This deviation was slightly increased when HLA-C or HLA-DQ was omitted from the input and was substantially decreased when using two-field resolution HLA genotype data of the recipient and serological split level HLA typing of the donor. Thus, our data suggest that our computational approach is a powerful tool to estimate PIRCHE-II/eplet values when high-resolution HLA genotype data is not available.

  14. A simplified method for screening siblings for HLA identity using short tandem repeat (STR) polymorphisms.

    PubMed

    Schiller, Jennifer J; Hopp, Kathleen A; Pietz, Bradley C; Bick, David P; Lau, Eduardo C; Ellis, Thomas M

    2013-05-01

    Identifying an HLA-matched sibling donor for hematopoietic stem cell transplantation (HSCT) is time-consuming and expensive, and often limited by reimbursement caps imposed by insurance providers. To improve the effectiveness and efficiency of screening for HLA-matched siblings, we developed an assay for determining HLA identity using a panel of nine informative short tandem repeat (STR) loci located throughout the HLA complex. The STR panel was assessed for accuracy in identifying HLA-matched siblings in 88 family workups comprising a total of 132 related donor and recipient typing comparisons. All sibling pairs with identical STR alleles were also HLA identical. Of the 48 pairs mismatched at one or more STR alleles, all were genotypically HLA non-identical at one or more loci. The sensitivity and specificity of STR analysis for identifying HLA-matched siblings were 91% and 100%, respectively. Three false negatives occurred due to an STR mutation or possible HLA-DPB1/DQB1 recombination. Additionally, STR genotyping provided additional information allowing determination of the extent of HLA identity in families where HLA haplotype inheritance was ambiguous, due to extensive homozygosity or shared parental haplotypes. The HLA STR assay is a reliable and rapid test that can be used to inexpensively screen potential sibling donors for HLA identity.

  15. Human lymphocyte antigens (HLA) and Graves' disease in Turkey.

    PubMed

    Orhan, Y; Azezli, A; Carin, M; Aral, F; Sencer, E; Molvalilar, S

    1993-09-01

    To evaluate the association of HLA types with Turkish patients with Graves' disease, HLA typing, clinical findings, and thyroid antibodies were correlated. The HLA types, clinical findings (ophthalmopathy and age at onset), and thyroid stimulating hormone (TSH) receptor (TRAb) and antithyroid microsomal antibodies (MAb) were analyzed. Seventy Turkish patients with Graves' disease and 306 control subjects were assessed. Serological HLA typing was performed in HLA A, B, C, DR, and DQ loci. There was a significantly increased prevalence of HLA B8, B49, DR3, DR4, and DR10 in Graves' disease. The association of Graves' disease with HLA DR3 was found to be less strong than previously described. The HLA DR4 antigen may contribute to the predisposition of Graves' disease in Turkey. The results suggest that HLA B7, B13, DR7, DQw2, and DQw3 may confer a protective effect for Graves' disease in Turkey. Patients carrying HLA B12, B18, and B44 haplotypes had a tendency to develop the disease at a later age. The difference from the other studies may be the result of the selection of the controls; in part, of the variability in serological typing reagents; and, also, of the rather weak HLA associations with the disease.

  16. Molecular analysis of HLA-DRB1, DQA1, DQB1, DQ promoter polymorphism and extended class I/class II haplotypes in the Seri Indians from Northwest Mexico.

    PubMed

    Alaez, C; Infante, E; Pujol, J; Duran, C; Navarro, J L; Gorodezky, C

    2002-05-01

    The study of the genetics of the Major Histocompatibility Complex (MHC) in Amerindians is of great value in understanding the origins and migrations of these native groups, as well as the impact of immunogenetics on the epidemiology of diseases affecting these populations. We analyzed, using Polymerase Chain Reaction and Sequence Specific Oligonucleotide Probes (PCR-SSOP), DRB1, DQA1, DQB1 alleles and the promoter regions of DQA1 and DQB1 genes in 31 unrelated and 24 related Seri, a Mexican Indian group, from the state of Sonora (Northwest Mexico). The class II genotypes of this population were found to be in genetic equilibrium. The allele frequency (AF) of the prevalent DRB1 alleles were DRB1*0407 (48.4%), DRB1*0802 (33.9%) and DRB1*1402 (16.1%). The most frequent DQA1 and DQB1 alleles were DQA1*03011 (AF = 50.00%), DQA1*0401 (AF = 33.87%) and DQA1*0501 (AF = 16.13%); DQB1*0302 (AF = 50.00%), DQB1*0402 (33.87%) and DQB1*0301 (16.13%); which were in combination with DRB1*0407, DRB1*0802 and DRB1*1402, respectively. Three QAP and three QBP alleles were present (QAP 3.1, 4.1, 4.2; QBP 3.1, 3.21, 4.1) associated with the typical published DQA1 and DQB1 alleles. Four class II haplotypes were present in family members: DRB1*0407-QAP-3.1-DQA1*03011-QBP-3.21-DQB1*0302; DRB1*0802-QAP-4.2-DQA1*0401-QBP-4.1-DQB1*0402; DRB1*1402-QAP-4.1-DQA1*0501-QBP-3.1-DQB1*0301 and DRB1*0701-QAP-2.1-DQA1*0201-QBP-2.1-DQB1*0201. The family data were used to confirm extended haplotypes. A total of 21 haplotypes were found when A* and B* loci were also considered. The three most frequent combinations included A*0201-B*3501-DRB1*0407, A*3101-B*5101-DRB1*0802, and A*0201-B*40-DRB1*1402.

  17. Haplotyping the human leukocyte antigen system from single chromosomes

    PubMed Central

    Murphy, Nicholas M.; Burton, Matthew; Powell, David R.; Rossello, Fernando J.; Cooper, Don; Chopra, Abha; Hsieh, Ming Je; Sayer, David C.; Gordon, Lavinia; Pertile, Mark D; Tait, Brian D.; Irving, Helen R.; Pouton, Colin W.

    2016-01-01

    We describe a method for determining the parental HLA haplotypes of a single individual without recourse to conventional segregation genetics. Blood samples were cultured to identify and sort chromosome 6 by bivariate flow cytometry. Single chromosome 6 amplification products were confirmed with a single nucleotide polymorphism (SNP) array and verified by deep sequencing to enable assignment of both alleles at the HLA loci, defining the two haplotypes. This study exemplifies a rapid and efficient method of haplotyping that can be applied to any chromosome pair, or indeed all chromosome pairs, using a single sorting operation. The method represents a cost-effective approach to complete phasing of SNPs, which will facilitate a deeper understanding of the links between SNPs, gene regulation and protein function. PMID:27461731

  18. HLA class I markers in Japanese patients with carbamazepine-induced cutaneous adverse reactions.

    PubMed

    Ikeda, Hiroko; Takahashi, Yukitoshi; Yamazaki, Etsuko; Fujiwara, Tateki; Kaniwa, Nahoko; Saito, Yoshiro; Aihara, Michiko; Kashiwagi, Mariko; Muramatsu, Masaaki

    2010-02-01

    Carbamazepine (CBZ) is frequently used for treating epilepsy, but this drug causes cutaneous adverse drug reactions (cADRs) that may range from mild to severe. It is reported recently that the human leukocyte antigen HLA-B*1502 is associated with Stevens-Johnson syndrome (SJS) induced by CBZ in Han Chinese. We examined HLA class I in 15 Japanese patients who fulfilled the diagnostic criteria for CBZ-induced cADRs (mild in 10 and severe = SJS in 5). HLA-B*1518, HLA-B*5901 and HLA-C*0704 alleles showed higher relative risks (above 10.0) for severe cADRs. The haplotype (HLA-A*2402-B*5901-C*0102) had high relative risk (16.09) for severe cADRs. In patients with severe cADRs, frequencies of HLA-A*1101, HLA-A*3303, HLA-B*1501, HLA-B*4403, HLA-B*5101, HLA-B*5201, HLA-C*0702, and HLA-C*1202 alleles are relatively lower than in the Japanese population. These data may suggest that HLA-B*5901 is one of the candidate markers for CBZ-induced SJS in Japanese.

  19. Understanding of HLA-conferred susceptibility to chronic hepatitis B infection requires HLA genotyping-based association analysis

    PubMed Central

    Nishida, Nao; Ohashi, Jun; Khor, Seik-Soon; Sugiyama, Masaya; Tsuchiura, Takayo; Sawai, Hiromi; Hino, Keisuke; Honda, Masao; Kaneko, Shuichi; Yatsuhashi, Hiroshi; Yokosuka, Osamu; Koike, Kazuhiko; Kurosaki, Masayuki; Izumi, Namiki; Korenaga, Masaaki; Kang, Jong-Hon; Tanaka, Eiji; Taketomi, Akinobu; Eguchi, Yuichiro; Sakamoto, Naoya; Yamamoto, Kazuhide; Tamori, Akihiro; Sakaida, Isao; Hige, Shuhei; Itoh, Yoshito; Mochida, Satoshi; Mita, Eiji; Takikawa, Yasuhiro; Ide, Tatsuya; Hiasa, Yoichi; Kojima, Hiroto; Yamamoto, Ken; Nakamura, Minoru; Saji, Hiroh; Sasazuki, Takehiko; Kanto, Tatsuya; Tokunaga, Katsushi; Mizokami, Masashi

    2016-01-01

    Associations of variants located in the HLA class II region with chronic hepatitis B (CHB) infection have been identified in Asian populations. Here, HLA imputation method was applied to determine HLA alleles using genome-wide SNP typing data of 1,975 Japanese individuals (1,033 HBV patients and 942 healthy controls). Together with data of an additional 1,481 Japanese healthy controls, association tests of six HLA loci including HLA-A, C, B, DRB1, DQB1, and DPB1, were performed. Although the strongest association was detected at a SNP located in the HLA-DP locus in a SNP-based GWAS using data from the 1,975 Japanese individuals, HLA genotyping-based analysis identified DQB1*06:01 as having the strongest association, showing a greater association with CHB susceptibility (OR = 1.76, P = 6.57 × 10−18) than any one of five HLA-DPB1 alleles that were previously reported as CHB susceptibility alleles. Moreover, HLA haplotype analysis showed that, among the five previously reported HLA-DPB1 susceptibility and protective alleles, the association of two DPB1 alleles (DPB1*09:01, and *04:01) had come from linkage disequilibrium with HLA-DR-DQ haplotypes, DRB1*15:02-DQB1*06:01 and DRB1*13:02-DQB1*06:04, respectively. The present study showed an example that SNP-based GWAS does not necessarily detect the primary susceptibility locus in the HLA region. PMID:27091392

  20. Major histocompatibility complex haplotype studies in Ashkenazi Jewish patients with pemphigus vulgaris.

    PubMed Central

    Ahmed, A R; Yunis, E J; Khatri, K; Wagner, R; Notani, G; Awdeh, Z; Alper, C A

    1990-01-01

    Of 26 Ashkenazi Jewish patients with pemphigus vulgaris, 24 (92.3%) carried the major histocompatibility complex (MHC) class II alleles HLA-DR4, DQw3, of which all were of the subtype DR4, DQw8. From studies of the patients and their families, haplotypes were defined. It was found that, of the patients who carried HLA-DR4, DQw8, 75% carried one or the other (and in one case, both) of two haplotypes [HLA-B38, SC21, DR4] or HLA-B35, SC31, DR4. The former is a known extended haplotype among normal Jews, with a frequency of 0.102, and the latter may also be an extended haplotype in this ethnic group, with a frequency of 0.017 among normal haplotypes from Jews. Of the remaining DR4-positive patients, all but one had a presumed D-region segment (defined as SC21, DR4, DQw8 or SC31, DR4, DQw8 with variable HLA-B) of these haplotypes. Only one patient had DR4, DQw8 without any other markers of the extended haplotypes. The number of homozygotes and heterozygotes for DR4, DQw8 was consistent with dominant but not recessive (P less than 0.01) inheritance of a class II or a class II-linked susceptibility gene for the disease. Since the disease is entirely attributable to the presence of an antibody to an intraepidermal intercellular cement substance, it is likely that the class II susceptibility gene (on [HLA-B38, SC21, DR4, DQw8], HLA-B35, SC31, DR4, DQw8, or their segments, in Jewish patients) controls the production of the antibody as a dominantly expressed immune response gene. Images PMID:2217197

  1. HLA-G and susceptibility to develop celiac disease.

    PubMed

    Catamo, Eulalia; Zupin, Luisa; Segat, Ludovica; Celsi, Fulvio; Crovella, Sergio

    2015-01-01

    The Human Leukocyte Antigen-G has immunomodulatory function and its expression has been associated with several diseases. In our study we analyzed HLA-G polymorphisms in order to evaluate their possible association with susceptibility to celiac disease development. A total of 420 celiac patients and 509 controls were genotyped for HLA-G polymorphisms. We sequenced 800bp upstream the ATG codon (5' upstream regulatory region) and the whole 3' untranslated region of the HLA-G gene, whereas the ΔC deletion at exon 3 was detected by RFLP-PCR. Five polymorphisms (namely -477 C>G, -369 C>A, 14bp del/ins, 3187 A>G, 3196 C>G) and one haplotype (TCGGTACGAAITCCCGAG) were significantly more frequent in celiac patients than controls and associated with increased disease susceptibility. The 14bp I/I, 3187 G/G, 3196 G/G genotypes and TCGGTACGAAITCCCGAG haplotype, were still significantly associated with increased disease susceptibility (and in addition also the 3003 C/C genotype) when the analysis was restricted to patients and controls presenting the DQ2.5 or DQ8 HLA-DQ celiac disease risk haplotypes. Our findings indicate an association between HLA-G gene polymorphisms and susceptibility to celiac disease development, suggesting that HLA-G molecule is possibly involved in the pathogenesis of the disease.

  2. Genetic HLA Study of Kurds in Iraq, Iran and Tbilisi (Caucasus, Georgia): Relatedness and Medical Implications

    PubMed Central

    Muñiz, Ester; Campos, Cristina; Alonso-Rubio, Javier; Gomez-Casado, Eduardo; Salih, Shadallah Fareq; Martin-Villa, Manuel; Al-Qadi, Rawand

    2017-01-01

    Kurds from Iraq (Dohuk and Erbil Area, North Iraq) have been analyzed for HLA genes. Their HLA genetic profile has been compared with that of other Kurd groups from Iran and Tbilisi (Georgia, Caucasus) and also Worldwide populations. A total of 7,746 HLA chromosomes have been used. Genetic distances, NJ dendrograms and correspondence analyses have been carried out. Haplotype HLA-B*52—DRB1*15 is present in all three analyzed Kurd populations. HLA-A*02-B*51-DRB1*11 is present in Iraq and Georgia Kurds. Haplotypes common to Iran and Iraq Kurds are HLA DRB1*11—DQB1*03, HLA DRB1*03—DQB1*02 and others in a lower frequency. Our HLA study conclusions are that Kurds most probably belong to an ancient Mediterranean / Middle East / Caucasian genetic substratum and that present results and those previously obtained by us in Kurds may be useful for Medicine in future Kurd transplantation programs, HLA Epidemiology (HLA linked diseases) and Pharmacogenomics (HLA-associated drug side effects) and also for Anthropology. It is discussed that one of the most ancient Kurd ancestor groups is in Hurrians (2,000 years BC). PMID:28114347

  3. [Detecting high risk pregnancy].

    PubMed

    Doret, Muriel; Gaucherand, Pascal

    2009-12-20

    Antenatal care is aiming to reduce maternal land foetal mortality and morbidity. Maternal and foetal mortality can be due to different causes. Their knowledge allows identifying pregnancy (high risk pregnancy) with factors associated with an increased risk for maternal and/or foetal mortality and serious morbidity. Identification of high risk pregnancies and initiation of appropriate treatment and/or surveillance should improve maternal and/or foetal outcome. New risk factors are continuously described thanks to improvement in antenatal care and development in biology and cytopathology, increasing complexity in identifying high risk pregnancies. Level of risk can change all over the pregnancy. Ideally, it should be evaluated prior to the pregnancy and at each antenatal visit. Clinical examination is able to screen for intra-uterin growth restriction, pre-eclampsia, threatened for preterm labour; ultrasounds help in the diagnosis of foetal morphological anomalies, foetal chromosomal anomalies, placenta praevia and abnormal foetal growth; biological exams are used to screen for pre-eclampsia, gestational diabetes, trisomy 21 (for which screening method just changed), rhesus immunisation, seroconversion for toxoplasmosis or rubeola, unknown infectious disease (syphilis, hepatitis B, VIH). During pregnancy, most of the preventive strategies have to be initiated during the first trimester or even before conception. Prevention for neural-tube defects, neonatal hypocalcemia and listeriosis should be performed for all women. On the opposite, some measures are concerning only women with risk factors such as prevention for toxoplasmosis, rhesus immunization (which recently changed), tobacco complications and pre-eclampsia and intra-uterine growth factor restriction.

  4. Detecting disease-predisposing variants: The haplotype method

    SciTech Connect

    Valdes, A.M.; Thomson, G.

    1997-03-01

    For many HLA-associated diseases, multiple alleles - and, in some cases, multiple loci - have been suggested as the causative agents. The haplotype method for identifying disease-predisposing amino acids in a genetic region is a stratification analysis. We show that, for each haplotype combination containing all the amino acid sites involved in the disease process, the relative frequencies of amino acid variants at sites not involved in disease but in linkage disequilibrium with the disease-predisposing sites are expected to be the same in patients and controls. The haplotype method is robust to mode of inheritance and penetrance of the disease and can be used to determine unequivocally whether all amino acid sites involved in the disease have not been identified. Using a resampling technique, we developed a statistical test that takes account of the nonindependence of the sites sampled. Further, when multiple sites in the genetic region are involved in disease, the test statistic gives a closer fit to the null expectation when some - compared with none - of the true predisposing factors are included in the haplotype analysis. Although the haplotype method cannot distinguish between very highly correlated sites in one population, ethnic comparisons may help identify the true predisposing factors. The haplotype method was applied to insulin-dependent diabetes mellitus (IDDM) HLA class II DQA1-DQB1 data from Caucasian, African, and Japanese populations. Our results indicate that the combination DQA1 No. 52 (Arg predisposing) DQB1 No. 57 (Asp protective), which has been proposed as an important IDDM agent, does not include all the predisposing elements. With rheumatoid arthritis HLA class H DRB1 data, the results were consistent with the shared-epitope hypothesis. 35 refs., 2 figs., 6 tabs.

  5. Analysis of genetic polymorphism of the HLA-B and HLA-DR loci in patients with dermatophytic onychomycosis and in their first-degree relatives.

    PubMed

    García-Romero, M T; Granados, J; Vega-Memije, M E; Arenas, R

    2012-01-01

    Onychomycosis is known to have predisposing factors and a high prevalence within families that cannot be explained by within-family transmission. We determined the frequency of HLA-B and HLA-DR haplotypes in 25 families of Mexican patients with onychomycosis in order to define the role of the class II major histocompatibility complex (MHC) in genetic susceptibility to this infection. Seventy-eight subjects participated in the study, 47 with onychomycosis and 31 healthy individuals. The frequencies of the HLA-B and HLA-DR haplotypes were compared with those found in first-degree relatives without onychomycosis and in a historic control group of healthy individuals. The frequencies in the controls were similar to those of the healthy relatives of the patients. However, on comparison of the patients with historic controls, we detected a higher frequency of the HLA-DR8 haplotype (P=.03; odds ratio, 1.89; 95% confidence interval, 0.98-36). These findings suggest that there are polymorphisms in genes of the MHC that increase susceptibility to onychomycosis, particularly haplotype HLA-DR8.

  6. [Analysis of genetic polymorphism of the HLA-B and HLA-DR loci in patients with dermatophytic onychomycosis and in their first-degree relatives].

    PubMed

    García-Romero, M T; Granados, J; Vega-Memije, M E; Arenas, R

    2012-01-01

    Onychomycosis is known to have predisposing factors and a high prevalence within families that cannot be explained by within-family transmission. We determined the frequency of HLA-B and HLA-DR haplotypes in 25 families of Mexican patients with onychomycosis in order to define the role of the class II major histocompatibility complex (MHC) in genetic susceptibility to this infection. Seventy-eight subjects participated in the study, 47 with onychomycosis and 31 healthy individuals. The frequencies of the HLA-B and HLA-DR haplotypes were compared with those found in first-degree relatives without onychomycosis and in a historic control group of healthy individuals. The frequencies in the controls were similar to those of the healthy relatives of the patients. However, on comparison of the patients with historic controls, we detected a higher frequency of the HLA-DR8 haplotype (P=.03; odds ratio, 1.89; 95% confidence interval, 0.98-36). These findings suggest that there are polymorphisms in genes of the MHC that increase susceptibility to onychomycosis, particularly haplotype HLA-DR8.

  7. Graft-versus-leukemia effect of HLA-haploidentical central-memory T-cells expanded with leukemic APCs and modified with a suicide gene.

    PubMed

    Casucci, Monica; Perna, Serena Kimi; Falcone, Laura; Camisa, Barbara; Magnani, Zulma; Bernardi, Massimo; Crotta, Alessandro; Tresoldi, Cristina; Fleischhauer, Katharina; Ponzoni, Maurilio; Gregori, Silvia; Caligaris Cappio, Federico; Ciceri, Fabio; Bordignon, Claudio; Cignetti, Alessandro; Bondanza, Attilio; Bonini, Chiara

    2013-02-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen (HLA)-haploidentical family donor (haplo-HSCT) is a readily available and potentially curative option for high-risk leukemia. In haplo-HSCT, alloreactivity plays a major role in the graft-versus-leukemia (GVL) effect, which, however, is frequently followed by relapse due to emerging leukemic cell variants that have lost the unshared HLA haplotype as a mechanism of immune escape. We report that stimulation of HLA-haploidentical donor T lymphocytes with leukemic antigen-presenting cells (L-APCs) expands a population of leukemia-reactive T cells, which, besides alloreactivity to unshared HLAs, contain leukemia-associated specificities restricted by shared HLAs. According to a preferential central-memory (T(CM)) phenotype and to high interleukin (IL)-7Rα expression, these T cells persist in vivo and sustain a major GVL effect in a clinically relevant xenograft model. Moreover, we demonstrate that modifying L-APC-expanded T cells to express the herpes simplex virus thymidine kinase (HSV-tk) suicide gene enables their elimination with the prodrug ganciclovir (GCV), therefore providing a safety switch in case of graft-versus-host disease (GVHD). These results warrant the clinical investigation of L-APC-expanded T cells modified with a suicide gene in the setting of haplo-HSCT.

  8. Structural analysis of the HLA-A/HLA-F subregion: Precise localization of two new multigene families closely associated with the HLA class I sequences

    SciTech Connect

    Pichon, L.; Carn, G.; Bouric, P.

    1996-03-01

    Positional cloning strategies for the hemochromatosis gene have previously concentrated on a target area restricted to a maximum genomic expanse of 400 kb around the HLA-A and HLA-F loci. Recently, the candidate region has been extended to 2-3 Mb on the distal side of the MHC. In this study, 10 coding sequences [hemochromatosis candidate genes (HCG) I to X] were isolated by cDNA selection using YACs covering the HLA-A/HLA-F subregion. Two of these (HCG II and HCG IV) belong to multigene families, as well as other sequences already described in this region, i.e., P5, pMC 6.7, and HLA class I. Fingerprinting of the four YACSs overlapping the region was performed and allowed partial localization of the different multigene family sequences on each YAC without defining their exact positions. Fingerprinting on cosmids isolated from the ICRF chromosome 6-specific cosmid library allowed more precise localization of the redundant sequences in all of the multigene families and revealed their apparent organization in clusters. Further examination of these intertwined sequences demonstrated that this structural organization resulted from a succession of complex phenomena, including duplications and contractions. This study presents a precise description of the structural organization of the HLA-A/HLA-F region and a determination of the sequences involved in the megabase size polymorphism observed among the A3, A24, and A31 haplotypes. 29 refs., 2 figs., 2 tabs.

  9. MHC Class II haplotypes of Colombian Amerindian tribes.

    PubMed

    Yunis, Juan J; Yunis, Edmond J; Yunis, Emilio

    2013-07-01

    We analyzed 1041 individuals belonging to 17 Amerindian tribes of Colombia, Chimila, Bari and Tunebo (Chibcha linguistic family), Embera, Waunana (Choco linguistic family), Puinave and Nukak (Maku-Puinave linguistic families), Cubeo, Guanano, Tucano, Desano and Piratapuyo (Tukano linguistic family), Guahibo and Guayabero (Guayabero Linguistic Family), Curripaco and Piapoco (Arawak linguistic family) and Yucpa (Karib linguistic family). for MHC class II haplotypes (HLA-DRB1, DQA1, DQB1). Approximately 90% of the MHC class II haplotypes found among these tribes are haplotypes frequently encountered in other Amerindian tribes. Nonetheless, striking differences were observed among Chibcha and non-Chibcha speaking tribes. The DRB1*04:04, DRB1*04:11, DRB1*09:01 carrying haplotypes were frequently found among non-Chibcha speaking tribes, while the DRB1*04:07 haplotype showed significant frequencies among Chibcha speaking tribes, and only marginal frequencies among non-Chibcha speaking tribes. Our results suggest that the differences in MHC class II haplotype frequency found among Chibcha and non-Chibcha speaking tribes could be due to genetic differentiation in Mesoamerica of the ancestral Amerindian population into Chibcha and non-Chibcha speaking populations before they entered into South America.

  10. MHC Class II haplotypes of Colombian Amerindian tribes

    PubMed Central

    Yunis, Juan J.; Yunis, Edmond J.; Yunis, Emilio

    2013-01-01

    We analyzed 1041 individuals belonging to 17 Amerindian tribes of Colombia, Chimila, Bari and Tunebo (Chibcha linguistic family), Embera, Waunana (Choco linguistic family), Puinave and Nukak (Maku-Puinave linguistic families), Cubeo, Guanano, Tucano, Desano and Piratapuyo (Tukano linguistic family), Guahibo and Guayabero (Guayabero Linguistic Family), Curripaco and Piapoco (Arawak linguistic family) and Yucpa (Karib linguistic family). for MHC class II haplotypes (HLA-DRB1, DQA1, DQB1). Approximately 90% of the MHC class II haplotypes found among these tribes are haplotypes frequently encountered in other Amerindian tribes. Nonetheless, striking differences were observed among Chibcha and non-Chibcha speaking tribes. The DRB1*04:04, DRB1*04:11, DRB1*09:01 carrying haplotypes were frequently found among non-Chibcha speaking tribes, while the DRB1*04:07 haplotype showed significant frequencies among Chibcha speaking tribes, and only marginal frequencies among non-Chibcha speaking tribes. Our results suggest that the differences in MHC class II haplotype frequency found among Chibcha and non-Chibcha speaking tribes could be due to genetic differentiation in Mesoamerica of the ancestral Amerindian population into Chibcha and non-Chibcha speaking populations before they entered into South America. PMID:23885196

  11. HLA-F coding and regulatory segments variability determined by massively parallel sequencing procedures in a Brazilian population sample.

    PubMed

    Lima, Thálitta Hetamaro Ayala; Buttura, Renato Vidal; Donadi, Eduardo Antônio; Veiga-Castelli, Luciana Caricati; Mendes-Junior, Celso Teixeira; Castelli, Erick C

    2016-10-01

    Human Leucocyte Antigen F (HLA-F) is a non-classical HLA class I gene distinguished from its classical counterparts by low allelic polymorphism and distinctive expression patterns. Its exact function remains unknown. It is believed that HLA-F has tolerogenic and immune modulatory properties. Currently, there is little information regarding the HLA-F allelic variation among human populations and the available studies have evaluated only a fraction of the HLA-F gene segment and/or have searched for known alleles only. Here we present a strategy to evaluate the complete HLA-F variability including its 5' upstream, coding and 3' downstream segments by using massively parallel sequencing procedures. HLA-F variability was surveyed on 196 individuals from the Brazilian Southeast. The results indicate that the HLA-F gene is indeed conserved at the protein level, where thirty coding haplotypes or coding alleles were detected, encoding only four different HLA-F full-length protein molecules. Moreover, a same protein molecule is encoded by 82.45% of all coding alleles detected in this Brazilian population sample. However, the HLA-F nucleotide and haplotype variability is much higher than our current knowledge both in Brazilians and considering the 1000 Genomes Project data. This protein conservation is probably a consequence of the key role of HLA-F in the immune system physiology.

  12. A novel and major association of HLA-C in Graves' disease that eclipses the classical HLA-DRB1 effect.

    PubMed

    Simmonds, Matthew J; Howson, Joanna M M; Heward, Joanne M; Carr-Smith, Jackie; Franklyn, Jayne A; Todd, John A; Gough, Stephen C L

    2007-09-15

    Association of the major histocompatibility complex (MHC) class II-encoded HLA-DRB1-DQA1-DQB1 haplotype with Graves' disease (GD) has been known for several years. Recent evidence from other autoimmune diseases has suggested that the HLA class I encoded HLA-B/-C molecules could be conferring HLA-DRB1-DQA1-DQB1 independent effects on disease. The aim of this study was to determine the effect of HLA-B and HLA-C in GD in a white ethnic group of 806 patients with GD and 487 control subjects from the UK. Of the five loci (HLA-B, -C, -DRB1, -DQA1, -DQB1), HLA-C demonstrated the strongest association (P = 1.20 x 10(-20)) with HLA-C*07 predisposing [OR = 1.63, 95% CI (1.23-2.17)] and both HLA-C*03 [OR = 0.54, 95% CI (0.38-0.77)], HLA-C*16 [OR = 0.36, 95% CI (0.21-0.61)] protective. The other loci were then tested for HLA-C-independent associations. HLA-B was found to be associated independently of HLA-C (P = 1.54 x 10(-6)) with the other three loci, HLA-DRB1, HLA-DQB1 and HLA-DQA1, also improving the model but with less confidence (P > 10(-5)). This study has for the first time provided evidence of a primary association of HLA-C, and to a lesser extent HLA-B, with GD. Class II loci could still have effects on GD, but they appear smaller than the HLA-C association. A full investigation of the MHC region, including all class I and II loci is now required. Our results point to a primary role for class I-mediated responses in GD, a condition classically assumed to be a straightforward HLA-class II-restricted autoantibody response to the thyroid stimulating hormone receptor.

  13. HLA and Celiac Disease Susceptibility: New Genetic Factors Bring Open Questions about the HLA Influence and Gene-Dosage Effects

    PubMed Central

    Medrano, Luz María; Dema, Bárbara; López-Larios, Arturo; Maluenda, Carlos; Bodas, Andrés; López-Palacios, Natalia; Figueredo, M. Ángeles; Fernández-Arquero, Miguel; Núñez, Concepción

    2012-01-01

    Celiac disease (CD) is a chronic inflammatory disorder triggered after gluten ingestion in genetically susceptible individuals. The major genetic determinants are HLA-DQA1*05 and HLA-DQB1*02, which encode the DQ2 heterodimer. These alleles are commonly inherited in cis with DRB1*03∶01, which is associated with numerous immune-related disorders, in some cases contributing with a different amount of risk depending on the haplotype context. We aimed at investigating those possible differences involving DRB1*03∶01-carrying haplotypes in CD susceptibility. A family (274 trios) and a case-control sample (369 CD cases/461 controls) were analyzed. DRB1*03∶01-carrying individuals were classified according to the haplotype present (ancestral haplotype (AH) 8.1, AH 18.2 or non-conserved haplotype) after genotyping of HLA-DRB1, -DQA1, -DQB1, -B8, TNF -308, TNF -376 and the TNFa and TNFb microsatellites. We observe that the AH 8.1 confers higher risk than the remaining DRB1*03∶01-carrying haplotypes, and this effect only involves individuals possessing a single copy of DQB1*02. CD risk for these individuals is similar to the one conferred by inherit DQA1*05 and DQB1*02 in trans. It seems that an additional CD susceptibility factor is present in the AH 8.1 but not in other DRB1*03∶01-carrying haplotypes. This factor could be shared with individuals possessing DQ2.5 trans, according to the similar risk observed in those two groups of individuals. PMID:23119005

  14. HLA and celiac disease susceptibility: new genetic factors bring open questions about the HLA influence and gene-dosage effects.

    PubMed

    Medrano, Luz María; Dema, Bárbara; López-Larios, Arturo; Maluenda, Carlos; Bodas, Andrés; López-Palacios, Natalia; Figueredo, M Ángeles; Fernández-Arquero, Miguel; Núñez, Concepción

    2012-01-01

    Celiac disease (CD) is a chronic inflammatory disorder triggered after gluten ingestion in genetically susceptible individuals. The major genetic determinants are HLA-DQA1*05 and HLA-DQB1*02, which encode the DQ2 heterodimer. These alleles are commonly inherited in cis with DRB1*03∶01, which is associated with numerous immune-related disorders, in some cases contributing with a different amount of risk depending on the haplotype context. We aimed at investigating those possible differences involving DRB1*03∶01-carrying haplotypes in CD susceptibility. A family (274 trios) and a case-control sample (369 CD cases/461 controls) were analyzed. DRB1*03∶01-carrying individuals were classified according to the haplotype present (ancestral haplotype (AH) 8.1, AH 18.2 or non-conserved haplotype) after genotyping of HLA-DRB1, -DQA1, -DQB1, -B8, TNF -308, TNF -376 and the TNFa and TNFb microsatellites. We observe that the AH 8.1 confers higher risk than the remaining DRB1*03∶01-carrying haplotypes, and this effect only involves individuals possessing a single copy of DQB1*02. CD risk for these individuals is similar to the one conferred by inherit DQA1*05 and DQB1*02 in trans. It seems that an additional CD susceptibility factor is present in the AH 8.1 but not in other DRB1*03∶01-carrying haplotypes. This factor could be shared with individuals possessing DQ2.5 trans, according to the similar risk observed in those two groups of individuals.

  15. HLA-E coding and 3' untranslated region variability determined by next-generation sequencing in two West-African population samples.

    PubMed

    Castelli, Erick C; Mendes-Junior, Celso T; Sabbagh, Audrey; Porto, Iane O P; Garcia, André; Ramalho, Jaqueline; Lima, Thálitta H A; Massaro, Juliana D; Dias, Fabrício C; Collares, Cristhianna V A; Jamonneau, Vincent; Bucheton, Bruno; Camara, Mamadou; Donadi, Eduardo A

    2015-12-01

    HLA-E is a non-classical Human Leucocyte Antigen class I gene with immunomodulatory properties. Whereas HLA-E expression usually occurs at low levels, it is widely distributed amongst human tissues, has the ability to bind self and non-self antigens and to interact with NK cells and T lymphocytes, being important for immunosurveillance and also for fighting against infections. HLA-E is usually the most conserved locus among all class I genes. However, most of the previous studies evaluating HLA-E variability sequenced only a few exons or genotyped known polymorphisms. Here we report a strategy to evaluate HLA-E variability by next-generation sequencing (NGS) that might be used to other HLA loci and present the HLA-E haplotype diversity considering the segment encoding the entire HLA-E mRNA (including 5'UTR, introns and the 3'UTR) in two African population samples, Susu from Guinea-Conakry and Lobi from Burkina Faso. Our results indicate that (a) the HLA-E gene is indeed conserved, encoding mainly two different protein molecules; (b) Africans do present several unknown HLA-E alleles presenting synonymous mutations; (c) the HLA-E 3'UTR is quite polymorphic and (d) haplotypes in the HLA-E 3'UTR are in close association with HLA-E coding alleles. NGS has proved to be an important tool on data generation for future studies evaluating variability in non-classical MHC genes.

  16. HLA-G profile of infertile couples who underwent assisted reproduction treatment.

    PubMed

    Costa, Cynthia Hernandes; Gelmini, Georgia Fernanda; Nardi, Fabiola Silva; Roxo, Valéria Maria Munhoz Sperandio; Schuffner, Alessandro; da Graça Bicalho, Maria

    2016-12-01

    HLA-G codes for a non-classical class I (Ib) protein which is mainly expressed in trophoblast cells. Many pieces of evidence pointed out its essential role conferring immunological tolerance to the fetus. Some HLA-G alleles have been linked to enhanced or reduced HLA-G protein levels expression, which have been associated with reproductive failure. In this study 33 couples undergoing ART (assisted reproduction treatment; n=66) and 120 couples who conceived naturally (controls; n=240) were enrolled in the study. Genotyping was performed by SBT and tagged an 1837bp at 5'URR as well as exons 2, 3 and4 of HLA-G. Alleles, genotypes and haplotypes were compared between infertile and control groups using Fisher Exact Test. The haplotype HLA-G(∗)010101b/HLA-G(∗)01:01:01 showed statistically significant higher frequency in control groups. The immunogenetics of infertility is complex and might be dependent on different genes involved in the establishment of a successful pregnancy. A better understanding of HLA-G alleles and haplotypes structure and how the genetic diversity at their regulatory sites could impact on their level of expression and build up the susceptibility or protection conditions may shed light on the comprehension of immunogenetics mechanisms acting at the fetus-maternal interface.

  17. Tumour necrosis factor microsatellites and HLA-DRB1*, HLA-DQA1*, and HLA-DQB1* alleles in Peruvian patients with rheumatoid arthritis

    PubMed Central

    Castro, F; Acevedo, E; Ciusani, E; Angulo, J; Wollheim, F; Sandberg-Wollheim, M

    2001-01-01

    OBJECTIVE—To study the association between rheumatoid arthritis (RA) and HLA and tumour necrosis factor (TNF) polymorphism in Peruvian mestizo patients in comparison with ethnically similar controls.
METHODS—Seventy nine patients with RA and 65 ethnically matched healthy controls were genotyped for HLA-DRB1, HLA-DQA1, HLA-DQB1, and TNFα and TNFβ alleles using PCR amplification. Clinical severity was assessed as mild, moderate, or severe in 35 of the patients.
RESULTS—TNFα6 showed the strongest association with disease susceptibility. The TNFα6 allele was more common in patients than in controls (p<0.0076) and the proportion of patients with at least one copy of this allele was greater (p<0.015, relative risk 2.35). Among the HLA-DRB1* alleles with the shared epitope sequence, only the DRB1*1402 allele was significantly increased in patients compared with controls (p<0.0311), as was the proportion of patients with at least one copy of this allele (p<0.0232, relative risk 2.74). In contrast, the overall frequency of alleles with the shared epitope was not different in patients and controls. The haplotype HLA-DRB1*1402-DQB1*0301-DQA1*0401 was significantly more common in patients. TNFα6 was more common in patients whether or not they had this haplotype. None of the 11 patients lacking the TNFα6 allele had severe disease.
CONCLUSIONS—This study shows for the first time that TNF gene polymorphism is associated with susceptibility to RA in a non-white population. TNFα6 and HLA-DRB1*1402 independently conferred significantly increased risk in Peruvian mestizo patients.

 PMID:11454644

  18. HIBAG--HLA genotype imputation with attribute bagging.

    PubMed

    Zheng, X; Shen, J; Cox, C; Wakefield, J C; Ehm, M G; Nelson, M R; Weir, B S

    2014-04-01

    Genotyping of classical human leukocyte antigen (HLA) alleles is an essential tool in the analysis of diseases and adverse drug reactions with associations mapping to the major histocompatibility complex (MHC). However, deriving high-resolution HLA types subsequent to whole-genome single-nucleotide polymorphism (SNP) typing or sequencing is often cost prohibitive for large samples. An alternative approach takes advantage of the extended haplotype structure within the MHC to predict HLA alleles using dense SNP genotypes, such as those available from genome-wide SNP panels. Current methods for HLA imputation are difficult to apply or may require the user to have access to large training data sets with SNP and HLA types. We propose HIBAG, HLA Imputation using attribute BAGging, that makes predictions by averaging HLA-type posterior probabilities over an ensemble of classifiers built on bootstrap samples. We assess the performance of HIBAG using our study data (n=2668 subjects of European ancestry) as a training set and HLA data from the British 1958 birth cohort study (n≈1000 subjects) as independent validation samples. Prediction accuracies for HLA-A, B, C, DRB1 and DQB1 range from 92.2% to 98.1% using a set of SNP markers common to the Illumina 1M Duo, OmniQuad, OmniExpress, 660K and 550K platforms. HIBAG performed well compared with the other two leading methods, HLA*IMP and BEAGLE. This method is implemented in a freely available HIBAG R package that includes pre-fit classifiers for European, Asian, Hispanic and African ancestries, providing a readily available imputation approach without the need to have access to large training data sets.

  19. Analysis of DR4 haplotypes in insulin dependent diabetes (IDD)

    SciTech Connect

    Monos, D.S.; Radka, S.F.; Zmijewski, C.M.; Kamoun, M.

    1986-03-05

    Population studies indicate that HLA-DR4 is implicated in the susceptibility of IDD. However, biochemical characterization of the serologically defined DR4 haplotype from normal individuals revealed five DR4 and three DQW3 molecular forms. Hence, in this study, they investigated the heterogeneity of the DR4 haplotype, using B-lymphoblastoid cell lines (B-LCL) generated from patients with IDD and seropositive for DR4. Class II molecules, metabolically labeled with /sup 35/S-methionine, were immunoprecipitated with monoclonal antibodies specific for DR(L243), DQ(N297), DQW3(IVD12) or DR and DQ(SG465) and analyzed by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). The isoelectrofocusing (IEF) conditions employed in this study allow representation only of the DR4 haplotype from either DR3/4 or DR4/4 cell lines. The analysis of six different DR4 haplotypes from seven IDD patients, revealed the presence of two DR4 ..beta.. and two DQW3 ..beta.. chains. Three of the six DR4 ..beta.. haplotypes analyzed shared the same DR4 ..beta.. chain and three others shared a different one. Additionally five of the six haplotypes shared a different one. Additionally five of the six haplotypes shared the same DQW3 ..beta.. chain and only one was carrying a different one. Different combinations of the two DR4 and two DQW3 ..beta.. chains constitute three distinct patterns of DR4 haplotypes. These results suggest the prevalence of a DQW3 ..beta.. chain in the small sample of IDD patients studied. Studies of a large number of patients should clarify whether IDD is associated with unique variants of DR4 or DQW3 ..beta.. chains.

  20. Linkage analysis of human leukocyte antigen (HLA) markers in familial psoriasis: strong disequilibrium effects provide evidence for a major determinant in the HLA-B/-C region.

    PubMed Central

    Jenisch, S; Henseler, T; Nair, R P; Guo, S W; Westphal, E; Stuart, P; Krönke, M; Voorhees, J J; Christophers, E; Elder, J T

    1998-01-01

    Although psoriasis is strongly associated with certain human leukocyte antigens (HLAs), evidence for linkage to HLA markers has been limited. The objectives of this study were (1) to provide more definitive evidence for linkage of psoriasis to HLA markers in multiplex families; (2) to compare the major HLA risk alleles in these families with those determined by previous case-control studies; and (3) to localize the gene more precisely. By applying the transmission/disequilibrium test (TDT) and parametric linkage analysis, we found evidence for linkage of psoriasis to HLA-C, -B, -DR, and -DQ, with HLA-B and -C yielding the most-significant results. Linkage was detectable by parametric methods only when marker-trait disequilibrium was considered. Case-control association tests and the TDT identified alleles belonging to the EH57.1 ancestral haplotype as the major risk alleles in our sample. Among individuals carrying recombinant ancestral haplotypes involving EH57. 1, the class I markers were retained selectively among affecteds four times more often than among unaffecteds; among the few affected individuals carrying only the class II alleles from the ancestral haplotype, all but one also carried Cw6. These data show that familial and "sporadic" psoriasis share the same risk alleles. They also illustrate that substantial parametric linkage information can be extracted by accounting for linkage disequilibrium. Finally, they strongly suggest that a major susceptibility gene resides near HLA-C. PMID:9634500

  1. Comparison of HLA-A, -B and -DRB1 Loci Polymorphism between Kidney Transplants of Uremia Patients and Healthy Individuals in Central China

    PubMed Central

    Gao, Shilin; Feng, Guiwen; Feng, Yonghua; Wang, Zhigang; Zhang, Xiaobai

    2016-01-01

    Chronic kidney disease is becoming a global public health problem, which will usually cause uremia at the end stage of chronic kidney failure. So far, kidney transplant is the most effective and proper therapy for uremia, however, the short supply of matched donor kidney has been a persistent bottleneck for transplantation. HLA matching of HLA-A, -B and -DRB1 loci is very important for the allocation of kidney transplants. In this study, we investigated genotypes of HLA-A, -B and -DRB1 loci based on 1,464 uremia patients and 10,000 unrelated healthy individuals in Henan province of China, and compared the frequency distribution of these HLA alleles and corresponding haplotypes between patient and healthy groups. We detected 23 HLA-A, 49 HLA-B and 17 HLA-DRB1 alleles in total. The predominant alleles of HLA-A, -B and -DRB1 loci in patients are the same as those in healthy group. The seven most frequent alleles account for about 87%, 50%, and 77% at HLA-A, -B and -DRB1 loci, respectively. The haplotypes (combinations of HLA-A, -B, and -DRB1) with significantly different frequency between patients and controls mostly account for less than 1%. Overall, this suggests that HLA matching is not a potential difficulty for kidney transplant of uremia patients. However, three of the top seven frequent HLA-DRB1 alleles have a significantly different distribution in patients and controls, while only one alleles for HLA-B and zero for HLA-A loci. These HLA-DRB1 alleles may be closely associated with uremia. This study sheds new lights on the composition and difference of HLA genotypes in uremia patients and healthy populations in Central China that can serve as a guide to HLA matching for kidney transplants and a resource for HLA typing-related studies. PMID:27780235

  2. An algorithm for haplotype analysis

    SciTech Connect

    Lin, Shili; Speed, T.P.

    1997-12-01

    This paper proposes an algorithm for haplotype analysis based on a Monte Carlo method. Haplotype configurations are generated according to the distribution of joint haplotypes of individuals in a pedigree given their phenotype data, via a Markov chain Monte Carlo algorithm. The haplotype configuration which maximizes this conditional probability distribution can thus be estimated. In addition, the set of haplotype configurations with relatively high probabilities can also be estimated as possible alternatives to the most probable one. This flexibility enables geneticists to choose the haplotype configurations which are most reasonable to them, allowing them to include their knowledge of the data under analysis. 18 refs., 2 figs., 1 tab.

  3. Multiple HLA class I and II associations in classical Hodgkin lymphoma and EBV status defined subgroups.

    PubMed

    Huang, Xin; Kushekhar, Kushi; Nolte, Ilja; Kooistra, Wierd; Visser, Lydia; Bouwman, Ilby; Kouprie, Niels; Veenstra, Rianne; van Imhoff, Gustaaf; Olver, Bianca; Houlston, Richard S; Poppema, Sibrand; Diepstra, Arjan; Hepkema, Bouke; van den Berg, Anke

    2011-11-10

    The pathogenesis of classical Hodgkin lymphoma (cHL) involves environmental and genetic factors. To explore the role of the human leukocyte antigen (HLA) genes, we performed a case-control genotyping study in 338 Dutch cHL patients and more than 5000 controls using a PCR-based sequence-specific oligonucleotide probe hybridization approach. HLA-A68 and HLA-DR11 (5) were significantly increased in the cHL patient population compared with the controls. Three class II associations were observed in the EBV(-) cHL population with an increase of HLA-DR15 (2) and a decrease of HLA-DR4 and HLA-DR7. Allele frequencies of HLA-A1, HLA-B37, and HLA-DR10 were significantly increased in the EBV(+) cHL population; these alleles are in strong linkage disequilibrium and form a common haplotype in whites. The allele frequency of HLA-A2 was significantly decreased in the EBV(+) cHL population. Sequence-specific oligonucleotide probe analysis revealed significant differences between EBV(+) and EBV(-) cHL patients for 19 probes that discriminate between HLA-A*01 and HLA-A*02. In conclusion, the HLA-A1 and HLA-A2 antigens and not specific single nucleotide variants shared by multiple alleles are responsible for the association with EBV(+) cHL. Furthermore, several new protective and predisposing HLA class I and II associations for the EBV(+), the EBV(-), and the entire cHL population were identified.

  4. HLA polymorphism in Sudanese renal donors.

    PubMed

    Dafalla, Ameer M; McCloskey, D J; Alemam, Almutaz A; Ibrahim, Amel A; Babikir, Adil M; Gasmelseed, Nagla; El Imam, Mohamed; Mohamedani, Ahmed A; Magzoub, Mubarak M

    2011-07-01

    The main objective of this study is to provide a database for renal transplantation in Sudan and to determine the HLA antigens and haplotype frequencies (HFs) in the study subjects. HLA typing was performed using the complement-dependant lymphocytotoxicity test in 250 unrelated healthy individuals selected as donors in the Sudanese Renal Transplantation Program. Considerable polymorphism was observed at each locus; A2 (0.28), A30 (0.12), A3 (0.09), A24 (0.09), A1 (0.09), and A68 (0.06) were the most frequent antigens in the A locus, while B51 (0.092), B41 (0.081), B39 (0.078), B57 (0.060), B35 (0.068), B 50 (0.053) and B 52 (0.051) were the most common B locus antigens. DR13 (0.444) and DR15 (0.160) showed the highest antigen frequencies (AFs) in the DR locus. In the DQ locus, DQ1 showed the highest gene frequency (0.498), while DQ2 and DQ3 AFs were (0.185) and (0.238), respectively. The most common HLA-A and -B haplotypes in positive linkage disequilibrium were A24, B38; A1, B7; and A3, B52. The common HLA-A and -B HFs in positive linkage disequilibrium in the main three tribe-stocks of the study subjects (Gaalia, Nile Nubian and Johyna) were A24, B38 for Gaalia; A24, B38 and A2, B7 for Johyna; and A2, B64 and A3, B53 for Nile Nubian. These results suggest that both class I and class II polymorphisms of the study subjects depict considerable heterogeneity, which reflects recent admixture of this group with neighboring Arabs and African populations.

  5. Association of HLA-A, -B, and -DRB1 with pulmonary tuberculosis in western Javanese Indonesia.

    PubMed

    Yuliwulandari, Rika; Sachrowardi, Qomariyah; Nakajima, Humiaki; Kashiwase, Koichi; Hirayasu, Kouyuki; Mabuchi, Akihiko; Sofro, Abdul Salam Mudzakir; Tokunaga, Katsushi

    2010-07-01

    Genetic studies of pulmonary tuberculosis (PTB), including those of human leukocyte antigen (HLA) genes, have been reported in several populations. Some studies also have reported these genes to have a stronger role in severe tuberculosis. We investigated HLA class I and II alleles and haplotypes to ascertain their role in susceptibility and resistance to new and recurrent PTB in 257 PTB patients (216 new and 41 recurrent PTB patients) and 236 healthy controls in Western Javanese (Indonesia). HLA-B*4006 was associated with new PTB (p = 0.044, p(adj) = ns), whereas HLA-B*1802, HLA-B*4001 and HLA-DRB1*1101 were associated with recurrent PTB (p = 0.013, p(adj) = 0.016; p = 0.015, p(adj) = 0.028; and p = 0.008, p(adj) = 0.027 for new PTB vs recurrent PTB, respectively). Except for HLA-B*4006, those associations remained significant after adjustment for age and gender by logistic regression analysis, although they disappeared after correction for multiple testing. Haplotype HLA-B*1802-DRB1*1202 was associated with susceptibility to recurrent PTB (p = 0.014, odds ratio = 3.8, 95% confidence interval = 1.18-12.27). In contrast, HLA-DRB1*1202 in the absence of HLA-B*1802 showed a significant association with resistance to recurrent PTB (p = 8.2 x 10(-4), odds ratio = 0.32, 95% confidence interval = 0.16-0.64), suggesting that stronger susceptibility effect of HLA-B*1802 masked the protective effect of HLA-DRB1*1202. Further studies using larger number of patients with recurrent PTB will be needed to confirm our findings.

  6. High-Resolution Analyses of Human Leukocyte Antigens Allele and Haplotype Frequencies Based on 169,995 Volunteers from the China Bone Marrow Donor Registry Program

    PubMed Central

    Zhou, Xiao-Yang; Zhu, Fa-Ming; Li, Jian-Ping; Mao, Wei; Zhang, De-Mei; Liu, Meng-Li; Hei, Ai-Lian; Dai, Da-Peng; Jiang, Ping; Shan, Xiao-Yan; Zhang, Bo-Wei; Zhu, Chuan-Fu; Shen, Jie; Deng, Zhi-Hui; Wang, Zheng-Lei; Yu, Wei-Jian; Chen, Qiang; Qiao, Yan-Hui; Zhu, Xiang-Ming; Lv, Rong; Li, Guo-Ying; Li, Guo-Liang; Li, Heng-Cong; Zhang, Xu; Pei, Bin; Jiao, Li-Xin; Shen, Gang; Liu, Ying; Feng, Zhi-Hui; Su, Yu-Ping; Xu, Zhao-Xia; Di, Wen-Ying; Jiang, Yao-Qin; Fu, Hong-Lei; Liu, Xiang-Jun; Liu, Xiang; Zhou, Mei-Zhen; Du, Dan; Liu, Qi; Han, Ying; Zhang, Zhi-Xin; Cai, Jian-Ping

    2015-01-01

    Allogeneic hematopoietic stem cell transplantation is a widely used and effective therapy for hematopoietic malignant diseases and numerous other disorders. High-resolution human leukocyte antigen (HLA) haplotype frequency distributions not only facilitate individual donor searches but also determine the probability with which a particular patient can find HLA-matched donors in a registry. The frequencies of the HLA-A, -B, -C, -DRB1, and -DQB1 alleles and haplotypes were estimated among 169,995 Chinese volunteers using the sequencing-based typing (SBT) method. Totals of 191 HLA-A, 244 HLA-B, 146 HLA-C, 143 HLA-DRB1 and 47 HLA-DQB1 alleles were observed, which accounted for 6.98%, 7.06%, 6.46%, 9.11% and 7.91%, respectively, of the alleles in each locus in the world (IMGT 3.16 Release, Apr. 2014). Among the 100 most common haplotypes from the 169,995 individuals, nine distinct haplotypes displayed significant regionally specific distributions. Among these, three were predominant in the South China region (i.e., the 20th, 31st, and 81sthaplotypes), another three were predominant in the Southwest China region (i.e., the 68th, 79th, and 95th haplotypes), one was predominant in the South and Southwest China regions (the 18th haplotype), one was relatively common in the Northeast and North China regions (the 94th haplotype), and one was common in the Northeast, North and Northwest China (the 40th haplotype). In conclusion, this is the first to analyze high-resolution HLA diversities across the entire country of China, based on a detailed and complete data set that covered 31 provinces, autonomous regions, and municipalities. Specifically, we also evaluated the HLA matching probabilities within and between geographic regions and analyzed the regional differences in the HLA diversities in China. We believe that the data presented in this study might be useful for unrelated HLA-matched donor searches, donor registry planning, population genetic studies, and anthropogenesis

  7. Protective and susceptible HLA polymorphisms in IgA nephropathy patients with end-stage renal failure.

    PubMed

    Doxiadis, I I; De Lange, P; De Vries, E; Persijn, G G; Claas, F H

    2001-04-01

    Idiopathic immunoglobulin A (IgA) nephropathy is characterised by an extreme variability in clinical course, leading to end-stage renal failure in 15-20% of adults. This subgroup of patients with IgA nephropathy is usually included in the waiting lists of organ exchange organisations. The frequency of HLA-A,B,DR antigens of this subset of IgA nephropathy patients was calculated and compared to controls. The antigens HLA-B35 and DR5 were significantly increased in the patients with relative risk values of 1.385 and 1.487, respectively. The antigens HLA-B7, B8, DR2, and DR3 were found in a significantly lower frequency in the patients as compared to the controls. The relative risk (RR) values ranged between 0.695 and 0.727. Consequently, the haplotypes HLA-A1, B8, DR3, HLA-A3, B7, DR2, HLA-A2, B7, DR2 together with HLA-A1, B15, DR4, HLA-A9, B12, DR7, and HLA-A10, B18, DR2 were found to be protective with RR values ranging from 0.309 to 0.587. The only susceptible haplotype observed was HLA-A2-B5, DR5 (RR=2.990).

  8. Characterisation of TNF block haplotypes affecting the production of TNF and LTA.

    PubMed

    Tan, J H; Temple, S E L; Kee, C; Waterer, G W; Tan, C R T; Gut, I; Price, P

    2011-02-01

    Polymorphisms in the central major histocompatibility complex (MHC) (particularly TNF and adjacent genes) associate with several immunopathological diseases and with susceptibility to pneumonia. The MHC is characterised by strong linkage disequilibrium (LD), so identification of loci affecting disease must be based on haplotypes. We have defined 31 tumour necrosis factor (TNF) block haplotypes (denoted FV1-31) in Caucasians, Asians and Australian Aboriginals. This study correlates the carriage of TNF block haplotypes with TNF and lymphotoxin alpha (LTA) protein production by peripheral blood mononuclear cells from 205 healthy Caucasian subjects, following in vitro stimulation with Streptococcus pneumoniae (S. pneumoniae; gram-positive bacteria), Escherichia coli (E. coli; gram-negative bacteria) or TNF over 4, 8 and 24 h. Fifteen haplotypes were present at >1%, accounting for 94.5% of the cohort. The haplotypes were grouped into five families based on common alleles. Following stimulation, cells from carriers of the FV10 haplotype (family 2) produced less LTA compared with non-FV10 carriers. Carriers of the FV18 haplotype (family 4) produced more LTA than other donors. Induction of TNF by S. pneumoniae following 24 h stimulation was also greater in donors with FV18. The FV18 haplotype associated with the 44.1 MHC ancestral haplotype (HLA-A2, -C5, -B44, -DRB1*0401 and -DQB1*0301) that has few disease associations. FV16 occurred in the 8.1 MHC haplotype (HLA-A2, B8, DR3) that is associated with multiple immunopathological diseases. FV16 did not affect TNF or LTA levels. The findings suggest that many genetic variations critical in vivo are not effectively modelled by short-term cultures.

  9. Identification of MHC Haplotypes Associated with Drug-induced Hypersensitivity Reactions in Cynomolgus Monkeys.

    PubMed

    Wu, Hong; Whritenour, Jessica; Sanford, Jonathan C; Houle, Christopher; Adkins, Karissa K

    2017-01-01

    Drug-induced hypersensitivity reactions can significantly impact drug development and use. Studies to understand risk factors for drug-induced hypersensitivity reactions have identified genetic association with specific human leukocyte antigen (HLA) alleles. Interestingly, drug-induced hypersensitivity reactions can occur in nonhuman primates; however, association between drug-induced hypersensitivity reactions and major histocompatibility complex (MHC) alleles has not been described. In this study, tissue samples were collected from 62 cynomolgus monkeys from preclinical studies in which 9 animals had evidence of drug-induced hypersensitivity reactions. Microsatellite analysis was used to determine MHC haplotypes for each animal. A total of 7 haplotypes and recombinant MHC haplotypes were observed, with distribution frequency comparable to known MHC I allele frequency in cynomolgus monkeys. Genetic association analysis identified alleles from the M3 haplotype of the MHC I B region (B*011:01, B*075:01, B*079:01, B*070:02, B*098:05, and B*165:01) to be significantly associated (χ(2) test for trend, p < 0.05) with occurrence of drug-induced hypersensitivity reactions. Sequence similarity from alignment of alleles in the M3 haplotype B region and HLA alleles associated with drug-induced hypersensitivity reactions in humans was 86% to 93%. These data demonstrate that MHC alleles in cynomolgus monkeys are associated with drug-induced hypersensitivity reactions, similar to HLA alleles in humans.

  10. Ancestral association between HLA and HFE H63D and C282Y gene mutations from northwest Colombia

    PubMed Central

    Rodriguez, Libia M; Giraldo, Mabel C; Velasquez, Laura I; Alvarez, Cristiam M; Garcia, Luis F; Jimenez-Del-Rio, Marlene; Velez-Pardo, Carlos

    2015-01-01

    A significant association between HFE gene mutations and the HLA-A*03-B*07 and HLA-A*29-B*44 haplotypes has been reported in the Spanish population. It has been proposed that these mutations are probably connected with Celtic and North African ancestry, respectively. We aimed to find the possible ancestral association between HLA alleles and haplotypes associated with the HFE gene (C282Y and H63D) mutations in 214 subjects from Antioquia, Colombia. These were 18 individuals with presumed hereditary hemochromatosis (“HH”) and 196 controls. The HLA-B*07 allele was in linkage disequilibrium (LD) with C282Y, while HLA-A*23, A*29, HLA-B*44, and B*49 were in LD with H63D. Altogether, our results show that, although the H63D mutation is more common in the Antioquia population, it is not associated with any particular HLA haplotype, whereas the C282Y mutation is associated with HLA-A*03-B*07, this supporting a northern Spaniard ancestry. PMID:25983618

  11. A Case Cluster Demonstrating the Relationship between HLA Concordance and Virologic and Disease Outcomes in Human Immunodeficiency Virus Infection

    PubMed Central

    Chaillon, A.; Gianella, S.; Luna, M. Massanella; Little, S.J.; Richman, D.D.; Mehta, S.R.

    2013-01-01

    We present a detailed analysis of sexual HIV transmission from one source partner to two recipients. The HLA haplotypes between the source partner and one recipient were very similar with 7 out of 8 HLA alleles from four loci (HLA A, B C and DRB) shared, while the other recipient shared only one allele. The immunologic outcomes between the two recipients differed dramatically, despite the absence of apparent virologic differences in their inoculums. We suggest that non-viral factors, which might be related to differences in the HLA profile, played a role in determining different CD4+ T-cells dynamics for these two recipients. PMID:24418543

  12. Analysis of HLA-DRB3 alleles and supertypical genotypes in the MHC Class II region in sporadic inclusion body myositis.

    PubMed

    Rojana-udomsart, Arada; Mitrpant, Chalermchai; James, Ian; Witt, Campbell; Needham, Merrilee; Day, Timothy; Kiers, Lynette; Corbett, Alastair; Martinez, Patricia; Wilton, Steve D; Mastaglia, Frank L

    2013-01-15

    We compared the carriage frequencies of HLA-DRB3 and its major alleles and of HLA-DRB4 and HLA-DRB5 in an Australian sIBM cohort and a population control group who had previously been genotyped for the HLA-DRB1*03:01 risk allele. There was a strong disease association with the carriage of the DRB3*01:01 allele which was accounted for by its linkage disequilibrium with DRB1*03:01. The carriage of HLA-DRB4 was found to be strongly protective and abrogated the risk effect of HLA-DRB1*03:01. The findings indicate that haplotypic combinations of alleles at the HLA-DRB1 and secondary HLA-DRB loci have important risk modifying effects in sIBM.

  13. HLA class II alleles and risk for peripheral neuropathy in type 2 diabetes patients

    PubMed Central

    Marzban, Ahmad; Kiani, Javad; Hajilooi, Mehrdad; Rezaei, Hamzeh; Kahramfar, Zohreh; Solgi, Ghasem

    2016-01-01

    The potential impact of human leukocyte antigen (HLA) genotype variations on development of diabetic peripheral neuropathy (DPN) is not well determined. This study aimed to identify the association of HLA class II alleles with DPN in type 2 diabetes (T2D) patients. Totally 106 T2D patients, 49 with DPN and 57 without DPN, and 100 ethnic-matched healthy controls were analyzed. Both groups of the patients were matched based on sex, age, body mass index (BMI) and duration of T2D. Polyneuropathy was diagnosed using electrodiagnostic methods. HLA-DRB1 and DQB1 genotyping was performed in all subjects by the polymerase chain reaction with sequence-specific primers (PCR-SSP) method. T2D patients with DPN showed higher frequencies of HLA-DRB1*10 and DRB1*12 alleles compared to control group (P = 0.04). HLA-DQB1*02 allele and HLA-DRB1*07-DQB1*02 haplotype were associated with a decreased risk for developing DPN in T2D patients (P = 0.02 and P = 0.05 respectively). Also, patients with severe neuropathy showed higher frequencies of DRB1*07 (P = 0.003) and DQB1*02 (P = 0.02) alleles than those with mild-to-moderate form of neuropathy. The distribution of DRB1 and DQB1 alleles and haplotypes were not statistically different between all patients and healthy controls. Our findings implicate a possible protective role of HLA-DQB1*02 allele and HLA-DRB1*07-DQB1*02 haplotype against development of peripheral neuropathy in T2D patients. Therefore, variations in HLA genotypes might be used as genetic markers for prediction and potentially management of neuropathy in T2D patients. PMID:28123430

  14. High-accuracy imputation for HLA class I and II genes based on high-resolution SNP data of population-specific references.

    PubMed

    Khor, S-S; Yang, W; Kawashima, M; Kamitsuji, S; Zheng, X; Nishida, N; Sawai, H; Toyoda, H; Miyagawa, T; Honda, M; Kamatani, N; Tokunaga, K

    2015-12-01

    Statistical imputation of classical human leukocyte antigen (HLA) alleles is becoming an indispensable tool for fine-mappings of disease association signals from case-control genome-wide association studies. However, most currently available HLA imputation tools are based on European reference populations and are not suitable for direct application to non-European populations. Among the HLA imputation tools, The HIBAG R package is a flexible HLA imputation tool that is equipped with a wide range of population-based classifiers; moreover, HIBAG R enables individual researchers to build custom classifiers. Here, two data sets, each comprising data from healthy Japanese individuals of difference sample sizes, were used to build custom classifiers. HLA imputation accuracy in five HLA classes (HLA-A, HLA-B, HLA-DRB1, HLA-DQB1 and HLA-DPB1) increased from the 82.5-98.8% obtained with the original HIBAG references to 95.2-99.5% with our custom classifiers. A call threshold (CT) of 0.4 is recommended for our Japanese classifiers; in contrast, HIBAG references recommend a CT of 0.5. Finally, our classifiers could be used to identify the risk haplotypes for Japanese narcolepsy with cataplexy, HLA-DRB1*15:01 and HLA-DQB1*06:02, with 100% and 99.7% accuracy, respectively; therefore, these classifiers can be used to supplement the current lack of HLA genotyping data in widely available genome-wide association study data sets.

  15. Neuroleptics under high risk conditions.

    PubMed

    Oyewumi, L K

    1983-08-01

    A critical review of various high risk situations in which neuroleptics could be used and have been used in clinical practice is presented. These high risk situations include: women of child bearing age (pregnant women, lactating and/or nursing mothers), the two extremes of life (children and the elderly), patients with sexual dysfunction, patients with tardive dyskinesia, non-psychotic psychiatric patients, physically ill and suicidal patients. The extraordinary applications of these drugs, such as for rapid tranquilization and megadose regimens are examined. The author provides guidelines for the use of neuroleptics in these clinical situations.

  16. Korean BAC library construction and characterization of HLA-DRA, HLA-DRB3.

    PubMed

    Park, Mi-Hyun; Lee, Hye-Ja; Bok, Jeong; Kim, Cheol-Hwan; Hong, Seong-Tshool; Park, Chan; Kimm, KuChan; Oh, Bermseok; Lee, Jong-Young

    2006-07-31

    A human bacterial artificial chromosome (BAC) library was constructed with high molecular weight DNA extracted from the blood of a male Korean. This Korean BAC library contains 100,224 clones of insert size ranging from 70 to 150 kb, with an average size of 86 kb, corresponding to a 2.9-fold redundancy of the genome. The average insert size was determined from 288 randomly selected BAC clones that were well distributed among all the chromosomes. We developed a pooling system and three-step PCR screen for the Korean BAC library to isolate desired BAC clones, and we confirmed its utility using primer pairs designed for one of the clones. The Korean BAC library and screening pools will allow PCR-based screening of the Korean genome for any gene of interest. We also determined the allele types of HLA-DRA and HLA-DRB3 of clone KB55453, located in the HLA class II region on chromosome 6p21.3. The HLA-DRA and DRB3 genes in this clone were identified as the DRA*010202 and DRB3*01010201 types, respectively. The haplotype found in this library will provide useful information in future human disease studies.

  17. [Frequency and linkage disequilibrium of specific HLA-DR and HLA-DQ genes in Chinese Han population].

    PubMed

    Yang, Su-Xia; Hu, Zhi-Fei; Zu, Qiang; Lu, Jin-Shan; Zhang, Xu; Dong, Jun

    2012-12-01

    This study was aimed to investigate the distribution feature of HLA-DR/DQ gene linkage disequilibrium in Chinese Han population and to improve the accuracy of HLA matching results. Genotyping of HLA-DR and HLA-DQ gene locus was performed using PCR-SSP typing in Chinese Han population receiving kidney transplantation. The results showed that there were 29 new linkage combinations in 1799 patients, in which DR13-DQ5, DR11-DQ8 and DR8-DQ8 were discovered for 11, 8 and 7 times respectively while DR9-DQ8, DR12-DQ6 and DR14-DQ4 were both discovered for 6 times. The linkage disequilibrium parameters of these haplotypes were negative, showing that these linkages were uncommon. It is concluded that this study not only enriches the classical HLA-DR/DQ linkage combinations, but also indicates the national relevance of combination distribution, and it has great importance in improving the accuracy of HLA matching experiments and reducing unnecessary repeated work.

  18. Plasma levels of soluble HLA-E and HLA-F at diagnosis may predict overall survival of neuroblastoma patients.

    PubMed

    Morandi, Fabio; Cangemi, Giuliana; Barco, Sebastiano; Amoroso, Loredana; Giuliano, Maria; Gigliotti, Anna Rita; Pistoia, Vito; Corrias, Maria Valeria

    2013-01-01

    The purpose of this study was to identify the plasma/serum biomarkers that are able to predict overall survival (OS) of neuroblastoma (NB) patients. Concentration of soluble (s) biomarkers was evaluated in plasma (sHLA-E, sHLA-F, chromogranin, and B7H3) or serum (calprotectin) samples from NB patients or healthy children. The levels of biomarkers that were significantly higher in NB patients were then analyzed considering localized or metastatic subsets. Finally, biomarkers that were significantly different in these two subsets were correlated with patient's outcome. With the exception of B7H3, levels of all molecules were significantly higher in NB patients than those in controls. However, only chromogranin, sHLA-E, and sHLA-F levels were different between patients with metastatic and localized tumors. sHLA-E and -F levels correlated with each other but not chromogranin. Chromogranin levels correlated with different event-free survival (EFS), whereas sHLA-E and -F levels also correlated with different OS. Association with OS was also detected considering only patients with metastatic disease. In conclusion, low levels of sHLA-E and -F significantly associated with worse EFS/OS in the whole cohort of NB patients and in patients with metastatic NB. Thus, these molecules deserve to be tested in prospective studies to evaluate their predictive power for high-risk NB patients.

  19. Non-HLA region genes in insulin dependent diabetes mellitus.

    PubMed

    Field, L L

    1991-09-01

    investigators, however the specific phenotypic interaction effects reported have differed. Nevertheless, pooled data from three studies of Gm/HLA haplotype segregation in affected sib pairs shows significantly increased sharing of Gm haplotypes in affected pairs who share both HLA haplotypes. The biological mechanisms underlying the direct (HLA, INS) and indirect (Gm-TCRB, Gm-HLA, Gm-INS) effects of these genetic regions on IDDM susceptibility remain to be elucidated.

  20. Perceptions of high risk sports.

    PubMed

    Pedersen, D M

    1997-10-01

    High risk sports were rated as to risk, appeal, and likelihood of participation by 282 men and 162 women. Ascending order of perceived risk was skiing, scuba diving, bungee jumping, rock climbing, motorcycle racing, hang gliding, cliff jumping, and skydiving. Profile analysis showed stated likelihood of participation to be directly related to appeal and inversely related to perceived risk.

  1. An Overview. High Risk Series.

    ERIC Educational Resources Information Center

    General Accounting Office, Washington, DC.

    This report provides an overview of efforts undertaken by the U.S. General Accounting Office (GAO) in 1990 to review and report on federal program areas its work identified as high risk because of vulnerabilities to waste, fraud, abuse, and mismanagement. It reviews the current status of efforts to address these concerns. The six categories of…

  2. Analysis of HLA and disease susceptibility: Chromosome 6 genes and sex influence long-QT phenotype

    SciTech Connect

    Weitkamp, L.R.; Moss, A.J.; Hall, W.J.; Robinson, J.L.; Guttormsen, S.A.; Lewis, R.A.; MacCluer, J.W.; Schwartz, P.J.; Locati, E.H.; Tzivoni, D.

    1994-12-01

    The long-QT (LQT) syndrome is a genetically complex disorder that is characterized by syncope and fatal ventricular arrhythmias. LQT syndrome, as defined by a prolonged electrocardiographic QT interval, has a higher incidence in females than in males and does not exhibit Mendelian transmission patterns in all families. Among those families that are nearly consistent with Mendelian transmission, linkage between a locus for LQT syndrome and the H-ras-1 locus on the short arm of chromosome 11 has been reported in some families but not in others. Earlier analyses suggesting that LQT syndrome might be caused by a gene in the HLA region of chromosome 6 were not confirmed by standard linkage analyses. Here, we present an analysis of HLA haplotype sharing among affected pedigree members, showing an excess of haplotype sharing in a previously published Japanese pedigree and possibly also in 15 families of European descent. The haplotypes shared by affected individuals derive from both affected and unaffected parents. In an analysis of independent (unrelated) HLA haplotypes, we also found a nonrandom distribution of HLA-DR genes in LQT syndrome patients compared with controls, suggesting an association between the LQT phenotype and specific HLA-DR genes. Our data indicate that DR2 has a protective effect and, particularly in males, that DR7 may increase susceptibility to the LQT syndrome. Thus, LQT syndrome may be influenced by genes on chromosomes 11 and 6, possibly with a sex-specific effect. These results provide a model for an effect of HLA-region genes inherited from either parent on the expression of an illness that may be determined principally by alleles at loci not linked to HLA.

  3. HLA genes in Uros from Titikaka Lake, Peru: origin and relationship with other Amerindians and worldwide populations.

    PubMed

    Arnaiz-Villena, A; Gonzalez-Alcos, V; Serrano-Vela, J I; Reguera, R; Barbolla, L; Parga-Lozano, C; Gómez-Prieto, P; Abd-El-Fatah-Khalil, S; Moscoso, J

    2009-06-01

    Uros population from the Titikaka Lake live in about 42 floating reed ('totora') islands in front of Puno City (Peru) at a 4000 m high altiplano. They present both an mtDNA and a human leucocyte antigen (HLA) profile different from the surrounding populations: mtDNA A2 haplogroup is common to Uros and Amazon forest lowland Amerindians. HLA genetic distances between populations have been calculated and neighbour-joining dendrograms and correspondence analyses were carried out. Approximately 15 006 HLA chromosomes from worldwide populations have been used for comparisons. Only eight HLA-A alleles have been found, three of them accounting for most of the frequencies. The same phenomenon is seen for HLA-B, HLA-DRB1 and HLA-DQB1 alleles: a few alleles (3, 4 and 3, respectively) are present in most individuals. The presence of HLA-B*4801 and HLA-DRB1*0901 alleles in a relatively high frequency (although not the most frequent alleles found) is a characteristic shared with Asians and some populations from the Andean altiplano. Three specific Uros haplotypes have been found among the most frequent ones: HLA-A*680102-B*3505-DRB1*0403-DQB1*0302; HLA-A*2402-B*1504-DRB1*1402-DQB1*0301; and HLA-A*2402-B*4801-DRB1*0403-DQB1*0302. The present study suggests that Uros may have been one of the first populations from the shores of the Titikaka Lake coming from the Amazonian forest, which might have given rise to other later differentiated ethnic group (i.e. Aymaras). Uros HLA profile is also useful to study genetic epidemiology of diseases linked to HLA and to construct a future transplant waiting list by adding up regional lists in order to get a bigger pool for transplanting with better HLA matching.

  4. HLA Class I and II study in a mestizo family with high incidence of autoimmune disease.

    PubMed

    de Sorrentino, Alicia Habegger; Young, Marcela; Marinic, Karina; Motta, Patricia Fabiana; Baruzzo, Carlos

    2013-01-01

    There are many factors that influence the pathogenesis of autoimmune disease of which host genetic factors play an important role. The aim of this study was to investigate the HLA Class I and II genes in a family with a high incidence of AID to establish whether they contribute to the development of these disease. Four of them had been diagnosed with SLE and one with AHA. The patients with SLE showed the presence of HLA-A*02 B*40 DRB1*04:07 DQB1*03:02 haplotype with a high statistical significance. This haplotype was not present in the healthy individuals and in the patient with AHA, although the DRB1*04:07 DQB1*03:02 haplotype (carried by both parents) was found in the AHA patients and one of the healthy individuals. We must consider how HLA Class I in linkage disequilibrium with HLA Class II may be involved in susceptibility or in the development of SLE. An extensive study in this population should be conducted to establish the true participation of the HLA Class I region.

  5. Nonfrequent but well-documented, rare and very rare HLA alleles observed in the Croatian population.

    PubMed

    Grubic, Z; Burek Kamenaric, M; Maskalan, M; Stingl Jankovic, K; Zunec, R

    2014-12-01

    The aim of the study was to evaluate the presence of nonfrequent, rare and very rare alleles among Croats and to estimate whether they are associated with specific alleles at other human leukocyte antigen (HLA) loci. This retrospective study included the typing results from the last 10 years; total number of individuals included was approximately 45,000. Among 17 alleles so far observed only once in our population, 6 (A*24:41, B*07:02:28, B*35:03:03, B*39:40N, DRB1*13:23 and DRB1*14:111) belong to very rare alleles, 2 (B*44:16 and DRB1*01:31) belong to rare alleles according to the 'Rare Alleles Detector' tool ( www.allelefrequencies.net), while for the B*35:101:01 allele published data exist only in the IMGT/HLA database. The remaining eight HLA alleles observed only once among Croats are considered as frequent according to the 'Rare Alleles Detector'. Those 17 HLA alleles are not declared as common well defined (CWD) alleles in the CWD allele catalogue 2.0.0. Haplotype analysis of nonfrequent alleles detected in our sample supports the idea that different populations, although similar in some aspects regarding HLA allele and haplotype distribution, still have some unique characteristics. This is the case for A*01:02, B*39:10 and DRB1*13:32 which form haplotypes unreported to date among our subjects.

  6. Localization of predisposition to Hodgkin disease in the HLA class II region

    SciTech Connect

    Klitz, W. ); Aldrich, C.L.; Fildes, N.; Begovich, A.B.; Horning, S.J. )

    1994-03-01

    Molecular typing of HLA class II loci has been performed on a sample of 196 patients with Hodgkin lymphoma. Division of patients into histological categories - nodular sclerosing Hodgkin disease versus all other types - shows significant overall association of the nodular sclerosing group with the HLA class II region. Haplotypes and alleles defined for the four loci typed - DRB1, DQA1, DQB1, and DPB1 - were present in both excess and deficit in the nodular sclerosing sample. Some of the effects are attributable to particular DRB1 and DQB1 alleles, while other effects are best explained by haplotypes marking the entire class II region or to particular combinations of alleles from two or more loci. These data also explain why earlier studies showed HLA linkage but not association, and they substantiate the specific involvement of the immune system in certain neoplastic diseases. 38 refs., 6 tabs.

  7. Association of HLA-G +3142 C>G polymorphism and breast cancer in Tunisian population.

    PubMed

    Zidi, Inès; Dziri, Olfa; Zidi, Nour; Sebai, Refaat; Boujelebene, Nadia; Ben Hassine, Amna; Ben Yahia, Hamza; Laaribi, Ahmed Baligh; Babay, Wafa; Rifi, Hela; Mezlini, Amel; Chelbi, Hanene

    2016-08-01

    HLA-G is highly expressed in cancer. Also, it is associated to its progression. Here, we explored the relationship between two HLA-G polymorphisms with breast cancer (BC) and tried to make a correlation with sHLA-G levels. We genotyped 104 patients with BC and 83 controls (CTRL) for HLA-G 14-bp insertion/deletion (Ins/Del) and HLA-G +3142 C>G polymorphisms. The mutations were identified with PCR and PCR-RFLP. The sHLA-G dosage was performed on plasma samples by a specific ELISA. A significant association with BC was found concerning the G allele in the +3142 C>G polymorphism (p = 0.0004). The G/G genotype is the protective genotype (1 % in BC patients vs. 13.1 % in CTRL, OR 0.065, 95 % CI 0.008-0.523). No statistically significant differences were observed for the 14-bp Ins/Del polymorphism between BC patients and controls frequencies. The protection by G/G genotype of +3142 C>G polymorphism is maintained in young patients (<50 years, p = 0.0006) and in early-diagnosed BC patients (<50 years, p = 0.0033). In addition, an association was found between the haplotypes inferred by both HLA-G polymorphisms and BC susceptibility. Indeed, the (DelG) haplotype is found as the protective haplotype against BC (OR 0.269, 95 % CI 0.081-0.895, p = 0.023). The ELISA dosage of sHLA-G revealed increased levels in BC compared to CTRL (p < 0.0001). We demonstrated also that sHLA-G is closely associated with advanced stages of BC without significance. sHLA-G is increased in TNM IV and SBR III subgroups. It is also enhanced in patients with a tumor size over 20 mm and in triple-negative patients. Taken together, our findings demonstrate, for the first time, the association of HLA-G +3142 C>G polymorphism with BC susceptibility in Tunisian population. Our results revealed also a potential implication of sHLA-G in advanced stages of BC.

  8. The peopling of Madeira Archipelago (Portugal) according to HLA genes.

    PubMed

    Arnaiz-Villena, A; Reguera, R; Ferri, A; Barbolla, L; Abd-El-Fatah-Khalil, S; Bakhtiyarova, N; Millan, P; Moscoso, J; Mafalda, A; Serrano-Vela, J I

    2009-02-01

    The Madeira-Porto Santo Archipelago was officially colonized in 1420 by Portuguese settlers. Its importance in Columbus' information for the American discovery and for slave traffic across the Atlantic is unquestionable. Thus, a complex peopling may have given rise to a present-day high admixture of ethnicities according to HLA genes. A sample of 173 healthy unrelated Madeirans was analysed and compared with 6986 HLA chromosomes from other worldwide populations. Genetic distances, neighbour-joining dendrograms and correspondence analyses were used for comparisons. Southern European, North African (including Canary Islands), Jewish and Mediterranean typical HLA alleles were found and genetic distances from Madeirans to these populations were the closest ones. In addition A*24-B*65-DRB1*0102-DQB1*0501 and A*68-B*08-DRB1*0301-DQB1*0201 haplotypes were newly found in Madeira and not found in any other population. Jewish-Armenian-Middle East haplotype (A*33-B*65-DRB1*0102-DQB1*0501) is one of the most common haplotypes; this haplotype is also present in Spaniards and North Africans. Quantitatively, Portuguese, North Africans (Algerians), Spaniards and Canary Islanders (in this order) are the most important parental populations to Madeirans. Results are discussed on the basis of the recorded historical peopling which does not show a noticeable African gene input in present-day Madeiran population according to our data; one of the closest related populations found is the Canary Islanders, suggesting that Guanche (Canary Islands first inhabitants) slaves gene flow is still noticed at present, both in Madeira and in Canary Islands populations.

  9. Association of Parkinson Disease with Structural and Regulatory Variants in the HLA Region

    PubMed Central

    Wissemann, William T.; Hill-Burns, Erin M.; Zabetian, Cyrus P.; Factor, Stewart A.; Patsopoulos, Nikolaos; Hoglund, Bryan; Holcomb, Cherie; Donahue, Ryan J.; Thomson, Glenys; Erlich, Henry; Payami, Haydeh

    2013-01-01

    Historically, association of disease with the major histocompatibility complex (HLA) genes has been tested with HLA alleles that encode antigen-binding affinity. The association with Parkinson disease (PD), however, was discovered with noncoding SNPs in a genome-wide association study (GWAS). We show here that several HLA-region SNPs that have since been associated with PD form two blocks tagged by rs3129882 (p = 9 × 10−11) and by rs9268515 and/or rs2395163 (p = 3 × 10−11). We investigated whether these SNP-associations were driven by HLA-alleles at adjacent loci. We imputed class I and class II HLA-alleles for 2000 PD cases and 1986 controls from the NeuroGenetics Research Consortium GWAS and sequenced a subset of 194 cases and 204 controls. We were therefore able to assess accuracy of two imputation algorithms against next-generation-sequencing while taking advantage of the larger imputed data sets for disease study. Additionally, we imputed HLA alleles for 843 cases and 856 controls from another GWAS for replication. PD risk was positively associated with the B∗07:02_C∗07:02_DRB5∗01_DRB1∗15:01_DQA1∗01:02_DQB1∗06:02 haplotype and negatively associated with the C∗03:04, DRB1∗04:04 and DQA1∗03:01 alleles. The risk haplotype and DQA1∗03:01 lost significance when conditioned on the SNPs, but C∗03:04 (OR = 0.72, p = 8 × 10−6) and DRB1∗04:04 (OR = 0.65, p = 4 × 10−5) remained significant. Similarly, rs3129882 and the closely linked rs9268515 and rs2395163 remained significant irrespective of HLA alleles. rs3129882 and rs2395163 are expression quantitative trait loci (eQTLs) for HLA-DR and HLA-DQ (9 × 10−5 ≥ PeQTL ≥ 2 × 10−79), suggesting that HLA gene expression might influence PD. Our data suggest that PD is associated with both structural and regulatory elements in HLA. Furthermore, our study demonstrates that noncoding SNPs in the HLA region can be associated with disease irrespective of HLA alleles, and that

  10. KIR haplotypes defined by segregation analysis in 59 Centre d'Etude Polymorphisme Humain (CEPH) families.

    PubMed

    Martin, M P; Single, R M; Wilson, M J; Trowsdale, J; Carrington, M

    2008-12-01

    The killer cell immunoglobulin-like receptor (KIR) gene cluster exhibits extensive allelic and haplotypic diversity. Variation at the locus is associated with an increasing number of human diseases, reminiscent of the HLA loci. Characterization of diversity at the KIR locus has progressed over the past several years, particularly since the sequence of entire KIR haplotypes have become available. To determine the extent of KIR haplotypic variability among individuals of northern European descent, we genotyped 59 CEPH families for presence/absence of all KIR genes and performed limited allelic subtyping at several KIR loci. A total of 20 unique haplotypes differing in gene content were identified, the most common of which was the previously defined A haplotype (f = 0.52). Several unusual haplotypes that probably arose as a consequence of unequal crossing over events were also identified. Linkage disequilibrium (LD) analysis indicated strong negative and positive LD between several pairs of genes, values that may be useful in determining haplotypic structure when family data are not available. These data provide a resource to aid in the interpretation of disease association data involving individuals of European descent.

  11. Detection of ancestry informative HLA alleles confirms the admixed origins of Japanese population.

    PubMed

    Nakaoka, Hirofumi; Mitsunaga, Shigeki; Hosomichi, Kazuyoshi; Shyh-Yuh, Liou; Sawamoto, Taiji; Fujiwara, Tsutomu; Tsutsui, Naohisa; Suematsu, Koji; Shinagawa, Akira; Inoko, Hidetoshi; Inoue, Ituro

    2013-01-01

    The polymorphisms in the human leukocyte antigen (HLA) region are powerful tool for studying human evolutionary processes. We investigated genetic structure of Japanese by using five-locus HLA genotypes (HLA-A, -B, -C, -DRB1, and -DPB1) of 2,005 individuals from 10 regions of Japan. We found a significant level of population substructure in Japanese; particularly the differentiation between Okinawa Island and mainland Japanese. By using a plot of the principal component scores, we identified ancestry informative alleles associated with the underlying population substructure. We examined extent of linkage disequilibrium (LD) between pairs of HLA alleles on the haplotypes that were differentiated among regions. The LDs were strong and weak for pairs of HLA alleles characterized by low and high frequencies in Okinawa Island, respectively. The five-locus haplotypes whose alleles exhibit strong LD were unique to Japanese and South Korean, suggesting that these haplotypes had been recently derived from the Korean Peninsula. The alleles characterized by high frequency in Japanese compared to South Korean formed segmented three-locus haplotype that was commonly found in Aleuts, Eskimos, and North- and Meso-Americans but not observed in Korean and Chinese. The serologically equivalent haplotype was found in Orchid Island in Taiwan, Mongol, Siberia, and Arctic regions. It suggests that early Japanese who existed prior to the migration wave from the Korean Peninsula shared ancestry with northern Asian who moved to the New World via the Bering Strait land bridge. These results may support the admixture model for peopling of Japanese Archipelago.

  12. Evolutionary analysis of classical HLA class I and II genes suggests that recent positive selection acted on DPB1*04:01 in Japanese population.

    PubMed

    Kawashima, Minae; Ohashi, Jun; Nishida, Nao; Tokunaga, Katsushi

    2012-01-01

    The human leukocyte antigen (HLA) genes exhibit the highest degree of polymorphism in the human genome. This high degree of variation at classical HLA class I and class II loci has been maintained by balancing selection for a long evolutionary time. However, little is known about recent positive selection acting on specific HLA alleles in a local population. To detect the signature of recent positive selection, we genotyped six HLA loci, HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, and HLA-DPB1 in 418 Japanese subjects, and then assessed the haplotype homozygosity (HH) of each HLA allele. There were 120 HLA alleles across the six loci. Among the 80 HLA alleles with frequencies of more than 1%, DPB1*04∶01, which had a frequency of 6.1%, showed exceptionally high HH (0.53). This finding raises the possibility that recent positive selection has acted on DPB1*04∶01. The DPB1*04∶01 allele, which was present in the most common 6-locus HLA haplotype (4.4%), A*33∶03-C*14∶03-B*44∶03-DRB1*13∶02-DQB1*06∶04-DPB1*04∶01, seems to have flowed from the Korean peninsula to the Japanese archipelago in the Yayoi period. A stochastic simulation approach indicated that the strong linkage disequilibrium between DQB1*06∶04 and DPB1*04∶01 observed in Japanese cannot be explained without positive selection favoring DPB1*04∶01. The selection coefficient of DPB1*04∶01 was estimated as 0.041 (95% credible interval 0.021-0.077). Our results suggest that DPB1*04∶01 has recently undergone strong positive selection in Japanese population.

  13. The Royan Public Umbilical Cord Blood Bank: Does It Cover All Ethnic Groups in Iran Based on HLA Diversity?

    PubMed Central

    Ebrahimkhani, Saeideh; Farjadian, Shirin; Ebrahimi, Marzieh

    2014-01-01

    Summary Background Umbilical cord blood (UCB) stem cells allow the transplantation of partially human leukocyte antigen (HLA)-matched grafts and are a valuable resource for the treatment of hematologic malignancies and heritable hematologic, immunologic and metabolic diseases, especially when a compatible bone marrow donor is unavailable. The aim of this study was to determine how many ethnic groups in Iran are covered by the available UCB units based on HLA diversity. Methods From 2009 until mid-2013, 4,981 (30.3%) of the 16,437 UCB samples collected met the storage criteria and were cryopreserved at a public cord blood bank (CBB) in Tehran, Iran. HLA-A, -B and -DRB1 were typed in 1,793 samples. Results The mean volume of the cryopreserved samples was 81.25 ± 20.3 ml. The range of total nucleated cells per unit was 51 × 107-107 × 107. The most common HLA alleles were HLA-A*2 (17%) and HLA-A*24 (15.6%), HLA-B*35 (16.8%) and HLA-B*51 (13.9%), and HLA-DRB1*11 (20%) and HLA-DRB1*15 (14%). The predominant haplotypes were HLA-A*24-B*35-DRB1*11 (2%), HLA-A*02-B*50-DR*07 (1.8%), and HLA-A*02-B*51-DRB1*11 (1.5%). Conclusions Based on the HLA-DRB1 profiles, the UCB units available at the Royan public UCB bank are a potentially adequate resource for hematopoietic stem cell transplantation for Iranian recipients belonging to particular ethnic groups. Regular educational programs to improve the public knowledge of UCB for transplantation can enhance the public CBB stocks for all Iranian ethnic groups in the future. PMID:24847189

  14. Pretransplant HLA mistyping in diagnostic samples of acute myeloid leukemia patients due to acquired uniparental disomy.

    PubMed

    Dubois, V; Sloan-Béna, F; Cesbron, A; Hepkema, B G; Gagne, K; Gimelli, S; Heim, D; Tichelli, A; Delaunay, J; Drouet, M; Jendly, S; Villard, J; Tiercy, J-M

    2012-09-01

    Although acquired uniparental disomy (aUPD) has been reported in relapse acute myeloid leukemia (AML), pretransplant aUPD involving chromosome 6 is poorly documented. Such events could be of interest because loss of heterozygosity (LOH) resulting from aUPD in leukemic cells may lead to erroneous results if HLA typing for hematopoietic stem cell donor searches is performed on blood samples drawn during blastic crisis. We report here six AML patients whose HLA typing was performed on DNA extracted from peripheral blood obtained at diagnosis. We observed LOH involving the entire HLA region (three patients), HLA-A, B, C (two patients) and HLA-A only (one patient). An array-comparative genomic hybridization showed that copy number was neutral for all loci, thus revealing partial aUPD of chromosome 6p21. When HLA typing was performed on remission blood samples both haplotypes were detected. A 3-4% LOH incidence was estimated in AML patients with high blast counts. Based on DNA mixing experiments, we determined by PCR sequence-specific oligonucleotide hybridization on microbeads arrays a detection threshold for HLA-A, B, DRB1 heterozygosity in blood samples with <80% blasts. Because aUPD may be partial, any homozygous HLA result should be confirmed by a second typing performed on buccal swabs or on blood samples from the patient in remission.

  15. Common variants in the HLA-DRB1-HLA-DQA1 Class II region are associated with susceptibility to visceral leishmaniasis

    PubMed Central

    Fakiola, Michaela; Strange, Amy; Cordell, Heather J.; Miller, E. Nancy; Pirinen, Matti; Su, Zhan; Mishra, Anshuman; Mehrotra, Sanjana; Monteiro, Gloria R.; Band, Gavin; Bellenguez, Céline; Dronov, Serge; Edkins, Sarah; Freeman, Colin; Giannoulatou, Eleni; Gray, Emma; Hunt, Sarah E.; Lacerda, Henio G.; Langford, Cordelia; Pearson, Richard; Pontes, Núbia N.; Rai, Madhukar; Singh, S.P.; Smith, Linda; Sousa, Olivia; Vukcevic, Damjan; Bramon, Elvira; Brown, Matthew A.; Casas, Juan P.; Corvin, Aiden; Duncanson, Audrey; Jankowski, Janusz; Markus, Hugh S.; Mathew, Christopher G.; Palmer, Colin N.A.; Plomin, Robert; Rautanen, Anna; Sawcer, Stephen J.; Trembath, Richard C.; Viswanathan, Ananth C.; Wood, Nicholas W.; Wilson, Mary E.; Deloukas, Panos; Peltonen, Leena; Christiansen, Frank; Witt, Campbell; Jeronimo, Selma M.B.; Sundar, Shyam; Spencer, Chris C.A.; Blackwell, Jenefer M.; Donnelly, Peter

    2013-01-01

    To identify susceptibility loci for visceral leishmaniasis we undertook genome-wide association studies in two populations; 989 cases and 1089 controls from India, and 357 cases in 308 Brazilian families (1970 individuals). The HLA-DRB1-HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, resulting in Pcombined=2.76×10−17 and OR(95%CI)=1.41(1.30-1.52) across the three cohorts at rs9271858. A conditional analysis provided evidence for multiple associations within the HLA-DRB1-HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion the HLA-DRB1-HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species. PMID:23291585

  16. The likelihood ratio and frequency of DQ2/DQ8 haplotypes in Iranian patients with celiac disease

    PubMed Central

    Khosravi, Asghar; Mansouri, Masoume; Rostami-Nejad, Mohammad; Shahbazkhani, Bijan; Ekhlasi, Golnaz; Kalantari, Ebrahim

    2016-01-01

    Aim: The aim of this study was to evaluate the likelihood ratio and frequency of DQ2 and DQ8 in Iranian patients with celiac disease (CD). Background: The HLA DQ2 and HLA DQ8 are the important mediators in the development of celiac disease. A few studies evaluated the frequency of HLA DQ2 and HLA DQ8 haplotypes among the Iranian population with low sample size. Patients and methods: In this cross-sectional study, to predict HLA–DQ2 and DQ8 haplotypes, 141(73 male, 78 female) confirmed CD patients compared to 151 healthy controls were enrolled into this study during 2013-2014. HLA DQ2/ DQ8 haplotypes was determined in cases and controls using PCR-SSP technique. Results: DQ2 and DQ8 were positive in 80% (n=111) and 49% (n= 69) of CD patients and 36% (n=61) and 13% (n=21) of control group respectively. Moreover, 32% (n=45) of CD patients and 5.3% (n=8) of the control group were carrier of both haplotypes. In the case group about one-third of patients (32.2%) were positive for carrying both DQ2 and DQ8 heterodimers while only 5.3% (n=8) of the control group were carrier. In addition, the positive likelihood ratio of DQ2 and DQ8 were 1.74 (CI: 1.4- 2.1), and 2.6 (CI: 1.8– 2.7), respectively. Conclusion: The result of this study showed that the frequency of DQ8 among our population is higher than those reported by European countries, but it is close to those founded in South America and Middle East. This result suggests that the higher prevalence of HLA DQ8 pattern in Iranian CD patients is similar to non-European patients. PMID:26744610

  17. Non-HLA type 1 diabetes genes modulate disease risk together with HLA-DQ and islet autoantibodies

    PubMed Central

    Maziarz, M; Hagopian, W; Palmer, JP; Sanjeevi, CB; Kockum, I; Breslow, N; Lernmark, Å

    2015-01-01

    The possible interrelations between HLA-DQ, non-HLA single nucleotide polymorphisms (SNPs) and islet autoantibodies were investigated at clinical onset in 1-34 year old type 1 diabetes (T1D) patients (n=305) and controls (n=203). Among the non-HLA SNPs reported by the Type 1 Diabetes Genetics Consortium, 24% were supported in this Swedish replication set including that the increased risk of minor PTPN22 allele and high risk HLA was modified by GAD65 autoantibodies. The association between T1D and the minor AA+AC genotype in ERBB3 gene was stronger among IA-2 autoantibody-positive patients (comparison p=0.047). The association between T1D and the common insulin (AA) genotype was stronger among insulin autoantibody (IAA)-positive patients (comparison p=0.008). In contrast, the association between T1D and unidentified 26471 gene was stronger among IAA-negative (comparison p=0.049) and IA-2 autoantibody-negative (comparison p=0.052) patients. Finally, the association between IL2RA and T1D was stronger among IAA-positive than among IAA-negative patients (comparison p=0.028). These results suggest that the increased risk of T1D by non-HLA genes is often modified by both islet autoantibodies and HLA-DQ. The interactions between non-HLA genes, islet autoantibodies and HLA-DQ should be taken into account in T1D prediction studies as well as in prevention trials aimed at inducing immunological tolerance to islet autoantigens. PMID:26513234

  18. Association of HLA-G 3' untranslated region variants with type 1 diabetes mellitus.

    PubMed

    de Albuquerque, Rafael S; Mendes-Junior, Celso Teixeira; Lucena-Silva, Norma; da Silva, Camila Leal Lopes; Rassi, Diane Meire; Veiga-Castelli, Luciana C; Foss-Freitas, Maria Cristina; Foss, Milton César; Deghaide, Neifi Hassan Saloum; Moreau, Philippe; Gregori, Silvia; Castelli, Erick C; Donadi, Eduardo Antônio

    2016-04-01

    Besides the well recognized association of HLA-DRB1 and DQB1 alleles with type 1 diabetes mellitus (T1D), linkage studies have identified a gene region close to the non-classical class I HLA-G gene as an independent susceptibility marker. HLA-G is constitutively expressed in the endocrine compartment of the human pancreas and may play a role in controlling autoimmune responses. We evaluated the genetic diversity of the 3' untranslated region (3'UTR) of HLA-G, which have been associated with HLA-G mRNA post-transcriptional regulation, in 120 Brazilian T1D patients and in 120 healthy controls. We found the +3001 T allele was observed only in T1D patients. Notably, the +3001 T allele was in linkage disequilibrium with polymorphic sites associated with low production of HLA-G mRNA or soluble HLA-G levels. Moreover, T1D patients showed a low frequency of the HLA-G 3'UTR-17 (14bpINS/+3001T/+3003T/+3010C/+3027C/+3035T/+3142G/+3187A/+3196C). The +3010 CC genotype and the UTR-3 haplotype (14bpDEL/+3001C/+3003T/+3010C/+3027C/+3035C/+3142G/+3187A/+3196C), associated with low and moderate soluble HLA-G expression, respectively, were underrepresented in patients. The decreased expression of HLA-G at the pancreas level should be detrimental in individuals genetically prone to produce less HLA-G.

  19. F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort

    PubMed Central

    Schwarz, John; Astermark, Jan; Menius, Erika D.; Carrington, Mary; Donfield, Sharyne M.; Gomperts, Edward D.; Nelson, George W.; Oldenburg, Johannes; Pavlova, Anna; Shapiro, Amy D.; Winkler, Cheryl A.; Berntorp, Erik

    2012-01-01

    Background Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in hemophilia A. It has been suggested that differences in the distribution of factor VIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk. Design and Methods Data from the HIGS Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1+H2) and inhibitor risk among individuals of genetically-determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and HLA were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed. Results H3 was associated with higher inhibitor risk among those genetically-identified (N=49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N=223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development. Conclusion H3 was not an independent predictor of inhibitor risk. Further, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual. PMID:22958194

  20. Haplotyping Problem, A Clustering Approach

    SciTech Connect

    Eslahchi, Changiz; Sadeghi, Mehdi; Pezeshk, Hamid; Kargar, Mehdi; Poormohammadi, Hadi

    2007-09-06

    Construction of two haplotypes from a set of Single Nucleotide Polymorphism (SNP) fragments is called haplotype reconstruction problem. One of the most popular computational model for this problem is Minimum Error Correction (MEC). Since MEC is an NP-hard problem, here we propose a novel heuristic algorithm based on clustering analysis in data mining for haplotype reconstruction problem. Based on hamming distance and similarity between two fragments, our iterative algorithm produces two clusters of fragments; then, in each iteration, the algorithm assigns a fragment to one of the clusters. Our results suggest that the algorithm has less reconstruction error rate in comparison with other algorithms.

  1. Haplotyping Problem, A Clustering Approach

    NASA Astrophysics Data System (ADS)

    Eslahchi, Changiz; Sadeghi, Mehdi; Pezeshk, Hamid; Kargar, Mehdi; Poormohammadi, Hadi

    2007-09-01

    Construction of two haplotypes from a set of Single Nucleotide Polymorphism (SNP) fragments is called haplotype reconstruction problem. One of the most popular computational model for this problem is Minimum Error Correction (MEC). Since MEC is an NP-hard problem, here we propose a novel heuristic algorithm based on clustering analysis in data mining for haplotype reconstruction problem. Based on hamming distance and similarity between two fragments, our iterative algorithm produces two clusters of fragments; then, in each iteration, the algorithm assigns a fragment to one of the clusters. Our results suggest that the algorithm has less reconstruction error rate in comparison with other algorithms.

  2. HLA and fertility

    SciTech Connect

    Ober, C.

    1995-11-01

    The recent paper by Jin et al., reporting that class 11 region major histocompatibility complex genes may influence embryonic loss in outbred couples supports previous results of our studies of HLA and fertility in the Hutterites. However, the authors have incorrectly cited our work and have omitted the reference that is most relevant to their results. The paper by Kostyu et al. is incorrectly referred to in the introduction as providing evidence for HLA sharing being associated with recurrent spontaneous abortion. The Kostyu et al. paper does not include any data on fertility or reproduction but reports frequencies of individuals who are homozygous at the HLA-A, -C, -B, -DR, and -DQ loci in the Hutterite population. In fact, recurrent spontaneous abortion has not been observed in any of the couples in our sample of >500 Hutterite couples. References more appropriate to the association between HLA sharing and recurrent miscarriage are those by Komlos et al., Schacter et al., Gerencer and Kastelan, and Beer et al. It might also be worth pointing out that many studies of recurrent miscarriage in outbred couples have not found an association with HLA sharing; examples include the studies of Ergolu et al., Oksenberg et al., and Christiansen et al., among others. 11 refs.

  3. Lab-on-a-chip enabled HLA diagnostic: combined sample preparation and real time PCR for HLA-B57 diagnosis

    NASA Astrophysics Data System (ADS)

    Gärtner, Claudia; Becker, Holger; Hlawatsch, Nadine; Klemm, Richard; Moche, Christian; Schattschneider, Sebastian; Frank, Rainer; Willems, Andreas

    2015-05-01

    The diverse human HLA (human leukocyte antigen) system is responsible for antigen presentation and recognition. It is essential for the immune system to maintain a stable defense line, but also is also involved in autoimmunity as well as metabolic disease. HLA-haplotype (HLA-B27), for instance, is associated with inflammatory diseases such as Bechterew's disease. The administration of the HIV drug Abacavir in combination with another HLA-haplotype (HLAB57) is associated with severe hypersensitivity reactions. Accordingly, the HLA status has to be monitored for diagnosis or prior to start of therapy. Along this line, a miniaturized microfluidic platform has been developed allowing performing the complete analytical process from "sample-in" to "answer-out" in a point-of-care environment. The main steps of the analytical cascade inside the integrated system are blood cell lysis and DNA isolation, DNA purification, real-time PCR and quantitative monitoring of the rise of a fluorescent signal appearing during the PCR based sequence amplification. All bio-analytical steps were intended to be performed inside one chip and will be actuated, controlled and monitored by a matching device. This report will show that all required processes are established and tested and all device components work well and interact with the functional modules on the chips in a harmonized fashion.

  4. HLA DRB1 alleles and hepatitis C virus infection in chronic kidney disease patients.

    PubMed

    Shaheen, Noha Mohamed Hosni; Soliman, Amin Roshdy; El-Khashab, Sahier Omar; Hanna, Mariam Onsy Farag

    2013-01-01

    T cell responses against HCV are regulated by the host's human leukocyte antigen (HLA) alleles, which thus are ideal candidate genes to investigate for associations with HCV susceptibility. We aimed to identify associations of HLA DRB1* alleles with HCV infection in a high risk of exposure population, chronic kidney disease (CKD) patients on dialysis, and to study any possible relationships with allele zygosity. The study population comprised 110 HCV infected and 143 HCV uninfected CKD patients undergoing regular hemodialysis. HLA DRB1* alleles were determined using polymerase chain reaction followed by hybridization with sequence-specific oligonucleotide probes. We found a significant negative association between HLA DRB1*03 and HCV infection, but the association did not retain significance after adjustment for multiple comparisons. HLA DRB1*03 was found at reduced frequency in HCV antibody positive compared to HCV antibody negative CKD patients on regular dialysis (corrected p was not significant). No significant association between HCV infection and HLA DRB1* zygosity was observed. Our results suggest that there is minimal evidence for a significant role of a particular HLA DRB1* allele or allele zygosity in the susceptibility or protection to HCV in high-risk hemodialysis patients with similar exposure to infection.

  5. Exact break point of a 50 kb deletion 8 kb centromeric of the HLA-A locus with HLA-A*24:02: the same deletion observed in other A*24 alleles and A*23:01 allele.

    PubMed

    Mitsunaga, Shigeki; Okudaira, Yuko; Kunii, Nanae; Cui, Tailin; Hosomichi, Kazuyoshi; Oka, Akira; Suzuki, Yasuo; Homma, Yasuhiko; Sato, Shinji; Inoue, Ituro; Inoko, Hidetoshi

    2011-08-01

    In a structural aberration analysis of patients with arthritis mutilans, a 50 kb deletion near the HLA-A locus with HLA-A*24:02 allele was detected. It was previously reported that HLA-A*24:02 haplotype harbored a large-scale deletion telomeric of the HLA-A gene in healthy individuals. In order to confirm that the deletion are the same in patients with arthritis mutilans and in healthy individuals, and to identify the break point of this deletion, the boundary sequences across the deletion in A*24:02 was amplified by polymerase chain reaction (PCR) as a 3.7 kb genomic fragment and subjected to nucleotide sequence determination. A comparison of these genomic sequences with those of the non-A*24:02 haplotype revealed that the deleted genomic region spanning 50 kb was flanked by 3.7 kb repetitive element-rich segments homologous to each other on both sides in non-A*24. The nucleotide sequences of the PCR products were identical in patients with arthritis mutilans and in healthy individuals, revealing that the deletion linked to A*24:02 is irrelevant to the onset of arthritis mutilans. The deletion was detected in all other A*24 alleles so far examined but not in other HLA-A alleles, except A*23:01. This finding, along with the phylogenic tree of HLA-A alleles and the presence of the 3.7 kb highly homologous segments at the boundary of the deleted genomic region in A*03 and A*32, may suggest that this HLA-A*24:02-linked deletion was generated by homologous recombination within two 3.7 kb homologous segments situated 50 kb apart in the ancestral A*24 haplotype after divergence from the A*03 and A*32 haplotypes.

  6. Association of genetic variants in the 3'UTR of HLA-G with Recurrent Pregnancy Loss.

    PubMed

    Amodio, Giada; Canti, Valentina; Maggio, Luana; Rosa, Susanna; Castiglioni, Maria Teresa; Rovere-Querini, Patrizia; Gregori, Silvia

    2016-10-01

    Human Leukocyte Antigen (HLA)-G is involved in reprogramming immune responses at fetal-maternal interface during pregnancy. We evaluated the genetic diversity of the 3' Un-Translated Region (UTR) of HLA-G, previously associated with HLA-G mRNA post-transcriptional regulation, in women with unexplained Recurrent Pregnancy Loss (RPL), with 2 pregnancy losses (RPL-2, n=28), or 3 or more pregnancy losses (RPL-3, n=24), and in 30 women with a history of successful pregnancy. Results showed in RPL-2, but not in RPL-3, women compared to controls: i) higher frequency of the 14bp Ins allele, in single and in double copy; ii) significantly lower frequency of DelG/X genotype, iii) reduced frequency of the UTR-2, and UTR-3 haplotypes; iv) higher frequencies of the UTR-5, UTR-7, and UTR-8 haplotypes. This pilot study supports the relevance of performing 3'UTR HLA-G genetic screening, not limited to a specific polymorphism, but considering the extended haplotypes, as a possible predictor of pregnancy outcome.

  7. Understanding Y haplotype matching probability.

    PubMed

    Brenner, Charles H

    2014-01-01

    The Y haplotype population-genetic terrain is better explored from a fresh perspective rather than by analogy with the more familiar autosomal ideas. For haplotype matching probabilities, versus for autosomal matching probabilities, explicit attention to modelling - such as how evolution got us where we are - is much more important while consideration of population frequency is much less so. This paper explores, extends, and explains some of the concepts of "Fundamental problem of forensic mathematics - the evidential strength of a rare haplotype match". That earlier paper presented and validated a "kappa method" formula for the evidential strength when a suspect matches a previously unseen haplotype (such as a Y-haplotype) at the crime scene. Mathematical implications of the kappa method are intuitive and reasonable. Suspicions to the contrary raised in rest on elementary errors. Critical to deriving the kappa method or any sensible evidential calculation is understanding that thinking about haplotype population frequency is a red herring; the pivotal question is one of matching probability. But confusion between the two is unfortunately institutionalized in much of the forensic world. Examples make clear why (matching) probability is not (population) frequency and why uncertainty intervals on matching probabilities are merely confused thinking. Forensic matching calculations should be based on a model, on stipulated premises. The model inevitably only approximates reality, and any error in the results comes only from error in the model, the inexactness of the approximation. Sampling variation does not measure that inexactness and hence is not helpful in explaining evidence and is in fact an impediment. Alternative haplotype matching probability approaches that various authors have considered are reviewed. Some are based on no model and cannot be taken seriously. For the others, some evaluation of the models is discussed. Recent evidence supports the adequacy of

  8. Human leukocyte antigen class II (DRB1 and DQB1) alleles and haplotypes frequencies in patients with pemphigus vulgaris among the Serbian population.

    PubMed

    Zivanovic, D; Bojic, S; Medenica, L; Andric, Z; Popadic, D

    2016-05-01

    The etiology of pemphigus vulgaris (PV) is multifactorial and includes genetic, environmental, hormonal, and immunological factors. Inheritance of certain Human class II leukocyte antigen (HLA) alleles is by far the best-established predisposing factor for the development of PV. Class II HLA alleles vary among racial/ethnic backgrounds. We have determined an association between HLA class II alleles and PV among the Serbian population. A total of 72 patients with confirmed diagnosis of PV were genotyped for HLA class II alleles. HLA frequencies were compared with unrelated healthy bone marrow donors. The statistical significance of differences between patients and controls was evaluated using Fisher's exact test. The DRB1*04 and DRB1*14 allelic groups were associated with PV (P adj = 4.45 × 10(-13) and 4.06 × 10(-19) respectively), while HLA-DRB1*11 was negatively associated with PV (P adj = 0.0067) suggesting a protective role. DRB1*04:02, DRB1*14:04, DQB1*03:02 and DQB1*05:03 alleles were shown to be strongly associated with PV (P adj = 1.63 × 10(-12), 5.20 × 10(-7), 1.28 × 10(-6), and 4.44 × 10(-5), respectively). The frequency of HLA DRB1*04-DQB1*03 and HLA DRB1*14-DQB1*05 haplotypes in PV patients was significantly higher than in controls (31.3% vs 8.8%, P adj =7.66 × 10(-8) and 30.6% vs 6.3%, P adj = 3.22 × 10(-10), respectively). At high-resolution level, statistical significance was observed in HLA-DRB1*04:02-DQB1*03:02 and HLA-DRB1*14:04-DQB1*05:03 haplotypes (P adj = 5.55 × 10(-12), and P adj = 3.91 × 10(-6), respectively). Our findings suggest that HLA-DRB1*04:02, DRB1*14:04, HLA-DQB1* 03:02 and DQB1*05:03 alleles and HLA-DRB1*04:02-DQB1*03:02 and HLA-DRB1*14:04-DQB1*05:03 haplotypes are genetic markers for susceptibility for PV, while DRB1*11 allelic group appears protective in Serbian population.

  9. The possible role of genomic imprinting at HLA-DQ/DR region in the pathogenesis of insulin-dependent diabetes mellitus

    SciTech Connect

    Sasaki, T.; Nemoto, M.; Nishimura, R.

    1994-09-01

    Insulin-dependent diabetes mellitus (IDDM) is an autoimmune endocrinopathy that often develops with anti glutamic acid decarboxylase autoantibody (GAD-Ab). Accumulated data indicate that specific alleles with HLA-DQA1{sup *}0301 strongly associate with IDDM so that its susceptible gene is localized at HLA class II DQ/DR region. The mode of transmission, however, remains still unclear. To investigate the possibility of involvement of genomic imprinting at the susceptible gene in IDDM, we conducted pedigree analysis of 16 IDDM probands who are positive for GAD-Ab and their first-degree relatives consisting of 14 mothers, 11 fathers and 11 sibs. The GAD-Ab was measured with RIA (cut off = 5 U/ml), and genotypes of DQA1 and DRB1 loci were determined with PCR-RFLP method. Of the observed 16 families, one had an affected brother who developed IDDM and was positive for GAD-Ab (144 U/ml), but the remaining 15 were simplex families. Except for the affected brother, all relatives appeared to be negative for GAD-Ab. DQA1 genotyping showed that 11 probands were homozygotes of high-risk DQA1{sup *}0301, but the five probands were heterozygous with DQA1{sup *}0301/X who were informative for the parental origin of DQA1{sup *}0301 allele. Pedigree analyses revealed that all DQA1{sup *}0301 alleles of the five affected heterozygotes were transmitted from their mothers. We next analyzed segregation pattern of DQA1-DRB1 haplotypes and found that the affected brother shared the same maternally transmitted allele with the proband. Further haplotype analysis indicated that the informative six unaffected sibs did not share the maternally transmitted DQA1{sup *}0301 alleles with their probands. From the exclusive association with maternally transmitted DQA{sup *}0301 alleles, we propose the hypothesis that maternal transmission of {open_quotes}affected alleles{close_quotes} are required for the development of IDDM with the mechanism of genomic imprinting at the HLA-DQ/DR region.

  10. Skin Cancer Risk Is Modified by KIR/HLA Interactions That Influence the Activation of Natural Killer Immune Cells.

    PubMed

    Vineretsky, Karin A; Karagas, Margaret R; Christensen, Brock C; Kuriger-Laber, Jacquelyn K; Perry, Ann E; Storm, Craig A; Nelson, Heather H

    2016-01-15

    Natural killer (NK)-cell phenotype is partially mediated through binding of killer-cell immunoglobulin-like receptors (KIR) with HLA class I ligands. The KIR gene family is highly polymorphic and not well captured by standard genome-wide association study approaches. Here, we tested the hypothesis that variations in KIR gene content combined with HLA class I ligand status is associated with keratinocyte skin cancers using a population-based study of basal cell carcinoma (BCC) and squamous cell carcinomas (SCC). We conducted an interaction analysis of KIR gene content variation and HLA-B (Bw4 vs. Bw6) and HLA-C (C1 vs. C2). KIR centromeric B haplotype was associated with significant risk of multiple BCC tumors (OR, 2.39; 95% confidence interval, 1.10-5.21), and there was a significant interaction between HLA-C and the activating gene KIR2DS3 for BCC (Pinteraction = 0.005). Furthermore, there was significant interaction between HLA-B and telomeric KIR B haplotype (containing the activating genes KIR3DS1 and KIR2DS1) as well as HLA-B and the activating KIR gene KIR2DS5 (Pinteraction 0.001 and 0.012, respectively). Similar but greatly attenuated associations were observed for SCC. Moreover, previous in vitro models demonstrated that p53 is required for upregulation of NK ligands, and accordingly, we observed there was a strong association between the KIR B haplotype and p53 alteration in BCC tumors, with a higher likelihood that KIR B carriers harbor abnormal p53 (P < 0.004). Taken together, our data suggest that functional interactions between KIR and HLA modify risks of BCC and SCC and that KIR encoded by the B genes provides selective pressure for altered p53 in BCC tumors.

  11. HLA Genotyping in Patients with End-Stage Renal Disease Waiting For Cadaveric Renal Transplantation in Federation of Bosnia and Herzegovina

    PubMed Central

    Fejzić, Elma; Karamehić, Jasenko; Eminović, Izet; Suljević, Damir; Alijagić, Andi; Bećirević, Semir; Šahović, Amela; Šišić, Sanela

    2017-01-01

    AIM: The research was conducted by genotyping two Human Leukocyte Antigen (HLA) gene classes. The main objective of this research was to investigate distribution and frequency of the allelic groups, genotypes and haplotypes in the gene loci of HLA class I (HLA-A*, -B*, -C*) and HLA class II (HLA-DRB1*, -DQB1*) in patients included in the program of cadaveric renal transplantation. MATERIAL AND METHODS: Our study covered 186 blood samples of patients who are registered on the list for cadaveric renal transplantation in Federation of Bosnia and Herzegovina and included 59 control, healthy unrelated individuals. For the HLA typing, we have used three different methods: micro lymphocyte cytotoxicity test (MLCT), Polymerase Chain Reaction (PCR) – Sequence Specific Primers (SSP) and PCR – Sequence-Specific Oligonucleotides (SSO) or Luminex technology. All patients and cadaveric donors were tested using the three methods because the system is polymorphic. RESULTS: Analysis of the results of genotyping HLA class I gene loci identified dominant HLA-A*02, HLA-B*35, HLA-C*07 allelic groups. Analysis of the HLA class II gene loci genotyping showed that HLA-DRB1*11 and HLA-DQB1*03 loci had the highest incidence in HLA class II. CONCLUSION: Based on our results and previous research, there were no observed differences between allelic frequencies and genotypes of healthy people and people with ESRD. Differences between allelic groups occurred, but they were not statistically significant, except HLA-C*01 (p = 0.020). PMID:28293306

  12. The HLA polymorphism of two distinctive South-American Indian tribes: the Kaingang and the Guarani.

    PubMed

    Petzl-Erler, M L; Luz, R; Sotomaior, V S

    1993-05-01

    The HLA-A, B, C, DR and DQ antigens of 240 Kaingang and 98 Guarani individuals have been characterized. The most frequent antigens found among the Kaingang are A31, 2, 24; B35, 51, 39, 48; Cw4, 7, 3, 1; DR8, 4, 2; DQ blank, 3. In the Guarani, they are A2, 28, 31; B40, 62, "53G"; Cw3, 4; DR2, 4, 8, 6; DQ3, blank. B " 53G" is an unusual antigen of the B5 cross-reactive group. DQ blank possibly corresponds to DQ4, not tested in this study. The reaction patterns of B35, B40 and DR4 indicate intra-tribal (of B35 and B40), and inter-tribal (DR4, B40 and B35) heterogeneity of these antigens. 408 Kaingang and 141 Guarani haplotypes were defined by segregation analysis. Of the commonest 10 Guarani and 9 Kaingang haplotypes, only one is shared by both tribes. Significant, positive linkage disequilibrium values for HLA-A,B; HLA-A,C; HLA-B,DR and most HLA-B,C antigen pairs were also different for the two populations. Genetic distance estimates between these two and another seven South-American Indian populations, and relative to the major human races (negroids, caucasoids, and mongoloids) reveal a comparatively high degree of divergence between the Kaingang and the Guarani, which is uncommon for Amerindian populations living close one to another.

  13. Differential HLA class I and class II associations in pemphigus foliaceus and pemphigus vulgaris patients from a prevalent Southeastern Brazilian region.

    PubMed

    Brochado, Maria José Franco; Nascimento, Daniela Francisca; Campos, Wagner; Deghaide, Neifi Hassan Saloum; Donadi, Eduardo Antonio; Roselino, Ana Maria

    Genetic factors, particularly those concerning HLA class II, have been associated with the pathogenesis of pemphigus. Taking advantage of an area where pemphigus foliaceus (PF) and pemphigus vulgaris (PV) are prevalent in the northeastern region of the state of São Paulo, Southeastern Brazil, we have studied the HLA class I (A, B and C) and class II (DRB1 and DQA1/DQB1) profiles in 86 and 83 patients with PF and PV, respectively, as compared with 1592 controls from the same region. Among all the HLA alleles described herein, the more prevalent susceptibility alleles for PF were HLA-A*11, 33, -B*14; -DRB1*01:01, *01:02; -DQA1*01:02; and -DQB1*05:01. In PV patients, the HLA-B*38; -C*12; -DRB1*04:02, *08:04, *14:01, *14:04; -DQA1*03:01; and -DQB1*03:02 and *05:03 alleles were associated with susceptibility. The HLA-DRB1*01:02 allele and the HLA-DRB1*01-DQA1*01-DQB1*05 haplotype in PF patients and the HLA-DRB1*04:02 and *14:01 alleles and the HLA-DRB1*14-DQA1*01-DQB1*05 haplotype in PV patients were related with the highest etiologic fraction values. Distinct genetic patterns and not yet described HLA susceptibility/protection alleles/haplotypes profiles have been observed in this series. Our findings corroborate the differential genetic markers in PF and PV in an area where pemphigus is prevalent but not yet reported.

  14. HLA-B alleles and complotypes in Mexican patients with seronegative spondyloarthropathies.

    PubMed Central

    Vargas-Alarcón, G; Garcia, A; Bahena, S; Melin-Aldana, H; Andrade, F; Ibañez-de-Kasep, G; Alcocer-Varela, J; Alarcón-Segovia, D; Granados, J

    1994-01-01

    OBJECTIVES--To analyse major histocompatibility complex (MHC) haplotypes in Mexican mestizo patients with seronegative spondyloarthropathies (SSpA) and normal controls, to discover if there are other antigens, besides B27, in the HLA region that might show association with the disease. METHODS--The study included 100 Mexican mestizo patients with SSpA and 200 of their first degree relatives. These groups were compared with 85 ethnically matched controls. The class I and class III MHC antigens were obtained by standard methods. The significance of differences between patients and controls was tested by chi 2 analysis; linkage disequilibrium among the different alleles in each haplotype was estimated by computing delta values. RESULTS--We found a significantly increased frequency of the HLA-B27 antigen (pcorr. = 1 x 10(-5), odds ratio (OR) = 33.4, 95% confidence interval (CI) = 9.3-142.0). In the group of 45 SSpA patients negative for the B27 antigen, independent increased frequencies of HLA-B49 antigen (pcorr. = 0.03, OR = 6.5, 95% CI = 1.5-32.8)) and the FC31 complotype (pcorr. = 0.04, OR = 3.7, 95% CI = 1.2-11.1) were found. Significant delta values were obtained for the [B27;SC30] haplotype (p = 0.0005) but not for haplotypes marked by the FC31 complotype. HLA-B antigens on the homologous chromosome in B27 positive patients were mainly HLA-B51 (18%) and HLA-B60 (16%); however, the observed genotypes B27/B51 and B27/B60 were not significantly different than expected from the allele frequencies alone. CONCLUSIONS--These data suggest that in Mexicans additional genes within the MHC region besides the HLA-B27 antigen, might be related to the genetic susceptibility for developing SSpA. Relevant antigens included the HLA-B49 and the FC31 complotype. PMID:7826137

  15. HLA antigens and Berger's disease.

    PubMed

    Bignon, J D; Houssin, A; Soulillou, J P; Denis, J; Guimbretiere, J; Guenel, J

    1980-07-01

    We have studied the frequencies of HLA-A, -B antigens in 73 Berger's disease patients, plus HLA-DR antigens in 35 of them, and compared the percentages of antigens frequencies with those of a local and national panel. This study does not confirm the positive associations with HLA-Bw35 or HLA-B12 which have been previously reported. The HLA-DR typing only showed increased frequency of blanks in the patients (P smaller than 0.01, but no significant corr.P). Patients with Berger's disease and renal failure have a higher (but still not significant) HLA-Bw35 frequency than those without renal failure. The reasons for the discrepancy between our group and others are analysed.

  16. Anthropological analysis of Koreans using HLA class II diversity among East Asians.

    PubMed

    Yang, J H; Sohn, Y-H; Ko, S-Y; Choi, S-E; Kim, M H; Oh, H-B

    2010-10-01

    Human leukocyte antigens (HLAs) are useful markers for anthropological investigations because the allele and haplotype distributions at these loci vary widely among ethnic groups. HLA frequencies in Koreans, however, have not previously been analyzed on a phylogenetic basis. We determined the allele frequencies of four HLA class II (HLA-DRB1, -DQA1, -DQB1, and -DPB1) loci in 149 unrelated Korean individuals using a sequence-based typing method. A total of 29 HLA-DRB1, 17 HLA-DQA1, 16 HLA-DQB1, and 15 HLA-DPB1 alleles were identified. The most common allele at each locus was DRB1*0901, DQA1*0102, DQB1*0301, and DPB1*0501, respectively. Four-locus allelic association analysis showed the existence of 25 DRB1-DQA1-DQB1-DPB1 haplotypes with a frequency greater than 0.010. A dataset comprising ethnicity-specific information from published literature and the dbMHC database, as well as the allele frequencies determined in this study, was subjected to phylogenetic analysis. The analysis showed that Koreans are most closely related to Japanese and Han Chinese from Shandong province. Correspondence analyses showed that the current Korean population is located in a position intermediate between the northern and southern East Asian groups, supporting the theory of a bi- and/or multidirectional route of migration of early Korean settlers. This report can be used for anthropological studies, and may also be of use in the International Hematopoietic Stem Cell Sharing program.

  17. HLA-A, -B and -DRB1 polymorphism in Koreans defined by sequence-based typing of 4128 cord blood units.

    PubMed

    Huh, J Y; Yi, D Y; Eo, S-H; Cho, H; Park, M H; Kang, M S

    2013-12-01

    Human leucocyte antigen (HLA) alleles and haplotypes differ significantly among different ethnic groups, and high-resolution typing methods allow for the detection of a wider spectrum of HLA variations. In this study, HLA-A, -B and -DRB1 genotypes were analysed in 4128 cord blood units obtained from Korean women using the sequence-based typing method. A total of 44 HLA-A, 67 HLA-B and 48 HLA-DRB1 most probable alleles were identified. Of these, high-frequency alleles found at a frequency of ≥5% were 6 HLA-A (A*02:01, A*02:06, A*11:01, A*24:02, A*31:01, A*33:03), 5 HLA-B (B*15:01, B*44:03, B*51:01, B*54:01, B*58:01) and 7 HLA-DRB1 (DRB1*01:01, DRB1*04:05, DRB1*07:01, DRB1*08:03, DRB1*09:01, DRB1*13:02, DRB1*15:01) alleles. At each locus, A*02, B*15 and DRB1*04 generic groups were most diverse at allelic level, consisting of 8, 11 and 10 different alleles, respectively. Two- and three-locus haplotypes estimated by the maximum likelihood method revealed 73 A-B, 74 B-DRB1 and 42 A-B-DRB1 haplotypes with frequencies of ≥0.3%. A total of 193 A-B-DRB1 haplotypes found at a frequency of ≥0.1% were presented, and the six most common haplotypes were A*33:03-B*44:03-DRB1*13:02 (4.6%), A*33:03-B*58:01-DRB1*13:02 (3.0%), A*24:02-B*07:02-DRB1*01:01 (2.7%), A*33:03-B*44:03-DRB1*07:01 (2.5%), A*30:01-B*13:02-DRB1*07:01 (2.2%) and A*24:02-B*52:01-DRB1*15:02 (2.1%). Compared with previous smaller scale studies, this study further delineated the allelic and haplotypic diversity in Koreans including low-frequency alleles and haplotypes. Information obtained in this study will be useful for the search for unrelated bone marrow donors and for anthropologic and disease association studies.

  18. HLA polymorphisms as incidence factor in the progression to end-stage renal disease in Brazilian patients awaiting kidney transplant.

    PubMed

    Crispim, J C; Mendes-Júnior, C T; Wastowski, I J; Palomino, G Martelli; Saber, L T; Rassi, D M; Donadi, E A

    2008-06-01

    Chronic renal failure (CRF) leads in the majority of instances to end-stage renal disease (ESRD) requiring renal replacement therapy. Age, gender, genetics, race, hypertension, and smoking among others are factors associated with ESRD. Our interest was to evaluate the possible associations of class I and II HLA antigens with ESRD renal disease independent of other factors, among patients with CRF, having various diagnoses in the Brazilian population of the São Paulo state. So 21 HLA-A, 31 HLA-B, and 13 HLA-DR were detected in 105 patients who were compared with 160 healthy controls of both sexes who were not related to the patients evaluated until 2005. We calculated allelic frequencies, haplotypes frequencies, etiological fractions (EF), preventive fractions, and relative risks (RR). We compared demographic data of patients and controls. The antigens positively associated with ESRD were: HLA-A78 (RR = 30.31 and EF = 0.96) and HLA-DR11 (RR = 18.87 and EF = 0.65). The antigens HLAB14 (RR = 29.90 and EF = 0.75) was present at a significantly lower frequency among patients compared with controls. In contrast, no haplotype frequency showed statically significant associations. Further molecular studies may clarify types and subtypes of alleles involved with ESRD progression.

  19. Common and Well-Documented HLA Alleles: 2012 Update to the CWD Catalogue

    PubMed Central

    Mack, Steven J.; Cano, Pedro; Hollenbach, Jill A.; He, Jun; Hurley, Carolyn Katovich; Middleton, Derek; Moraes, Maria Elisa; Pereira, Shalini E.; Kempenich, Jane H.; Reed, Elaine F.; Setterholm, Michelle; Smith, AnaJane G.; Tilanus, Marcel G.; Torres, Margareth; Varney, Michael D.; Voorter, Christien E. M.; Fischer, Gottfried F.; Fleischhauer, Katharina; Goodridge, Damian; Klitz, William; Little, Ann-Margaret; Maiers, Martin; Marsh, Steven G. E.; Müller, Carlheinz R.; Noreen, Harriet; Rozemuller, Erik H.; Sanchez-Mazas, Alicia; Senitzer, David; Trachtenberg, Elizabeth; Fernandez-Vina, Marcelo

    2013-01-01

    We have updated the catalogue of common and well-documented (CWD) HLA alleles to reflect current understanding of the prevalence of specific allele sequences. The original CWD catalogue designated 721 alleles at the HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, and –DPB1 loci in IMGT/HLA Database release 2.15.0 as being CWD. The updated CWD catalogue designates 1122 alleles at the HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, -DPA1 and –DPB1 loci as being CWD, and represents 14.3% of the HLA alleles in IMGT/HLA Database release 3.9.0. In particular, we identified 415 of these alleles as being “common” (having known frequencies) and 707 as being “well-documented” on the basis of ~140,000 sequence-based typing observations and available HLA haplotype data. Using these allele prevalence data, we have also assigned CWD status to specific G and P designations. We identified 147/151 G groups and 290/415 P groups as being CWD. The CWD catalogue will be updated on a regular basis moving forward, and will incorporate changes to the IMGT/HLA Database as well as empirical data from the histocompatibility and immunogenetics community. This version 2.0.0 of the CWD catalogue is available online at cwd.immunogenomics.org, and will be integrated into the Allele Frequencies Net Database, the IMGT/HLA Database and National Marrow Donor Program’s bioinformatics web pages. PMID:23510415

  20. HLA genes of Aleutian Islanders living between Alaska (USA) and Kamchatka (Russia) suggest a possible southern Siberia origin.

    PubMed

    Moscoso, Juan; Crawford, Michael H; Vicario, Jose L; Zlojutro, Mark; Serrano-Vela, Juan I; Reguera, Raquel; Arnaiz-Villena, Antonio

    2008-02-01

    Aleuts HLA profile has been compared with that of neighboring and worldwide populations. Thirteen thousand one hundred and sixty-four chromosomes have been used for this study. Computer programs have obtained HLA allele frequencies, genetic distances between populations, NJ relatedness dendrograms, correspondence analysis and most frequent HLA extended haplotypes. Aleuts have inhabited Aleutian Islands since about 9000 years BP according to fossil and genetic (mtDNA) records. They are genetically different to Eskimo, Amerindian and Na-Dene speakers according to their HLA profile; this correlates with cultural and anthropological Aleut distinctiveness. No typical Amerindian HLA alleles have been found in a significant frequency. Their HLA relatedness to Saami (or Lapps, northern Scandinavians), Finns and Pomors (North-West Russia) indicates an ancient possible origin from the Baikal Lake Area (southern Siberia) around the present day Buryat peopling area; other origins are not discarded. Aleuts characteristic HLA profile may influence future transplantation programs in the region and be useful to study diseases linked to HLA epidemiology.

  1. Polymorphic SVA retrotransposons at four loci and their association with classical HLA class I alleles in Japanese, Caucasians and African Americans.

    PubMed

    Kulski, Jerzy K; Shigenari, Atsuko; Inoko, Hidetoshi

    2010-04-01

    Polymorphic insertion frequencies of the retrotransposons known as the "SVA" elements were investigated at four loci in the MHC class I genomic region to determine their allele and haplotype frequencies and associations with the HLA-A, -B or -C genes for 100 Japanese, 100 African Americans, 174 Australian Caucasians and 66 reference cell lines obtained from different ethnic groups. The SVA insertions representing different subfamily members varied in frequency between none for SVA-HF in Japanese and 65% for SVA-HB in Caucasians or African Americans with significant differences in frequencies between the three populations at least at three loci. The SVA loci were in Hardy-Weinberg equilibrium except for the SVA-HA locus which deviated significantly in African Americans and Caucasians possibly because of a genomic deletion of this locus in individuals with the HLA-A*24 allele. Strong linkage disequilibria and high percentage associations between the human leucocyte antigen (HLA) class I gene alleles and some of the SVA insertions were detected in all three populations in spite of significant frequency differences for the SVA and HLA class I alleles between the three populations. The highest percentage associations (>86%) were between SVA-HB and HLA-B*08, -B*27, -B*37 to -B*41, -B*52 and -B*53; SVA-HC and HLA-B*07; SVA-HA and HLA-A*03, -A*11 and -A*30; and SVA-HF and HLA-A*03 and HLA-B*47. From pairwise associations in the three populations and the homozygous cell line results, it was possible to deduce the SVA and HLA class I allelic combinations (haplotypes), population differences and the identity by descent of several common HLA-A allelic lineages.

  2. Analysis of HLA-DM polymorphisms in the Chinese Han population.

    PubMed

    Feng, M L; Liu, R Z; Shen, T; Zhao, Y L; Zhu, Z Y; Liu, D Z

    2012-03-01

    Non-classical human leukocyte antigen (HLA)-DM plays an important and unique role in the processing and presentation of exogenous antigens. Polymorphisms of certain genes and frequency of alleles in populations may indicate susceptibility to certain diseases. In this study, the analysis of HLA-DMA and HLA-DMB gene polymorphisms and haplotypes in the Chinese Han population was conducted to obtain population genetic data. HLA-DM typing has been performed previously by other groups by polymerase chain reaction (PCR)-restriction fragment length polymorphism and PCR-sequence-specific oligonucleotide probe techniques. In this study, we established a TaqMan PCR typing method as an alternative to these techniques to survey the frequency of DMA and DMB alleles in the population. Genotyping was conducted in 1000 unrelated individuals of Han nationality in South and North China using TaqMan PCR typing. Four different DMA alleles and six different DMB alleles were detected. All loci met the Hardy-Weinberg equilibrium principle that both allele and genotype frequencies in a population remain constant. We found that the DMA*01:01 (69.35%) and DMB*01:01 (52.5%) alleles were more frequent in Chinese Hans. Analysis of the haplotypes for two loci of DMA and DMB showed that a highly significant positive linkage disequilibrium (LD) presented for DMA*01:01-DMB*01:02, DMA*01:01-DMB*01:03, DMA*01:01-DMB*01:04, DMA*01:02-DMB*01:01, DMA*01:02-DMB*01:05, DMA*01:03-DMB*01:07, and DMA*01:04-DMB*01:01 haplotypes. Analysis of haplotypes for four loci associated with antigen processing (DMA-DMB-TAP1-TAP2) showed a highly significant LD in DMA*01:01-DMB*01:04-TAP1*02:01:01-TAP2*01:02, DMA*01: 02-DMB*01:05-TAP1*01:01-TAP2*01:01, and DMA*01:01-DMB*01:03-TAP1* 04:01-TAP2*01:01 haplotypes. The comparison between the Chinese Han population and non-Chinese populations showed that no significant differences were found at the HLA-DMA locus in the Chinese Han population compared with people of German

  3. Detecting structure of haplotypes and local ancestry

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We present a two-layer hidden Markov model to detect the structure of haplotypes for unrelated individuals. This allows us to model two scales of linkage disequilibrium (one within a group of haplotypes and one between groups), thereby taking advantage of rich haplotype information to infer local an...

  4. Las Alpujarras region (South East Spain) HLA genes study: evidence of a probable success of 17th century repopulation from North Spain.

    PubMed

    Longás, Javier; Martínez-Laso, Jorge; Rey, Diego; Areces, Cristina; Casado, Eduardo Gómez; Parga-Lozano, Carlos; Luna, Francisco; de Salamanca, Mercedes Enriquez; Moral, Pedro; Arnaiz-Villena, Antonio

    2012-02-01

    Conquest of Granada Muslim Kingdom (1492 AD) finished with Muslim occupation; they were mostly North African Berbers who had reached Iberia by 711 AD. A politics of Iberian Christianization followed after this date: Jewish were expelled in 1492 and Moriscos (Spaniards practicing Muslim religion or speaking Arab) were expelled from all Spanish territory on 1609 AD. Las Alpujarras is a southern Spain mountainous secluded region, which underwent a repopulation from North Spain and a specific Muslim (Moriscos)-Christian war took place according to historical records. Both Las Alpujarras repopulation by northern Iberians and Moriscos expulsion success have been debated and are regarded as non-clarified episodes. In this study, we have addressed the question whether the repopulation succeeded by determining HLA genes of present day Las Alpujarras inhabitants and compared with those of other Mediterranean populations HLA frequencies and genealogies. HLA frequencies show ambiguous results because of extant HLA similar gene frequencies there exist in North Africa and Spain. This is reflected by the finding of North and South western Mediterraneans close relatedness of HLA dendrograms and correspondence analyses. However, the genealogical study of extended HLA haplotypes particularly Alpujarran high frequency of HLA-A29-B44-DRB1*0701-DQA1*02-DQB1*02 (not found in Algerians but frequent in North and Central Spain) and Alpujarran low frequency extended haplotype HLA-A3-B7-DRB1*1501-DQA1*0102-DQB1*0602 (frequent in North Europe) reveals that a significant HLA gene flow from North Spain is observed in present day Alpujarrans: both haplotypes are characteristic of North Spain and North Europe, respectively. This may indicate that enforced Alpujarran repopulation from North Spain may have been a success, which was started by Spanish King Philip II in 1571 AD.

  5. An integrated genotyping approach for HLA and other complex genetic systems.

    PubMed

    Nelson, Wyatt C; Pyo, Chul-Woo; Vogan, David; Wang, Ruihan; Pyon, Yoon-Soo; Hennessey, Carly; Smith, Anajane; Pereira, Shalini; Ishitani, Akiko; Geraghty, Daniel E

    2015-12-01

    Clinical immunogenetics laboratories performing routine sequencing of human leukocyte antigen (HLA) genes in support of hematopoietic cell transplantation are motivated to upgrade to next-generation sequencing (NGS) technology by its potential for cost savings as well as testing accuracy and flexibility. While NGS machines are available and simple to operate, there are few systems available that provide comprehensive sample preparation and data analysis workflows to complete the process. We report on the development and testing of the Integrated Genotyping System (IGS), which has been designed to specifically address the challenges associated with the adoption of NGS in clinical laboratories. To validate the system for a variety of sample DNA sources, we have tested 336 DNA specimens from whole blood, dried blood spots, buccal swabs, and lymphoblastoid cell lines. HLA class I and class II genotypes were derived from amplicon sequencing of HLA-A, -B, -C for exons 1-7 and HLA-DPA1, -DPB1, -DQA1, -DQB1, -DRB1, -DRB3, -DRB4, -DRB5 for exons 1-4. Additionally, to demonstrate the extensibility of the IGS to other genetic loci, KIR haplotyping of 93 samples was carried out in parallel with HLA typing using a workflow based on the HLA system. These results are discussed with respect to their applications in the clinical setting and consequent potential for advancing precision medicine.

  6. Mixtec Mexican Amerindians: an HLA alleles study for America peopling, pharmacogenomics and transplantation.

    PubMed

    Arnaiz-Villena, Antonio; Vargas-Alarcón, Gilberto; Areces, Cristina; Enríquez-de-Salamanca, Mercedes; Abd-El-Fatah-Khalil, Sedeka; Fernández-Honrado, Mercedes; Marco, Javier; Martín-Villa, José Manuel; Rey, Diego

    2014-01-01

    HLA-A, -B and -DRB1 alleles have been studied in a Mixtec Mexican Amerindian population by indirect DNA sequencing. HLA relatedness has been tested by comparing results with other Amerindians and worldwide populations; a total of 15,681 chromosomes have been used. Genetic distances between populations, Neighbour Joining (NJ) dendrograms and correspondence analyses have been carried out. Conclusions are: 1) Our Mixtec sample from Oaxaca Coastal Mexican area shows an HLA profile different to that of Oaxaca Central Mountains area showing that genes and languages do not correlate which is inferred both by plane genetic distances and NJ dendrograms and correspondence analyses. 2) Genetic distances and NJ dendrograms join together Mazatecan Mexican Amerindians with our studied Coastal Mixtec group; it fits with the historical relationship between Mixtec and Mazatecans. 3) A*24:02-B*35:14-DRB1*04:11, A*02:01-B*15:15-DRB1*04:11 and A*68:03-B*39:08-DRB1*08:02 extended HLA haplotypes have been "de novo" found in our Mixtec Coastal sample. 4) Shared HLA alleles are found between our Pacific Coast Mixtec Amerindians and Pacific Islanders. 5) These results are useful for establishing a future area transplantation waiting list, for the study of HLA linked diseases epidemiology and for pharmacogenomics in certain drug therapy.

  7. HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies

    PubMed Central

    Fernandez, Christian A.; Smith, Colton; Yang, Wenjian; Daté, Mihir; Bashford, Donald; Larsen, Eric; Bowman, W. Paul; Liu, Chengcheng; Ramsey, Laura B.; Chang, Tamara; Turner, Victoria; Loh, Mignon L.; Raetz, Elizabeth A.; Winick, Naomi J.; Hunger, Stephen P.; Carroll, William L.; Onengut-Gumuscu, Suna; Chen, Wei-Min; Concannon, Patrick; Rich, Stephen S.; Scheet, Paul; Jeha, Sima; Pui, Ching-Hon; Evans, William E.; Devidas, Meenakshi

    2014-01-01

    Asparaginase is a therapeutic enzyme used to treat leukemia and lymphoma, with immune responses resulting in suboptimal drug exposure and a greater risk of relapse. To elucidate whether there is a genetic component to the mechanism of asparaginase-induced immune responses, we imputed human leukocyte antigen (HLA) alleles in patients of European ancestry enrolled on leukemia trials at St. Jude Children’s Research Hospital (n = 541) and the Children’s Oncology Group (n = 1329). We identified a higher incidence of hypersensitivity and anti-asparaginase antibodies in patients with HLA-DRB1*07:01 alleles (P = 7.5 × 10−5, odds ratio [OR] = 1.64; P = 1.4 × 10−5, OR = 2.92, respectively). Structural analysis revealed that high-risk amino acids were located within the binding pocket of the HLA protein, possibly affecting the interaction between asparaginase epitopes and the HLA-DRB1 protein. Using a sequence-based consensus approach, we predicted the binding affinity of HLA-DRB1 alleles for asparaginase epitopes, and patients whose HLA genetics predicted high-affinity binding had more allergy (P = 3.3 × 10−4, OR = 1.38). Our results suggest a mechanism of allergy whereby HLA-DRB1 alleles that confer high-affinity binding to asparaginase epitopes lead to a higher frequency of reactions. These trials were registered at www.clinicaltrials.gov as NCT00137111, NCT00549848, NCT00005603, and NCT00075725. PMID:24970932

  8. HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies.

    PubMed

    Fernandez, Christian A; Smith, Colton; Yang, Wenjian; Daté, Mihir; Bashford, Donald; Larsen, Eric; Bowman, W Paul; Liu, Chengcheng; Ramsey, Laura B; Chang, Tamara; Turner, Victoria; Loh, Mignon L; Raetz, Elizabeth A; Winick, Naomi J; Hunger, Stephen P; Carroll, William L; Onengut-Gumuscu, Suna; Chen, Wei-Min; Concannon, Patrick; Rich, Stephen S; Scheet, Paul; Jeha, Sima; Pui, Ching-Hon; Evans, William E; Devidas, Meenakshi; Relling, Mary V

    2014-08-21

    Asparaginase is a therapeutic enzyme used to treat leukemia and lymphoma, with immune responses resulting in suboptimal drug exposure and a greater risk of relapse. To elucidate whether there is a genetic component to the mechanism of asparaginase-induced immune responses, we imputed human leukocyte antigen (HLA) alleles in patients of European ancestry enrolled on leukemia trials at St. Jude Children's Research Hospital (n = 541) and the Children's Oncology Group (n = 1329). We identified a higher incidence of hypersensitivity and anti-asparaginase antibodies in patients with HLA-DRB1*07:01 alleles (P = 7.5 × 10(-5), odds ratio [OR] = 1.64; P = 1.4 × 10(-5), OR = 2.92, respectively). Structural analysis revealed that high-risk amino acids were located within the binding pocket of the HLA protein, possibly affecting the interaction between asparaginase epitopes and the HLA-DRB1 protein. Using a sequence-based consensus approach, we predicted the binding affinity of HLA-DRB1 alleles for asparaginase epitopes, and patients whose HLA genetics predicted high-affinity binding had more allergy (P = 3.3 × 10(-4), OR = 1.38). Our results suggest a mechanism of allergy whereby HLA-DRB1 alleles that confer high-affinity binding to asparaginase epitopes lead to a higher frequency of reactions. These trials were registered at www.clinicaltrials.gov as NCT00137111, NCT00549848, NCT00005603, and NCT00075725.

  9. HaplotypeCN: copy number haplotype inference with Hidden Markov Model and localized haplotype clustering.

    PubMed

    Lin, Yen-Jen; Chen, Yu-Tin; Hsu, Shu-Ni; Peng, Chien-Hua; Tang, Chuan-Yi; Yen, Tzu-Chen; Hsieh, Wen-Ping

    2014-01-01

    Copy number variation (CNV) has been reported to be associated with disease and various cancers. Hence, identifying the accurate position and the type of CNV is currently a critical issue. There are many tools targeting on detecting CNV regions, constructing haplotype phases on CNV regions, or estimating the numerical copy numbers. However, none of them can do all of the three tasks at the same time. This paper presents a method based on Hidden Markov Model to detect parent specific copy number change on both chromosomes with signals from SNP arrays. A haplotype tree is constructed with dynamic branch merging to model the transition of the copy number status of the two alleles assessed at each SNP locus. The emission models are constructed for the genotypes formed with the two haplotypes. The proposed method can provide the segmentation points of the CNV regions as well as the haplotype phasing for the allelic status on each chromosome. The estimated copy numbers are provided as fractional numbers, which can accommodate the somatic mutation in cancer specimens that usually consist of heterogeneous cell populations. The algorithm is evaluated on simulated data and the previously published regions of CNV of the 270 HapMap individuals. The results were compared with five popular methods: PennCNV, genoCN, COKGEN, QuantiSNP and cnvHap. The application on oral cancer samples demonstrates how the proposed method can facilitate clinical association studies. The proposed algorithm exhibits comparable sensitivity of the CNV regions to the best algorithm in our genome-wide study and demonstrates the highest detection rate in SNP dense regions. In addition, we provide better haplotype phasing accuracy than similar approaches. The clinical association carried out with our fractional estimate of copy numbers in the cancer samples provides better detection power than that with integer copy number states.

  10. The Genetic Profile from HLA and Non-HLA Loci Allows Identification of Atypical Type 2 Diabetes Patients

    PubMed Central

    Fabregat, Matias; Fernandez, Mariana; Javiel, Gerardo; Vitarella, Graciela; Mimbacas, Adriana

    2015-01-01

    The complex diagnosis and treatment of diabetes highlight the need for markers to define how to monitor patients correctly during the course of their disease. Different studies demonstrate the existence of patients who cannot be clearly classified. We have previously shown that it is possible to differentiate “atypical diabetic patients” based on genotyping the HLA. In this work we show that the analysis of non-HLA related to type 1 diabetes in the INS-VNTR, SNP rs689, and rs3842753 improves the identification of these patients. We genotyped 913 individuals comprising controls from the general population and “classic” and “atypical” diabetic patients. We compared the distribution of these loci and analyzed linkage disequilibrium. The haplotype was in LD for all the SNPs that were evaluated. Regarding their association with the disease, the haplotype IAC was associated with type 1 (odds 2.60, 1.82–3.72, CI 95%) and “atypical diabetes” (odds 1.50, 1.01–2.23, CI 95%), whereas we did not observe an association with type 2 diabetes. Therefore, our results confirm that atypical diabetes is a different entity of the disease where the patient presents with a genetic background of T1D and a T2D phenotype, findings that are likely to be relevant for patient diagnosis and management in the clinic. PMID:26273670

  11. The Genetic Profile from HLA and Non-HLA Loci Allows Identification of Atypical Type 2 Diabetes Patients.

    PubMed

    Fabregat, Matias; Fernandez, Mariana; Javiel, Gerardo; Vitarella, Graciela; Mimbacas, Adriana

    2015-01-01

    The complex diagnosis and treatment of diabetes highlight the need for markers to define how to monitor patients correctly during the course of their disease. Different studies demonstrate the existence of patients who cannot be clearly classified. We have previously shown that it is possible to differentiate "atypical diabetic patients" based on genotyping the HLA. In this work we show that the analysis of non-HLA related to type 1 diabetes in the INS-VNTR, SNP rs689, and rs3842753 improves the identification of these patients. We genotyped 913 individuals comprising controls from the general population and "classic" and "atypical" diabetic patients. We compared the distribution of these loci and analyzed linkage disequilibrium. The haplotype was in LD for all the SNPs that were evaluated. Regarding their association with the disease, the haplotype IAC was associated with type 1 (odds 2.60, 1.82-3.72, CI 95%) and "atypical diabetes" (odds 1.50, 1.01-2.23, CI 95%), whereas we did not observe an association with type 2 diabetes. Therefore, our results confirm that atypical diabetes is a different entity of the disease where the patient presents with a genetic background of T1D and a T2D phenotype, findings that are likely to be relevant for patient diagnosis and management in the clinic.

  12. HLA antigens in South India: II. Selected caste groups of Tamil Nadu.

    PubMed

    Rajasekar, R; Kakkanaiah, V N; Pitchappan, R M

    1987-09-01

    HLA-A, B antigen and haplotype frequencies were studied in four different caste groups of Tamil Nadu living in Madurai. A total number of 101 Nadars, 36 Kallars, 54 Iyers and 57 Telugu-speaking Naidus were studied. HLA A3 and B15 were significantly higher in Nadars; A10 & B8 in Kallars and Aw19, B12 & B35 in Iyers. HLA A-B haplotypes A10-B7, A28-B17 & A24-B- were characteristic of Nadars; A10-B8 & A1-B-, Kallars; Aw19-B12 & A1-B15, Iyers and A2-B-, Naidus. Negative linkage disequilibria for Aw19-B7, A28-B15 & A9-B51 were significant in Nadars; A1-B5, A1-B12 & Aw19-B- in Iyers and A2-B17 in Naidus. Heterogeneity chi-square based on antigen frequency and genetic distance also suggest the heterogeneous nature of the population of South India. Will these caste groups with such diverse haplotypic combinations differ from one another in their immune response and susceptibility to a given epidemic or infection?

  13. Exploring the diabetogenicity of the HLA-B18-DR3 CEH: independent association with T1D genetic risk close to HLA-DOA.

    PubMed

    Santin, I; Castellanos-Rubio, A; Aransay, A M; Gutierrez, G; Gaztambide, S; Rica, I; Vicario, J L; Noble, J A; Castaño, L; Bilbao, J R

    2009-09-01

    The objective of this study was to identify additional diabetes susceptibility markers in the MHC that could be responsible for the differential diabetogenicity of different HLA-DR3 CEHs. High-resolution SNP genotyping of the MHC was carried out in 15 type 1 diabetes (T1D) patients and 39 non-diabetic controls, homozygous for DR3-DQ2 and with one copy of the A(*)30-B(*)18-MICA(*)4-F1C30-DRB1(*)0301-DQB1(*)0201-DPB1(*)0202 HLA haplotype. Significantly associated SNPs were replicated in an independent sample of 554 T1D patients and 841 controls without HLA matching. Electrophoretic mobility shift assay was used to show a functional effect of an associated SNP. Seven SNPs showed evidence of association in the initial discovery experiment. Upon replication, only rs419434 (upstream HLA-DOA gene) remained significant. A functional variant (rs432375) in complete LD with rs419434 was shown to affect USF-1 binding and could be responsible for the association signal in the region. We have identified a new susceptibility locus within the MHC with a modest contribution to T1D (OR=1.93; CI: 1.52-2.44; P=10(-8)) that is independent of HLA-DRB1 locus.

  14. Lack of associations between HLA class II alleles and resistance to HIV-1 infection among white, non-Hispanic homosexual men.

    PubMed

    Liu, Chenglong; Carrington, Mary; Kaslow, Richard A; Gao, Xiaojiang; Rinaldo, Charles R; Jacobson, Lisa P; Margolick, Joseph B; Phair, John; O'Brien, Stephen J; Detels, Roger

    2004-10-01

    HLA class II alleles were molecularly typed for 100 high-risk seronegative men and 184 low-risk seroconverters from the Multicenter AIDS Cohort Study (MACS). Seven resistant individuals homozygous for CCR5 Delta32 deletions were excluded from analysis. In the univariate analysis, no significant HLA class II associations with resistance/susceptibility to HIV type 1 infection were identified. However, the transporter associated with antigen presentation 2 (TAP2) Ala 665 variant associated with resistance in earlier analyses in the MACS was in linkage disequilibrium with some HLA class II alleles. After adjusting for the established associations with HLA-A*0205 subgroup and TAP2 Ala 665 variant, no HLA class II alleles were independently associated with resistance/susceptibility to HIV-1 infection. Other genetic factors in the HLA class II-TAP region of the major histocompatibility complex might be involved.

  15. Allele frequency net 2015 update: new features for HLA epitopes, KIR and disease and HLA adverse drug reaction associations.

    PubMed

    González-Galarza, Faviel F; Takeshita, Louise Y C; Santos, Eduardo J M; Kempson, Felicity; Maia, Maria Helena Thomaz; da Silva, Andrea Luciana Soares; Teles e Silva, André Luiz; Ghattaoraya, Gurpreet S; Alfirevic, Ana; Jones, Andrew R; Middleton, Derek

    2015-01-01

    It has been 12 years since the Allele Frequency Net Database (AFND; http://www.allelefrequencies.net) was first launched, providing the scientific community with an online repository for the storage of immune gene frequencies in different populations across the world. There have been a significant number of improvements from the first version, making AFND a primary resource for many clinical and scientific areas including histocompatibility, immunogenetics, pharmacogenetics and anthropology studies, among many others. The most widely used part of AFND stores population frequency data (alleles, genes or haplotypes) related to human leukocyte antigens (HLA), killer-cell immunoglobulin-like receptors (KIR), major histocompatibility complex class I chain-related genes (MIC) and a number of cytokine gene polymorphisms. AFND now contains >1400 populations from more than 10 million healthy individuals. Here, we report how the main features of AFND have been updated to include a new section on 'HLA epitope' frequencies in populations, a new section capturing the results of studies identifying HLA associations with adverse drug reactions (ADRs) and one for the examination of infectious and autoimmune diseases associated with KIR polymorphisms-thus extending AFND to serve a new user base in these growing areas of research. New criteria on data quality have also been included.

  16. Use of synthetic oligonucleotides for genomic DNA dot hybridization to split the DQw3 haplotype

    SciTech Connect

    Martell, M.; Le Gall, I.; Millasseau, P.; Dausset, J.; Cohen, D.

    1988-04-01

    Comparison of two different HLA-DQ..beta..gene sequences from two DR4 individuals, probably corresponding to DQw3.2 (DQR4) and DQw3.1 (DQR5) specificities, has shown several nucleotide variations. Eight oligonucleotides (24 bases long), derived from these polymorphic areas, have been synthesized. Each oligonucleotide was hybridized to BamHI-digested DNA samples from eight families with HLA-DR4 individuals. Four polymorphic BamHI fragments were detected. Two of eight oligonucleotides gave a single signal (8.9 kilobases) on DQw3.2-positive haplotypes. The authors used one of these oligonucleotides in a genomic DNA dot hybridization and detected a hybridization signal only in DQw3.2-positive individuals. A very simple test like this allows the screening of a large population sample within a very short period.

  17. Allelic associations and homozygosity at loci from HLA-B to D6S299 in genetic haemochromatosis.

    PubMed Central

    Raha-Chowdhury, R; Bowen, D J; Burnett, A K; Worwood, M

    1995-01-01

    Haemochromatosis (GH) is an autosomal recessive disorder in which increased iron absorption causes iron overload. The gene (HFE) is closely linked to HLA-A on chromosome 6 (6p21.3) but has not yet been identified. We have examined eight polymorphic loci, HLA-B (most centromeric), I82, D6S265, HLA-A, D6S128, HLA-F, D6S105, and D6S299 (most telomeric) in 37 unrelated patients and 60 control subjects. There are also significant positive associations between GH and alleles at all loci except D6S299. Analysis of 48 GH chromosomes in which haplotypes could be established showed that the most common haplotype was I82-2:D6S265-1:HLA-A3:D6S128-2:HLA-F1:D6S105-8. This was present in 28 of 48 chromosomes. In 14 the haplotype included HLA-B7 but only in seven did this extend beyond the telomere to D6S299-2 (the most common allele on GH chromosomes at this locus). In 36 out of 48 chromosomes the two locus haplotype, F1:D6S105-8 was present. Since haemochromatosis appears to originate from a founder mutation we have examined linkage disequilibrium between these various loci and GH using calculations of pexcess. The maximum value (0.72, 95% CI 0.55-0.85) is given by D6S105-8 but is not significantly different from values for HLA-A3 and HLA-F1 (0.50, 95% CI 0.34-0.61 and 0.49, 0.25-0.66 respectively). However, both HLA-A and D6S105 give a value for pexcess which is significantly higher than that for the most centromeric marker, HLA-B (0.17, 95% CI 0.02-0.30). We have counted the number of patients who are homozygous for the common allele at each locus. At D6S105, 22 patients are homozygous for allele 8, with 18 homozygous for HLA-F1 and 10 homozygous for A3. The pattern of cumulative homozygosity suggests a gene location closer to D6S105 than HLA-A. We have also analysed our data for divergence from the apparent founder haplotype (A3:F1:105-8) and have calculated the theoretical frequencies of crossovers between loci. These data suggest a location telomeric to D6S105. A more

  18. NATO HLA Certification

    DTIC Science & Technology

    2002-06-01

    les M&S (NMSG), a été implantée au sein de l’organisation de recherche et technologie (RTO). Les activités du NMSG sont organisées selon un plan...le cadre de son plan d’action, le NMSG a décidé la création d’un groupe de travail chargé de comparer différentes possibilités pour implanter ... une capacité de certification de conformité au standard HLA des simulations développées et utilisées par l’OTAN. Ce groupe de travail (le MSG-011

  19. The heterogeneous HLA genetic makeup of the Swiss population.

    PubMed

    Buhler, Stéphane; Nunes, José Manuel; Nicoloso, Grazia; Tiercy, Jean-Marie; Sanchez-Mazas, Alicia

    2012-01-01

    This study aims at investigating the HLA molecular variation across Switzerland in order to determine possible regional differences, which would be highly relevant to several purposes: optimizing donor recruitment strategies in hematopoietic stem cell transplantation (HSCT), providing reliable reference data in HLA and disease association studies, and understanding the population genetic background(s) of this culturally heterogeneous country. HLA molecular data of more than 20,000 HSCT donors from 9-13 recruitment centers of the whole country were analyzed. Allele and haplotype frequencies were estimated by using new computer tools adapted to the heterogeneity and ambiguity of the data. Non-parametric and resampling statistical tests were performed to assess Hardy-Weinberg equilibrium, selective neutrality and linkage disequilibrium among different loci, both in each recruitment center and in the whole national registry. Genetic variation was explored through genetic distance and hierarchical analysis of variance taking into account both geographic and linguistic subdivisions in Switzerland. The results indicate a heterogeneous genetic makeup of the Swiss population: first, allele frequencies estimated on the whole national registry strongly deviate from Hardy-Weinberg equilibrium, by contrast with the results obtained for individual centers; second, a pronounced differentiation is observed for Ticino, Graubünden, and, to a lesser extent, Wallis, suggesting that the Alps represent(ed) a barrier to gene flow; finally, although cultural (linguistic) boundaries do not represent a main genetic differentiation factor in Switzerland, the genetic relatedness between population from south-eastern Switzerland and Italy agrees with historical and linguistic data. Overall, this study justifies the maintenance of a decentralized donor recruitment structure in Switzerland allowing increasing the genetic diversity of the national--and hence global--donor registry. It also

  20. The Heterogeneous HLA Genetic Makeup of the Swiss Population

    PubMed Central

    Buhler, Stéphane; Nunes, José Manuel; Nicoloso, Grazia; Tiercy, Jean-Marie; Sanchez-Mazas, Alicia

    2012-01-01

    This study aims at investigating the HLA molecular variation across Switzerland in order to determine possible regional differences, which would be highly relevant to several purposes: optimizing donor recruitment strategies in hematopoietic stem cell transplantation (HSCT), providing reliable reference data in HLA and disease association studies, and understanding the population genetic background(s) of this culturally heterogeneous country. HLA molecular data of more than 20,000 HSCT donors from 9–13 recruitment centers of the whole country were analyzed. Allele and haplotype frequencies were estimated by using new computer tools adapted to the heterogeneity and ambiguity of the data. Non-parametric and resampling statistical tests were performed to assess Hardy-Weinberg equilibrium, selective neutrality and linkage disequilibrium among different loci, both in each recruitment center and in the whole national registry. Genetic variation was explored through genetic distance and hierarchical analysis of variance taking into account both geographic and linguistic subdivisions in Switzerland. The results indicate a heterogeneous genetic makeup of the Swiss population: first, allele frequencies estimated on the whole national registry strongly deviate from Hardy-Weinberg equilibrium, by contrast with the results obtained for individual centers; second, a pronounced differentiation is observed for Ticino, Graubünden, and, to a lesser extent, Wallis, suggesting that the Alps represent(ed) a barrier to gene flow; finally, although cultural (linguistic) boundaries do not represent a main genetic differentiation factor in Switzerland, the genetic relatedness between population from south-eastern Switzerland and Italy agrees with historical and linguistic data. Overall, this study justifies the maintenance of a decentralized donor recruitment structure in Switzerland allowing increasing the genetic diversity of the national—and hence global—donor registry. It also

  1. The absence of HLA class I expression in non-small cell lung cancer correlates with the tumor tissue structure and the pattern of T cell infiltration.

    PubMed

    Perea, Francisco; Bernal, Mónica; Sánchez-Palencia, Abel; Carretero, Javier; Torres, Cristina; Bayarri, Clara; Gómez-Morales, Mercedes; Garrido, Federico; Ruiz-Cabello, Francisco

    2017-02-15

    We wanted to analyze whether tumor HLA class I (HLA-I) expression influences the pattern of the immune cell infiltration and stromal cell reaction in the tumor microenvironment. Tumor tissues obtained from 57 patients diagnosed with lung carcinomas were analyzed for HLA expression and leukocyte infiltration. 28 patients out of the 57 were completely negative for HLA-I expression (49.1%) or showed a selective HLA-A locus downregulation (three patients, 5.2%). In 26 out of 57 tumors (47.8%) we detected a positive HLA-I expression but with a percentage of HLA-I negative cells between 10 and 25%. The HLA-I negative phenotype was produced by a combination of HLA haplotype loss and a transcriptional downregulation of β2-microglobulin (β2-m) and LMP2 and LMP7 antigen presentation machinery genes. The analysis and localization of different immune cell populations revealed the presence of two major and reproducible patterns. One pattern, which we designated "immune-permissive tumor microenvironment (TME)," was characterized by positive tumor HLA-I expression, intratumoral infiltration with cytotoxic T-CD8+ cells, M1-inflammatory type macrophages, and a diffuse pattern of FAP+ cancer-associated fibroblasts. In contrast, another pattern defined as "non-immune-permissive TME" was found in HLA-I negative tumors with strong stromal-matrix interaction, T-CD8+ cells surrounding tumor nests, a dense layer of FAP+ fibroblasts and M2/repair-type macrophages. In conclusion, this study revealed marked differences between HLA class I-positive and negative tumors related to tissue structure, the composition of leukocyte infiltration and stromal response in the tumor microenvironment.

  2. HLA-B27 Test

    MedlinePlus

    ... arthritis , juvenile rheumatoid arthritis (JRA) , or sometimes anterior uveitis . The HLA-B27 test is not a definitive ... form of arthritis that occurs in children. Anterior uveitis is associated with recurring inflammation of the structures ...

  3. The role of HLA-DRB1 matching in corneal grafting.

    PubMed

    Mravicić, I; Gabrić, N; Dekaris, I; Karaman, Z; Kerhin-Brkljacić, V; Grubić, Z; Spoljarić, N

    2001-01-01

    The aim of the study was to evaluate the role of HLA-DRB1 (Human Leukocyte Antigens) matching in corneal transplantation. Fifty-two patients were observed. Low-risk group consisted of 28 patients and high-risk group consisted of 24 patients. All the patients and donors were tissue typed with Polymerase Chain Reaction (PCR) on the HLA-DRB1 gen. The primary corneal disease preceding keratoplasty was keratopathia (15), leucoma (10), keratoconus (7), Re-KPP (6), impending perforation (4), combustio corneae (3), degenerative disorders (2), keratoglobus (1), keratouveitis (1), corneal maculae (1), and corneal melting syndrome (1). The graft rejection frequency was higher in the group of high-risk patients (29%) than in the group of low risk patients (7.1%). The rejection rate of compatible grafts was 37% for high risk and 2% for low risk group, while the rejection rate of incompatible was 44% in high risk and 5% in low risk group. We can conclude that HLA-DRB1 matching does not improve corneal graft survival.

  4. Analysis of the contribution of HLA genes to genetic predisposition in inflammatory bowel disease

    SciTech Connect

    Naom, I.; Haris, I.; Hodgson, S.V.; Mathew, C.G.

    1996-07-01

    Crohn disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBDs) of unknown etiology. First-degree relatives of IBD patients have a 10-fold increase in risk of developing the same disease, and distinct associations between specific HLA types and both CD and UC have been reported. We have evaluated the contribution of genes at the HLA locus to susceptibility in IBD by linkage analysis of highly informative microsatellite polymorphisms in 43 families with multiple affected cases. No evidence for linkage of HLA to IBD was obtained under any of the four models tested. Analysis of HLA haplotype sharing in affected relatives indicated that the relative risk to a sibling conferred by the HLA locus was 1.11 in UC and 0.75 in CD, with upper (95%) confidence limits of 2.41 and 1.37, respectively. This suggests that other genetic or environmental factors are responsible for most of the familial aggregation in IBD. 31 refs., 1 fig., 2 tabs.

  5. Comparison of HLA allelic imputation programs.

    PubMed

    Karnes, Jason H; Shaffer, Christian M; Bastarache, Lisa; Gaudieri, Silvana; Glazer, Andrew M; Steiner, Heidi E; Mosley, Jonathan D; Mallal, Simon; Denny, Joshua C; Phillips, Elizabeth J; Roden, Dan M

    2017-01-01

    Imputation of human leukocyte antigen (HLA) alleles from SNP-level data is attractive due to importance of HLA alleles in human disease, widespread availability of genome-wide association study (GWAS) data, and expertise required for HLA sequencing. However, comprehensive evaluations of HLA imputations programs are limited. We compared HLA imputation results of HIBAG, SNP2HLA, and HLA*IMP:02 to sequenced HLA alleles in 3,265 samples from BioVU, a de-identified electronic health record database coupled to a DNA biorepository. We performed four-digit HLA sequencing for HLA-A, -B, -C, -DRB1, -DPB1, and -DQB1 using long-read 454 FLX sequencing. All samples were genotyped using both the Illumina HumanExome BeadChip platform and a GWAS platform. Call rates and concordance rates were compared by platform, frequency of allele, and race/ethnicity. Overall concordance rates were similar between programs in European Americans (EA) (0.975 [SNP2HLA]; 0.939 [HLA*IMP:02]; 0.976 [HIBAG]). SNP2HLA provided a significant advantage in terms of call rate and the number of alleles imputed. Concordance rates were lower overall for African Americans (AAs). These observations were consistent when accuracy was compared across HLA loci. All imputation programs performed similarly for low frequency HLA alleles. Higher concordance rates were observed when HLA alleles were imputed from GWAS platforms versus the HumanExome BeadChip, suggesting that high genomic coverage is preferred as input for HLA allelic imputation. These findings provide guidance on the best use of HLA imputation methods and elucidate their limitations.

  6. Comparison of HLA allelic imputation programs

    PubMed Central

    Shaffer, Christian M.; Bastarache, Lisa; Gaudieri, Silvana; Glazer, Andrew M.; Steiner, Heidi E.; Mosley, Jonathan D.; Mallal, Simon; Denny, Joshua C.; Phillips, Elizabeth J.; Roden, Dan M.

    2017-01-01

    Imputation of human leukocyte antigen (HLA) alleles from SNP-level data is attractive due to importance of HLA alleles in human disease, widespread availability of genome-wide association study (GWAS) data, and expertise required for HLA sequencing. However, comprehensive evaluations of HLA imputations programs are limited. We compared HLA imputation results of HIBAG, SNP2HLA, and HLA*IMP:02 to sequenced HLA alleles in 3,265 samples from BioVU, a de-identified electronic health record database coupled to a DNA biorepository. We performed four-digit HLA sequencing for HLA-A, -B, -C, -DRB1, -DPB1, and -DQB1 using long-read 454 FLX sequencing. All samples were genotyped using both the Illumina HumanExome BeadChip platform and a GWAS platform. Call rates and concordance rates were compared by platform, frequency of allele, and race/ethnicity. Overall concordance rates were similar between programs in European Americans (EA) (0.975 [SNP2HLA]; 0.939 [HLA*IMP:02]; 0.976 [HIBAG]). SNP2HLA provided a significant advantage in terms of call rate and the number of alleles imputed. Concordance rates were lower overall for African Americans (AAs). These observations were consistent when accuracy was compared across HLA loci. All imputation programs performed similarly for low frequency HLA alleles. Higher concordance rates were observed when HLA alleles were imputed from GWAS platforms versus the HumanExome BeadChip, suggesting that high genomic coverage is preferred as input for HLA allelic imputation. These findings provide guidance on the best use of HLA imputation methods and elucidate their limitations. PMID:28207879

  7. Polymorphisms of HLA-DRB1, -DQA1 and -DQB1 in Inhabitants of Astana, the Capital City of Kazakhstan

    PubMed Central

    Kuranov, Alexandr B.; Vavilov, Mikhail N.; Abildinova, Gulshara Zh.; Akilzhanova, Ainur R.; Iskakova, Aisha N.; Zholdybayeva, Elena V.; Boldyreva, Margarita N.; Müller, Claudia A.; Momynaliev, Kuvat T.

    2014-01-01

    Background Kazakhstan has been inhabited by different populations, such as the Kazakh, Kyrgyz, Uzbek and others. Here we investigate allelic and haplotypic polymorphisms of human leukocyte antigen (HLA) genes at DRB1, DQA1 and DQB1 loci in the Kazakh ethnic group, and their genetic relationship between world populations. Methodology/Principal Findings A total of 157 unrelated Kazakh ethnic individuals from Astana were genotyped using sequence based typing (SBT-Method) for HLA-DRB1, -DQA1 and -DQB1 loci. Allele frequencies, neighbor-joining method, and multidimensional scaling analysis have been obtained for comparison with other world populations. Statistical analyses were performed using Arlequin v3.11. Applying the software PAST v. 2.17 the resulting genetic distance matrix was used for a multidimensional scaling analysis (MDS). Respectively 37, 17 and 19 alleles were observed at HLA-DRB1, -DQA1 and -DQB1 loci. The most frequent alleles were HLA-DRB1*07:01 (13.1%), HLA-DQA1*03:01 (13.1%) and HLA-DQB1*03:01 (17.6%). In the observed group of Kazakhs DRB1*07:01-DQA1*02:01-DQB1*02:01 (8.0%) was the most common three loci haplotype. DRB1*10:01-DQB1*05:01 showed the strongest linkage disequilibrium. The Kazakh population shows genetic kinship with the Kazakhs from China, Uyghurs, Mongolians, Todzhinians, Tuvinians and as well as with other Siberians and Asians. Conclusions/Significance The HLA-DRB1, -DQA1and -DQB1 loci are highly polymorphic in the Kazakh population, and this population has the closest relationship with other Asian and Siberian populations. PMID:25531278

  8. Determination of high-risk cargo

    NASA Astrophysics Data System (ADS)

    Morris, Leo A.; Smith, Douglas E.; Khan, Siraj M.

    1994-10-01

    The approach and methodology used in the determination of the type of cargo containing concealments of commercial quantities of narcotics such as cocaine and heroin is described. This high-risk cargo enters the United States through border crossings at land, seaports and airports. The volume and variety of cargos make it a complex and challenging task for the U.S. Customs Service.

  9. High-Risk Workers: The Eczematous Hand

    PubMed Central

    Barber, Kirk A.

    1989-01-01

    The hand is the most commonly involved site in occupation — related skin disease, and contact eczema is the most common diagnosis. The identification of workers at high risk for this condition is possible and will help in their management and assessment. ImagesFigure 1Figure 2Figure 3 PMID:21248925

  10. Teaching Art to High Risk Groups.

    ERIC Educational Resources Information Center

    Rossol, Monona

    The role of art therapy is considered in working with such high risk groups as the institutionalized, mentally retarded, elderly, visually impaired, physically handicapped, asthmatic, hyper- and hypo-active children, hearing impaired, and patients on mind altering drugs. The special risks of infectious diseases (such as serum hepatitis), and…

  11. Micronutrient requirements of high-risk infants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Micronutrient requirements are well-established for healthy full-term infants. However, few such recommendations exist for high-risk infants, including full-term infants with a variety of medical disorders or very preterm infants. Key micronutrients considered in this review are calcium, phosphorus,...

  12. Innovative Materials for High Risk ABE Students.

    ERIC Educational Resources Information Center

    Connett, Dian; Rathburn, Rene

    This resource book contains innovative group activities, units of instruction, writing packets, and math activities that were developed to serve high-risk adult basic education (ABE) students. Included in the first section are units of study dealing with the following topics: Oregon history, personal health issues, controversial issues in science,…

  13. HLA-DQA1/B1 alleles as putative susceptibility markers in congenital toxoplasmosis

    PubMed Central

    Shimokawa, Paulo Tadashi; Targa, Lília Spaleta; Yamamoto, Lidia; Rodrigues, Jonatas Cristian; Kanunfre, Kelly Aparecida; Okay, Thelma Suely

    2016-01-01

    ABSTRACT Host and parasite genotypes are among the factors associated with congenital toxoplasmosis pathogenesis. As HLA class II molecules play a key role in the immune system regulation, the aim of this study was to investigate whether HLA-DQA1/B1 alleles are associated with susceptibility or protection to congenital toxoplasmosis. One hundred and twenty-two fetuses with and 103 without toxoplasmosis were studied. The two study groups were comparable according to a number of socio-demographic and genetic variables. HLA alleles were typed by PCR-SSP. In the HLA-DQA1 region, the allele frequencies showed that *01:03 and *03:02 alleles could confer susceptibility (OR= 3.06, p = 0.0002 and OR= 9.60, p= 0.0001, respectively) as they were more frequent among infected fetuses. Regarding the HLA-DQB1 region, the *05:04 allele could confer susceptibility (OR = 6.95, p < 0.0001). Of the 122 infected fetuses, 10 presented susceptibility haplotypes contrasting with only one in the non-infected group. This difference was not statistically significant after correction for multiple comparison (OR = 9.37, p=0.011). In the casuistic, there were two severely damaged fetuses with high parasite loads determined in amniotic fluid samples and HLA-DQA1 susceptibility alleles. In the present study, a discriminatory potential of HLA-DQA1/B1 alleles to identify susceptibility to congenital toxoplasmosis and the most severe cases has been shown. PMID:26856406

  14. Fine mapping analysis of HLA-DP/DQ gene clusters on chromosome 6 reveals multiple susceptibility loci for HBV infection.

    PubMed

    Tao, Jingjing; Su, Kunkai; Yu, Chengbo; Liu, Xiaoli; Wu, Wei; Xu, Wei; Jiang, Bingxun; Luo, Rui; Yao, Jian; Zhou, Jiawei; Zhan, Yan; Ye, Chao; Yuan, Wenji; Jiang, Xianzhong; Cui, Wenyan; Li, Ming D; Li, Lianjuan

    2015-12-01

    Recent genome-wide association studies have revealed the HLA region on chromosome 6p21 as a susceptibility locus for hepatitis B virus (HBV) infection, a finding subsequently replicated in independent samples. However, only limited single nucleotide polymorphisms (SNPs) were analyzed in most of these studies, and it remains to be determined which SNPs contribute to the detected association. After genotyping 140 SNPs within this genomic region in a total of 1657 HBV-positive patients and 1456 HBV-negative controls, we conducted a series of genetic epidemiological and bioinformatics analysis, including individual SNP-based association analysis, haplotype-based association analysis, and conditional analysis. We identified 76 SNPs and 5 LD blocks in HLA-DP/DQ clusters that are significantly associated with HBV infection, with the smallest P value being 3.88 × 10(-18) for rs9277535 in HLA-DPB1. With conditional analysis, we further revealed that the genes contributing to the effects of variants in HLA-DP/DQ on infection are independent of each other, and the LD block 5 in the 3'-UTR region of HLA-DPB1 had a predominant effect in the association of HLA-DP with HBV infection. We also found that the SNPs in the 3'-UTR region of HLA-DPB1 were significant between the subgroups of inactive HBV carrier, chronic hepatitis B, or hepatic cirrhosis from the case group and the spontaneous HBV-clearance subgroup from the control group. Finally, we did further association analysis of SNPs in this region with different subgroups from the case group, which revealed no association of these SNPs with the progression of HBV-related diseases. In sum, we showed, for the first time, that the HLA-DP/DQ clusters contribute independently to HBV infection, and the 3'-UTR region of HLA-DPB1 represents an important functional region involved in HBV infection.

  15. Role of CYP1A1 haplotypes in modulating susceptibility to coronary artery disease.

    PubMed

    Lakshmi, Sana Venkata Vijaya; Naushad, Shaik Mohammad; Saumya, Kankanala; Rao, Damera Seshagiri; Kutala, Vijay Kumar

    2012-10-01

    To investigate the role of cytochrome P450 1A1 (CYP1A1) haplotypes in modulating susceptibility to coronary artery disease (CAD), a case-control study was conducted by enrolling 352 CAD cases and 282 healthy controls. PCR-RFLP, multiplex PCR, competitive ELISA techniques were employed for the analysis of CYP1A1 [ml (T-->C), m2 (A-->G) and m4 (C-->A)] haplotypes, glutathione-S-transferase (GST)T1/GSTM1 null variants and plasma 8-oxo-2'deoxyguanosine (8-oxodG) respectively. Two CYP1A1 haplotypes, i.e. CAC and TGC showed independent association with CAD risk, while all-wild CYP1A1 haplotype i.e. TAC showed reduced risk for CAD. All the three variants showed mild linkage disequilibrium (D': 0.05 to 0.17). GSTT1 null variant also exerted independent association with CAD risk (OR: 2.53, 95% CI 1.55-4.12). Among the conventional risk factors, smoking showed synergetic interaction with CAC haplotype of CYP1A1 and GSTT1 null genotype in inflating CAD risk. High risk alleles of this pathway showed dose-dependent association with percentage of stenosis and number of vessels affected. Elevated 8-oxodG levels were observed in subjects with CYP1A1 CAC haplotype and GSTT1 null variant. Multiple linear regression model of these xenobiotic variants explained 36% variability in 8-oxodG levels. This study demonstrated the association of CYP1A1 haplotypes and GSTT1 null variant with CAD risk and this association was attributed to increased oxidative DNA damage.

  16. Power laws for heavy-tailed distributions: modeling allele and haplotype diversity for the national marrow donor program.

    PubMed

    Slater, Noa; Louzoun, Yoram; Gragert, Loren; Maiers, Martin; Chatterjee, Ansu; Albrecht, Mark

    2015-04-01

    Measures of allele and haplotype diversity, which are fundamental properties in population genetics, often follow heavy tailed distributions. These measures are of particular interest in the field of hematopoietic stem cell transplant (HSCT). Donor/Recipient suitability for HSCT is determined by Human Leukocyte Antigen (HLA) similarity. Match predictions rely upon a precise description of HLA diversity, yet classical estimates are inaccurate given the heavy-tailed nature of the distribution. This directly affects HSCT matching and diversity measures in broader fields such as species richness. We, therefore, have developed a power-law based estimator to measure allele and haplotype diversity that accommodates heavy tails using the concepts of regular variation and occupancy distributions. Application of our estimator to 6.59 million donors in the Be The Match Registry revealed that haplotypes follow a heavy tail distribution across all ethnicities: for example, 44.65% of the European American haplotypes are represented by only 1 individual. Indeed, our discovery rate of all U.S. European American haplotypes is estimated at 23.45% based upon sampling 3.97% of the population, leaving a large number of unobserved haplotypes. Population coverage, however, is much higher at 99.4% given that 90% of European Americans carry one of the 4.5% most frequent haplotypes. Alleles were found to be less diverse suggesting the current registry represents most alleles in the population. Thus, for HSCT registries, haplotype discovery will remain high with continued recruitment to a very deep level of sampling, but population coverage will not. Finally, we compared the convergence of our power-law versus classical diversity estimators such as Capture recapture, Chao, ACE and Jackknife methods. When fit to the haplotype data, our estimator displayed favorable properties in terms of convergence (with respect to sampling depth) and accuracy (with respect to diversity estimates). This

  17. A novel HLA-B*14 allele - B*14:53 - genetics and serology.

    PubMed

    Street, J; Davies, E; Darke, C

    HLA-B*14:53 was found in a UK European normal blood donor prior to registration on the Welsh Bone Marrow Donor Registry. It differs from B*14:13 by one base (103G>T) in exon 2 resulting in a substitution of alanine (A) in B*14:13 to serine (S) in B*14:53. Unique among current HLA-B*14 alleles, B*14:53 and B*14:13 share a motif of 59 bases between positions 361 and 419 in exon 3. This motif is present in numerous HLA-B alleles the commonest overall being B*08:01, suggesting that both B*14:53 and B*14:13 arose from intralocus gene conversion events with B*08:01. Thus, B*14:53 probably arose from B*14:01:01 (which has TCC at codon 11 (S), while B*14:13 arose from B*14:02:01:01 which has GCC at codon 11 (A). Additionally, the two likely B*14:53-bearing and B*14:13-bearing haplotypes are typical of B*14:01:01-bearing and B*14:02:01:01-bearing haplotypes, respectively. Serological testing, using 49 antisera with HLA-B64, or B64, B65 reactivity, showed that the B*14:53 specificity did not react as a B64 (B*14:01) specificity and may appear as a short/weak HLA-B14. This implies that residues additional to S at position 11 are involved in HLA-B64 serological identity; for example, the motif 11S 97W 116F is possessed by B*14:01 and many other B*14 products (and B*39:79 plus some HLA-C products) but not B65 (B*14:02) or the B*14:53 specificity. B*14:53 was found in a random HLA sequence-based typed population of 32 530 normal subjects indicating a low precision allele frequency of 0.000015 in subjects resident in Wales.

  18. Population structure with localized haplotype clusters.

    PubMed

    Browning, Sharon R; Weir, Bruce S

    2010-08-01

    We propose a multilocus version of F(ST) and a measure of haplotype diversity using localized haplotype clusters. Specifically, we use haplotype clusters identified with BEAGLE, which is a program implementing a hidden Markov model for localized haplotype clustering and performing several functions including inference of haplotype phase. We apply this methodology to HapMap phase 3 data. With this haplotype-cluster approach, African populations have highest diversity and lowest divergence from the ancestral population, East Asian populations have lowest diversity and highest divergence, and other populations (European, Indian, and Mexican) have intermediate levels of diversity and divergence. These relationships accord with expectation based on other studies and accepted models of human history. In contrast, the population-specific F(ST) estimates obtained directly from single-nucleotide polymorphisms (SNPs) do not reflect such expected relationships. We show that ascertainment bias of SNPs has less impact on the proposed haplotype-cluster-based F(ST) than on the SNP-based version, which provides a potential explanation for these results. Thus, these new measures of F(ST) and haplotype-cluster diversity provide an important new tool for population genetic analysis of high-density SNP data.

  19. Genetic variation among the Golla pastoral caste subdivisions of Andhra Pradesh, India, according to the HLA system.

    PubMed

    Crawford, M H; Reddy, B M; Martinez-Laso, J; Mack, S J; Erlich, H A

    2001-09-01

    The HLA allele frequency distributions have been characterized for the HLA class I and class II loci of the Golla pastoral caste, from Southeast India, subdivided into the subcastes (Puja, Punugu, Kurava, Pokanati, Karnam, and Doddi). Genetic distances, neighbor-joining, correspondence, and haplotype analyses all indicate that the subcastes exhibit a high haplotype variability and that their genetic substratum may be the result of European-Middle East/Asian admixture with the autochthonous populations. The Karnam subcaste seems to be the one that has undergone a higher degree of admixture, when compared with the other subcastes. The Golla speak an old Indian Dravidian language and should theoretically represent the basic Indian substratum that existed before the postulated "Aryan" invasion.

  20. HLA profile of three ethnic groups living in the North-Western region of Russia.

    PubMed

    Evseeva, I; Spurkland, A; Thorsby, E; Smerdel, A; Tranebjaerg, L; Boldyreva, M; Groudakova, E; Gouskova, I; Alexeev, L L

    2002-01-01

    HLA class II alleles were determined by PCR-SSO and PCR-SSP typing of DNA samples from 55 Nentsy, 81 Saami and 73 Pomor individuals from the North-European part of Russia. The results were compared with similar data from Russians. A high frequency of the DRB1*04-DQA1*0301-DQB1*0302 haplotype and a low frequency of the DRB1*11-DQA1*0501-DQB1*0301 haplotype, observed in all three ethnic groups, may indicate a common aboriginal component in their ancestry. Saami and Pomors displayed a similar pattern of allele and haplotype distribution, with the exception of the DRB1*04-DQA1*0304-DQB1*0301 haplotype, which was significantly higher among Saami compared Nentsy, Pomors and Russians. Nentsy individuals had a particularly high frequency of the DRB1*09-DQA1*0301-DQB1*0303 and the DRB1*12-DQA1*0501-DQB1*0301 haplotypes. Genetic distances and correspondence analysis show that Pomors have a close relationship with Norwegians and Finns, whereas Nentsy and Saami are more closely related to Oriental populations.

  1. HLA-Mismatched Renal Transplantation without Maintenance Immunosuppression

    PubMed Central

    Kawai, Tatsuo; Cosimi, A. Benedict; Spitzer, Thomas R.; Tolkoff-Rubin, Nina; Suthanthiran, Manikkam; Saidman, Susan L.; Shaffer, Juanita; Preffer, Frederic I.; Ding, Ruchuang; Sharma, Vijay; Fishman, Jay A.; Dey, Bimalangshu; Ko, Dicken S.C.; Hertl, Martin; Goes, Nelson B.; Wong, Waichi; Williams, Winfred W.; Colvin, Robert B.; Sykes, Megan; Sachs, David H.

    2010-01-01

    Summary Five patients with end-stage renal disease received combined bone marrow and kidney transplants from HLA single-haplotype mismatched living related donors, with the use of a nonmyeloablative preparative regimen. Transient chimerism and reversible capillary leak syndrome developed in all recipients. Irreversible humoral rejection occurred in one patient. In the other four recipients, it was possible to discontinue all immunosuppressive therapy 9 to 14 months after the transplantation, and renal function has remained stable for 2.0 to 5.3 years since transplantation. The T cells from these four recipients, tested in vitro, showed donor-specific unresponsiveness and in specimens from allograft biopsies, obtained after withdrawal of immunosuppressive therapy, there were high levels of P3 (FOXP3) messenger RNA (mRNA) but not granzyme B mRNA. PMID:18216355

  2. HLA-linked rheumatoid arthritis

    SciTech Connect

    Hasstedt, S.J.; Clegg, D.O.; Ingles, L.; Ward, R.H.

    1994-10-01

    Twenty-eight pedigrees were ascertained through pairs of first-degree relatives diagnosed with rheumatoid arthritis (RA). RA was confirmed in 77 pedigree members including probands; the absence of disease was verified in an additional 261 pedigree members. Pedigree members were serologically typed for HLA. We used likelihood analysis to statistically characterize the HLA-linked RA susceptibility locus. The genetic model assumed tight linkage to HLA. The analysis supported the existence of an HLA-linked RA susceptibility locus, estimated the lifetime penetrance as 41% in male homozygotes and as 48% in female homozygotes. Inheritance was recessive in males and was nearly recessive in females. In addition, the analysis attributed 78% of the variance within genotypes to genetic or environmental effects shared by siblings. The genetic model inferred in this analysis is consistent with previous association, linkage, and familial aggregation studies of RA. The inferred HLA-linked RA susceptibility locus accounts for approximately one-fifth of the RA in the population. Although other genes may account for the remaining familial RA, a large portion of RA cases may occur sporadically. 79 refs., 9 tabs.

  3. HLA-linked rheumatoid arthritis.

    PubMed Central

    Hasstedt, S. J.; Clegg, D. O.; Ingles, L.; Ward, R. H.

    1994-01-01

    Twenty-eight pedigrees were ascertained through pairs of first-degree relatives diagnosed with rheumatoid arthritis (RA). RA was confirmed in 77 pedigree members including probands; the absence of disease was verified in an additional 261 pedigree members. Pedigree members were serologically typed for HLA. We used likelihood analysis to statistically characterize the HLA-linked RA susceptibility locus. The genetic model assumed tight linkage to HLA. The analysis supported the existence of an HLA-linked RA susceptibility locus, estimated the susceptibility allele frequency as 2.16%, and estimated the lifetime penetrance as 41% in male homozygotes and as 48% in female homozygotes. Inheritance was recessive in males and was nearly recessive in females. In addition, the analysis attributed 78% of the variance within genotypes to genetic or environmental effects shared by siblings. The genetic model inferred in this analysis is consistent with previous association, linkage, and familial aggregation studies of RA. The inferred HLA-linked RA susceptibility locus accounts for approximately one-half of familial RA, although it accounts for only approximately one-fifth of the RA in the population. Although other genes may account for the remaining familial RA, a large portion of RA cases may occur sporadically. PMID:7942852

  4. Meta-analysis reveals association between most common class II haplotype in full-heritage Native Americans and rheumatoid arthritis.

    PubMed

    Williams, R C; Jacobsson, L T; Knowler, W C; del Puente, A; Kostyu, D; McAuley, J E; Bennett, P H; Pettitt, D J

    1995-01-01

    The association of RA with the alleles at the HLA system was tested among Pima and Tohono O'odham Indians (Pimans) of the Gila River Indian Community of Arizona. Serologic class I (HLA-A, -B, and -C) alleles were typed in 51 individuals with RA and in 302 without RA. Serologic class II (HLA-DR, DQ; DR52 DR53) alleles were typed in a subset of 47 with RA and 147 without RA. Molecular subtypes of DR3X6, DRB1*1402, and *1406 were determined in 29 individuals, 16 with RA and 13 without RA. Among the cases with RA, 46 of 47 had the serologic antigen HLA-DR3X6, as did 140 of 147 of those without the disease. However, this association was not statistically significant because of the high prevalence of the antigen in the controls. Data from Pimans were analyzed with similar results from the Tlingit and Yakima Indians. A meta-analysis employing the Mantel-Haenszel procedure, stratified by tribe, revealed a statistically significant association between the most common haplotype, DRB1*1402 DQA1*0501 DQB1*0301 DRB3*0101, and RA (summary odds ratio = 2.63, 95% confidence interval = 1.08, 6.46). There was also a statistically significant difference in the genotype distributions of one class I locus, HLA-C, between those with and without RA (chi 2 = 12.4, 5 df; p = 0.03). It is concluded that the association with the most common class II haplotype in full-heritage Native Americans might help explain their high prevalence of RA.

  5. Polymorphism in the upstream regulatory region of DQA1 genes and DRB1, QAP, DQA1, and DQB1 haplotypes in the German population.

    PubMed

    Haas, J P; Kimura, A; Andreas, A; Hochberger, M; Keller, E; Brünnler, G; Bettinotti, M P; Nevinny-Stickel, C; Hildebrandt, B; Sierp, G

    1994-01-01

    Polymorphism in the URR of the MHC class II DQA1 gene defines ten different alleles named QAP. Oligotyping for the alleles of DRB1, QAP, DQA1, and DQB1 have been performed in 210 unrelated healthy controls from Germany. Moreover, 83 HTCs from the Tenth IHWS have been tested. Four point loci haplotypes (DRB1, QAP, DQA1, and DQB1) have been analyzed in the unrelated healthy population sample. Computer analysis of the linkage disequilibria leads to the conclusion that QAP alleles are in strong linkage disequilibrium with alleles either the DQA1 or the DRB1 locus. One typical ("common") haplotype was found to be associated with each DRB1 allele in the majority (86%) of the tested persons. Apart from that, 25 other less frequent ("unusual") haplotypes, with an overall frequency of 14% have been defined. Some of these "unusual" MHC class II haplotypes were found to differ only in the regulatory alleles of DQA1 (QAP alleles) while they are identical for the alleles coding for structural elements (DRB1, DQA1, and DQB1). Most of the "unusual" haplotypes were found to carry HLA-DQ6. Assuming that "unusual" (= rare) haplotypes have arisen from "common" (= frequent) haplotypes by point mutation and recombination, we propose the existence of three recombination sites in the MHC DR-DQ region: one between DRB1 and QAP, the second between QAP and DQA1, and the third between DQA1 and DQB1.

  6. Association between rapidly progressive glomerulonephritis and the properdin factor BfF and different HLA-D region products.

    PubMed

    Müller, G A; Gebhardt, M; Kömpf, J; Baldwin, W M; Ziegenhagen, D; Bohle, A

    1984-01-01

    Frequencies of the HLA antigens ABC, DR and MT, as well as of the properdin factor alleles were determined in 24 unrelated patients presenting with immune complex mediated idiopathic rapidly progressive glomerulonephritis (RPGN) type II. As in Goodpasture syndrome (RPGN type I with pulmonary hemorrhage), a significant association with the B-cell alloantigen HLA-DR 2 was demonstrated (relative risk for HLA-DR 2 positive individuals was 3.54; P less than 0.01). In addition a marked increase of the HLA specificity MT 3 was shown, which is supposed to belong to an antigen system of a second HLA-D region locus. The highest relative risk of 14.67 (P less than 0.00001), however, was calculated for all patients carrying the BfF phenotype. Increased numbers of patients positive for HLA-DR 2 and -MT 3, as well as BfF suggested immune response genes or disease-related mutations on different haplotypes responsible for a MHC (major histocompatibility complex) associated predisposition of RPGN type II.

  7. The HLA-DRβ1 amino acid positions 11-13-26 explain the majority of SLE-MHC associations.

    PubMed

    Kim, Kwangwoo; Bang, So-Young; Lee, Hye-Soon; Okada, Yukinori; Han, Buhm; Saw, Woei-Yuh; Teo, Yik-Ying; Bae, Sang-Cheol

    2014-12-23

    Genetic association of the major histocompatibility complex (MHC) locus is well established in systemic lupus erythematosus (SLE), but the causal functional variants in this region have not yet been discovered. Here we conduct the first fine-mapping study, which thoroughly investigates the SLE-MHC associations down to the amino acid level of major HLA genes in 5,342 unrelated Korean case-control subjects, taking advantages of HLA imputation with a newly constructed Asian HLA reference panel. The most significant association is mapped to amino acid position 13 of HLA-DRβ1 (P=2.48 × 10(-17)) and its proxy position 11 (P=4.15 × 10(-17)), followed by position 26 in a stepwise conditional analysis (P=2.42 × 10(-9)). Haplotypes defined by amino acid positions 11-13-26 support the reported effects of most classical HLA-DRB1 alleles in Asian and European populations. In conclusion, our study identifies the three amino acid positions at the epitope-binding groove of HLA-DRβ1 that are responsible for most of the association between SLE and MHC.

  8. HLA-DR4 subtype frequencies in rheumatoid arthritis indicate that DRB1 is the major susceptibility locus within the HLA class II region

    SciTech Connect

    Wordsworth, B.P.; Bell, J.I. ); Lanchbury, J.S.S.; Sakkas, L.I.; Welsh, K.I.; Panayi, G.S. )

    1989-12-01

    Susceptibility to rheumatoid arthritis (RA) may be due to the presence of shared functional epitopes common the HLA-DR {beta} chains of several RA-associated haplotypes. The authors have obtained direct evidence for this hypothesis by using the polymerase chain reaction and sequencing the DRB1 and DQB1 genes from RA patients. A highly conserved epitope present on DR {beta} chains of DR4 and DR1 haplotypes was found in 83% of 149 patients with classical or definite RA but was found in only 46% of 100 control individuals. Two Dw subtypes of DR4 (Dw4 and Dw14) were associated with disease susceptibility but two other subtypes (Dw10 and Dw13) were not. Sequence differences between these subtypes implicate those residues around the putative antigen binding site of the DR {beta} molecule in the pathogenesis of RA. These data provide a basis for understanding host susceptibility to RA at a molecular level.

  9. Novel HLA-A and HLA-B alleles.

    PubMed

    Hurley, C K; Steiner, N; Kosman, C; Mitton, W; Koester, R; Bei, M; Bush, J; McCormack, J; Hahn, A; Henson, V; Hoyer, R; Wade, J A; Hartzman, R J; Ng, J

    1998-07-01

    Nine novel HLA-A and HLA-B alleles are described: A*2609, A*6803, A*6806, B*1539, B*1540, B*2712, B*4103, B*5109, and B*5603. Most appear to have arisen by gene conversion events. B*5603 appears to have arisen by a reciprocal recombination event joining exon 2 of a B*55/ *56 allele with exon 3 of a B*15 allele. Serologically, the antigen encoded by this allele types with broad B22- and Bw6-specific alloantisera. Also unique, the antigen encoded by B*2712 does not react with B27-specific alloantisera but does react with Bw6-specific alloantisera.

  10. HLA class II diversity in HIV-1 uninfected individuals from the placebo arm of the RV144 Thai vaccine efficacy trial

    PubMed Central

    Baldwin, Karen M.; Ehrenberg, Philip K.; Geretz, Aviva; Prentice, Heather A.; Nitayaphan, Sorachai; Rerks-Ngarm, Supachai; Kaewkungwal, Jaranit; Pitisuttithum, Punnee; O’Connell, Robert J.; Kim, Jerome H.; Thomas, Rasmi

    2015-01-01

    The RV144 HIV vaccine trial in Thailand elicited antibody responses to the envelope of HIV-1, which correlated significantly with the risk of HIV-1 acquisition. Human leukocyte antigen (HLA) class II molecules are essential in antigen presentation to CD4 T cells for activation of B cells to produce antibodies. We genotyped the classical HLA-DRB1, DQB1, and DPB1 genes in 450 individuals from the placebo arm of the RV144 study to determine the background allele and haplotype frequencies of these genes in this cohort. High-resolution 4 and 6-digit class II HLA typing data was generated using sequencing-based methods. The observed diversity for the HLA loci was 33 HLA-DRB1, 15 HLA-DQB1, and 26 HLA-DPB1 alleles. Common alleles with frequencies greater than 10% were DRB1*07:01, DRB1*09:01, DRB1*12:02, DRB1*15:02, DQB1*02:01/02, DQB1*03:01, DQB1*03:03, DQB1*05:01, DQB1*05:02, DPB1*04:01:01, DPB1*05:01:01, and DPB1*13:01:01. We identified 28 rare alleles with frequencies of less than 1% in the Thai individuals. Ambiguity for HLA-DPB1*28:01 in exon 2 was resolved to DPB1*296:01 by next-generation sequencing of all exons. Multi-locus haplotypes including HLA class I and II loci were reported in this study. This is the first comprehensive report of allele and haplotype frequencies of all three HLA class II genes from a Thai population. A high-resolution genotyping method such as next-generation sequencing avoids missing rare alleles and resolves ambiguous calls. The HLA class II genotyping data generated in this study will be beneficial not only for future disease association/vaccine efficacy studies related to the RV144 study, but also for similar studies in other diseases in the Thai population, as well as population genetics and transplantation studies. PMID:25626602

  11. HLA class II diversity in HIV-1 uninfected individuals from the placebo arm of the RV144 Thai vaccine efficacy trial.

    PubMed

    Baldwin, K M; Ehrenberg, P K; Geretz, A; Prentice, H A; Nitayaphan, S; Rerks-Ngarm, S; Kaewkungwal, J; Pitisuttithum, P; O'Connell, R J; Kim, J H; Thomas, R

    2015-02-01

    The RV144 HIV vaccine trial in Thailand elicited antibody responses to the envelope of HIV-1, which correlated significantly with the risk of HIV-1 acquisition. Human leukocyte antigen (HLA) class II molecules are essential in antigen presentation to CD4 T cells for activation of B cells to produce antibodies. We genotyped the classical HLA-DRB1, DQB1, and DPB1 genes in 450 individuals from the placebo arm of the RV144 study to determine the background allele and haplotype frequencies of these genes in this cohort. High-resolution 4 and 6-digit class II HLA typing data was generated using sequencing-based methods. The observed diversity for the HLA loci was 33 HLA-DRB1, 15 HLA-DQB1, and 26 HLA-DPB1 alleles. Common alleles with frequencies greater than 10% were DRB1*07:01, DRB1*09:01, DRB1*12:02, DRB1*15:02, DQB1*02:01/02, DQB1*03:01, DQB1*03:03, DQB1*05:01, DQB1*05:02, DPB1*04:01:01, DPB1*05:01:01, and DPB1*13:01:01. We identified 28 rare alleles with frequencies of less than 1% in the Thai individuals. Ambiguity for HLA-DPB1*28:01 in exon 2 was resolved to DPB1*296:01 by next-generation sequencing of all exons. Multi-locus haplotypes including HLA class I and II loci were reported in this study. This is the first comprehensive report of allele and haplotype frequencies of all three HLA class II genes from a Thai population. A high-resolution genotyping method such as next-generation sequencing avoids missing rare alleles and resolves ambiguous calls. The HLA class II genotyping data generated in this study will be beneficial not only for future disease association/vaccine efficacy studies related to the RV144 study, but also for similar studies in other diseases in the Thai population, as well as population genetics and transplantation studies.

  12. High-Risk Series: An Update

    DTIC Science & Technology

    2015-02-01

    Interests a • Improving Federal Oversight of Food Safety a • Protecting Public Health through Enhanced Oversight of Medical Products a • Transforming...255 Improving Federal Oversight of Food Safety 262 Protecting Public Health through Enhanced Oversight of Medical Products 268 Contents...has been sufficient for us to narrow the scope of the high-risk issue. Specifically, the Food and Drug Administration (FDA) made progress by

  13. Management of high-risk pregnancy.

    PubMed

    Coco, L; Giannone, T T; Zarbo, G

    2014-08-01

    Today, 88% of pregnancies has a physiological course during which just basic care, while in 12% of cases there is a high-risk pregnancy that requires additional assistance and specific. The approach that should be used is that of supervision in all pregnant women considering their potential to have a normal pregnancy until there is no clear evidence to the contrary. Pregnancy is considered at risk if there are medical conditions that may affect maternal or fetal health or life of the mother, fetus or both. Among the risk factors for pregnancy there is first the woman's age, in fact the increase in high-risk pregnancies in the last 20 years is attributable to the increase in the average age of women who face pregnancy. In addition, the diet is very important during pregnancy and diabetes or autoimmune diseases often lead to the failure of a pregnancy. Risk factors for pregnancy, also, are the complications that occur during its course as hypertension during pregnancy, and infectious diseases. Fears and anxieties typical of a high-risk pregnancy prevent the couple to live happily in the months of gestation. Effective communication, control and early detection are important tools that doctors must be able to ensure that women in order to plan the best treatment strategies and to minimize the risks of maternal and / or fetal.

  14. Electroconvulsive therapy during high-risk pregnancy.

    PubMed

    Walker, R; Swartz, C M

    1994-09-01

    Pregnancy increases the risk of injury associated with mental illness. The varieties of malnutrition, substance abuse, and aggression that may accompany mental illness can injure the unborn child in more severe ways than the patient herself. Dangers associated with illness-related behavior can outweight the risks of pharmacotherapy, but no psychotropic drug is approved for use during pregnancy. Failure to produce a prompt or lasting remission of psychiatric symptoms also is a significant possibility with medication. The morbidity from continued illness and the incompletely described adverse effects of psychotropic drugs increases the attractiveness of ECT for severely depressed pregnant patients, especially with associated high-risk conditions. This paper discusses physiologic changes occurring during pregnancy and ECT and reviews contemporary monitors of maternal and fetal well-being. Guidelines are suggested for ECT during regular and high-risk pregnancies. The authors conclude that using additional precautions with high-risk pregnant patients permits ECT to be given with relative safety; medical and obstetric risk factors need not prevent its use.

  15. Direct analysis of unphased SNP genotype data in population-based association studies via Bayesian partition modelling of haplotypes.

    PubMed

    Morris, Andrew P

    2005-09-01

    We describe a novel method for assessing the strength of disease association with single nucleotide polymorphisms (SNPs) in a candidate gene or small candidate region, and for estimating the corresponding haplotype relative risks of disease, using unphased genotype data directly. We begin by estimating the relative frequencies of haplotypes consistent with observed SNP genotypes. Under the Bayesian partition model, we specify cluster centres from this set of consistent SNP haplotypes. The remaining haplotypes are then assigned to the cluster with the "nearest" centre, where distance is defined in terms of SNP allele matches. Within a logistic regression modelling framework, each haplotype within a cluster is assigned the same disease risk, reducing the number of parameters required. Uncertainty in phase assignment is addressed by considering all possible haplotype configurations consistent with each unphased genotype, weighted in the logistic regression likelihood by their probabilities, calculated according to the estimated relative haplotype frequencies. We develop a Markov chain Monte Carlo algorithm to sample over the space of haplotype clusters and corresponding disease risks, allowing for covariates that might include environmental risk factors or polygenic effects. Application of the algorithm to SNP genotype data in an 890-kb region flanking the CYP2D6 gene illustrates that we can identify clusters of haplotypes with similar risk of poor drug metaboliser (PDM) phenotype, and can distinguish PDM cases carrying different high-risk variants. Further, the results of a detailed simulation study suggest that we can identify positive evidence of association for moderate relative disease risks with a sample of 1,000 cases and 1,000 controls.

  16. HLA Class I and II Blocks Are Associated to Susceptibility, Clinical Subtypes and Autoantibodies in Mexican Systemic Sclerosis (SSc) Patients

    PubMed Central

    Rodriguez-Reyna, Tatiana S.; Mercado-Velázquez, Pamela; Yu, Neng; Alosco, Sharon; Ohashi, Marina; Lebedeva, Tatiana; Cruz-Lagunas, Alfredo; Núñez-Álvarez, Carlos; Vargas-Alarcón, Gilberto; Granados, Julio; Zúñiga, Joaquin; Yunis, Edmond

    2015-01-01

    Introduction Human leukocyte antigen (HLA) polymorphism studies in Systemic Sclerosis (SSc) have yielded variable results. These studies need to consider the genetic admixture of the studied population. Here we used our previously reported definition of genetic admixture of Mexicans using HLA class I and II DNA blocks to map genetic susceptibility to develop SSc and its complications. Methods We included 159 patients from a cohort of Mexican Mestizo SSc patients. We performed clinical evaluation, obtained SSc-associated antibodies, and determined HLA class I and class II alleles using sequence-based, high-resolution techniques to evaluate the contribution of these genes to SSc susceptibility, their correlation with the clinical and autoantibody profile and the prevalence of Amerindian, Caucasian and African alleles, blocks and haplotypes in this population. Results Our study revealed that class I block HLA-C*12:03-B*18:01 was important to map susceptibility to diffuse cutaneous (dc) SSc, HLA-C*07:01-B*08:01 block to map the susceptibility role of HLA-B*08:01 to develop SSc, and the C*07:02-B*39:05 and C*07:02-B*39:06 blocks to map the protective role of C*07:02 in SSc. We also confirmed previous associations of HLA-DRB1*11:04 and –DRB1*01 to susceptibility to develop SSc. Importantly, we mapped the protective role of DQB1*03:01 using three Amerindian blocks. We also found a significant association for the presence of anti-Topoisomerase I antibody with HLA-DQB1*04:02, present in an Amerindian block (DRB1*08:02-DQB1*04:02), and we found several alleles associated to internal organ damage. The admixture estimations revealed a lower proportion of the Amerindian genetic component among SSc patients. Conclusion This is the first report of the diversity of HLA class I and II alleles and haplotypes Mexican patients with SSc. Our findings suggest that HLA class I and class II genes contribute to the protection and susceptibility to develop SSc and its different clinical

  17. A High-Risk Screen for Psychiatric Discharge Planning.

    ERIC Educational Resources Information Center

    Christ, Winifred R.; And Others

    1994-01-01

    Tested ability of 16-item high-risk screening list to accurately predict high-risk status by comparing admission and discharge high-risk scores for 448 patients with range of psychiatric disorders. Sixty-six percent of patients rated high risk at admission were identically rated at discharge. (Author/NB)

  18. Conserved 33-kb haplotype in the MHC class III region regulates chronic arthritis

    PubMed Central

    Yau, Anthony C. Y.; Tuncel, Jonatan; Norin, Ulrika; Houtman, Miranda; Padyukov, Leonid; Holmdahl, Rikard

    2016-01-01

    Genome-wide association studies have revealed many genetic loci associated with complex autoimmune diseases. In rheumatoid arthritis (RA), the MHC gene HLA-DRB1 is the strongest candidate predicting disease development. It has been suggested that other immune-regulating genes in the MHC contribute to the disease risk, but this contribution has been difficult to show because of the strong linkage disequilibrium within the MHC. We isolated genomic regions in the form of congenic fragments in rats to test whether there are additional susceptibility loci in the MHC. By both congenic mapping in inbred strains and SNP typing in wild rats, we identified a conserved, 33-kb large haplotype Ltab-Ncr3 in the MHC-III region, which regulates the onset, severity, and chronicity of arthritis. The Ltab-Ncr3 haplotype consists of five polymorphic immunoregulatory genes: Lta (lymphotoxin-α), Tnf, Ltb (lymphotoxin-β), Lst1 (leukocyte-specific transcript 1), and Ncr3 (natural cytotoxicity-triggering receptor 3). Significant correlation in the expression of the Ltab-Ncr3 genes suggests that interaction of these genes may be important in keeping these genes clustered together as a conserved haplotype. We studied the arthritis association and the spliceo-transcriptome of four different Ltab-Ncr3 haplotypes and showed that higher Ltb and Ncr3 expression, lower Lst1 expression, and the expression of a shorter splice variant of Lst1 correlate with reduced arthritis severity in rats. Interestingly, patients with mild RA also showed higher NCR3 expression and lower LST1 expression than patients with severe RA. These data demonstrate the importance of a conserved haplotype in the regulation of complex diseases such as arthritis. PMID:27303036

  19. A specific haplotype at the INS/TH loci confers high susceptibility to IDDM

    SciTech Connect

    Doria, A.; Lee, J.; Warram, J.H.; Krolewski, A.S.

    1994-09-01

    Polymorphism at the insulin locus (INS) have consistently been found to be associated with insulin-dependent diabetes mellitus (IDDM). We investigated whether a combined analysis of the INS locus with the 5{prime} flanking tyrosine hydroxylase (TH) locus increases the specificity of this association. A group of 308 Caucasians (201 IDDM CASES and 107 non-diabetic CONTROLS) were genotyped for the two-allele markers, INS/1127PstI and TH/Rsal, by PCR-DGGE. INS/1127PstI allele 2 was more common in CASES than CONTROLS (0.84 vs. 0.68, p<0.0001). The relative risk of IDDM for homozygotes for this allele (2/2) was 3.3 in comparison with the other genotypes (95% CI 2.0-5.3). Similarly, homozygotes for allele 2 of TH/RsaI, which is in moderate linkage disequilibrium with INS/1127PstI ({Delta} = 0.45), had a relative risk of IDDM of 2.5 (1.6-4.2). By haplotyping individuals for the two markers, INS/1127PstI 2/2 genotypes were subdivided on the basis of their INS-TH haplotypes. The excess of INS/1127PstI 2/2 homozygotes in IDDM cases was mainly contributed by homozygotes for the INS-TH haplotype 22. Thus, among hapotypes carrying INS/1127 PstI allele 2, the INS-TH 22 haplotype is a more specific marker of IDDM risk than the INS-TH 21 haplotype. The association of the INS-TH 22/22 genotype with IDDM was independent of HLA, being similar among carriers and non-carriers of IDDM-predisposing DQ{beta} alleles 0302 and 0201-DR3.

  20. CD34-selected allogeneic hematopoietic stem cell transplantation for patients with relapsed, high-risk multiple myeloma

    PubMed Central

    Smith, Eric; Devlin, Sean M.; Orlando, Evelyn; Landau, Heather; Lesokhin, Alex M.; Chung, David J.; Hassoun, Hani; Lendvai, Nikoletta; Landgren, Ola; Giralt, Sergio; Chari, Ajai; Jagannath, Sundar; Koehne, Guenther

    2016-01-01

    We report results of a retrospective analysis of 44 patients with relapsed and high-risk multiple myeloma (MM) undergoing allogeneic CD34-selected hematopoietic stem-cell transplantation (CD34-selected HSCT) from human leukocyte antigen (HLA)-compatible donors. Patients had multiply relapsed disease including relapse at <15 months after autologous transplant and most patients (28/44; 65%) also had high-risk cytogenetics. Before transplant, patients received busulfan (0.8 mg/kg X 10 doses), melphalan (70 mg/m2 X 2 days), fludarabine (25 mg/m2 X 5 days), and rabbit anti-thymocyte globulin (2.5 mg/kg X 2 days). Patients with 10/10 HLA-matched donors were treated prophylactically with low doses of donor lymphocyte infusions (0.5 to 1 X 106 CD3+/kg) starting at 4–6 months post CD34-selected HSCT. Acute (grade II–IV) graph-versus-host disease (GVHD) and transplant-related mortality at 12 months were 2% and 18%, respectively. Chronic GVHD was not observed in any patient. Overall and progression-free survival at 2 years was 54% and 31%, respectively. By multivariate analyses, the outcomes of CD34-selected HSCT were influenced by presence of extramedullary disease, disease status prior to CD34-selected HSCT and age. This study demonstrates notable safety and efficacy of CD34-selected HSCT in patients with multiply relapsed MM including those with high-risk cytogenetics. PMID:26325439

  1. HLA class I and class II allele distribution in the Bubi population from the island of Bioko (Equatorial Guinea).

    PubMed

    de Pablo, R; García-Pacheco, J M; Vilches, C; Moreno, M E; Sanz, L; Rementería, M C; Puente, S; Kreisler, M

    1997-12-01

    We determined the HLA frequency distribution in a sample of 100 Bubi individuals born on the island of Bioko (Equatorial Guinea). HLA-A, -B and -C typing was performed by serology and PCR-SSP. DRB1/3/4/5, DQB1 and DQA1 alleles were determined by PCR-SSOP. The HLA allele distribution of this population group resembles those found in other Bantu-speaking groups; however, the higher frequency of A30, A32, B44, DRB1*1301 in the Bubi with respect to other Bantu groups and the absence of DR4 deserve special mention. The cloning and sequencing of class I and II genes in this population allowed the description of five new allelic variants: B*4407, Cw*0706, Cw*1801, Cw*1802 and DQB1*0612 and five confirmatory sequences: B*3910, B*5703, B*8101, Cw*1203 and Cw*1701. The following new HLA-C,B haplotypes have been found in Bubi: Cw*08-B*57, Cw*18-B*57, Cw*0302-B*53, Cw*07-B*53 and Cw*1601-B*63. The most frequent seven-locus haplotype is: A*30-Cw*17-B*42-DRB1*1102-DRB3*0202-DQA1*05-DQB1 *0301. In terms of genetic distance, the Bubi are closer to other Bantu groups than to West African populations.

  2. HLA Object Model Data Dictionary System

    DTIC Science & Technology

    2007-11-02

    OMDDS DB Tier 3: Thin Client Tier 2: CGI Tier 1: Data Server Web Browser OMDD DIF Oracle RDBMS HLA OMDDS Design Walk-through 3 KEY External Site Internal...Design Walk-through 4 HLA OMDDS WEB SITE DESIGN Open Navbar Query Utilities AboutBrowse HLA FEDEP DMSO mailto: HLAOMDDS HLA OMDDS Design Walk-through 5...AboutTools ARL DMSO AboutScreenAboutMenu Netscape Microsoft OMDD Briefing (.ppt) OMDD DIF (.doc) HLA OMDDS Design Walk-through 9 BSearchEngine UtilMenu

  3. [Labor monitoring in high-risk situations].

    PubMed

    Houfflin-Debarge, V; Closset, E; Deruelle, P

    2008-02-01

    Intrapartum asphyxia is increased in several situations such as intrauterine growth retardation, preterm labor, postdate pregnancy or maternal diabetes. In all these cases, fetal heart rate monitoring should be preferred to intermittent auscultation. Fetal scalp blood pH or lactates can be used to identify fetuses at risk of intrapartum asphyxia. However, fetal scalp blood sampling should not delay delivery in case of severe abnormal fetal heart rate as fetal asphyxia could occur rapidly in theses high-risk pregnancies. Data is insufficient to recommend fetal pulse oximetry or ECG analysis. Research should be undertaken to evaluate their performance in these situations.

  4. Aspartic acid at position 57 of the HLA-DQ beta chain protects against type I diabetes: a family study.

    PubMed Central

    Morel, P A; Dorman, J S; Todd, J A; McDevitt, H O; Trucco, M

    1988-01-01

    One hundred seventy-two members from 27 randomly selected multiple case Caucasian families of patients with insulin-dependent diabetes mellitus (IDDM) were studied at the DNA level to ascertain the reliability of codon 57 of the HLA-DQ beta-chain gene as a disease protection/susceptibility marker. The analysis was carried out by polymerase chain reaction amplification of DNA encoding the first domain of the DQ beta chain and by dot blot analysis of the amplified material with allele-specific oligonucleotide probes. One hundred twenty-three randomly selected healthy Caucasian donors were also tested. The results demonstrated that haplotypes carrying an aspartic acid in position 57 (Asp-57) of their DQ beta chain were significantly increased in frequency among nondiabetic haplotypes (23/38), while non-Asp-57 haplotypes were significantly increased in frequency among diabetic haplotypes (65/69). Ninety-six percent of the diabetic probands in our study were homozygous non-Asp/non-Asp as compared to 19.5% of healthy unrelated controls. This conferred a relative risk of 107 (chi 2 = 54.97; P = 0.00003) for non-Asp-57 homozygous individuals. Even though the inheritance and genetic features of IDDM are complex and are not necessarily fully explained by DQ beta chain polymorphism, this approach is much more sensitive than HLA serolog in assessing risk for IDDM. PMID:3186714

  5. HLA class II associations with rheumatic heart disease among clinically homogeneous patients in children in Latvia

    PubMed Central

    Stanevicha, Valda; Eglite, Jelena; Sochnevs, Arturs; Gardovska, Dace; Zavadska, Dace; Shantere, Ruta

    2003-01-01

    Genetic control of immune reactions has a major role in the development of rheumatic heart disease (RHD) and differs between patients with rheumatic fever (RF). Some authors think the risk of acquiring RHD is associated with the HLA class II DR and DQ loci, but other views exist, due to the various HLA-typing methods and ways of grouping cases. Our goal was to determine the relations between HLA class II alleles and risk of or protection from RF in patients with relatively homogeneous clinical manifestations. A total of 70 RF patients under the age of 18 years were surveyed in Latvia. HLA genotyping of DRB1*01 to DRB1*18 and DQB1*0201-202, *0301-305, *0401-402, *0501-504, and *0601-608 was performed using polymerase chain reaction sequence-specific primers. Data for a control group of 100 healthy individuals typed for HLA by the same method were available from the databank of the Immunology Institute of Latvia. Of the RF patients, 47 had RHD and 8 had Sydenham's chorea. We concluded that HLA class II DRB1*07-DQB1*0401-2 and DRB1*07-DQB1*0302 could be the risk alleles and HLA class II DRB1*06 and DQB1*0602-8, the protective ones. Patients with mitral valve regurgitation more often had DRB1*07 and DQB1*0401-2, and patients with multivalvular lesions more often had DRB1*07 and DQB1*0302. In Sydenham's chorea patients, the DQB1*0401-2 allele was more frequent. Genotyping control showed a high risk of RF and RHD in patients with DRB1*01-DQB1*0301-DRB1*07-DQB1*0302 and DRB1*15-DQB1*0302-DRB1*07-DQB1*0303. PMID:14680508

  6. Common Genetic Variants Found in HLA and KIR Immune Genes in Autism Spectrum Disorder.

    PubMed

    Torres, Anthony R; Sweeten, Thayne L; Johnson, Randall C; Odell, Dennis; Westover, Jonna B; Bray-Ward, Patricia; Ward, David C; Davies, Christopher J; Thomas, Aaron J; Croen, Lisa A; Benson, Michael

    2016-01-01

    The "common variant-common disease" hypothesis was proposed to explain diseases with strong inheritance. This model suggests that a genetic disease is the result of the combination of several common genetic variants. Common genetic variants are described as a 5% frequency differential between diseased vs. matched control populations. This theory was recently supported by an epidemiology paper stating that about 50% of genetic risk for autism resides in common variants. However, rare variants, rather than common variants, have been found in numerous genome wide genetic studies and many have concluded that the "common variant-common disease" hypothesis is incorrect. One interpretation is that rare variants are major contributors to genetic diseases and autism involves the interaction of many rare variants, especially in the brain. It is obvious there is much yet to be learned about autism genetics. Evidence has been mounting over the years indicating immune involvement in autism, particularly the HLA genes on chromosome 6 and KIR genes on chromosome 19. These two large multigene complexes have important immune functions and have been shown to interact to eliminate unwanted virally infected and malignant cells. HLA proteins have important functions in antigen presentation in adaptive immunity and specific epitopes on HLA class I proteins act as cognate ligands for KIR receptors in innate immunity. Data suggests that HLA alleles and KIR activating genes/haplotypes are common variants in different autism populations. For example, class I allele (HLA-A2 and HLA-G 14 bp-indel) frequencies are significantly increased by more than 5% over control populations (Table 2). The HLA-DR4 Class II and shared epitope frequencies are significantly above the control populations (Table 2). Three activating KIR genes: 3DS1, 2DS1, and 2DS2 have increased frequencies of 15, 22, and 14% in autism populations, respectively. There is a 6% increase in total activating KIR genes in autism over

  7. Common Genetic Variants Found in HLA and KIR Immune Genes in Autism Spectrum Disorder

    PubMed Central

    Torres, Anthony R.; Sweeten, Thayne L.; Johnson, Randall C.; Odell, Dennis; Westover, Jonna B.; Bray-Ward, Patricia; Ward, David C.; Davies, Christopher J.; Thomas, Aaron J.; Croen, Lisa A.; Benson, Michael

    2016-01-01

    The “common variant—common disease” hypothesis was proposed to explain diseases with strong inheritance. This model suggests that a genetic disease is the result of the combination of several common genetic variants. Common genetic variants are described as a 5% frequency differential between diseased vs. matched control populations. This theory was recently supported by an epidemiology paper stating that about 50% of genetic risk for autism resides in common variants. However, rare variants, rather than common variants, have been found in numerous genome wide genetic studies and many have concluded that the “common variant—common disease” hypothesis is incorrect. One interpretation is that rare variants are major contributors to genetic diseases and autism involves the interaction of many rare variants, especially in the brain. It is obvious there is much yet to be learned about autism genetics. Evidence has been mounting over the years indicating immune involvement in autism, particularly the HLA genes on chromosome 6 and KIR genes on chromosome 19. These two large multigene complexes have important immune functions and have been shown to interact to eliminate unwanted virally infected and malignant cells. HLA proteins have important functions in antigen presentation in adaptive immunity and specific epitopes on HLA class I proteins act as cognate ligands for KIR receptors in innate immunity. Data suggests that HLA alleles and KIR activating genes/haplotypes are common variants in different autism populations. For example, class I allele (HLA-A2 and HLA-G 14 bp-indel) frequencies are significantly increased by more than 5% over control populations (Table 2). The HLA-DR4 Class II and shared epitope frequencies are significantly above the control populations (Table 2). Three activating KIR genes: 3DS1, 2DS1, and 2DS2 have increased frequencies of 15, 22, and 14% in autism populations, respectively. There is a 6% increase in total activating KIR genes in

  8. No gender differences in the frequencies of HLA-DRB3/B4/B5 heterozygotes in newborns and adults in Koreans.

    PubMed

    Song, Eun Young; Roh, Eun Youn; Shin, Sue; Yoon, Jong Hyun; Park, Myoung Hee

    2012-01-01

    HLA class II haplotypes often contain a second expressed HLA-DRB locus tightly linked to the classical HLA-DRB1 locus on the haplotype, which can be either HLA-DRB3, -DRB4 or -DRB5. These encode the HLA-DR51, -DR52 or -DR53 supertypic specificities and mark the ancestral lineages. HLA-DRB3/B4/B5 heterozygote excess in Welsh male newborns has been reported, suggesting a possibility of male-specific major histocompatibility complex (MHC)-mediated prenatal selection. However, it has not been confirmed in newborns of other ethnic groups or in adult populations. We analyzed the HLA-DRB1 and HLA-DRB3/B4/B5 genes in Korean newborns and healthy adults to examine whether MHC-mediated prenatal or postnatal selection exists. A total of 1,038 newborns (cord blood registry, 516 males and 522 females) and 2,082 healthy adults (hematopoietic stem cell donor registry, 1,111 males and 971 females) were HLA typed. HLA-DRB1/B3/B4/B5 DNA typing was performed using Dynal RELI HLA-DRB SSO Kit (Dyanl Biotech, Wirral, U.K.). Genotype frequencies and homozygosity and heterozygosity rates for DRB3/B4/B5 supertypic loci were compared between males and females in newborns and adults. There were no significant differences in the HLA-DRB3/B4/B5 homozygosity and heterozygosity rates between males and females in both newborns and adults. In the comparison between newborns and adults, homozygosity rate was significantly higher in newborn females than in adult females (31.0% vs 25.0%, p=0.01). Whether there is an age-related change from newborns toward adults has not been well studied in other populations, and further studies are warranted. In conclusion, male-specific heterozygosity excess reported in Welsh newborns has not been observed in Korean population, and there might be some ethnic differences in the gender-specific prenatal selection events.

  9. Origin of Mexican Nahuas (Aztecs) according to HLA genes and their relationships with worldwide populations.

    PubMed

    Vargas-Alarcon, Gilberto; Moscoso, Juan; Martinez-Laso, Jorge; Rodriguez-Perez, Jose Manuel; Flores-Dominguez, Carmina; Serrano-Vela, Juan Ignacio; Moreno, Almudena; Granados, Julio; Arnaiz-Villena, Antonio

    2007-02-01

    A Nahua Aztec isolated group from Morelos State (Mexico) was studied for their HLA profile. The relationship with other Amerindians and worldwide populations was studied by using 13,818 chromosomes and calculating Nei's chord genetic distances (DA), neighbor-joining dendrograms and correspondence multidimensional values. Three new HLA extended haplotypes were found in our group: A*30-B*49-DRB1*1001-DQB1*0501 (the most frequent one in this population), A*02-B*52-DRB1*1402-DQB1*0301 and A*68-B*61-DRB1*1602-DQB1*0303. Both genetic distances and correspondence analyses clearly show that our Nahua isolated group is genetically close to some of the most ancient groups living in Mexico (Mayans, Zapotecans, Mixtecans). This suggests that Nahua language (Nahuatl) may have been imposed to scattered groups throughout Mexico; otherwise Aztecs may have been living in Mexico long before their postulated immigration in the XII century AD.

  10. HLA-DR,DQ sequence polymorphisms in Polynesians, Micronesians, and Javanese.

    PubMed

    Gao, X; Zimmet, P; Serjeantson, S W

    1992-07-01

    The origins of the Polynesians remain an enigma. Linguistic reconstructions of proto-Austronesian languages suggest a shared origin for Polynesians, Micronesians, and Javanese with dispersal from northern Borneo and Sulawesi. Analysis of 810 chromosomes for nucleotide sequence polymorphism at HLA-DRB1, DRB3, DRB5, DQA1, and DQB1 loci in Polynesian (Rarotonga, Western Samoa, and Niue), Micronesian (Nauru and Kiribati), and Javanese populations showed virtually no overlap of HLA class II haplotypes between contemporary Polynesians and Javanese. Further, there were marked differences in population distributions of some HLA-DRB1 alleles that could not be distinguished in earlier serologic or restriction fragment length polymorphism (RFLP) studies, e.g., for DR12, DRB1*1201 had a frequency of 15%-30% in Polynesians (1% in Micronesians and Javanese), whereas DRB1*1202 had a frequency of 28%-38% in Micronesians and 51% in Javanese (1% in Polynesians). A novel DR6-related allele, DRB1*1408, was found in all three Polynesian study populations. The Polynesian HLA class II genetic repertoire is not readily derived from the island Southeast Asian gene pool.

  11. Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia.

    PubMed

    Marrosu, M G; Murru, R; Murru, M R; Costa, G; Zavattari, P; Whalen, M; Cocco, E; Mancosu, C; Schirru, L; Solla, E; Fadda, E; Melis, C; Porru, I; Rolesu, M; Cucca, F

    2001-12-01

    Several studies have indicated that multiple sclerosis (MS) is associated and linked to the major histocompatibility complex (MHC)/human leukocyte antigen (HLA) region of chromosome 6p21.3, but the exact location and nature of the primarily associated locus within the HLA complex is still controversial and largely presumptive. By linkage disequilibrium mapping, we have systematically investigated this chromosome region in the founder population of Sardinia to determine the relative associations of the various loci with MS. An overall 11.4 Mb region, which encompasses the whole HLA complex, was scanned with 19 microsatellite markers and with single nucleotide polymorphisms within 12 functional candidate genes and assessed for MS association using the extended transmission disequilibrium test (ETDT). A peak of association represented by the three adjacent DRB1, -DQA1 and -DQB1 loci was detected in the class II region. Two additional less significant areas of association were detected, respectively, in the centromeric side of the class II region at the DPB1 locus and, telomeric of the classically defined class I loci, at the D6S1683 microsatellite. Conditional ETDT analysis indicated that these regions of association could be independent of each other. Within the main peak of association, DRB1 and DQB1 contribute to the disease association independently of each other whereas DQA1 had no detectable primary genetic effects. We evaluated the haplotype distribution at the region showing the strongest association and found five DQB1-DRB1 haplotypes positively associated with MS in Sardinia. These consistently included all the haplotypes previously found associated with MS in the various human populations, thus supporting a primary effect of the products of these loci in MS. Overall these results are consistent with a multilocus model of the MHC encoded susceptibility to MS.

  12. Epistatic interaction of ERAP1 and HLA-B in Behçet disease: a replication study in the Spanish population.

    PubMed

    Conde-Jaldón, Marta; Montes-Cano, Marco Antonio; García-Lozano, José Raul; Ortiz-Fernández, Lourdes; Ortego-Centeno, Norberto; González-León, Rocío; Espinosa, Gerard; Graña-Gil, Genaro; Sánchez-Bursón, Juan; González-Gay, Miguel Angel; Barnosi-Marín, Ana Celia; Solans, Roser; Fanlo, Patricia; Carballeira, Mónica Rodríguez; Camps, Teresa; Castañeda, Santos; Martín, Javier; González-Escribano, María Francisca

    2014-01-01

    Behçet's disease (BD) is a multifactorial disorder associated with the HLA region. Recently, the ERAP1 gene has been proposed as a susceptibility locus with a recessive model and with epistatic interaction with HLA-B51. ERAP1 trims peptides in the endoplasmic reticulum to optimize their length for MHC-I binding. Polymorphisms in this gene have been related with the susceptibility to other immune-mediated diseases associated to HLA class I. Our aim was, the replication in the Spanish population of the association described in the Turkish population between ERAP1 (rs17482078) and BD. Additionally, in order to improve the understanding of this association we analyzed four additional SNPs (rs27044, rs10050860, rs30187 and rs2287987) associated with other diseases related to HLA class I and the haplotype blocks in this gene region. According to our results, frequencies of the homozygous genotypes for the minor alleles of all the SNPs were increased among patients and the OR values were higher in the subgroup of patients with the HLA-B risk factors, although differences were not statistically significant. Moreover, the presence of the same mutation in both chromosomes increased the OR values from 4.51 to 10.72 in individuals carrying the HLA-B risk factors. Therefore, although they were not statistically significant, our data were consistent with an association between ERAP1 and BD as well as with an epistatic interaction between ERAP1 and HLA-B in the Spanish population.

  13. [Cardiovascular polypill in high risk patients].

    PubMed

    Lafeber, Melvin; Spiering, Wilko; Bots, Michiel L; de Valk, Vincent; Visseren, Frank L J; Grobbee, Diederick E

    2011-01-01

    The initial theoretical concept of a polypill was a fixed-dosed combination pill containing an antiplatelet agent, a cholesterol-lowering agent and multiple blood pressure-lowering agents aimed at the prevention of atherosclerotic vascular disease in the population aged 55 years and up. The reduction in the risk of cardiovascular disease does not depend on the cholesterol level and blood pressure at the start of treatment. The pharmacological reduction in risk factors in individuals with a high risk of atherosclerotic vascular disease is often suboptimal, partly due to the complexity of the guidelines and low adherence to the therapy. A polypill may offer opportunities for improvement. Research has shown that the use of combination products leads to a greater reduction in risk factors than the use of separate substances, possibly through improved adherence to the therapy. The use of a polypill in the prevention of vascular disease in high-risk patients may lead to a more effective reduction in risk, a decrease in costs and a reduction in pharmacological expenditure.

  14. Variation analysis and gene annotation of eight MHC haplotypes: the MHC Haplotype Project.

    PubMed

    Horton, Roger; Gibson, Richard; Coggill, Penny; Miretti, Marcos; Allcock, Richard J; Almeida, Jeff; Forbes, Simon; Gilbert, James G R; Halls, Karen; Harrow, Jennifer L; Hart, Elizabeth; Howe, Kevin; Jackson, David K; Palmer, Sophie; Roberts, Anne N; Sims, Sarah; Stewart, C Andrew; Traherne, James A; Trevanion, Steve; Wilming, Laurens; Rogers, Jane; de Jong, Pieter J; Elliott, John F; Sawcer, Stephen; Todd, John A; Trowsdale, John; Beck, Stephan

    2008-01-01

    The human major histocompatibility complex (MHC) is contained within about 4 Mb on the short arm of chromosome 6 and is recognised as the most variable region in the human genome. The primary aim of the MHC Haplotype Project was to provide a comprehensively annotated reference sequence of a single, human leukocyte antigen-homozygous MHC haplotype and to use it as a basis against which variations could be assessed from seven other similarly homozygous cell lines, representative of the most common MHC haplotypes in the European population. Comparison of the haplotype sequences, including four haplotypes not previously analysed, resulted in the identification of >44,000 variations, both substitutions and indels (insertions and deletions), which have been submitted to the dbSNP database. The gene annotation uncovered haplotype-specific differences and confirmed the presence of more than 300 loci, including over 160 protein-coding genes. Combined analysis of the variation and annotation datasets revealed 122 gene loci with coding substitutions of which 97 were non-synonymous. The haplotype (A3-B7-DR15; PGF cell line) designated as the new MHC reference sequence, has been incorporated into the human genome assembly (NCBI35 and subsequent builds), and constitutes the largest single-haplotype sequence of the human genome to date. The extensive variation and annotation data derived from the analysis of seven further haplotypes have been made publicly available and provide a framework and resource for future association studies of all MHC-associated diseases and transplant medicine.

  15. HLA-DP, HLA-DQ, and HLA-DR-restricted epitopes in GRA5 of toxoplasma gondii strains

    NASA Astrophysics Data System (ADS)

    Haryati, S.; Sari, Y.; Prasetyo, A. A.; Sariyatun, R.

    2016-01-01

    The dense granular (GRA) proteins of Toxoplasma gondii(T. gondii) have been demonstrated as potential sources of T. gondii vaccine antigens. However, data of the GRA5 protein are limited. This study analyzed twenty-one complete GRA5 sequences of T. gondii GT1, RH, ME49, VEG, MAS, RUB, FOU, p89, VAND, and GAB2-2007-GAL-DOM2 strains to identify potential epitopes restricted by Major Histocompatibility Complex class II (MHC- II) molecules (human leukocyte antigen (HLA)-DP, HLA-DQ, and HLA-DR) in the protein. In all T. gondii strains, peptides positioned at amino acid (aa) 15-29, 16-30, 17-31, 18-32, 19-33, 83-97, 84-98, 86-100, 87-101, 89-103, and 90-104 were predicted to pose high affinity and binding with HLA-DRB1*0101, HLA-DRB1*0301 (DR17), HLA-DRB1*0401 (DR4Dw4), HLA-DRB1*0701, HLA-DRB1*1101, HLA-DRB1*1501 (DR2b), and/or HLA-DRB5*0101. Considering the epitope's affinity, ligation strength, and hydrophilicity, LRLLRRRRRRAIQEE sequence (aa 90-104) restricted by HLA-DRB1*0101, HlA- DRB1*0301 (DR17), and HLA-DRB1*0401 (DR4Dw4) was considered as the most potential MHC-II epitope in GRA5 of T. gondii. These results would be useful for studies concerning in developing T. gondii vaccine and diagnostic method.

  16. Association of HLA Genetic Risk Burden With Disease Phenotypes in Multiple Sclerosis

    PubMed Central

    Isobe, Noriko; Keshavan, Anisha; Gourraud, Pierre-Antoine; Zhu, Alyssa H.; Datta, Esha; Schlaeger, Regina; Caillier, Stacy J.; Santaniello, Adam; Lizée, Antoine; Himmelstein, Daniel S.; Baranzini, Sergio E.; Hollenbach, Jill; Cree, Bruce A. C.; Hauser, Stephen L.; Oksenberg, Jorge R.; Henry, Roland G.

    2016-01-01

    and the atrophy of subcortical gray matter fraction in women with relapsing-onset MS (standard β = −1.20 × 10−1; P = 1.7 × 10−2 and standard β = −1.67 × 10−1; P = 2.3 × 10−4, respectively), which were driven mainly by the HLA-DRB1*15:01 haplotype. In addition, we observed the distinct role of the HLA-A*24:02-B*07:02-DRB1*15:01 haplotype among the other common DRB1*15:01 haplotypes and a nominally protective effect of HLA-B*44:02 to the subcortical gray atrophy (standard β = −1.28 × 10−1; P = 5.1 × 10−3 and standard β = 9.52 × 10−2; P = 3.6 × 10−2, respectively). CONCLUSIONS AND RELEVANCE We confirm and extend previous observations linking HLA MS susceptibility alleles with disease progression and specific clinical and magnetic resonance imaging phenotypic traits. PMID:27244296

  17. HLA-DM interactions with intermediates in HLA-DR maturation and a role for HLA-DM in stabilizing empty HLA-DR molecules.

    PubMed

    Denzin, L K; Hammond, C; Cresswell, P

    1996-12-01

    Major histocompatibility complex (MHC) class II-positive cell lines which lack HLA-DM expression accumulate class II molecules associated with residual invariant (I) chain fragments (class II-associated invariant chain peptides [CLIP]). In vitro, HLA-DM catalyzes CLIP dissociation from class II-CLIP complexes, promoting binding of antigenic peptides. Here the physical interaction of HLA-DM with HLA-DR molecules was investigated. HLA-DM complexes with class II molecules were detectable transiently in cells, peaking at the time when the class II molecules entered the MHC class II compartment. HLA-DR alpha beta dimers newly released from I chain, and those associated with I chain fragments, were found to associate with HLA-DM in vivo. Mature, peptide-loaded DR molecules also associated at a low level. These same species, but not DR-I chain complexes, were also shown to bind to purified HLA-DM molecules in vitro. HLA-DM interaction was quantitatively superior with DR molecules isolated in association with CLIP. DM-DR complexes generated by incubating HLA-DM with purified DR alpha beta CLIP contained virtually no associated CLIP, suggesting that this superior interaction reflects a prolonged HLA-DM association with empty class II dimers after CLIP dissociation. Incubation of peptide-free alpha beta dimers in the presence of HLA-DM was found to prolong their ability to bind subsequently added antigenic peptides. Stabilization of empty class II molecules may be an important property of HLA-DM in facilitating antigen processing.

  18. Stabilization of high-risk plaques

    PubMed Central

    Takata, Kohei; Zhang, Bo; Miura, Shin-ichiro; Saku, Keijiro

    2016-01-01

    The prevalence of atherosclerotic cardiovascular diseases (ASCVDs) is increasing globally and they have become the leading cause of death in most countries. Numerous experimental and clinical studies have been conducted to identify major risk factors and effective control strategies for ASCVDs. The development of imaging modalities with the ability to determine the plaque composition enables us to further identify high-risk plaque and evaluate the effectiveness of different treatment strategies. While intensive lipid-lowering by statins can stabilize or even regress plaque by various mechanisms, such as the reduction of lipid accumulation in a necrotic lipid core, the reduction of inflammation, and improvement of endothelial function, there are still considerable residual risks that need to be understood. We reviewed important findings regarding plaque vulnerability and some encouraging emerging approaches for plaque stabilization. PMID:27500090

  19. Electrophoretic analysis of HLA-DR2 molecules isolated from HLA-Dw2 and HLA-Dw12 cell lines.

    PubMed

    Takenouchi, T; Kasahara, M; Ogasawara, K; Ikeda, H; Ishikawa, N; Hawkin, S; Wakisaka, A; Aizawa, M

    1985-02-01

    To answer the question of whether or not polymorphism exists among HLA-DR2 molecules derived from cells homozygous for HLA-DR2, but expressing different HLA-D specificities, HLA-DR2 molecules were isolated from HLA-Dw2 and HLA-Dw12 homozygous cells using a monoclonal antibody operationally monospecific for HLA-DR2, and were compared to each other by two-dimensional gel electrophoresis. No electrophoretically discernible polymorphism was found in either the heavy or the light chain subunits of the HLA-DR2 molecules. These findings are in marked contrast with previous observations that each of the HLA-DR4-associated HLA-D clusters expresses an electrophoretically distinct HLA-DR4 light chain.

  20. Quantitative assessment of common genetic variations in HLA-DP with hepatitis B virus infection, clearance and hepatocellular carcinoma development

    PubMed Central

    Yu, Lei; Cheng, Yi-ju; Cheng, Ming-liang; Yao, Yu-mei; Zhang, Quan; Zhao, Xue-ke; Liu, Hua-juan; Hu, Ya-xin; Mu, Mao; Wang, Bi; Yang, Guo-zhen; Zhu, Li-li; Zhang, Shuai

    2015-01-01

    Hepatitis B virus (HBV) infection is the predominant risk factor for chronic hepatitis B (CHB), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Recently, genome-wide association studies have identified human leukocyte antigen (HLA)-DP polymorphisms (rs3077 and rs9277535) as a new chronic HBV infection susceptibility locus. Since then, the relationship between HLA-DP polymorphisms and various outcomes of HBV infection has been reported. However, the results have been inconclusive. To derive a more precise estimation of the relationship between HLA-DP polymorphisms and various outcomes of HBV infection, a meta-analysis of 62,050 subjects from 29 case-control studies was performed. We found that rs3077 and rs9277535 in HLA-DP significantly decreased HBV infection risks and increased HBV clearance possibility in a dose-dependent manner. In the subgroup analysis by ethnicity, study design and sample size, significant associations were found for these polymorphisms in almost all comparisons. Meanwhile, haplotype analyses of the two polymorphisms revealed a significant association between the combination of these alleles and HBV infection outcomes. However, no significant results were observed in HCC development. Our results further confirm that genetic variants in the HLA-DP locus are strongly associated with reduced HBV infection and increased the likelihood of spontaneous viral clearance. PMID:26462556

  1. Human leucocyte antigen-G (HLA-G) and its murine functional homolog Qa2 in the Trypanosoma cruzi Infection.

    PubMed

    Dias, Fabrício C; Mendes-Junior, Celso T; Silva, Maria C; Tristão, Fabrine S M; Dellalibera-Joviliano, Renata; Moreau, Philippe; Soares, Edson G; Menezes, Jean G; Schmidt, André; Dantas, Roberto O; Marin-Neto, José A; Silva, João S; Donadi, Eduardo A

    2015-01-01

    Genetic susceptibility factors, parasite strain, and an adequate modulation of the immune system seem to be crucial for disease progression after Trypanosoma cruzi infection. HLA-G and its murine functional homolog Qa2 have well-recognized immunomodulatory properties. We evaluated the HLA-G 3' untranslated region (3'UTR) polymorphic sites (associated with mRNA stability and target for microRNA binding) and HLA-G tissue expression (heart, colon, and esophagus) in patients presenting Chagas disease, stratified according to the major clinical variants. Further, we investigated the transcriptional levels of Qa2 and other pro- and anti-inflammatory genes in affected mouse tissues during T. cruzi experimental acute and early chronic infection induced by the CL strain. Chagas disease patients exhibited differential HLA-G 3'UTR susceptibility allele/genotype/haplotype patterns, according to the major clinical variant (digestive/cardiac/mixed/indeterminate). HLA-G constitutive expression on cardiac muscle and colonic cells was decreased in Chagasic tissues; however, no difference was observed for Chagasic and non-Chagasic esophagus tissues. The transcriptional levels of Qa2 and other anti and proinflammatory (CTLA-4, PDCD1, IL-10, INF-γ, and NOS-2) genes were induced only during the acute T. cruzi infection in BALB/c and C57BL/6 mice. We present several lines of evidence indicating the role of immunomodulatory genes and molecules in human and experimental T. cruzi infection.

  2. Human Leucocyte Antigen-G (HLA-G) and Its Murine Functional Homolog Qa2 in the Trypanosoma cruzi Infection

    PubMed Central

    Dias, Fabrício C.; Mendes-Junior, Celso T.; Silva, Maria C.; Tristão, Fabrine S. M.; Dellalibera-Joviliano, Renata; Soares, Edson G.; Menezes, Jean G.; Schmidt, André; Dantas, Roberto O.; Marin-Neto, José A.; Silva, João S.; Donadi, Eduardo A.

    2015-01-01

    Genetic susceptibility factors, parasite strain, and an adequate modulation of the immune system seem to be crucial for disease progression after Trypanosoma cruzi infection. HLA-G and its murine functional homolog Qa2 have well-recognized immunomodulatory properties. We evaluated the HLA-G 3′ untranslated region (3′UTR) polymorphic sites (associated with mRNA stability and target for microRNA binding) and HLA-G tissue expression (heart, colon, and esophagus) in patients presenting Chagas disease, stratified according to the major clinical variants. Further, we investigated the transcriptional levels of Qa2 and other pro- and anti-inflammatory genes in affected mouse tissues during T. cruzi experimental acute and early chronic infection induced by the CL strain. Chagas disease patients exhibited differential HLA-G 3′UTR susceptibility allele/genotype/haplotype patterns, according to the major clinical variant (digestive/cardiac/mixed/indeterminate). HLA-G constitutive expression on cardiac muscle and colonic cells was decreased in Chagasic tissues; however, no difference was observed for Chagasic and non-Chagasic esophagus tissues. The transcriptional levels of Qa2 and other anti and proinflammatory (CTLA-4, PDCD1, IL-10, INF-γ, and NOS-2) genes were induced only during the acute T. cruzi infection in BALB/c and C57BL/6 mice. We present several lines of evidence indicating the role of immunomodulatory genes and molecules in human and experimental T. cruzi infection. PMID:25688175

  3. Analysis of HLA class I alterations in tumors: choosing a strategy based on known patterns of underlying molecular mechanisms.

    PubMed

    Cabrera, T; Maleno, I; Collado, A; Lopez Nevot, M A; Tait, B D; Garrido, F

    2007-04-01

    The application of peptide-based immunotherapy in the treatment of cancer has known limitations in patients with loss or downregulation of human leukocyte antigen (HLA) class I expression on tumor cells. These alterations diminish the ability of cancer cells to present tumor peptides to T cells and therefore lead to failure of peptide-based cancer vaccination. Abnormal expression of HLA class I molecules in malignant cells is a frequent event that ranges from total loss of class I molecules to partial loss of HLA-specific haplotypes or alleles. Different mechanisms underlie these alterations and might require different therapeutic approaches. A complete characterization of molecular defects may suggest strategies for the selection and follow-up of patients undergoing T-cell based immunotherapy. Moreover, a precise identification of the mechanism leading to HLA class I defects in patients with cancer will help develop new, personalized patient-tailored treatment protocols. Here, we describe several examples showing the necessity and feasibility of making detailed individual analysis of HLA alteration mechanisms based on previously described molecular patterns in different types of malignancy. We recommend using this approach, at least in some patients, to enhance the therapeutic benefit of cancer immunotherapy.

  4. Detection of HLA-D/DR-related DNA polymorphism in HLA-D homozygous typing cells.

    PubMed Central

    Owerbach, D; Lernmark, A; Rask, L; Peterson, P A; Platz, P; Svejgaard, A

    1983-01-01

    Sequences of different sizes are generated when DNA from homozygous HLA-Dw/DR typing cells are digested with restriction endonuclease and analyzed by hybridization with a HLA-D region class II antigen beta-chain cDNA probe. The patterns of hybridization were highly polymorphic but one endonuclease, BamHI, defined sequences unique to all HLA-Dw/DR specificities 1-8 except HLA-Dw/DR 2 and 6; however, these two specificities were resolved with the enzyme EcoRI. Digestion with other endonucleases such as Pst I results in patterns of restriction fragments that differ between homozygous typing cells of the same HLA-Dw/DR specificity. HLA-D region beta-chain probes permit HLA-D region genotyping at the DNA level and may allow detection of genes controlling the association of HLA specificities with a wide variety of diseases. Images PMID:6304735

  5. HLA and Delayed Drug-Induced Hypersensitivity.

    PubMed

    Sousa-Pinto, Bernardo; Correia, Cláudia; Gomes, Lídia; Gil-Mata, Sara; Araújo, Luís; Correia, Osvaldo; Delgado, Luís

    2016-01-01

    Delayed drug allergy reactions (DDAR) are potentially fatal. Certain human leukocyte antigen (HLA) alleles have been associated with delayed allergy reactions following the administration of particular drugs. Examples are HLA-B*57:01 (abacavir), HLA-B*15:02/HLA-A*31:01 (carbamazepine), and HLA-B*58:01 (allopurinol). Based on the identification of these associations, it may now be possible to prevent certain allergy reactions that were, until recently, considered unpredictable. In this review, we will focus on the pharmacogenetics of the best-studied associations between specific HLA alleles and delayed allergy reactions and describe the pathogenesis models proposed so far. Finally, we will evaluate the genetic screening strategies available and discuss the clinical relevance of a better understanding of the immunogenetics and mechanisms involved in DDAR.

  6. MHC Class I Chain-Related Gene A Polymorphisms and Linkage Disequilibrium with HLA-B and HLA-C Alleles in Ocular Toxoplasmosis

    PubMed Central

    Ayo, Christiane Maria; Camargo, Ana Vitória da Silveira; Frederico, Fábio Batista; Siqueira, Rubens Camargo; Previato, Mariana; Murata, Fernando Henrique Antunes; Silveira-Carvalho, Aparecida Perpétuo; Barbosa, Amanda Pires; Brandão de Mattos, Cinara de Cássia; de Mattos, Luiz Carlos

    2015-01-01

    This study investigated whether polymorphisms of the MICA (major histocompatibility complex class I chain-related gene A) gene are associated with eye lesions due to Toxoplasma gondii infection in a group of immunocompetent patients from southeastern Brazil. The study enrolled 297 patients with serological diagnosis of toxoplasmosis. Participants were classified into two distinct groups after conducting fundoscopic exams according to the presence (n = 148) or absence (n = 149) of ocular scars/lesions due to toxoplasmosis. The group of patients with scars/lesions was further subdivided into two groups according to the type of the ocular manifestation observed: primary (n = 120) or recurrent (n = 28). Genotyping of the MICA and HLA alleles was performed by the polymerase chain reaction-sequence specific oligonucleotide technique (PCR-SSO; One Lambda®) and the MICA-129 polymorphism (rs1051792) was identified by nested polymerase chain reaction (PCR-RFLP). Significant associations involving MICA polymorphisms were not found. Although the MICA*002~HLA-B*35 haplotype was associated with increased risk of developing ocular toxoplasmosis (P-value = 0.04; OR = 2.20; 95% CI = 1.05–4.60), and the MICA*008~HLA-C*07 haplotype was associated with protection against the development of manifestations of ocular toxoplasmosis (P-value = 0.009; OR: 0.44; 95% CI: 0.22–0.76), these associations were not statistically significant after adjusting for multiple comparisons. MICA polymorphisms do not appear to influence the development of ocular lesions in patients diagnosed with toxoplasmosis in this study population. PMID:26672749

  7. Founder mitochondrial haplotypes in Amerindian populations.

    PubMed Central

    Bailliet, G.; Rothhammer, F.; Carnese, F. R.; Bravi, C. M.; Bianchi, N. O.

    1994-01-01

    It had been proposed that the colonization of the New World took place by three successive migrations from northeastern Asia. The first one gave rise to Amerindians (Paleo-Indians), the second and third ones to Nadene and Aleut-Eskimo, respectively. Variation in mtDNA has been used to infer the demographic structure of the Amerindian ancestors. The study of RFLP all along the mtDNA and the analysis of nucleotide substitutions in the D-loop region of the mitochondrial genome apparently indicate that most or all full-blooded Amerindians cluster in one of four different mitochondrial haplotypes that are considered to represent the founder maternal lineages of Paleo-Indians. We have studied the mtDNA diversity in 109 Amerindians belonging to 3 different tribes, and we have reanalyzed the published data on 482 individuals from 18 other tribes. Our study confirms the existence of four major Amerindian haplotypes. However, we also found evidence supporting the existence of several other potential founder haplotypes or haplotype subsets in addition to the four ancestral lineages reported. Confirmation of a relatively high number of founder haplotypes would indicate that early migration into America was not accompanied by a severe genetic bottleneck. PMID:7517626

  8. Founder mitochondrial haplotypes in Amerindian populations.

    PubMed

    Bailliet, G; Rothhammer, F; Carnese, F R; Bravi, C M; Bianchi, N O

    1994-07-01

    It had been proposed that the colonization of the New World took place by three successive migrations from northeastern Asia. The first one gave rise to Amerindians (Paleo-Indians), the second and third ones to Nadene and Aleut-Eskimo, respectively. Variation in mtDNA has been used to infer the demographic structure of the Amerindian ancestors. The study of RFLP all along the mtDNA and the analysis of nucleotide substitutions in the D-loop region of the mitochondrial genome apparently indicate that most or all full-blooded Amerindians cluster in one of four different mitochondrial haplotypes that are considered to represent the founder maternal lineages of Paleo-Indians. We have studied the mtDNA diversity in 109 Amerindians belonging to 3 different tribes, and we have reanalyzed the published data on 482 individuals from 18 other tribes. Our study confirms the existence of four major Amerindian haplotypes. However, we also found evidence supporting the existence of several other potential founder haplotypes or haplotype subsets in addition to the four ancestral lineages reported. Confirmation of a relatively high number of founder haplotypes would indicate that early migration into America was not accompanied by a severe genetic bottleneck.

  9. Influence of HLA-C Expression Level on HIV Control

    PubMed Central

    Apps, Richard; Qi, Ying; Carlson, Jonathan M.; Chen, Haoyan; Gao, Xiaojiang; Thomas, Rasmi; Yuki, Yuko; Del Prete, Greg Q.; Goulder, Philip; Brumme, Zabrina L.; Brumme, Chanson J.; John, Mina; Mallal, Simon; Nelson, George; Bosch, Ronald; Heckerman, David; Stein, Judy L.; Soderberg, Kelly A.; Moody, M. Anthony; Denny, Thomas N.; Zeng, Xue; Fang, Jingyuan; Moffett, Ashley; Lifson, Jeffrey D.; Goedert, James J.; Buchbinder, Susan; Kirk, Gregory D.; Fellay, Jacques; McLaren, Paul; Deeks, Steven G.; Pereyra, Florencia; Walker, Bruce; Michael, Nelson L.; Weintrob, Amy; Wolinsky, Steven; Liao, Wilson; Carrington, Mary

    2013-01-01

    A variant upstream of human leukocyte antigen C (HLA-C) shows the most significant genome-wide effect on HIV control in European Americans and is also associated with the level of HLA-C expression. We characterized the differential cell surface expression levels of all common HLA-C allotypes and tested directly for effects of HLA-C expression on outcomes of HIV infection in 5243 individuals. Increasing HLA-C expression was associated with protection against multiple outcomes independently of individual HLA allelic effects in both African and European Americans, regardless of their distinct HLA-C frequencies and linkage relationships with HLA-B and HLA-A. Higher HLA-C expression was correlated with increased likelihood of cytotoxic T lymphocyte responses and frequency of viral escape mutation. In contrast, high HLA-C expression had a deleterious effect in Crohn’s disease, suggesting a broader influence of HLA expression levels in human disease. PMID:23559252

  10. [Analysis of gene polymorphism of HPA and HLA-I in Chinese Xi'an voluntary platelet donors].

    PubMed

    Wang, Xiao-Fang; Liu, Meng-Li; Zhou, Dang-Xia; Qi, Jun; Liu, Sheng; Wang, Tian-Ju

    2011-12-01

    To study the allele frequencies and their polymorphism characteristics of human platelet antigen (HPA) and human leucocyte antigen-I (HLA-I) in Chinese xi'an population, the types of HPA and HLA-I in 375 Chinese xi'an voluntary platelet donors were detected by PCR-SSP and PCR-SSO as well as flow cytometry with magnetic beads, and were analyzed. The results showed that there was no polymorphism in HPA-7-HPA-14, HPA-16 and HPA-17 which only expressed-aa type, the -bb type was only detected in HPA-3 and HPA-15, 9 out of 16 samples for the HPA-5ab phenotype simultaneously expressed HPA-15ab, the other 7 samples expressed HPA-15bb, no HPA-15aa phenotype was observed. Phenotypes detected in this study were HPA-1aa-17aa, HPA-1ab, -2ab, -3ab, -3bb, -4ab, -5ab, -6ab, -15ab and -15bb. Among 375 cases, HLA-A specificity of 16 species was observed, which accounted for 76% (16/21) of detectable phenotype specificity in this locus, moreover, 11 species showed frequency > 1%; HLA-B specificity of 36 species was observed which accounted for 84% (36/43) of detectable phenotype specificity in this locus, moreover 23 species showed frequency > 1%, these species were covered by common specific HLA-I in northern China, 264 species haplotype HLA-A-B were found in 375 cases, the frequency of 30 species was > 1%. It is concluded that the gene frequency distribution of HPA and HLA-I in Chinese Xi'an population is in accordance with population of northern China on the whole, but it has its own characteristics.

  11. First report on the antibody verification of HLA-DR, HLA-DQ and HLA-DP epitopes recorded in the HLA Epitope Registry.

    PubMed

    Duquesnoy, Rene J; Marrari, Marilyn; Tambur, Anat R; Mulder, Arend; Sousa, Luiz Cláudio Demes da Mata; da Silva, Adalberto Socorro; do Monte, Semiramis J H

    2014-11-01

    The International Registry of Antibody-Defined HLA Epitopes (http://www.epregistry.com.br) has been recently established as a tool to understand humoral responses to HLA mismatches. These epitopes can be structurally defined as eplets by three-dimensional molecular modeling and amino acid sequence differences between HLA antigens. A major goal is to identify HLA eplets that have been verified experimentally with informative antibodies. This report addresses class II epitopes encoded by genes in the HLA-D region. Our analysis included reviews of many publications about epitope specificity of class II reactive human and murine monoclonal antibodies and informative alloantibodies from HLA sensitized patients as well as our own antibody testing results. As of July 1, 2014, 24 HLA-DRB1/3/4/5, 15 DQB, 3 DQA and 8 DPB antibody-verified epitopes have been identified and recorded. The Registry is still a work-in-progress and will become a useful resource for HLA professionals interested in histocompatibility testing at the epitope level and investigating antibody responses to HLA mismatches in transplant patients.

  12. [The HLA system and habitual abortion].

    PubMed

    Hajek-Rosenmayr, A

    1990-01-01

    HLA-antigens are extremely polymorphic. A calculation of the polymorphism shows a number of 398.476.343 possible HLA-phenotypes, if HLA-A, -B, -C and -DR antigens are taken into account. The compatibility of HLA-antigens of recipient and donor plays a crucial role in transplantation: HLA-antigens are the traits, which are recognized by the immune system of the recipient in the frame of a rejection of the transplant or by the donor in the frame of a graft-versus-host reaction. Large international statistics show that HLA-incompatibility between recipient and donor leads to short transplant function periods, while compatibility brings about good transplant function. Therefore, matching of HLA-antigens plays an important role in transplantation of solid organs, mainly kidneys (3, 4, 5), and is completely necessary in bone marrow transplantation. Also in pregnancy, HLA-antigens are important: If HLA compatibility between mother and child is high, the risk for habitual abortion is higher than in normal pregnancies (6, 7).

  13. HLA-E expression in cervical adenocarcinomas: association with improved long-term survival

    PubMed Central

    2012-01-01

    Background Cervical cancer is the third most common cancer in women worldwide. The most common histopathological subtype is cervical squamous cell carcinoma (SCC, 75-80%), followed by adenocarcinoma (AC) and adenosquamous carcinoma (ASC; together 15-20%). Rising incidence rates of AC have been observed relative and absolute to SCC and evidence is accumulating that cervical AC is a distinct clinical entity. Cervical SCC, ASC, and AC are caused by a persistent infection with high-risk human papillomavirus (HPV) and failed control of the immune system plays a pivotal role in the carcinogenesis of all three histopathological subtypes. Human leukocyte antigen E (HLA-E), a non-classical HLA class Ib molecule, plays an important role in immune surveillance and immune escape of virally infected cells. In this study we investigated HLA-E expression in three well-defined cohorts of cervical AC, ASC, and SCC patients, and determined whether HLA-E expression was associated with histopathological parameters and patient survival. Methods and results HLA-E expression was assessed by immunohistochemistry on formalin-fixed, paraffin-embedded tissue sections of 79 SCC, 38 ASC, and 75 AC patients. All patients included were International Federation of Gynaecology and Obstetrics stage I-II and underwent radical hysterectomy with lymphadenectomy as primary treatment. Significant differences between the histopathological subgroups were detected for age distribution, HPV positivity, HPV type distribution, tumour size, tumour infiltration depth, lymph-vascular space invasion, and adjuvant radiotherapy. High expression of HLA-E was found in 107/192 (56%) cervical carcinomas, with significantly more overexpression in cervical AC compared to SCC and ASC (37/79 SCC, 18/38 ASC, and 52/75 AC; P = 0.010). High HLA-E expression in cervical AC was associated with favourable long term disease-specific and recurrence-free survival (P = 0.005 and P = 0.001, respectively). Conclusion

  14. Phylogeny- and Parsimony-Based Haplotype Inference with Constraints

    NASA Astrophysics Data System (ADS)

    Elberfeld, Michael; Tantau, Till

    Haplotyping, also known as haplotype phase prediction, is the problem of predicting likely haplotypes based on genotype data. One fast computational haplotyping method is based on an evolutionary model where a perfect phylogenetic tree is sought that explains the observed data. In their CPM 2009 paper, Fellows et al. studied an extension of this approach that incorporates prior knowledge in the form of a set of candidate haplotypes from which the right haplotypes must be chosen. While this approach may help to increase the accuracy of haplotyping methods, it was conjectured that the resulting formal problem constrained perfect phylogeny haplotyping might be NP-complete. In the present paper we present a polynomial-time algorithm for it. Our algorithmic ideas also yield new fixed-parameter algorithms for related haplotyping problems based on the maximum parsimony assumption.

  15. Power comparisons between similarity-based multilocus association methods, logistic regression, and score tests for haplotypes.

    PubMed

    Lin, Wan-Yu; Schaid, Daniel J

    2009-04-01

    Recently, a genomic distance-based regression for multilocus associations was proposed (Wessel and Schork [2006] Am. J. Hum. Genet. 79:792-806) in which either locus or haplotype scoring can be used to measure genetic distance. Although it allows various measures of genomic similarity and simultaneous analyses of multiple phenotypes, its power relative to other methods for case-control analyses is not well known. We compare the power of traditional methods with this new distance-based approach, for both locus-scoring and haplotype-scoring strategies. We discuss the relative power of these association methods with respect to five properties: (1) the marker informativity; (2) the number of markers; (3) the causal allele frequency; (4) the preponderance of the most common high-risk haplotype; (5) the correlation between the causal single-nucleotide polymorphism (SNP) and its flanking markers. We found that locus-based logistic regression and the global score test for haplotypes suffered from power loss when many markers were included in the analyses, due to many degrees of freedom. In contrast, the distance-based approach was not as vulnerable to more markers or more haplotypes. A genotype counting measure was more sensitive to the marker informativity and the correlation between the causal SNP and its flanking markers. After examining the impact of the five properties on power, we found that on average, the genomic distance-based regression that uses a matching measure for diplotypes was the most powerful and robust method among the seven methods we compared.

  16. High risk factors of pancreatic carcinoma.

    PubMed

    Camara, Soriba Naby; Yin, Tao; Yang, Ming; Li, Xiang; Gong, Qiong; Zhou, Jing; Zhao, Gang; Yang, Zhi-Yong; Aroun, Tajoo; Kuete, Martin; Ramdany, Sonam; Camara, Alpha Kabinet; Diallo, Aissatou Taran; Feng, Zhen; Ning, Xin; Xiong, Jiong-Xin; Tao, Jing; Qin, Qi; Zhou, Wei; Cui, Jing; Huang, Min; Guo, Yao; Gou, Shan-Miao; Wang, Bo; Liu, Tao; Olivier, Ohoya Etsaka Terence; Conde, Tenin; Cisse, Mohamed; Magassouba, Aboubacar Sidiki; Ballah, Sneha; Keita, Naby Laye Moussa; Souare, Ibrahima Sory; Toure, Aboubacar; Traore, Sadamoudou; Balde, Abdoulaye Korse; Keita, Namory; Camara, Naby Daouda; Emmanuel, Dusabe; Wu, He-Shui; Wang, Chun-You

    2016-06-01

    Over the past decades, cancer has become one of the toughest challenges for health professionals. The epidemiologists are increasingly directing their research efforts on various malignant tumor worldwide. Of note, incidence of cancers is on the rise more quickly in developed countries. Indeed, great endeavors have to be made in the control of the life-threatening disease. As we know it, pancreatic cancer (PC) is a malignant disease with the worst prognosis. While little is known about the etiology of the PC and measures to prevent the condition, so far, a number of risk factors have been identified. Genetic factors, pre-malignant lesions, predisposing diseases and exogenous factors have been found to be linked to PC. Genetic susceptibility was observed in 10% of PC cases, including inherited PC syndromes and familial PC. However, in the remaining 90%, their PC might be caused by genetic factors in combination with environmental factors. Nonetheless, the exact mechanism of the two kinds of factors, endogenous and exogenous, working together to cause PC remains poorly understood. The fact that most pancreatic neoplasms are diagnosed at an incurable stage of the disease highlights the need to identify risk factors and to understand their contribution to carcinogenesis. This article reviews the high risk factors contributing to the development of PC, to provide information for clinicians and epidemiologists.

  17. Y chromosome haplotype reference database (YHRD): update.

    PubMed

    Willuweit, Sascha; Roewer, Lutz

    2007-06-01

    The freely accessible YHRD (Y Chromosome Haplotype Reference Database, www.yhrd.org) is designed to store Y chromosome haplotypes from global populations and had replaced three earlier database versions collecting European, Asian and US American Y chromosomes separately. The focus is to disseminate haplotype frequency data to forensic analysts, researchers, and to everyone who is interested in historical and family genetics. YHRD considers reduction of the available number of polymorphisms on the Y chromosome to a uniform data string of 11 highly variable Y-STR loci as an efficient way to rapidly screen many world populations and to make their Y chromosome profiles comparable. Typing of the YHRD 11-locus core set is facilitated by commercial products, namely diagnostic PCR kits, and endorsed by scientific and forensic analyst's societies as ISFG or SWGDAM. YHRD is structured by the assignment of each submitted population sample to a set of populations sharing a common linguistic, demographic, genetic or geographic background (metapopulations). This principle facilitates the statistical evaluation of haplotype matches due to a significant enlargement of sample sizes. With the rapid growth of the database the definition of homogeneous metapopulations is now also feasible solely on the basis of the genetic data as exemplified for the whole dataset of YHRD, release 19 (August 2006). Large sample numbers within genetically defined metapopulations also allows the development of biostatistical methods to estimate the frequency of unobserved or rare haplotypes ("haplotype frequency surveying method"). Essential for the YHRD project is its collaborative character relying on the engagement of individual laboratories to make their data accessible via YHRD and to share the YHRD standards regarding data quality.

  18. HLA-class I markers and multiple sclerosis susceptibility in the Italian population

    PubMed Central

    Bergamaschi, L; Leone, M A; Fasano, M E; Guerini, F R; Ferrante, D; Bolognesi, E; Barizzone, N; Corrado, L; Naldi, P; Agliardi, C; Dametto, E; Salvetti, M; Visconti, A; Galimberti, D; Scarpini, E; Vercellino, M; Bergamaschi, R; Monaco, F; Caputo, D; Momigliano-Richiardi, P; D'Alfonso, S

    2009-01-01

    Previous studies reported an association with multiple sclerosis (MS) of distinct HLA-class I markers, namely HLA-A*02, HLA-Cw*05 and MOG-142L. In this work, we tested the association with MS of A*02 and Cw*05 in 1273 Italian MS patients and 1075 matched controls, which were previously analyzed for MOG-142, and explored the relationship among these three markers in modulating MS risk. HLA-A*02 conferred a statistically robust MS protection (odds ratio, OR=0.61; 95% confidence intervals, CI=0.51–0.72, P<10−9), which was independent of DRB1*15 and of any other DRB1* allele and remained similar after accounting for the other two analyzed class I markers. Conversely, the protective effect we previously observed for MOG-142L was secondary to its linkage disequilibrium with A*02. Cw*05 was not associated considering the whole sample, but its presence significantly enhanced the protection in the HLA-A*02-positive group, independently of DRB1: the OR conferred by A*02 in Cw*05-positive individuals (0.22, 95% CI=0.13–0.38) was significantly lower than in Cw*05-negative individuals (0.69, 95% CI=0.58–0.83) with a significant (P=4.94 × 10−5) multiplicative interaction between the two markers. In the absence of A*02, Cw*05 behaved as a risk factor, particularly in combination with DRB1*03 (OR=3.89, P=0.0006), indicating that Cw*05 might be a marker of protective or risk haplotypes, respectively. PMID:19907433

  19. HIGH-RISK PROGRAM: Information on Selected High-Risk Areas.

    DTIC Science & Technology

    2007-11-02

    United States General Accounting Office GAO Information for House MajorityLeader Richard Armey and Representative Pete Sessions May 1997 GH-RISK ID...Information on Selected High-Risk Areas Corporate Author Or Publisher: General Accounting Office, GAO, Washington, DC 20548 Report Number: GAO/IHR-97-30 Report...Library: 000001 Record ID: 45053 GAO United States General Accounting OfficeWashington, D.C. 20548 Accounting and Information Management Division May

  20. High-risk sex offenders may not be high risk forever.

    PubMed

    Hanson, R Karl; Harris, Andrew J R; Helmus, Leslie; Thornton, David

    2014-10-01

    This study examined the extent to which sexual offenders present an enduring risk for sexual recidivism over a 20-year follow-up period. Using an aggregated sample of 7,740 sexual offenders from 21 samples, the yearly recidivism rates were calculated using survival analysis. Overall, the risk of sexual recidivism was highest during the first few years after release, and decreased substantially the longer individuals remained sex offense-free in the community. This pattern was particularly strong for the high-risk sexual offenders (defined by Static-99R scores). Whereas the 5-year sexual recidivism rate for high-risk sex offenders was 22% from the time of release, this rate decreased to 4.2% for the offenders in the same static risk category who remained offense-free in the community for 10 years. The recidivism rates of the low-risk offenders were consistently low (1%-5%) for all time periods. The results suggest that offense history is a valid, but time-dependent, indicator of the propensity to sexually reoffend. Further research is needed to explain the substantial rate of desistance by high-risk sexual offenders.

  1. Human Leukocyte Antigens-A, -B, -C, -DRB1 allele and haplotype frequencies in Americans originating from Southern Europe: Contrasting patterns of population differentiation between Italian and Spanish Americans

    PubMed Central

    Mack, Steven J.; Tu, Bin; Yang, Ruyan; Masaberg, Carly; Ng, Jennifer; Hurley, Carolyn Katovich

    2010-01-01

    High resolution DNA sequencing was used to identify the HLA-A, -B, -C, and -DRB1 alleles found in 552 individuals from the United States indicating Southern European (Italian or Spanish) heritage. A total of 46 HLA-A, 80 HLA-B, 32 HLA-C, and 50 DRB1 alleles were identified. Frequent alleles included A*02:01:01G (allele frequency = 0.26 in Italian Americans; 0.22 in Spanish Americans); B*07:02:01G (Italian Americans allele frequency = 0.11); B*44:03 (Spanish Americans allele frequency = 0.07); C*04:01:01G and C*07:01:01G (allele frequency = 0.13 and 0.16, respectively, in Italian Americans; 0.15 and 0.12, respectively, in Spanish Americans); and DRB1*07:01:01 (allele frequency = 0.12 in each population). The action of balancing selection was inferred at the HLA-B and -C loci in both populations. The A*01:01:01G-C*07:01:01G-B*08:01:01G-DRB1*03:01:01 haplotype was the most frequent A-C-B-DRB1 haplotype in Italian Americans (haplotype frequency = 0.049), and was the second most frequent haplotype in Spanish Americans (haplotype frequency = 0.021). A*29:02:01-C*16:01:01-B*44:03-DRB1*07:01:01 was the most frequent A-C-B-DRB1 haplotype in Spanish Americans (haplotype frequency = 0.023), and was observed at a frequency of 0.015 in Italian Americans. Pairwise F’st values measuring the degree of differentiation between these Southern European-American populations and European and European-American populations suggest that Spanish Americans constitute a distinct subset of the European-American population, most similar to Mexican Americans, whereas Italian Americans cannot be distinguished from the larger European-American population. PMID:20974205

  2. Separation of Y-chromosomal haplotypes from male DNA mixtures via multiplex haplotype-specific extraction.

    PubMed

    Rothe, Jessica; Nagy, Marion

    2015-11-01

    In forensic analysis, the interpretation of DNA mixtures is the subject of ongoing debate and requires expertise knowledge. Haplotype-specific extraction (HSE) is an alternative method that enables the separation of large chromosome fragments or haplotypes by using magnetic beads in conjunction with allele-specific probes. HSE thus allows physical separation of the components of a DNA mixture. Here, we present the first multiplex HSE separation of a Y-chromosomal haplotype consisting of six Yfiler short tandem repeat markers from a mixture of male DNA.

  3. HLA-DRB1, -DRB3, -DRB4 and -DRB5 genotyping at a super-high resolution level by long range PCR and high-throughput sequencing.

    PubMed

    Ozaki, Y; Suzuki, S; Shigenari, A; Okudaira, Y; Kikkawa, E; Oka, A; Ota, M; Mitsunaga, S; Kulski, J K; Inoko, H; Shiina, T

    2014-01-01

    Super high-resolution single molecule sequence-based typing (SS-SBT) is a human leukocyte antigen (HLA) DNA typing method to the field 4 level of allelic resolution (formerly known as eight-digit typing) to efficiently detect new and null alleles without phase ambiguity by combination of long ranged polymerase chain reaction (PCR) amplification and next-generation sequencing (NGS) technologies. We previously reported the development and application of the SS-SBT method for the eight classical HLA loci, A, B, C, DRB1, DQA1, DQB1, DPA1 and DPB1. In this article, we describe the development of the SS-SBT method for three DRB1 linked loci, DRB3, DRB4 and DRB5 (DRB3/4/5) and characterization of DRB1-DRB3/4/5 haplotype structures to the field 4 level. Locus specific PCR primers for DRB3/4/5 were designed to amplify the gene regions from intron 1 to exon 6 [3' untranslated region (3'UTR)]. In total 20 DRB1 and 13 DRB3/4/5 allele sequences were determined by the SS-SBT to the field 4 level without phase ambiguity using 19 DR51, DR52 and DR53 positive genomic DNA samples obtained from Japanese. Moreover, 18 DRB1-DRB3/4/5 haplotypes were estimated to the field 4 level by the SS-SBT method in contrast to 10 haplotypes estimated by conventional methods to the field 1 level (formerly known as two digit typing). Therefore, DRB1-DRB3/4/5 haplotyping by SS-SBT is expected to provide informative data for improved HLA matching in medical research, transplantation procedures, HLA-related disease studies and human population diversity studies.

  4. Relevance of HLA-G, HLA-E and IL-10 expression in lip carcinogenesis.

    PubMed

    Gonçalves, Andréia Souza; Oliveira, Jéssica Petini; Oliveira, Carolina Ferrari Piloni; Silva, Tarcília Aparecida; Mendonça, Elismauro Francisco; Wastowski, Isabela Jubé; Batista, Aline Carvalho

    2016-09-01

    HLA-G, HLA-E and IL-10 are molecules which can provide tumor immunosuppression as well as the capacity of evasion to the immune system host. This study set out to evaluate HLA-G, HLA-E and IL-10 expression in lip squamous cell carcinoma (LSCC) and in a potentially malignant disorder (actinic cheilitis - AC), correlating the expression of these proteins with the degree of epithelial dysplasia. Immunohistochemistry was undertaken to identify HLA-G, HLA-E and IL-10 in samples from patients with LSCC (n=20), AC (n=30) and healthy lip mucosa (control) (n=10). A semiquantitative scoring system was used for analysis. Differences between the groups were evaluated using the Pearson Chi-Squared test. The percentage of LSCC samples showing high immunoreactivity (IRS>2) for HLA-G, HLA-E and IL-10 (neoplastic/epithelial cells) and HLA-E (stroma/connective tissue) was significantly higher that of the control (P<0.05). A tendency for a progressive increase in the proteins analyzed was observed from the control to AC and to LSCC. The degree of dysplasia in the AC samples was not significantly associated with the proteins evaluated (P>0.05). The high expression of HLA-G, HLA-E and IL-10 in AC and LSCC reflects the capacity that these pathologies have for evasion and progression.

  5. Genetic diversity of the HLA-G coding region in Amerindian populations from the Brazilian Amazon: a possible role of natural selection.

    PubMed

    Mendes-Junior, C T; Castelli, E C; Meyer, D; Simões, A L; Donadi, E A

    2013-12-01

    HLA-G has an important role in the modulation of the maternal immune system during pregnancy, and evidence that balancing selection acts in the promoter and 3'UTR regions has been previously reported. To determine whether selection acts on the HLA-G coding region in the Amazon Rainforest, exons 2, 3 and 4 were analyzed in a sample of 142 Amerindians from nine villages of five isolated tribes that inhabit the Central Amazon. Six previously described single-nucleotide polymorphisms (SNPs) were identified and the Expectation-Maximization (EM) and PHASE algorithms were used to computationally reconstruct SNP haplotypes (HLA-G alleles). A new HLA-G allele, which originated in Amerindian populations by a crossing-over event between two widespread HLA-G alleles, was identified in 18 individuals. Neutrality tests evidenced that natural selection has a complex part in the HLA-G coding region. Although balancing selection is the type of selection that shapes variability at a local level (Native American populations), we have also shown that purifying selection may occur on a worldwide scale. Moreover, the balancing selection does not seem to act on the coding region as strongly as it acts on the flanking regulatory regions, and such coding signature may actually reflect a hitchhiking effect.

  6. The Psychosis High-Risk State

    PubMed Central

    Fusar-Poli, Paolo; Borgwardt, Stefan; Bechdolf, Andreas; Addington, Jean; Riecher-Rössler, Anita; Schultze-Lutter, Frauke; Keshavan, Matcheri; Wood, Stephen; Ruhrmann, Stephan; Seidman, Larry J.; Valmaggia, Lucia; Cannon, Tyrone; Velthorst, Eva; De Haan, Lieuwe; Cornblatt, Barbara; Bonoldi, Ilaria; Birchwood, Max; McGlashan, Thomas; Carpenter, William; McGorry, Patrick; Klosterkötter, Joachim; McGuire, Philip; Yung, Alison

    2014-01-01

    Context During the past 2 decades, a major transition in the clinical characterization of psychotic disorders has occurred. The construct of a clinical high-risk (HR) state for psychosis has evolved to capture the prepsychotic phase, describing people presenting with potentially prodromal symptoms. The importance of this HR state has been increasingly recognized to such an extent that a new syndrome is being considered as a diagnostic category in the DSM-5. Objective To reframe the HR state in a comprehensive state-of-the-art review on the progress that has been made while also recognizing the challenges that remain. Data Sources Available HR research of the past 20 years from PubMed, books, meetings, abstracts, and international conferences. Study Selection and Data Extraction Critical review of HR studies addressing historical development, inclusion criteria, epidemiologic research, transition criteria, outcomes, clinical and functional characteristics, neurocognition, neuroimaging, predictors of psychosis development, treatment trials, socioeconomic aspects, nosography, and future challenges in the field. Data Synthesis Relevant articles retrieved in the literature search were discussed by a large group of leading worldwide experts in the field. The core results are presented after consensus and are summarized in illustrative tables and figures. Conclusions The relatively new field of HR research in psychosis is exciting. It has the potential to shed light on the development of major psychotic disorders and to alter their course. It also provides a rationale for service provision to those in need of help who could not previously access it and the possibility of changing trajectories for those with vulnerability to psychotic illnesses. PMID:23165428

  7. BAT2 and BAT3 polymorphisms as novel genetic risk factors for rejection after HLA-related stem cell transplantation

    PubMed Central

    Piras, Ignazio Stefano; Angius, Andrea; Andreani, Marco; Testi, Manuela; Lucarelli, Guido; Floris, Matteo; Marktel, Sarah; Ciceri, Fabio; La Nasa, Giorgio; Fleischhauer, Katharina; Roncarolo, Maria Grazia; Bulfone, Alessandro

    2014-01-01

    The genetic background of donor and recipient is an important factor determining the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We applied a whole genome analysis to investigate genetic variants - other than HLA class I and II - associated with negative outcome after HLA-identical sibling allo-HSCT in a cohort of 110 β-Thalassemic patients. We identified two single nucleotide polymorphisms in BAT2 (A/G) and BAT3 (T/C) genes, SNP rs11538264 and SNP rs10484558, both located in the HLA class III region, in strong Linkage Disequilibrium between each other (R2=0.92). When considered as single SNP, none of them reached a significant association with graft rejection (nominal P < 0.00001 for BAT2 SNP rs11538264, and P < 0.0001 for BAT3 SNP rs10484558). Whereas, the BAT2/BAT3 A/C haplotype was present at significantly higher frequency in patients who rejected as compared to those with functional graft (30.0% vs. 2.6%, nominal P = 1.15×10−8; and adjusted P = 0.0071). The BAT2/BAT3 polymorphisms and specifically the A/C haplotype may represent novel immunogenetic factor associated with graft rejection in patients undergoing allo-HSCT. PMID:25111513

  8. Monocytic HLA DR antigens in schizophrenic patients.

    PubMed

    Krause, Daniela; Wagner, Jenny; Matz, Judith; Weidinger, Elif; Obermeier, Michael; Riedel, Michael; Gruber, Rudolf; Schwarz, Markus; Mueller, Norbert

    2012-01-01

    A genetic association of specific human leukocyte antigens (HLA) DR genes and schizophrenia has recently been shown. These HLA play a fundamental role in the control of immune responses. Furthermore infectious agents have been proposed to be involved in the pathogenesis of schizophrenia. In this study we investigated the rate of HLA DR positive monocytes in schizophrenic patients compared to controls with a special focus on the adaption to in vitro stimulation with toll-like receptor ligands. Patients with schizophrenia and matched controls were included. For each individual, we evaluated the rate of HLA DR positive monocytes (either incubated at 37 °C or after stimulation with lipopolysaccharide or Poly I:C). We found a significantly higher percentage of schizophrenic patients with elevated HLA DR positive cells (p=0.045) as compared to controls. The adjustment rate from baseline levels of monocytic HLA DR positive cells to stimulation with Poly I:C was significantly lower in schizophrenic patients (p=0.038). The increased monocytic HLA DR in schizophrenic patients and the maladjustment of their monocytic HLA DR levels to an infectious stimulus might be a sign for a disturbed monocytic immune balance in schizophrenic individuals.

  9. Soluble HLA-G expression and renal graft acceptance.

    PubMed

    Qiu, J; Terasaki, P I; Miller, J; Mizutani, K; Cai, J; Carosella, E D

    2006-09-01

    HLA-G is a potentially interesting molecule associated with immunosuppressive function. We survey here the presence of soluble HLA-G (sHLA-G) in serial serum samples of renal transplants. A total of 330 sera of from 65 patients were tested for sHLA-G with ELISA. IgG/IgM antibodies to HLA, and MICA antibodies were also previously tested. After serial analysis of the 65 patients' 330 sera, 50% of 26 patients in functioning group had consistent sHLA-G expression or became positive, in comparison to 20.5% among 39 patients who rejected their transplants (p=0.013). Thus sHLA-G was associated with functioning transplants. Eighty percent (77 of 96) of the HLA IgG positive sera had no sHLA-G expression, while 81.4% (83 of 102) of the HLA-G(+) sera had no HLA IgG (p=0.005), which showed a negative association between sHLA-G and the presence of HLA IgG antibodies (which was previously been shown to be associated with failure). In this preliminary survey, sHLA-G was found in the serum of about 30% of renal transplant patients. sHLA-G had a negative association with allograft failure from chronic rejection, and a negative relationship with the production of HLA IgG antibodies. The significance of sHLA-G in renal transplants remains to be determined.

  10. Applications of haplotypes in dairy farm management

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Haplotypes from genomic tests are now available for almost 100,000 dairy cows and heifers in the U.S.. Genomic EBV values are accelerating the rate of genetic improvement in dairy cattle, but genomic information also is useful for making improved decisions on the farm. Mate selection strategies have...

  11. Haplotype assembly from aligned weighted SNP fragments.

    PubMed

    Zhao, Yu-Ying; Wu, Ling-Yun; Zhang, Ji-Hong; Wang, Rui-Sheng; Zhang, Xiang-Sun

    2005-08-01

    Given an assembled genome of a diploid organism the haplotype assembly problem can be formulated as retrieval of a pair of haplotypes from a set of aligned weighted SNP fragments. Known computational formulations (models) of this problem are minimum letter flips (MLF) and the weighted minimum letter flips (WMLF; Greenberg et al. (INFORMS J. Comput. 2004, 14, 211-213)). In this paper we show that the general WMLF model is NP-hard even for the gapless case. However the algorithmic solutions for selected variants of WMFL can exist and we propose a heuristic algorithm based on a dynamic clustering technique. We also introduce a new formulation of the haplotype assembly problem that we call COMPLETE WMLF (CWMLF). This model and algorithms for its implementation take into account a simultaneous presence of multiple kinds of data errors. Extensive computational experiments indicate that the algorithmic implementations of the CWMLF model achieve higher accuracy of haplotype reconstruction than the WMLF-based algorithms, which in turn appear to be more accurate than those based on MLF.

  12. Y-chromosome haplotype analysis in Antioquia (Colombia).

    PubMed

    Gaviria, A A; Ibarra, A A; Palacio, O D; Posada, Y C; Triana, O; Ochoa, L M; Acosta, M A; Brión, M; Lareu, M V; Carracedo, A

    2005-06-30

    Allele frequencies and haplotype analysis have been performed for eight Y-chromosome STRs (DYS19, DYS385 I and II, DYS389 I and II, DYS390, DYS391, DYS392, DYS393). Population data was obtained from a sample of 400 unrelated individuals living in Antioquia (Colombia). A total of 270 different haplotypes were found, and the haplotype diversity was 0.989. The first and second most frequent haplotypes where shared by 8 and 6% of the individuals, respectively.

  13. The heterogeneous HLA genetic composition of the Brazilian population and its relevance to the optimization of hematopoietic stem cell donor recruitment.

    PubMed

    Fabreti-Oliveira, R A; Nascimento, E; Fonseca, C G; Santos, M A

    2014-08-01

    The aim of this study was to investigate the human leukocyte antigen (HLA) molecular variation across the Brazilian population in order to determine possible regional differences, which would be highly relevant to optimizing donor recruitment strategies in hematopoietic stem cell transplantation (HSCT) and understanding the population genetic background of this heterogeneous country. HLA data of 551 HSCT donors from five Brazilian regions were characterized by high-resolution DNA alleles at the HLA-A, -B, -C, -DRB1 and -DQB1 loci and compared with other populations in Brazil and worldwide populations. Allele and haplotype frequencies were estimated. The analysis was performed to assess Hardy-Weinberg equilibrium (HWE) and linkage disequilibrium (LD) among different loci in each recruitment center. Genetic variation was explored through genetic distance analyzed by using a new algorithm based on linear algebra, taking into account geographic regions of Brazil. The results indicated a heterogeneous genetic composition of the Brazilian population, such that HLA allele and haplotype frequencies exhibit different distributions among Brazilian regions, which has important implications for donor matching. In addition, a pronounced differentiation was observed by the absence of clustering of the regional populations in the reduced-dimension space. These data may be useful for increasing donor recruitment with more genetic representativeness in the Brazilian Volunteer Bone Marrow Donors Registry (REDOME).

  14. HLA is unlikely to be a major component of risk in familial inflammatory bowl disease

    SciTech Connect

    Mathew, C.G.; Naom, I.S.; Hodgson, S.V.

    1994-09-01

    Inflammatory bowel disease (IBD) is a chronic inflammation of the bowel which is confined to the colon in ulcerative colitis (UC) or may affect any part of the gastrointestinal tract in Crohn`s disease (CD). The cause of IBD is unknown, but a genetic component is suggested by a 10-fold increase in risk to first degree relatives, and a higher concordance of disease in MZ versus DZ twins. Distinct associations of HLA DR2 with UC and DR1/DQw5 with CD have been reported. We are searching for susceptibility genes in IBD by linkage analysis in a panel of 43 families with 3 or more living affected members, which includes 12 families with CD, 17 with UC and 14 {open_quotes}mixed{close_quotes} families with UC and CD. In view of the reported HLA associations in IBD, we have analyzed 5 microsatellite markers from the major histocompatibility complex for linkage to IBD using both parametric and nonparametric methods. LOD scores were calculated for 4 different genetic models, including both dominant and recessive inheritance, and haplotype sharing was analyzed in affected siblings. LOD scores for the MHC locus were negative in the full data set, and in the 3 classes of family (UC,CD,mixed). Haplotype sharing in affected sibs was very close to that expected if no linkage was present. We conclude that genes from the HLA region are unlikely to be a major component of risk in familial IBD. Linkage analysis of genes which cause chronic colitis when disrupted in transgenic mice is in progress.

  15. Haplotype reconstruction and estimation of haplotype frequencies from nuclear families with only one parent available.

    PubMed

    Ding, Xiangdong; Zhang, Qin; Flury, Christine; Simianer, Henner

    2006-01-01

    Recent literature has suggested that haplotype inference through close relatives, especially from nuclear families can be an alternative strategy in determining the linkage phase. In this paper, haplotype reconstruction and estimation of haplotype frequencies via expectation maximization (EM) algorithm including nuclear families with only one parent available is proposed. Parent and his (her) child are treated as parent-child pair with one shared haplotype. This reduces the number of potential haplotype pairs for both parent and child separately, resulting in a higher accuracy of the estimation. In a series of simulations, the comparisons of PHASE, GENEHUNTER, EM-based approach for complete nuclear families and our approach are carried out. In all situations, EM-based approach for trio data is comparable but slightly worse error rate than PHASE, our approach is slightly better and much faster than PHASE for incomplete trios, the performance of GENEHUNTER is very bad in simple nuclear family settings and dramatically decreased with the number of markers being increased. On the other hand, the comparison result of different sampling designs demonstrates that sampling trios is the most efficient design to estimate haplotype frequencies in populations under same genotyping cost.

  16. HLA-DPB1 and HLA Class I Confer Risk of and Protection from Narcolepsy

    PubMed Central

    Ollila, Hanna M.; Ravel, Jean-Marie; Han, Fang; Faraco, Juliette; Lin, Ling; Zheng, Xiuwen; Plazzi, Giuseppe; Dauvilliers, Yves; Pizza, Fabio; Hong, Seung-Chul; Jennum, Poul; Knudsen, Stine; Kornum, Birgitte R.; Dong, Xiao Song; Yan, Han; Hong, Heeseung; Coquillard, Cristin; Mahlios, Joshua; Jolanki, Otto; Einen, Mali; Lavault, Sophie; Högl, Birgit; Frauscher, Birgit; Crowe, Catherine; Partinen, Markku; Huang, Yu Shu; Bourgin, Patrice; Vaarala, Outi; Désautels, Alex; Montplaisir, Jacques; Mack, Steven J.; Mindrinos, Michael; Fernandez-Vina, Marcelo; Mignot, Emmanuel

    2015-01-01

    Type 1 narcolepsy, a disorder caused by a lack of hypocretin (orexin), is so strongly associated with human leukocyte antigen (HLA) class II HLA-DQA1∗01:02-DQB1∗06:02 (DQ0602) that very few non-DQ0602 cases have been reported. A known triggering factor for narcolepsy is pandemic 2009 influenza H1N1, suggesting autoimmunity triggered by upper-airway infections. Additional effects of other HLA-DQ alleles have been reported consistently across multiple ethnic groups. Using over 3,000 case and 10,000 control individuals of European and Chinese background, we examined the effects of other HLA loci. After careful matching of HLA-DR and HLA-DQ in case and control individuals, we found strong protective effects of HLA-DPA1∗01:03-DPB1∗04:02 (DP0402; odds ratio [OR] = 0.51 [0.38–0.67], p = 1.01 × 10−6) and HLA-DPA1∗01:03-DPB1∗04:01 (DP0401; OR = 0.61 [0.47–0.80], p = 2.07 × 10−4) and predisposing effects of HLA-DPB1∗05:01 in Asians (OR = 1.76 [1.34–2.31], p = 4.71 × 10−05). Similar effects were found by conditional analysis controlling for HLA-DR and HLA-DQ with DP0402 (OR = 0.45 [0.38–0.55] p = 8.99 × 10−17) and DP0501 (OR = 1.38 [1.18–1.61], p = 7.11 × 10−5). HLA-class-II-independent associations with HLA-A∗11:01 (OR = 1.32 [1.13–1.54], p = 4.92 × 10−4), HLA-B∗35:03 (OR = 1.96 [1.41–2.70], p = 5.14 × 10−5), and HLA-B∗51:01 (OR = 1.49 [1.25–1.78], p = 1.09 × 10−5) were also seen across ethnic groups in the HLA class I region. These effects might reflect modulation of autoimmunity or indirect effects of HLA class I and HLA-DP alleles on response to viral infections such as that of influenza. PMID:25574827

  17. DHLAS: A web-based information system for statistical genetic analysis of HLA population data.

    PubMed

    Thriskos, P; Zintzaras, E; Germenis, A

    2007-03-01

    DHLAS (database HLA system) is a user-friendly, web-based information system for the analysis of human leukocyte antigens (HLA) data from population studies. DHLAS has been developed using JAVA and the R system, it runs on a Java Virtual Machine and its user-interface is web-based powered by the servlet engine TOMCAT. It utilizes STRUTS, a Model-View-Controller framework and uses several GNU packages to perform several of its tasks. The database engine it relies upon for fast access is MySQL, but others can be used a well. The system estimates metrics, performs statistical testing and produces graphs required for HLA population studies: (i) Hardy-Weinberg equilibrium (calculated using both asymptotic and exact tests), (ii) genetics distances (Euclidian or Nei), (iii) phylogenetic trees using the unweighted pair group method with averages and neigbor-joining method, (iv) linkage disequilibrium (pairwise and overall, including variance estimations), (v) haplotype frequencies (estimate using the expectation-maximization algorithm) and (vi) discriminant analysis. The main merit of DHLAS is the incorporation of a database, thus, the data can be stored and manipulated along with integrated genetic data analysis procedures. In addition, it has an open architecture allowing the inclusion of other functions and procedures.

  18. HLA-Cw*1214 allele arisen via recombination between HLA-Cw*070201 and HLA-Cw*120201.

    PubMed

    Lebedeva, T V; Ohashi, M; Huang, A; Vasconcellos, S; Alosco, S M; Kempenich, J; Yu, N

    2004-12-01

    Allelic polymorphism of the major histocompatibility complex arises mostly from gene conversion. Intralocus gene conversion usually involves limited fragments of DNA, whereas recombination involving large fragments of DNA is considered to be a rare event. During routine sequencing-based typing of donors for the National Marrow Donor Program, a new HLA-C allele was identified in a Caucasian donor. The allele, HLA-Cw*1214, proved to be the product of recombination between HLA-Cw*070201 and HLA-Cw*120201. Exons 1, 2, the 3' end of exon 3 and exon 4 (with one mismatch) belong to HLA-Cw*120201, whereas part of exon 3 belongs to HLA-Cw*070201. Sequencing with primers based in exon 2 and exon 3 showed that intron 2 of the new allele also belonged completely to HLA-Cw*1202. The recombination event apparently occurred within exon 3 with the first point of recombination somewhere between codons 92 and 134 and the second one between codons 157 and 181.

  19. The IPD-IMGT/HLA Database - New developments in reporting HLA variation.

    PubMed

    Robinson, James; Soormally, Anup R; Hayhurst, James D; Marsh, Steven G E

    2016-03-01

    IPD-IMGT/HLA is a constituent of the Immuno Polymorphism Database (IPD), which was developed to provide a centralised system for the study of polymorphism in genes of the immune system. The IPD project works with specialist groups of nomenclature committees who provide and curate individual sections before they are submitted to IPD for online publication. The primary database within the IPD project is the IPD-IMGT/HLA Database, which provides a locus-specific database for the hyper-polymorphic allele sequences of the genes in the HLA system, also known as the human Major Histocompatibility Complex. The IPD-IMGT/HLA Database was first released over 17 years ago, building on the work of the WHO Nomenclature Committee for Factors of the HLA system that was initiated in 1968. The IPD-IMGT/HLA Database enhanced this work by providing the HLA community with an online, searchable repository of highly curated HLA sequences. Many of the genes encode proteins of the immune system and are hyper polymorphic, with some genes currently having over 4000 known allelic variants. Through the work of the HLA Informatics Group and in collaboration with the European Bioinformatics Institute we are able to provide public access to this data through the website, http://www.ebi.ac.uk/ipd/imgt/hla.

  20. HLA expression and HLA type associations in relation to EBV status in Hispanic Hodgkin lymphoma patients

    PubMed Central

    Fletcher, Luke B.; Veenstra, Rianne N.; Loo, Eric Y.; Hwang, Amie E.; Siddiqi, Imran N.; Visser, Lydia; Hepkema, Bouke G.; Nolte, Ilja M.; van den Berg, Anke; Cozen, Wendy; Diepstra, Arjan

    2017-01-01

    A proportion of classical Hodgkin lymphomas harbor the Epstein Barr virus (EBV). We previously demonstrated that associations between Human Leukocyte Antigen (HLA) alleles and susceptibility to EBV+ classical Hodgkin lymphoma differ between European and Chinese populations. Data on Hispanic populations is missing. Here we examined the association between HLA type, tumor cell HLA expression and other characteristics in Hispanic Hodgkin lymphoma patients. Hispanic Hodgkin lymphoma patients diagnosed at the Los Angeles County-University of Southern California Medical Center from 2000–2012 were included (n = 65). Formalin-fixed paraffin-embedded tumor tissue was analyzed for EBV by in situ hybridization and for HLA class I and class II expression by immunohistochemistry. HLA typing was performed by HLA-A specific quantitative PCR of genomic DNA from tissue. Thirty patients (46%) had EBV+ tumors. Expression of HLA class I (p = 0.0006) was significantly associated with EBV+ tumor status in Hispanic patients, similar to Europeans and Chinese. A positive association between HLA class II expression and EBV+ tumor status, as present in large studies in Europeans, was not found (p = 0.06). The prevalences of the specific European HLA-A*01 risk and European HLA-A*02 protective types were not significantly associated with EBV+ tumors among these Hispanic patients, however numbers were too low to draw firm conclusions. The HLA-A*02:07 allele, that is associated with EBV+ Hodgkin lymphoma in Chinese, was absent. In conclusion, the association between EBV positivity in tumor cells and HLA class I expression appears to be consistent across different populations. Larger studies in Hispanics are needed to evaluate HLA allele susceptibility associations. PMID:28334025

  1. Expression of HLA-ABC, HLA-DR and intercellular adhesion molecule-1 in oesophageal carcinoma.

    PubMed Central

    Rockett, J C; Darnton, S J; Crocker, J; Matthews, H R; Morris, A G

    1995-01-01

    AIM--To examine the expression of HLA-ABC and HLA-DR major histocompatibility (MHC) antigens and intercellular adhesion molecule (ICAM)-1 in normal, inflamed, metaplastic, and neoplastic oesophageal tissue and in freshly disaggregated tumours. METHODS--Sequential sections of frozen tissue and cytospins of freshly disaggregated tumour were stained using the ABC peroxidase system and monoclonal antibodies specific for HLA-ABC, HLA-DR and ICAM-1. RESULTS--Normal oesophageal tissue showed positive staining for HLA-ABC in the basal layers of the oesophageal squamous epithelium and on the epithelial cells of the submucosal oesophageal glands. HLA-DR and ICAM-1 were not detected in either of these cell types. In 20 of 37 (54%) carcinomas HLA-ABC was expressed weakly, with heterogeneous expression in nine (24%). Two tumours showed strong expression of HLA-ABC, but 15 of 37 (41%) were negative. HLA-DR and ICAM-1 were expressed weakly in six of 37 (16%) carcinomas without correlation with each other or with the expression of HLA-ABC. CONCLUSIONS--HLA-ABC is absent from a high proportion of oesophageal carcinomas (41%) and is otherwise variably and weakly expressed with strong expression in only a small fraction (3%). In other carcinomas there is a higher level of HLA-ABC expression. This discrepancy may partly explain the aggressive nature of oesophageal carcinomas. HLA-DR and ICAM-1 are not normally expressed on those cells from which oesophageal carcinomas are thought to arise. The limited expression found here could suggest a partial or inhibited immune response against oesophageal carcinoma. In vivo repressive factors may be involved. Images PMID:7665697

  2. The association between functional HLA-G 14bp insertion/deletion and +3142 C>G polymorphisms and susceptibility to multiple sclerosis.

    PubMed

    Ben Fredj, Nadia; Sakly, Kaouthar; Bortolotti, Daria; Aissi, Mouna; Frih-Ayed, Mahbouba; Rotola, Antonella; Caselli, Elisabetta; Cura, Franscesca; Sakly, Nabil; Aouni, Mahjoub; Di Luca, Dario; Rizzo, Roberta

    2016-12-01

    We aimed to investigate two main polymorphisms in the 3' untranslated region (3'UTR) of the HLA-G gene [14bp insertion/deletion (INS/DEL) and +3142 C>G] and to assess their impact on the soluble HLA-G (sHLA-G) production in patients with multiple sclerosis (MS). This study included 60 patients with relasping-remitting (RR) MS and 112 healthy donors (HD). Mutations were identified by PCR and PCR-RFLP, and serum sHLA-G quantification was performed by ELISA. For the 14bp INS/DEL polymorphism, variants frequencies were similar in patients and controls, whereas a significant increased frequency of the +3142 G allele was found in MS patients compared to HD (63.4% vs 52.3%, p=0.04; OR=1.58, 95%CI=1.003-2.48). In addition, an association was found between MS susceptibility and the haplotypes regrouping both studied polymorphisms. Indeed, the 14bp DEL/+3142 G haplotype frequency was significantly increased in MS patients compared to HD (20.8% vs 12.5%, p=0.04, OR=1.84). On the other hand, no associations were detected between both polymorphisms and clinical parameters, except the lower age of disease onset (ADO) in patients with the +3142 C/C genotype. Moreover, our study doesn't show any significant variation of sHLA-G serum levels between patients and controls. Our findings showed that the +3142 C>G, but not the 14bp INS/DEL, polymorphism may constitute a genetic susceptibility factor to MS in the Tunisian population. However, no association was found between the two polymorphisms and sHLA-G serum levels.

  3. [HL-A antigens in dust allergy in children].

    PubMed

    Seignalet, J; Levallois, C; Lapinski, H; Jean, R

    1976-12-01

    The distribution of 29 HLA antigens has been compared in 60 unrelated children presenting a dust allergy and in 300 healthy controls. We observed an increased frequency for HLA-Aw19 and HLA-B5 in patients. Yet, the differences are not very significant and there is probably no association between one HLA gene and the dust allergy.

  4. Age-dependent HLA profiles of the Israeli population: impact on hematopoietic cell donor recruitment and availability.

    PubMed

    Israeli, Moshe; Oudshoorn, Machteld; Haasnoot, Geert W; Klein, Tirza; Zisser, Bracha; Bach, Gideon; Claas, Frans H J

    2014-10-01

    Approximately three million people have immigrated to the state of Israel since it was founded. Consequently, the immunogenetic profile of the younger generation may consist of a genetic mixture of formerly distinct population groups. We aimed to investigate whether HLA profiles in the Israeli population are age dependent and how this influences representation of various age groups in local donor registries. We determined HLA-A*, HLA-B*, and HLA-DRB1* low-resolution phenotypes of three age groups (n = 4,169 in each): (1) cord blood units collected between 2009 and 2013 (BABIES) and adult registry donors (2) aged 18-28 years (YOUNG) and (3) aged 49-60 years (OLD). We compared the results with virtual groups that simulate the offspring of the actual study groups. None of the three actual age groups were in Hardy-Weinberg equilibrium. The YOUNG presented four HLA-B alleles that were absent in the OLD and BABIES. A significantly higher percentage among the OLD and BABIES had a "matched" individual within their group in comparison to the YOUNG. In the YOUNG, the 10 most common haplotypes account for 16.7 % of the population, in comparison to 18.2 % in the OLD or 19.8 % in the BABIES group. The BABIES group was genetically remote from all other groups. Further disparities were found between the actual and the corresponding virtual groups. We conclude that discrete age groups in Israel present distinct immunogenetic profiles, where the younger generation is more heterogeneous. The population dynamics of the age-dependent HLA profile is multifactorial: gradual intersubgroup admixture, nonrandom mating, and entry of new alleles.

  5. Prevalence of High-Risk Human Papillomavirus Among Older Women

    PubMed Central

    Lindau, Stacy Tessler; Drum, Melinda L.; Gaumer, Elyzabeth; Surawska, Hanna; Jordan, Jeanne A.

    2009-01-01

    Objective To estimate the prevalence, genotypes, and individual-level correlates of high-risk human papillomavirus (HPV) among women aged 57–85. Methods Community-residing women (n=1550), aged 57–85, were drawn from a nationally-representative probability sample. In-home interviews and biomeasures, including a self-collected vaginal specimen, were obtained between 2005 and 2006. Specimens were analyzed for high-risk HPV DNA using probe hybridization and signal amplification (hc2); of 1,028 specimens provided, 1,010 were adequate for analysis. All samples testing positive were analyzed for HPV DNA by L1 consensus polymerase chain reaction followed by type-specific hybridization. Results The overall population-based weighted estimate of high-risk HPV prevalence by hc2 was 6.0% (95% confidence interval [CI] = 4.5 to 7.9). Current marital and smoking status, frequency of sexual activity, history of cancer, and hysterectomy were associated with high-risk HPV positivity. Among high-risk HPV+ women, 63% had multiple type infections. HPV 16 or 18 was present in 17.4% of all high-risk HPV+ women. The most common high-risk genotypes among high-risk HPV+ women were HPV 61 (19.1%), 31 (13.1%), 52 (12.9%), 58 (12.5%), 83 (12.3%), 66(12.0%), 51 (11.7%), 45 (11.2%), 56 (10.3%), 53 (10.2%), 16 (9.7%), and 62 (9.2%). Being married and having an intact uterus were independently associated with lower prevalence of high-risk HPV. Among unmarried women, current sexual activity and smoking were independently and positively associated with high-risk HPV infection. Conclusions In this nationally representative population, nearly 1 in 16 women aged 57–85 were found to have high-risk HPV and prevalence was stable across older age groups. PMID:18978096

  6. Derivation of HLA types from shotgun sequence datasets.

    PubMed

    Warren, René L; Choe, Gina; Freeman, Douglas J; Castellarin, Mauro; Munro, Sarah; Moore, Richard; Holt, Robert A

    2012-01-01

    The human leukocyte antigen (HLA) is key to many aspects of human physiology and medicine. All current sequence-based HLA typing methodologies are targeted approaches requiring the amplification of specific HLA gene segments. Whole genome, exome and transcriptome shotgun sequencing can generate prodigious data but due to the complexity of HLA loci these data have not been immediately informative regarding HLA genotype. We describe HLAminer, a computational method for identifying HLA alleles directly from shotgun sequence datasets (http://www.bcgsc.ca/platform/bioinfo/software/hlaminer). This approach circumvents the additional time and cost of generating HLA-specific data and capitalizes on the increasing accessibility and affordability of massively parallel sequencing.

  7. HLA-DQBl*0402 alleles polymorphisms detected in Javanese HIV patients with positive anti-Toxoplasma gondii IgM

    NASA Astrophysics Data System (ADS)

    Sari, Yulia; Haryati, Sri; Prasetyo, Afiono Agung; Hartono, Adnan, Zainal Arifin

    2017-02-01

    The human leukocyte antigen (HLA)-DQB1 gene polymorphisms may associated with the infection risk of Toxoplasma gondii in HIV patients. The HLA-DQB1*0402 in HIV-1-positive patients could be considered risk factors for developing neurological opportunistic infections, mainly Toxoplasma encephalitis. However, the HLA-DQB1*0402 gene polymorphisms status in the Javanese HIV patients is unknown. This study evaluated the prevalence of HLA-DQB*0402 alleles polymorphisms in Javanese HIV patients with positive anti-Toxoplasma gondii IgM status. Since 2009 our research group performing a molecular epidemiology of blood borne viruses in Central Java Indonesia, by collecting the epidemiological and clinical data from the high risk communities. All blood samples were screened for blood borne pathogens by serological and molecular assays including for HIV and Toxoplasma gondii. The genomic DNA was isolated from the whole blood samples. Genetic polymorphisms of HLA-DQB1*0402 alleles were detected with polymerase chain reaction-sequence-specific primers (PCR-SSPs) technique. The genotypes were defined according to generated fragment patterns in the agarose gel electrophoresis analysis of PCR products. All of the samples were tested at least in duplicate. HLA-DQB1*0402 alleles were detected in 20.8% (16/77) patients and not detected in all HIV positive samples with negative anti-Toxoplasma gondii IgM status (n= 200). The HLA-DQB1*0402 alleles polymorphisms were detected in Javanese HIV patients with positive anti-Toxoplasma gondii IgM. The polymorphisms found may have association with the infection risk of Toxoplasma gondii in HIV patients.

  8. Coding variants at hexa-allelic amino acid 13 of HLA-DRB1 explain independent SNP associations with follicular lymphoma risk.

    PubMed

    Foo, Jia Nee; Smedby, Karin E; Akers, Nicholas K; Berglund, Mattias; Irwan, Ishak D; Jia, Xiaoming; Li, Yi; Conde, Lucia; Darabi, Hatef; Bracci, Paige M; Melbye, Mads; Adami, Hans-Olov; Glimelius, Bengt; Khor, Chiea Chuen; Hjalgrim, Henrik; Padyukov, Leonid; Humphreys, Keith; Enblad, Gunilla; Skibola, Christine F; de Bakker, Paul I W; Liu, Jianjun

    2013-07-11

    Non-Hodgkin lymphoma represents a diverse group of blood malignancies, of which follicular lymphoma (FL) is a common subtype. Previous genome-wide association studies (GWASs) have identified in the human leukocyte antigen (HLA) class II region multiple independent SNPs that are significantly associated with FL risk. To dissect these signals and determine whether coding variants in HLA genes are responsible for the associations, we conducted imputation, HLA typing, and sequencing in three independent populations for a total of 689 cases and 2,446 controls. We identified a hexa-allelic amino acid polymorphism at position 13 of the HLA-DR beta chain that showed the strongest association with FL within the major histocompatibility complex (MHC) region (multiallelic p = 2.3 × 10⁻¹⁵). Out of six possible amino acids that occurred at that position within the population, we classified two as high risk (Tyr and Phe), two as low risk (Ser and Arg), and two as moderate risk (His and Gly). There was a 4.2-fold difference in risk (95% confidence interval = 2.9-6.1) between subjects carrying two alleles encoding high-risk amino acids and those carrying two alleles encoding low-risk amino acids (p = 1.01 × 10⁻¹⁴). This coding variant might explain the complex SNP associations identified by GWASs and suggests a common HLA-DR antigen-driven mechanism for the pathogenesis of FL and rheumatoid arthritis.

  9. HLA-DRB and -DQB1 polymorphism in the Macedonian population.

    PubMed

    Hristova-Dimceva, A; Verduijn, W; Schipper, R F; Schreuder, G M

    2000-01-01

    HLA-DRB1, DRB3/4/5 and DQB1 polymorphism has been studied in a population of 80 unrelated healthy Macedonians using molecular methods. Twenty-five different DRB1 alleles were identified of which DRB1*1104, *1501, *1601, and *1101 were found most frequently. Among the 15 identified DQB1 alleles, two were predominant: DQB1*0301 and *0502. The most frequent three-locus haplotypes were DRB1*1104-DRB3*02-DQB1*0301 (18%/), DRB1*1101-DRB3*02-DQB1*0301 (9%) and DRB1*1601-DRB5*02-DQB1*0502 (10%). Polymorphism for DRB1*04, *13 and *15 haplotypes was extensive. Eleven different DR2-related haplotypes were found, some of which were unusual for European populations: DRB1*1501-DRB5*0102-DQB1*0502, DRB1*1501-DRB5*02-DQB1*0502, DRB1*1501-DRB5*0102-DQB1*0601.

  10. Sequence-based definition of eight short tandem repeat loci located within the HLA-region in an Austrian population.

    PubMed

    Dauber, Eva-Maria; Wenda, Sabine; Schwartz-Jungl, Elisabeth Maria; Glock, Barbara; Mayr, Wolfgang R

    2015-01-01

    Sequenced allelic ladders are a prerequisite for reliable genotyping of short tandem repeat (STR) polymorphisms and consistent results across instrument platforms. For eight STR-loci located on the short arm of chromosome 6 (6p21.3), a sequenced based nomenclature was established according to international recommendations. Publicly available reference DNA samples were sequenced enabling interested laboratories to construct their own allelic ladders. Three tetrameric (D6S2691, D6S2678, DQIV), one trimeric (D6S2906) and four dimeric repeat loci (D6S2972, D6S2792, D6S2789, D6S273) were investigated. Apart from the very complex sequence structure at the DQIV locus, three loci showed a compound and four loci a simple repeat pattern. In the flanking regions of some loci additional single nucleotide and insertion/deletion polymorphisms occurred as well as sequence polymorphisms within the repeat region of alleles with the same length. In an Austrian Caucasoid population sample (n=293) between eight and 22 alleles were found. No significant deviation from Hardy-Weinberg expectations was observed, the power of discrimination ranged from 0.826 to 0.978. The loci cover the HLA-coding region from HLA-A to HLA-DQB1 and can be used for a better definition of HLA haplotypes for population and disease association studies, recombination point mapping, haematopoietic stem cell transplantation as well as for identity and relationship testing.

  11. HLA A/B recombination in a white woman with the S-s-phenotype of the MNS system.

    PubMed

    Salaru, N N

    1995-01-01

    In cases of disputed parentage, the possibility of simultaneous occurrence of rare events in the population must be considered. PURPOSE--To report a case in which HLA-A/B recombination and homozygosity of a silent allele, typical of Negroes, in an individual apparently without this miscegenation were coexistent. METHODS--Alleged father, mother and dizygotic twin children were racially classified according to their apparent somatic characters. Blood group genetic markers of ABO, Rh, MNS, Kell, Duffy, HLA-A, -B systems were phenotyped; mother's HLA genotyping was performed by her parents test. RESULTS--The phenotype of the White mother, in the MNS system, was M+; N-; S-; s-. Alleged father and both twins were phenotipically compatible. The assumed maternity relating to both children was possible if mother presented an HLA-A/B recombination. CONCLUSION--In miscegenated populations, the breakup between ethnical appearance and blood group markers is foreseeable. Allele/haplotypic frequencies of these populations should be estimated. Casuistically, the association of events with low frequency in the population can be the cause of apparent exclusions of parentage.

  12. A Prevention Program for Middle-School High Risk Youth.

    ERIC Educational Resources Information Center

    Gittman, Elizabeth; Cassata, Marian

    A 5-year federally funded substance abuse prevention program targeted 426 high risk middle-school youth from 4 school districts in Nassau County, New York. Combining a child-centered model with a systemic approach, the program's goal was to prevent or delay the onset of alcohol and other drug use. High-risk youth were identified by school…

  13. Serving Teenage Mothers and Their High-Risk Infants

    ERIC Educational Resources Information Center

    Levenson, Phyllis; And Others

    1978-01-01

    Describes the program of the Demonstration and Training Center for High Risk or Mentally Retarded Infants of Teenage Mothers (ITAM), which aims at providing stimulation to the high-risk infant in order to enhance his/her development, and to offer educational and supportive programs for the teenage mother. (CM)

  14. 40 CFR 35.6790 - High risk recipients.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 1 2010-07-01 2010-07-01 false High risk recipients. 35.6790 Section 35.6790 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GRANTS AND OTHER FEDERAL ASSISTANCE... Actions Other Administrative Requirements for Cooperative Agreements § 35.6790 High risk recipients....

  15. 15 CFR 14.14 - High risk special award conditions.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false High risk special award conditions. 14.14 Section 14.14 Commerce and Foreign Trade Office of the Secretary of Commerce UNIFORM...-PROFIT, AND COMMERCIAL ORGANIZATIONS Pre-Award Requirements § 14.14 High risk special award...

  16. Influence of the HLA characteristics of Italian patients on donor search outcome in unrelated hematopoietic stem cell transplantation.

    PubMed

    Testi, M; Andreani, M; Locatelli, F; Arcese, W; Troiano, M; Battarra, M; Gaziev, J; Lucarelli, G

    2014-08-01

    The information regarding the probability of finding a matched unrelated donor (MUD) within a relatively short time is crucial for the success of hematopoietic stem cell transplantation (HSCT), particularly in patients with malignancies. In this study, we retrospectively analyzed 315 Italian patients who started a search for a MUD, in order to assess the distribution of human leukocyte antigen (HLA) alleles and haplotypes in this population of patients and to evaluate the probability of finding a donor. Comparing two groups of patients based on whether or not a 10/10 HLA-matched donor was available, we found that patients who had a fully-matched MUD possessed at least one frequent haplotype more often than the others (45.6% vs 14.3%; P = 0.000003). In addition, analysis of data pertaining to the HLA class I alleles distribution showed that, in the first group of patients, less common alleles were under-represented (20.2% vs 40.0%; P = 0.006). Therefore, the presence of less frequent alleles represents a negative factor for the search for a potential compatible donor being successful, whereas the presence of one frequent haplotype represents a positive predictive factor. Antigenic differences between patient and donor observed at C and DQB1 loci, were mostly represented by particular B/C or DRB1/DQB1 allelic associations. Thus, having a particular B or DRB1 allele, linked to multiple C or DQB1 alleles, respectively, might be considered to be associated with a lower probability of a successful search. Taken together, these data may help determine in advance the probability of finding a suitable unrelated donor for an Italian patient.

  17. Systemic Immunomodulatory Strategies in High-risk Corneal Transplantation

    PubMed Central

    Abud, Tulio B.; Di Zazzo, Antonio; Kheirkhah, Ahmad; Dana, Reza

    2017-01-01

    The cornea is the most commonly transplanted tissue in the body. Although corneal grafts generally have high success rates, transplantation onto inflamed and vascularized host beds, or so-called high-risk corneal transplantation, has a high rate of graft rejection. The management of this high-risk corneal transplantation is challenging and involves numerous measures. One of the key measures to prevent graft rejection in these cases is the use of systemic immunosuppressive agents. In this article, we will review the systemic immunosuppressive agents most commonly used for high-risk corneal transplantation, which include corticosteroids, cysclosporine A, tacrolimus, mycophenolate mofetil, and rapamycin. Benefits, risks, and published data on the use of these medications for high-risk corneal transplantation will be detailed. We will also summarize novel immunoregulatory approaches that may be used to prevent graft rejection in high-risk corneal transplantation. PMID:28299010

  18. Systemic Immunomodulatory Strategies in High-risk Corneal Transplantation.

    PubMed

    Abud, Tulio B; Di Zazzo, Antonio; Kheirkhah, Ahmad; Dana, Reza

    2017-01-01

    The cornea is the most commonly transplanted tissue in the body. Although corneal grafts generally have high success rates, transplantation onto inflamed and vascularized host beds, or so-called high-risk corneal transplantation, has a high rate of graft rejection. The management of this high-risk corneal transplantation is challenging and involves numerous measures. One of the key measures to prevent graft rejection in these cases is the use of systemic immunosuppressive agents. In this article, we will review the systemic immunosuppressive agents most commonly used for high-risk corneal transplantation, which include corticosteroids, cysclosporine A, tacrolimus, mycophenolate mofetil, and rapamycin. Benefits, risks, and published data on the use of these medications for high-risk corneal transplantation will be detailed. We will also summarize novel immunoregulatory approaches that may be used to prevent graft rejection in high-risk corneal transplantation.

  19. The influence of HLA alleles and HBV subgenotyes on the outcomes of HBV infections in Northeast China.

    PubMed

    Li, Xingku; Liu, Wei; Wang, Hongyan; Jin, Xi; Fang, Shaohong; Shi, Yuguang; Liu, Zhen; Zhang, Shuyun; Yang, Shufen

    2012-01-01

    Hepatitis B virus (HBV) infection has a wide variety of clinical outcomes, it could be spontaneouly recovered and also could develop fulminant liver failure or cirrhosis with hepatocellular carcinoma. Human leukocyte antigen (HLA) polymorphism and HBV (sub)genotypes have been speculated to associate with the outcome of HBV infection because the data obtained from various populations who bear different HLA alleles have shown a HLA polymorphism associated outcome of HBV infection. However, as the most important viral and host genetic factors, the impact of HBV (sub)genotypes in combination with HLA polymorphism on the clinical outcomes of HBV infections remains unclear. To demonstrate the association of HLA allele polymorphism in combination with HBV subgenotypes with the outcome of HBV infection in Northeastern Han Chinese population, a total of 230 HBV-infected individuals (Infection group) were compared to 210 random selected controls (Control group) who are negative for HBV infection for their HLA alleles frequency as well as the associations with the virus infection, clearance and persistence in combination with HBV subgenotypes. Of the 230 HBV-infected subjects, 54 were acute self-limited hepatitis (ASH) with HBV subgenotype C2 (ASH-C2), 144 were chronic hepatitis (CH) with HBV subgenotype C2 and B2 (CH-C2 and CH-B2), and 32 were spontaneously recovered (SR) without subgenotype results. When two groups are compared, the results suggest that B*48, B*51 and DRB1*12 carrier may have a high risk for HBV infection, but B*51 is likely association with spontaneous recovery and DRB1*07, 12 may be implied in viral persistence. HLA-B*15, DRB1*11 and 14 associated with viral clearance in the cases of HBV-C2 infection; HLA-B*54 carriers in chronic group are more sensitive to with the infection of HBV subgenotype B2; HLA-B*07 and DRB1*13 may protect subjects from HBV infection. The data presented a link between HLA polymorphism and HBV pathogenesis and suggested potential

  20. [Analysis and application of haplotype in forensic medicine].

    PubMed

    Ye, Yi; Luo, Hai-Bo; Hou, Yi-Ping

    2009-04-01

    Haplotype is a lineable combination of alleles at multiple loci that are transmitted together on chromosome or mitochondrion. In October 2002, the international HapMap project started and aimed at mapping the haplotype blocks of human being and discovering the Tag SNPs by determining the DNA sequence variation patterns, variation frequency and their relationship. This review summarizes the formation and distribution of the haplotype and the current three haplotype-analysis methods including the methodology of experiment, the deduction from pedigrees and the statistic method. When an allele linkage disequilibrium occurs, the genetic probability would be evaluated by haplotype. The importance of haplotype has been recognized and its application has been gradually increased in forensic sciences. The current focus on haplotype study in forensic science involves Chromosome Y, Mitochondrial DNA and Chromosome X, which are useful supplements of genetic marks.

  1. Very high risk localized prostate cancer: definition and outcomes

    PubMed Central

    Sundi, Debasish; Wang, Vinson M.; Pierorazio, Phillip M.; Han, Misop; Bivalacqua, Trinity J.; Ball, Mark W.; Antonarakis, Emmanuel S.; Partin, Alan W.; Schaeffer, Edward M.; Ross, Ashley E.

    2013-01-01

    Purpose Outcomes in men with NCCN high-risk prostate cancer (PCa) can vary substantially--some will have excellent cancer-specific survival, whereas others will experience early metastasis even after aggressive local treatments. Current nomograms, which yield continuous risk probabilities, do not separate high-risk PCa into distinct sub-strata. Here we derive a binary definition of very-high-risk (VHR) localized PCa to aid in risk stratification at diagnosis and selection of therapy. Materials and Methods We queried the Johns Hopkins radical prostatectomy database to identify 753 men with NCCN high-risk localized PCa (Gleason sum 8–10, PSA >20 ng/ml, or clinical stage ≥T3). 28 alternate permutations of adverse grade, stage, and cancer volume were compared by their hazard ratios for metastasis and cancer-specific mortality. VHR criteria with top-ranking hazard ratios were further evaluated by multivariable analyses and inclusion of a clinically meaningful proportion of the high-risk cohort. Results The VHR cohort was best defined by primary pattern 5 present on biopsy, or ≥5 cores with Gleason sum 8–10, or multiple NCCN high-risk features. These criteria encompassed 15.1% of the NCCN high-risk cohort. Compared to other high-risk men, VHR men were at significantly higher risk for metastasis (H.R. 2.75) and cancer-specific mortality (H.R. 3.44) (p <0.001 for both). Among high-risk men, VHR men also had significantly worse 10-year metastasis-free survival (37% vs 78%) and cancer-specific survival (62% vs 90%). Conclusions Men who meet VHR criteria form a subgroup within the current NCCN high-risk classification who have particularly poor oncologic outcomes. Use of these characteristics to distinguish VHR localized PCa may help in counseling and selection optimal candidates for multimodal treatments or clinical trials. PMID:24189998

  2. Possible Interaction Between Cigarette Smoking and HLA-DRB1 Variation in the Risk of Follicular Lymphoma.

    PubMed

    Baecklund, Fredrik; Foo, Jia-Nee; Askling, Johan; Eloranta, Sandra; Glimelius, Ingrid; Liu, Jianjun; Hjalgrim, Henrik; Rosenquist, Richard; Padyukov, Leonid; Smedby, Karin E

    2017-03-28

    Follicular lymphoma (FL) risk is strongly associated with germline genetic variation in human leukocyte antigen (HLA) class II. Cigarette smoking has been suggested to increase FL risk, primarily among women. We hypothesized that amino acids in HLA-antigen D-related β1 subunit (DRB1) interact with smoking in FL risk, as shown for rheumatoid arthritis. We analyzed 373 patients with FL and 818 controls from 2 population-based case-control studies in Sweden and Denmark (1999-2003). Haplotypes in HLA-DRB1 were imputed at amino acid positions 11, 13, 28, 30, and 70-74 (shared epitope). We estimated the relative risk of FL as odds ratios with 95% confidence intervals for different smoking status/haplotype combinations. Interaction was defined as departure from additivity of effects and quantified by the attributable proportion (AP). Relative to never-smokers carrying no shared epitope alleles, smoking was associated with the risk of FL among all subjects (for former smokers, odds ratio (OR) = 2.20, 95% confidence interval (CI): 1.10, 4.41; ORcurrent = 3.56, 95% CI: 1.60, 7.92) and women (ORformer = 2.95, 95% CI: 1.18, 7.37; ORcurrent = 5.63, 95% CI: 2.07, 15.3) carrying 2 shared epitope alleles but not among those carrying zero or 1 shared epitope allele. Smoking and shared epitope status interacted significantly as measured by AP (overall, AP = 0.6, 95% CI: 0.15, 1.0; for women, AP = 0.5, 95% CI: 0.005, 1.0). These results suggest a possible interaction between smoking and HLA-DRB1-associated antigen presentation in FL risk and provide a model to further unravel FL etiology.

  3. HLA-DRB1 and HLA-DQB1 methylation changes promote the occurrence and progression of Kazakh ESCC.

    PubMed

    Hu, Jian Ming; Li, Ling; Chen, Yun Zhao; Liu, Chunxia; Cui, Xiaobin; Yin, Liang; Yang, Lan; Zou, Hong; Pang, Lijuan; Zhao, Jin; Qi, Yan; Cao, Yuwen; Jiang, Jinfang; Liang, Weihua; Li, Feng

    2014-10-01

    Human leukocyte antigen II (HLA-II) plays an important role in host immune responses to cancer cells. Changes in gene methylation may result in aberrant expression of HLA-II, serving a key role in the pathogenesis of Kazakh esophageal squamous cell carcinoma (ESCC). We analyzed the expression level of HLA-II (HLA-DP, -DQ, and -DR) by immunohistochemistry, as well as the methylation status of HLA-DRB1 and HLA-DQB1 by MassARRAY spectrometry in Xinjiang Kazakh ESCC. Expression of HLA-II in ESCC was significantly higher than that in cancer adjacent normal (ACN) samples (P < 0.05). Decreased HLA-II expression was closely associated with later clinical stages of ESCC (P < 0.05). Hypomethylation of HLA-DRB1 and hypermethylation of HLA-DQB1 was significantly correlated with occurrence of Kazakh ESCC (P < 0.01), and mainly manifested as hypomethylation of CpG9, CpG10-11, and CpG16 in HLA-DRB1 and hypermethylation of CpG6-7 and CpG16-17 in HLA-DQB1 (P < 0.01). Moreover, hypomethylation of HLA-DQB1 CpG6-7 correlated with poor differentiation in ESCCs, whereas hypermethylation of HLA-DRB1 CpG16 and hypomethylation of HLA-DQB1 CpG16-17 were significantly associated with later stages of ESCC (P < 0.05). A significant inverse association between HLA-DRB1 CpG9 methylation and HLA-II expression was found in ESCC (P < 0.05). These findings suggest aberrant HLA-DRB1 and HLA-DQB1 methylation contributes to the aberrant expression of HLA-II. These molecular changes may influence the immune response to specific tumor epitopes, promoting the occurrence and progression of Kazakh ESCC.

  4. Identification of a new HLA-G allele, HLA-G*01:19, by cloning and phasing.

    PubMed

    Wang, W Y; Tian, W

    A new HLA-G allelic variant, HLA-G*01:19, was identified in a southern Chinese Han population by polymerase chain reaction-sequence-based typing (PCR-SBT), cloning and phasing. HLA-G*01:19 differs from HLA-G*01:04:01 by a nonsynonymous cytosine at position 99 in exon 2, resulting in amino acid change from valine to leucine at codon 34 of the mature HLA-G molecule.

  5. The Frequency of HLA-A, HLA-B, and HLA-DRB1 Alleles in Patients with Acute Lymphoblastic Leukemia in the Turkish Population: A Case-Control Study

    PubMed Central

    Patıroğlu, Türkan; Akar, H. Haluk

    2016-01-01

    We studied the frequencies of human leukocyte antigen alleles (A, B, and DRB1) in 90 patients with acute lymphoblastic leukemia (ALL) and then compared them with 126 controls in this study. Although the frequencies of the A*03 allele, the DRB1*03 allele, the DRB1*04 allele, the A*02/B*35/DRB1*13 haplotype, and homozygosity of A*02 were higher in patients (p=0.006, p=0.003, p=0.002, p=0.01, and p=0.02, respectively), the frequencies of the A*23, B*13, B*40, and DRB1*13 alleles were lower (p=0.002, p=0.07, p=0.002, and p=0.003, respectively) in patients than controls. The frequencies of the DRB1*04 and DRB1*07 alleles were higher in patients in the high-risk group and standard-risk group, respectively (p=0.009 and p=0.007, respectively). This study indicated that the frequency of the A*03 allele, the DRB1*03 allele, the DRB1*04 allele, the A*02/B*35/DRB1*13 haplotype, and A*02 homozygosity may play a predisposing role in patients with ALL in the Turkish population. The frequency of the DRB1*04 and DRB1*07 alleles may also be associated with high risk and standard risk in patients with ALL, respectively. PMID:27095065

  6. The Frequency of HLA-A, HLA-B, and HLA-DRB1 Alleles in Patients with Acute Lymphoblastic Leukemia in the Turkish Population: A Case-Control Study.

    PubMed

    Patıroğlu, Türkan; Akar, H Haluk

    2016-12-01

    We studied the frequencies of human leukocyte antigen alleles (A, B, and DRB1) in 90 patients with acute lymphoblastic leukemia (ALL) and then compared them with 126 controls in this study. Although the frequencies of the A*03 allele, the DRB1*03 allele, the DRB1*04 allele, the A*02/B*35/DRB1*13 haplotype, and homozygosity of A*02 were higher in patients (p=0.006, p=0.003, p=0.002, p=0.01, and p=0.02, respectively), the frequencies of the A*23, B*13, B*40, and DRB1*13 alleles were lower (p=0.002, p=0.07, p=0.002, and p=0.003, respectively) in patients than controls. The frequencies of the DRB1*04 and DRB1*07 alleles were higher in patients in the high-risk group and standard-risk group, respectively (p=0.009 and p=0.007, respectively). This study indicated that the frequency of the A*03 allele, the DRB1*03 allele, the DRB1*04 allele, the A*02/B*35/DRB1*13 haplotype, and A*02 homozygosity may play a predisposing role in patients with ALL in the Turkish population. The frequency of the DRB1*04 and DRB1*07 alleles may also be associated with high risk and standard risk in patients with ALL, respectively.

  7. Association of HLA class II alleles with hepatitis C virus clearance and persistence in thalassemia patients from Iran.

    PubMed

    Samimi-Rad, Katayoun; Sadeghi, Farzin; Amirzargar, Aliakbar; Eshraghian, Mohamad Reza; Alavian, Seyed-Moayed; Rahimnia, Ramin

    2015-09-01

    There is no published data on association of HLA class II alleles with clearance or persistence after acute hepatitis C virus (HCV) infection in patients from Iran. HLA DRB1, DQA1, and DQB1 alleles were determined using polymerase chain reaction amplification with sequence specific primers (PCR-SSP) on a total of 117 thalassemia patients (63 with chronic infection, and 54 with viral clearance) and 120 healthy controls. HLA-DRB1*0301 and DQA1*0501 alleles were found significantly present in patients with HCV clearance compared to those with chronic infection (P = 0.03 and P = 0.0007, respectively). By contrast, DRB1*0701, DQA1*0201, and DQB1*0602 alleles occurred significantly in those with chronic infection compared to those with viral clearance (P = 0.004, P = 0.007, and P = 0.02, respectively). As compared to the controls, DRB1*0301, DRB1*11, DQA1*0501, and DQB1*0301 alleles showed a significant decrease in chronic patients (P = 0.002, P = 0.001, P = 0.0001, and P = 0.0004, respectively). Furthermore, the haplotype frequencies of DRB1*0301, DQA1*0501, DQB1*0201, and DRB1*1101, DQA1*0501, DQB1*0301 were found significantly higher (P = 0.004 and P = 0.04, respectively) in patients with HCV clearance than those with chronic infection. By contrast, the haplotype DRB1*0701, DQA1*0201, DQB1*0201 occurred more frequently (P = 0.02) in those with chronic infection compared with those with viral clearance. These findings suggest that particular HLA alleles and related haplotypes may have an influence on the outcome of HCV infection among the Iranian patients. Some of the HLA alleles found in the Iranian patients are different from those reported elsewhere, suggesting that the immunogenetic makeup for HCV clearance or persistence may vary based on the ethnicity.

  8. Synergistic effect and VEGF/HSP70-hom haplotype analysis: relationship to prostate cancer risk and clinical outcome.

    PubMed

    Sfar, Sana; Saad, Hamadi; Mosbah, Faouzi; Chouchane, Lotfi

    2010-04-01

    Prostate cancer (PCa) is a complex disorder resulting from the combined effects of multiple environmental and genetic factors. Our previous single-locus analysis showed that VEGF and HSP70-hom polymorphisms were significantly associated with PCa susceptibility and prognosis. Both genes encoding these proteins were located on chromosome 6p21, and combining the neighboring single nucleotide polymorphisms (SNPs) into haplotypes may increase the association with the disease. Three tagging polymorphisms, the HSP70-hom 2437 T/C, the VEGF-1154 G/A, and the VEGF-634 G/C SNPs were genotyped in 101 cases and 80 controls. For the combined analysis of VEGF and HSP70-hom, we found a positive gradient in the odds ratios (ORs) related to the number of high-risk genotypes with a 3.53-fold increase of prostate carcinoma risk (OR = 3.53; p = 0.015). Furthermore, the TAG and CAG haplotypes at positions HSP70-hom, VEGF -1154 and VEGF -634 exhibited a two-fold (OR = 0.46; p = 0.014) and a seven-fold (OR = 0.14; p = 0.00005) reduction in PCa risk, respectively. Regarding PCa prognosis, the TAG haplotype had a negative association with the aggressive phenotype as defined by the histopathological grade (OR = 0.28; p = 0.006). Our findings confirm the role of at-risk haplotype across the HSP70-hom/VEGF gene cluster in determining susceptibility to PCa.

  9. Umbra's High Level Architecture (HLA) Interface

    SciTech Connect

    GOTTLIEB, ERIC JOSEPH; MCDONALD, MICHAEL J.; OPPEL III, FRED J.

    2002-04-01

    This report describes Umbra's High Level Architecture HLA library. This library serves as an interface to the Defense Simulation and Modeling Office's (DMSO) Run Time Infrastructure Next Generation Version 1.3 (RTI NG1.3) software library and enables Umbra-based models to be federated into HLA environments. The Umbra library was built to enable the modeling of robots for military and security system concept evaluation. A first application provides component technologies that ideally fit the US Army JPSD's Joint Virtual Battlespace (JVB) simulation framework for Objective Force concept analysis. In addition to describing the Umbra HLA library, the report describes general issues of integrating Umbra with RTI code and outlines ways of building models to support particular HLA simulation frameworks like the JVB.

  10. Early Molecular Stratification of High-risk Primary Biliary Cholangitis.

    PubMed

    Hardie, Claire; Green, Kile; Jopson, Laura; Millar, Ben; Innes, Barbara; Pagan, Sarah; Tiniakos, Dina; Dyson, Jessica; Haniffa, Muzlifah; Bigley, Venetia; Jones, David E; Brain, John; Walker, Lucy J

    2016-12-01

    High-risk primary biliary cholangitis (PBC), defined by inadequate response at one year to Ursodeoxycholic acid (UDCA), is associated with disease progression and liver transplantation. Stratifying high-risk patients early would facilitate improved approaches to care. Using long-term follow-up data to define risk at presentation, 6 high-risk PBC patients and 8 low-risk patients were identified from biopsy, transplant and biochemical archival records. Formalin-fixed paraffin-embedded (FFPE) liver biopsies taken at presentation were graded (Scheuer and Nakanuma scoring) and gene expression analysed using the NanoString® nCounter PanCancer Immunity 770-gene panel. Principle component analysis (PCA) demonstrated discrete gene expression clustering between controls and high- and low-risk PBC. High-risk PBC was characterised by up-regulation of genes linked to T-cell activation and apoptosis, INF-γ signalling and leukocyte migration and down-regulation of those linked to the complement pathway. CDKN1a, up-regulated in high-risk PBC, correlated with significantly increased expression of its gene product, the senescence marker p21(WAF1/Cip), by biliary epithelial cells. Our findings suggest high- and low-risk PBC are biologically different from disease outset and senescence an early feature in high-risk disease. Identification of a high-risk 'signal' early from standard FFPE tissue sections has clear clinical utility allowing for patient stratification and second-line therapeutic intervention.

  11. HLA-E polymorphism and soluble HLA-E plasma levels in chronic hepatitis B patients.

    PubMed

    Zidi, I; Laaribi, A B; Bortolotti, D; Belhadj, M; Mehri, A; Yahia, H B; Babay, W; Chaouch, H; Zidi, N; Letaief, A; Yacoub, S; Boukadida, J; Di Luca, D; Hannachi, N; Rizzo, R

    2016-03-01

    Chronic hepatitis B virus (HBV) infection occurs in association to a deregulation of immune system. Human leukocyte antigen E (HLA-E) is an immune-tolerant nonclassical HLA class I molecule that could be involved in HBV progression. To measure soluble (s) HLA-E in patients with chronic HBV hepatitis (CHB). We tested the potential association of HLA-E*01:01/01:03 A > G gene polymorphism to CHB. Our cohort consisted of 93 Tunisian CHB patients (stratified in CHB with high HBV DNA levels and CHB with low HBV DNA levels) and 245 healthy donors. Plasma sHLA-E was determined using enzyme-linked immunosorbent assay (ELISA). Genotyping was performed using polymerase chain reaction sequence-specific primer. No association between HLA-E*01:01/01:03 A > G polymorphism and HBV DNA levels in CHB patients was found. G/G genotype is less frequent in CHB patients without significance. sHLA-E is significantly enhanced in CHB patients compared with healthy controls (P = 0.0017). Stratification according to HBV DNA levels showed that CHB patients with low HBV DNA levels have higher sHLA-E levels compared with CHB patients with high HBV DNA levels. CHB patients with G/G genotype have enhanced sHLA-E levels compared with other genotypes (P = 0.037). This significant difference is maintained only for CHB women concerning G/G genotypes (P = 0.042). Finally, we reported enhanced sHLA-E in CHB patients with advanced stages of fibrosis (P = 0.032). We demonstrate, for the first time, the association of sHLA-E to CHB. Owing to the positive correlation of HLA-E*01:01/01:03 A > G polymorphism and the association of sHLA-E to advanced fibrosis stages, HLA-E could be a powerful predictor for CHB progression. Further investigations will be required to substantiate HLA-E role as a putative clinical biomarker of CHB.

  12. HLA and insulin-dependent diabetes: an overview.

    PubMed

    Svejgaard, A; Ryder, L P

    1989-01-01

    The present knowledge of the HLA system and its biological function is summarized as a basis for the subsequent discussion of the associations between this system and insulin-dependent diabetes (IDDM) and some mechanisms that may explain them. Although the serologically detectable DR determinants are still the most handy markers, there is now increasing evidence from studies of restriction enzyme fragment length polymorphism (RFLP) in IDDM that DQ determinants may play a primary role in causing susceptibility and/or resistance to this disease. Thus, it is now evident that about 90% of DR4-positive diabetics carry the DQw8 determinant present in only about 65% of DR4-positive controls. Most recently, it has been claimed that an aspartic acid in position 57 of the DQB1 (DQ-beta-1) chain confers resistance to IDDM. Although this may be true, it does not explain the disproportionate decrease of DR2 or the particularly high risk of DR3/4 heterozygotes, which is still good evidence that several HLA genes are involved. Because Class II antigens show the strongest associations, the most plausible hypothesis about the mechanism(s) involves specific presentation of as yet unknown antigenic peptides to T-helper lymphocytes, which may induced the formation of both anti-islet cell antibodies and T-cytotoxic lymphocytes capable of destroying beta cells. However, T-suppressor lymphocytes also may be involved. If this hypothesis is correct, the most urgent task is to define the antigenic peptides in question, whether they are environmental (e.g., viral) or autologous.

  13. Low T cell production of TNFα and IFNγ in ankylosing spondylitis: its relation to HLA-B27 and influence of the TNF-308 gene polymorphism

    PubMed Central

    Rudwaleit, M; Siegert, S; Yin, Z; Eick, J; Thiel, A; Radbruch, A; Sieper, J; Braun, J

    2001-01-01

    positive patients with AS and healthy HLA-B27 positive controls may contribute to the increased susceptibility of HLA-B27 positive subjects to develop AS. Preliminary genotype-phenotype correlations suggest that in HLA-B27 positive subjects TNF2 at -308 or a linked gene results in higher TNFα production and, therefore, might be a marker for a protective haplotype.

 PMID:11114280

  14. Connecting with Students to Limit High-Risk Behaviors.

    ERIC Educational Resources Information Center

    Mendler, Allen N.

    2002-01-01

    Many youth use substances and engage in other high-risk behaviors in an attempt to allay the emptiness accompanying broken belongings. Schools can play important roles in fostering connections and creating the natural high that comes from success. (Author)

  15. A Preventive Dental Program for "High Risk" Children

    ERIC Educational Resources Information Center

    Meskin, Lawrence H.; And Others

    1977-01-01

    A dental health program in an elementary school succeeded in identifying children considered to be "high risk" in oral health and, through treatment and education, significantly improved their dental health. (JD)

  16. Treating Patients with High-Risk Smoldering Myeloma

    Cancer.gov

    In this phase III clinical trial, patients with smoldering myeloma classified as high risk for progression will be randomly assigned to undergo standard observation or six 4-week courses of treatment with the drug lenalidomide.

  17. Genomic sequence of 'Candidatus Liberibacter solanacearum' haplotype C and its comparison with haplotype A and B genomes

    PubMed Central

    Haapalainen, Minna; Schott, Thomas; Thompson, Sarah M.; Smith, Grant R.; Nissinen, Anne I.; Pirhonen, Minna

    2017-01-01

    Haplotypes A and B of ‘Candidatus Liberibacter solanacearum’ (CLso) are associated with diseases of solanaceous plants, especially Zebra chip disease of potato, and haplotypes C, D and E are associated with symptoms on apiaceous plants. To date, one complete genome of haplotype B and two high quality draft genomes of haplotype A have been obtained for these unculturable bacteria using metagenomics from the psyllid vector Bactericera cockerelli. Here, we present the first genomic sequences obtained for the carrot-associated CLso. These two genomic sequences of haplotype C, FIN114 (1.24 Mbp) and FIN111 (1.20 Mbp), were obtained from carrot psyllids (Trioza apicalis) harboring CLso. Genomic comparisons between the haplotypes A, B and C revealed that the genome organization differs between these haplotypes, due to large inversions and other recombinations. Comparison of protein-coding genes indicated that the core genome of CLso consists of 885 ortholog groups, with the pan-genome consisting of 1327 ortholog groups. Twenty-seven ortholog groups are unique to CLso haplotype C, whilst 11 ortholog groups shared by the haplotypes A and B, are not found in the haplotype C. Some of these ortholog groups that are not part of the core genome may encode functions related to interactions with the different host plant and psyllid species. PMID:28158295

  18. Epistatic Interaction of ERAP1 and HLA-B in Behçet Disease: A Replication Study in the Spanish Population

    PubMed Central

    Conde-Jaldón, Marta; Montes-Cano, Marco Antonio; García-Lozano, José Raul; Ortiz-Fernández, Lourdes; Ortego-Centeno, Norberto; González-León, Rocío; Espinosa, Gerard; Graña-Gil, Genaro; Sánchez-Bursón, Juan; González-Gay, Miguel Angel; Barnosi-Marín, Ana Celia; Solans, Roser; Fanlo, Patricia; Carballeira, Mónica Rodríguez; Camps, Teresa; Castañeda, Santos; Martín, Javier; González-Escribano, María Francisca

    2014-01-01

    Behçet's disease (BD) is a multifactorial disorder associated with the HLA region. Recently, the ERAP1 gene has been proposed as a susceptibility locus with a recessive model and with epistatic interaction with HLA-B51. ERAP1 trims peptides in the endoplasmic reticulum to optimize their length for MHC-I binding. Polymorphisms in this gene have been related with the susceptibility to other immune-mediated diseases associated to HLA class I. Our aim was, the replication in the Spanish population of the association described in the Turkish population between ERAP1 (rs17482078) and BD. Additionally, in order to improve the understanding of this association we analyzed four additional SNPs (rs27044, rs10050860, rs30187 and rs2287987) associated with other diseases related to HLA class I and the haplotype blocks in this gene region. According to our results, frequencies of the homozygous genotypes for the minor alleles of all the SNPs were increased among patients and the OR values were higher in the subgroup of patients with the HLA-B risk factors, although differences were not statistically significant. Moreover, the presence of the same mutation in both chromosomes increased the OR values from 4.51 to 10.72 in individuals carrying the HLA-B risk factors. Therefore, although they were not statistically significant, our data were consistent with an association between ERAP1 and BD as well as with an epistatic interaction between ERAP1 and HLA-B in the Spanish population. PMID:25019531

  19. The HLA-A, -B and -DRB1 polymorphism in a large dataset of South Brazil bone marrow donors from Rio Grande do Sul.

    PubMed

    Boquett, J A; Nunes, J M; Buhler, S; de Oliveira, M Z; Jobim, L F; Jobim, M; Fagundes, N J R; Schüler-Faccini, L; Sanchez-Mazas, A

    2017-01-01

    Human leukocyte antigen (HLA) genes are very informative in population genetics studies and their variability has been widely used to reconstruct the history of geographic and/or demographic expansions of human populations. The characterization of HLA diversity at the population level is also fundamental in clinical studies, particularly for bone marrow transplantation programs. In this study, we investigated the HLA molecular variation in Rio Grande do Sul, South Brazil, in order to identify possible regional differences across this state. More than 97,000 bone marrow donors were typed at the HLA- A, -B and -DRB1 loci and analyzed by considering two kinds of subdivisions based on both self-identified ethnicity and place of residence: (a) the official geographic subdivision defined by the Brazilian Institute of Geography and Statistics and (b) known information about the colonization history of the state. HLA allele and haplotype frequencies were estimated and compared among the defined subgroups. The results indicate a lack of correlation between genetic variation and geography and thus no clear HLA genetic structure based on geographic criteria. On the other hand, major differences were observed regarding ethnicity. In addition, local populations from Rio Grande do Sul were found to be genetically similar to their corresponding parental European populations from Germany, Italy and Portugal, as documented by historical data. Overall, this study provides a thorough characterization of the HLA genetic variation in Rio Grande do Sul and a better understanding of its demographic history, being most useful for the development of more efficient strategies in bone marrow donors' recruitment.

  20. Immunomodulation by imiquimod in patients with high-risk primary melanoma

    PubMed Central

    Narayan, Rupa; Nguyen, Hong; Bentow, Jason J.; Moy, Lauren; Lee, Diana K.; Greger, Stephanie; Haskell, Jacquelyn; Vanchinathan, Veena; Chang, Pei-Lin; Tsui, Shanli; Konishi, Tamiko; Comin-Anduix, Begonya; Dauphine, Christine; Vargas, Hernan I.; Economou, James S.; Ribas, Antoni; Bruhn, Kevin W.; Craft, Noah

    2011-01-01

    Imiquimod is a synthetic Toll-like receptor 7 (TLR7) agonist approved for the topical treatment of actinic keratoses, superficial basal cell carcinoma, and genital warts. Imiquimod leads to an 80–100% cure rate of lentigo maligna, but studies of invasive melanoma are lacking. We conducted a pilot study to characterize the local, regional, and systemic immune responses induced by imiquimod in patients with high-risk melanoma. After treatment of the primary melanoma biopsy site with placebo or imiquimod cream, we measured immune responses in the treated skin, sentinel lymph nodes (SLN), and peripheral blood. Treatment of primary melanomas with 5% imiquimod cream was associated with an increase in both CD4+ and CD8+ T cells in the skin, and CD4+ T cells in the SLN. Most of the CD8+ T cells in the skin were CD25 negative. We could not detect any increases in CD8+ T cells specifically recognizing HLA-A*0201-restricted melanoma epitopes in the peripheral blood. The findings from this small pilot study demonstrate that topical imiquimod treatment results in enhanced local and regional T cell numbers in both the skin and SLN. Further research into TLR7 immunomodulating pathways as a basis for effective immunotherapy against melanoma in conjunction with surgery is warranted. PMID:21850019

  1. ALTERNATIVE DONORS EXTEND TRANSPLANTATION FOR PATIENTS WITH LYMPHOMA WHO LACK AN HLA MATCHED DONOR

    PubMed Central

    Bachanova, Veronika; Burns, Linda J.; Wang, Tao; Carreras, Jeanette; Gale, Robert Peter; Wiernik, Peter H.; Ballen, Karen K.; Wirk, Baldeep; Munker, Reinhold; Rizzieri, David A.; Chen, Yi-Bin; Gibson, John; Akpek, Görgün; Costa, Luciano J.; Kamble, Rammurti T.; Aljurf, Mahmoud D.; Hsu, Jack W.; Cairo, Mitchell S.; Schouten, Harry C.; Bacher, Ulrike; Savani, Bipin N.; Wingard, John R.; Lazarus, Hillard M.; Laport, Ginna G.; Montoto, Silvia; Maloney, David G.; Smith, Sonali M.; Brunstein, Claudio; Saber, Wael

    2015-01-01

    Alternative donor transplantation is increasingly used for high risk lymphoma patients. We analyzed 1593 transplant recipients (2000 to 2010) and compared transplant outcomes in recipients of 8/8 allele human leukocyte antigen (HLA)-A, -B, -C, and DRB1 matched unrelated donors (MUD; n=1176), 7/8 allele HLA-matched unrelated donors (MMUD; n=275) and umbilical cord blood donors (1 or 2 units UCB; n=142). Adjusted 3-year non-relapse mortality of MMUD (44%) was higher as compared to MUD (35%; p=0.004), but similar to UCB recipients (37%; p=0.19), although UCB had lower rates of neutrophil and platelet recovery compared to unrelated donor groups. With a median follow-up of 55 months, 3-year adjusted cumulative incidence of relapse was lower after MMUD compared with MUD (25% vs 33%, p=0.003) but similar between UCB and MUD (30% vs 33%; p=0.48). In multivariate analysis UCB recipients had lower risks of acute and chronic graft versus host disease compared with adult donor groups (UCB vs MUD: HR=0.68, p=0.05; HR=0.35; p<0.001). Adjusted 3-year overall survival was comparable (43% MUD, 37% MMUD and 41% UCB). Data highlight that patients with lymphoma have acceptable survival after alternative donor transplantation. MMUD and UCB can expand the curative potential of allotransplant to patients who lack suitable HLA-matched sibling or MUD. PMID:25402415

  2. iHAP – integrated haplotype analysis pipeline for characterizing the haplotype structure of genes

    PubMed Central

    Song, Chun Meng; Yeo, Boon Huat; Tantoso, Erwin; Yang, Yuchen; Lim, Yun Ping; Li, Kuo-Bin; Rajagopal, Gunaretnam

    2006-01-01

    Background The advent of genotype data from large-scale efforts that catalog the genetic variants of different populations have given rise to new avenues for multifactorial disease association studies. Recent work shows that genotype data from the International HapMap Project have a high degree of transferability to the wider population. This implies that the design of genotyping studies on local populations may be facilitated through inferences drawn from information contained in HapMap populations. Results To facilitate analysis of HapMap data for characterizing the haplotype structure of genes or any chromosomal regions, we have developed an integrated web-based resource, iHAP. In addition to incorporating genotype and haplotype data from the International HapMap Project and gene information from the UCSC Genome Browser Database, iHAP also provides capabilities for inferring haplotype blocks and selecting tag SNPs that are representative of haplotype patterns. These include block partitioning algorithms, block definitions, tag SNP definitions, as well as SNPs to be "force included" as tags. Based on the parameters defined at the input stage, iHAP performs on-the-fly analysis and displays the result graphically as a webpage. To facilitate analysis, intermediate and final result files can be downloaded. Conclusion The iHAP resource, available at , provides a convenient yet flexible approach for the user community to analyze HapMap data and identify candidate targets for genotyping studies. PMID:17137522

  3. High-resolution genotyping of HLA-DQA1 in the GoKinD study and identification of novel alleles HLA-DQA1*040102, HLA-DQA1*0402 and HLA-DQA1*0404.

    PubMed

    Cordovado, S K; Hancock, L N; Simone, A E; Hendrix, M; Mueller, P W

    2005-05-01

    In order to achieve high-resolution HLA-DQA1 genotyping, it is necessary to identify polymorphisms in exons 1, 2 and 3. We present a high-resolution sequence-based typing (SBT) strategy for genotyping exons 1, 2 and 3 of the polymorphic HLA-DQA1 locus. This method is an improvement upon previously presented methods, because it utilizes the minimum number of SSP-PCR assays to obtain clear DNA sequence in both the forward and reverse directions of all three exons. All known HLA-DQA1 alleles are resolved with the exception of HLA-DQA1*010101 and HLA-DQA1*010102 for which the distinguishing polymorphism is located in exon 4 and does not result in an amino acid change. This method has enabled our laboratory to identify three new HLA-DQA1 alleles - HLA-DQA1*040102, HLA- DQA1*0402 and HLA-DQA1*0404 - in the Genetics of Kidneys in Diabetes (GoKinD) study population. Additionally, we present single-allele amplification methods, which identify the coding sequences of HLA-DQA1 exons 1, 2, 3, intron 2 and 300 bp of the HLA-DQA1 promoter (QAP). This study, also describes the QAP for most of the known HLA-DQA1 alleles, three HLA-DQA2 promoter sequences and the intron 2 sequences for HLA-DQA1*040101, HLA-DQA1*040102, HLA-DQA1*0402 and HLA-DQA1*0404.

  4. A large population-based association study between HLA and KIR genotypes and measles vaccine antibody responses

    PubMed Central

    Ovsyannikova, Inna G.; Schaid, Daniel J.; Larrabee, Beth R.; Haralambieva, Iana H.; Kennedy, Richard B.; Poland, Gregory A.

    2017-01-01

    Human antibody response to measles vaccine is highly variable in the population. Host genes contribute to inter-individual antibody response variation. The killer cell immunoglobulin-like receptors (KIR) are recognized to interact with HLA molecules and possibly influence humoral immune response to viral antigens. To expand on and improve our previous work with HLA genes, and to explore the genetic contribution of KIR genes to the inter-individual variability in measles vaccine-induced antibody responses, we performed a large population-based study in 2,506 healthy immunized subjects (ages 11 to 41 years) to identify HLA and KIR associations with measles vaccine-induced neutralizing antibodies. After correcting for the large number of statistical tests of allele effects on measles-specific neutralizing antibody titers, no statistically significant associations were found for either HLA or KIR loci. However, suggestive associations worthy of follow-up in other cohorts include B*57:01, DQB1*06:02, and DRB1*15:05 alleles. Specifically, the B*57:01 allele (1,040 mIU/mL; p = 0.0002) was suggestive of an association with lower measles antibody titer. In contrast, the DQB1*06:02 (1,349 mIU/mL; p = 0.0004) and DRB1*15:05 (2,547 mIU/mL; p = 0.0004) alleles were suggestive of an association with higher measles antibodies. Notably, the associations with KIR genotypes were strongly nonsignificant, suggesting that KIR loci in terms of copy number and haplotypes are not likely to play a major role in antibody response to measles vaccination. These findings refine our knowledge of the role of HLA and KIR alleles in measles vaccine-induced immunity. PMID:28158231

  5. Genomic evolution in domestic cattle: ancestral haplotypes and healthy beef.

    PubMed

    Williamson, Joseph F; Steele, Edward J; Lester, Susan; Kalai, Oscar; Millman, John A; Wolrige, Lindsay; Bayard, Dominic; McLure, Craig; Dawkins, Roger L

    2011-05-01

    We have identified numerous Ancestral Haplotypes encoding a 14-Mb region of Bota C19. Three are frequent in Simmental, Angus and Wagyu and have been conserved since common progenitor populations. Others are more relevant to the differences between these 3 breeds including fat content and distribution in muscle. SREBF1 and Growth Hormone, which have been implicated in the production of healthy beef, are included within these haplotypes. However, we conclude that alleles at these 2 loci are less important than other sequences within the haplotypes. Identification of breeds and hybrids is improved by using haplotypes rather than individual alleles.

  6. Bayesian Modeling of Haplotype Effects in Multiparent Populations

    PubMed Central

    Zhang, Zhaojun; Wang, Wei; Valdar, William

    2014-01-01

    A general Bayesian model, Diploffect, is described for estimating the effects of founder haplotypes at quantitative trait loci (QTL) detected in multiparental genetic populations; such populations include the Collaborative Cross (CC), Heterogeneous Socks (HS), and many others for which local genetic variation is well described by an underlying, usually probabilistically inferred, haplotype mosaic. Our aim is to provide a framework for coherent estimation of haplotype and diplotype (haplotype pair) effects that takes into account the following: uncertainty in haplotype composition for each individual; uncertainty arising from small sample sizes and infrequently observed haplotype combinations; possible effects of dominance (for noninbred subjects); genetic background; and that provides a means to incorporate data that may be incomplete or has a hierarchical structure. Using the results of a probabilistic haplotype reconstruction as prior information, we obtain posterior distributions at the QTL for both haplotype effects and haplotype composition. Two alternative computational approaches are supplied: a Markov chain Monte Carlo sampler and a procedure based on importance sampling of integrated nested Laplace approximations. Using simulations of QTL in the incipient CC (pre-CC) and Northport HS populations, we compare the accuracy of Diploffect, approximations to it, and more commonly used approaches based on Haley–Knott regression, describing trade-offs between these methods. We also estimate effects for three QTL previously identified in those populations, obtaining posterior intervals that describe how the phenotype might be affected by diplotype substitutions at the modeled locus. PMID:25236455

  7. Early identification of renal transplant recipients with high risk of polyomavirus-associated nephropathy.

    PubMed

    Teutsch, K; Schweitzer, F; Knops, E; Kaiser, R; Pfister, H; Verheyen, J; Göbel, H; Cingöz, T; Di Cristanziano, V

    2015-12-01

    Polyomavirus BK (BKPyV) is ubiquitous among humans. Following primary infection, the virus remains latent predominantly in the hosts' uroepithelial cells. Up to 10 % of renal transplant recipients show a viral reactivation that can lead to polyomavirus-associated nephropathy (PyVAN). In the absence of early treatments, the risk of graft loss is up to 80 %. Monitoring viral load in urine and plasma by real-time PCR after transplantation is the most common diagnostic tool to detect viral reactivation. In the present retrospective study, BKPyV-DNA loads in urine and plasma by quantitative real-time PCR were associated with clinical data, including HLA haplotype, blood parameters and viral genotype, of 40 renal transplant recipients at the University Clinics of Cologne. Seventeen out of 329 patients screened for BKPyV from January 2009 to October 2013 were detected BKPyV positive in urine only, whereas in 23 patients the virus became additionally detectable in plasma. Among these, ten patients progressed to PyVAN. Overall, the present study showed that the detection from the third month onwards after transplantation of a first viruric episode with a median viral load of 1 × 10(8) copies/mL, followed after few days by a first viremic episode with a median viral load of >1 × 10(4) copies/mL, was strongly associated with the development of PyVAN. In conclusion, the viral load and the temporal profile of the first viruric and viremic episode post-transplantation, in combination with specific features of the host immune response, should be considered as relevant clinical determinants of the risk of renal transplant recipients to progress to PyVAN.

  8. A Comparison of Two Types of Rabbit Antithymocyte Globulin Induction Therapy in Immunological High-Risk Kidney Recipients: A Prospective Randomized Control Study

    PubMed Central

    Burkhalter, F.; Schaub, S.; Bucher, Ch.; Gürke, L.; Bachmann, A.; Hopfer, H.; Dickenmann, M.; Steiger, J.; Binet, I.

    2016-01-01

    Background Induction treatment with rabbit polyclonal antithymocyte globulins (ATGs) is frequent used in kidney transplant recipients with donorspecific HLA antibodies and shows acceptable outcomes. The two commonly used ATGs, Thymoglobulin and ATG-F have slightly different antigen profile and antibody concentrations. The two compounds have never been directly compared in a prospective trial in immunological high-risk recipients. Therefore we performed a prospective randomized controlled study comparing the two compounds in immunological high-risk kidney recipients in terms of safety and efficacy. Methods Immunological high-risk kidney recipients, defined as the presence of HLA DSA but negative CDC-B and T-cell crossmatches were randomized 1:1 to receive ATG-F or Thymoglobulin. Maintenance immunosuppressive therapy consisted of tacrolimus, mycophenolate mofetil and steroids. Results The per-protocol analysis included 35 patients. There was no immediate infusion reaction observed with both compounds. No PTLD or malignancy occurred during the follow-up in both groups. The incidence of viral and bacterial infections was similar in both groups (p = 0.62). The cumulative incidence of clinical and subclinical antibody mediated allograft rejection as well as T-cell mediated allograft rejection during the first year between ATG-F and Thymoglobulin was similar (35% versus 19%; p = 0.30 and 11% versus 18%; 0.54 respectively). The two-year graft function was similar with a median eGFR of 56 ml/min/1.73m2 (range 21–128) (ATG-F-group) and 51 ml/min/1.73m2 (range 22–132) (Thymo-group) (p = 0.69). Conclusion We found no significant differences between the compared study drugs for induction treatment in immunological high-risk patients regarding safety and efficacy during follow-up with good allograft function at 2 years after transplantation. PMID:27855166

  9. HLA-B*51 and Behçet Disease.

    PubMed

    Gul, Ahmet; Ohno, Shigeaki

    2012-02-01

    Behçet disease (BD) is a multisystem inflammatory disorder of unknown etiology. BD has a multifactorial pathogenesis, and genetics plays a critical role in the development of the disease. Association of HLA-B5/B*51 has been recognized as the strongest genetic susceptibility factor for BD discovered so far. Pathogenic role of HLA-B*51 in BD has yet to be clarified, and available data suggest that there is possibly no single mechanism associated with HLA-B*51. HLA-B*51 may accomplish its effects as a combination of different HLA class I-associated functions and/or structural properties of HLA-B*51 heavy chain. There is no evidence supporting the use of HLA-B*51 as a diagnostic or prognostic marker for BD, and more clinical data must be collected in addition to basic immunological studies to exploit the potential of HLA-B*51 as a biomarker for BD management.

  10. A gene feature enumeration approach for describing HLA allele polymorphism.

    PubMed

    Mack, Steven J

    2015-12-01

    HLA genotyping via next generation sequencing (NGS) poses challenges for the use of HLA allele names to analyze and discuss sequence polymorphism. NGS will identify many new synonymous and non-coding HLA sequence variants. Allele names identify the types of nucleotide polymorphism that define an allele (non-synonymous, synonymous and non-coding changes), but do not describe how polymorphism is distributed among the individual features (the flanking untranslated regions, exons and introns) of a gene. Further, HLA alleles cannot be named in the absence of antigen-recognition domain (ARD) encoding exons. Here, a system for describing HLA polymorphism in terms of HLA gene features (GFs) is proposed. This system enumerates the unique nucleotide sequences for each GF in an HLA gene, and records these in a GF enumeration notation that allows both more granular dissection of allele-level HLA polymorphism and the discussion and analysis of GFs in the absence of ARD-encoding exon sequences.

  11. HLA molecular markers in Tuvinians: a population with both Oriental and Caucasoid characteristics.

    PubMed

    Martinez-Laso, J; Sartakova, M; Allende, L; Konenkov, V; Moscoso, J; Silvera-Redondo, C; Pacho, A; Trapaga, J; Gomez-Casado, E; Arnaiz-Villena, A

    2001-05-01

    HLA class I and class II alleles have been studied for the first time in the Turkish-speaking Tuvinian population, which lives in Russia, North of Mongolia and close to the Altai mountains. Comparisons have been done with about 11000 chromosomes from other worldwide populations, and extended haplotypes, genetic distances, neighbor joining dendrograms and correspondence analyses have been calculated. Tuvinians show an admixture of Mongoloid and Caucasoid characters, the latter probably coming from the ancient Kyrgyz background or, less feasibly, more recent Russian Caucasoid admixture. However, Siberian population traits are not found and thus Tuvinians are closer to Central Asian populations. Siberians are more related to Na-Dene and Eskimo American Indians; Amerindians (from nowadays Iberian--America) are not related to any other group, including Pacific Islanders, Siberians or other American Indians. The 'more than one wave' model for the peopling of the Americas is supported.

  12. Effect of HLA-B and HLA-DR genes on susceptibility to and severity of spondyloarthropathies in Mexican patients

    PubMed Central

    Vargas-Alarcon, G; Londono, J; Hernandez-Pacheco, G; Pacheco-Tena, C; Castillo, E; Cardiel, M; Granados, J; Burgos-Vargas, R

    2002-01-01

    Objective: To investigate the role of HLA-B and HLA-DR genes as contributors to genetic susceptibility and clinical expression of the spondyloarthropathies (SpA) in the Mexican population. Methods: The study included 172 patients with SpA (undifferentiated SpA 83, ankylosing spondylitis (AS) 64, and reactive arthritis 25) and 99 healthy controls. The HLA-B and HLA-DR alleles were detected by the polymerase chain reaction with sequence-specific primers technique. Patient assessment included demographic data, diagnostic categories, and disease patterns. Statistical methods included the Mantel-Haenzel χ2 test, Fisher's exact test, and Woolf method for odds ratio (OR). Differences of continuous variables between HLA allele groups were calculated by Student's t test. Results: Increased frequencies of HLA-B27 (pCh10-3, OR=28.7), HLA-DR1 (pC=0.045, OR=2.77), and HLA-B15 (p=0.034, pC=NS, OR=2.04) alleles in the whole group were found. HLA-B27 strength of association (OR) was 41.4 in AS; 20.9 in undifferentiated SpA; 27.2 in reactive arthritis. HLA-DR1 and HLA-B15 were increased in undifferentiated SpA (pC=0.045, OR=2.98 and p=0.004, pC=NS, OR=2.75). By analysing 58 HLA-B27 negative patients it was found that HLA-B15 and HLA-DR1 associations with SpA were independent of HLA-B27; increased frequencies of HLA-B15 were found in the whole SpA group and in patients with undifferentiated SpA (pC=0.03, OR=3.09 and pCh0.01, OR=3.77) and of HLA-DR1 in the latter (p=0.04, pC=NS, OR=3.15). HLA-B27 positive patients were younger than HLA-B27 negative patients at onset (p=0.03), but HLA-DR1 positive patients were older than HLA-DR1 negative patients (p=0.03). Bath indices for disease activity and functioning were higher in HLA-B27 positive patients (p=0.006 and p=0.004 v HLA-B27 negative patients). In contrast, neither HLA-DR1 nor HLA-B15 influenced these indices. Conclusion: Apart from HLA-B27, there is a significant association of HLA-DR1 and HLA-B15 with SpA in Mexicans which is

  13. Haplotyping using a combination of polymerase chain reaction-single-strand conformational polymorphism analysis and haplotype-specific PCR amplification.

    PubMed

    Zhou, Huitong; Li, Shaobin; Liu, Xiu; Wang, Jiqing; Luo, Yuzhu; Hickford, Jon G H

    2014-12-01

    A single nucleotide polymorphism (SNP) may have an impact on phenotype, but it may also be influenced by multiple SNPs within a gene; hence, the haplotype or phase of multiple SNPs needs to be known. Various methods for haplotyping SNPs have been proposed, but a simple and cost-effective method is currently unavailable. Here we describe a haplotyping approach using two simple techniques: polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) and haplotype-specific PCR. In this approach, individual regions of a gene are analyzed by PCR-SSCP to identify variation that defines sub-haplotypes, and then extended haplotypes are assembled from the sub-haplotypes either directly or with the additional use of haplotype-specific PCR amplification. We demonstrate the utility of this approach by haplotyping ovine FABP4 across two variable regions that contain seven SNPs and one indel. The simplicity of this approach makes it suitable for large-scale studies and/or diagnostic screening.

  14. Influence of a latrophilin 3 (LPHN3) risk haplotype on event-related potential measures of cognitive response control in attention-deficit hyperactivity disorder (ADHD).

    PubMed

    Fallgatter, Andreas J; Ehlis, Ann-Christine; Dresler, Thomas; Reif, Andreas; Jacob, Christian P; Arcos-Burgos, Mauricio; Muenke, Maximilian; Lesch, Klaus-Peter

    2013-06-01

    Current research strategies have made great efforts to further elucidate the complex genetic architecture of attention-deficit hyperactivity disorder (ADHD). The present study examined the impact of an LPHN3 haplotype that has recently been associated with ADHD (Arcos-Burgos et al., 2010) on neural activity in a visual Go-NoGo task. Two hundred sixteen adult ADHD patients completed a Continuous Performance Test (CPT) while the ongoing EEG was simultaneously recorded. Results showed that patients carrying two copies of the LPHN3 risk haplotype (n=114) made more omission errors and had a more anterior Go-centroid of the P300 than patients carrying at least one LPHN3 non-risk haplotype (n=102). Accordingly, the NoGo-Anteriorization (NGA; topographical ERP difference of the Go- and NoGo-condition), a neurophysiological marker of prefrontal functioning, was reduced in the LPHN3 high risk group. However, in the NoGo-condition itself no marked differences attributable to the LPHN3 haplotype could be found. Our findings indicate that, within a sample of ADHD patients, the LPHN3 gene impacts behavioral and neurophysiological measures of cognitive response control. The results of our study further strengthen the concept of an LPHN3 risk haplotype for ADHD and support the usefulness of the endophenotype approach in psychiatric and psychological research.

  15. HLA class I variation controlled for genetic admixture in the Gila River Indian Community of Arizona: a model for the Paleo-Indians.

    PubMed

    Williams, R C; McAuley, J E

    1992-01-01

    The genetic distribution of the HLA class I loci is presented for 619 "full blooded" Pima and Tohono O'odham Native Americans (Pimans) in the Gila River Indian Community. Variation in the Pimans is highly restricted. There are only three polymorphic alleles at the HLA-A locus, *A2, *A24, and *A31, and only 10 alleles with a frequency greater than 0.01 at HLA-B where *Bw48 (0.187), *B35 (0.173), and the new epitope *BN21 (0.143) have the highest frequencies. Two and three locus disequilibria values and haplotype frequencies are presented. Ten three-locus haplotypes account for more than 50% of the class I variation, with *A24 *BN21 *Cw3 (0.085) having the highest frequency. Gm allotypes demonstrate that little admixture from non-Indian populations has entered the Community since the 17th century when Europeans first came to this area. As a consequence many alleles commonly found in Europeans and European Americans are efficient markers for Caucasian admixture, while the "private" Indian alleles, *BN21 and *Bw48, can be used to measure Native American admixture in Caucasian populations. It is suggested that this distribution in "full blooded" Pimans approximates that of the Paleo-Indian migrants who first entered the Americas between 20,000 and 40,000 years ago.

  16. Functional Haplotypes in Interleukin 4 Gene Associated with Periodontitis

    PubMed Central

    Mayer, Marcia Pinto Alves; Rossa, Carlos

    2017-01-01

    Chronic periodontitis (CP) is an infectious inflammatory disease that affects tooth-supporting structures and in which dental plaque bacteria, immune mechanisms and genetic predisposition play important roles. Interleukin 4 (IL-4) is a key anti-inflammatory cytokine with relevant action in imbalances in inflamed periodontal tissue. Individuals carrying the TCI/CCI genotype (S-haplotype) of the IL-4 gene are 5 times more susceptible to CP, whereas the CTI/TTD genotype (P-haplotype) confers protection against CP. Compared with the S-haplotype, subjects with the P-haplotype produce higher levels of the IL-4 protein after non-surgical periodontal therapy. The present in vitro study aimed to investigate the functionality of IL-4 haplotypes in immune cells to obtain insight into the influence of these genetic variations in regulating immune responses to CP-associated bacteria. Peripheral blood was collected from 6 subjects carrying each haplotype, and their immune cells were challenged with periodontopathogens to compare responses of the different haplotypes with regard to gene expression, protein secretion and the immunophenotype of T helper responses. We found higher IL-4 mRNA and protein levels in the P-haplotype, which also presented higher levels of anti-inflammatory cytokines. In contrast, cells from S-haplotype subjects responded with higher levels of pro-inflammatory cytokines. S-haplotype individuals exhibited significantly greater polarization toward the Th1 phenotype, whereas the P-haplotype was associated with an attenuated response to periodontopathogens, with suggestive skewing toward Th2/M2 phenotypes. In conclusion, IL-4 genetic variations associated with susceptibility to or protection against chronic periodontitis are directly associated with influencing the response of immune cells to periodontopathogens. PMID:28114408

  17. Brachytherapy boost and cancer-specific mortality in favorable high-risk versus other high-risk prostate cancer

    PubMed Central

    Muralidhar, Vinayak; Xiang, Michael; Orio, Peter F.; Martin, Neil E.; Beard, Clair J.; Feng, Felix Y.; Hoffman, Karen E.

    2016-01-01

    Purpose Recent retrospective data suggest that brachytherapy (BT) boost may confer a cancer-specific survival benefit in radiation-managed high-risk prostate cancer. We sought to determine whether this survival benefit would extend to the recently defined favorable high-risk subgroup of prostate cancer patients (T1c, Gleason 4 + 4 = 8, PSA < 10 ng/ml or T1c, Gleason 6, PSA > 20 ng/ml). Material and methods We identified 45,078 patients in the Surveillance, Epidemiology, and End Results database with cT1c-T3aN0M0 intermediate- to high-risk prostate cancer diagnosed 2004-2011 treated with external beam radiation therapy (EBRT) only or EBRT plus BT. We used multivariable competing risks regression to determine differences in the rate of prostate cancer-specific mortality (PCSM) after EBRT + BT or EBRT alone in patients with intermediate-risk, favorable high-risk, or other high-risk disease after adjusting for demographic and clinical factors. Results EBRT + BT was not associated with an improvement in 5-year PCSM compared to EBRT alone among patients with favorable high-risk disease (1.6% vs. 1.8%; adjusted hazard ratio [AHR]: 0.56; 95% confidence interval [CI]: 0.21-1.52, p = 0.258), and intermediate-risk disease (0.8% vs. 1.0%, AHR: 0.83, 95% CI: 0.59-1.16, p = 0.270). Others with high-risk disease had significantly lower 5-year PCSM when treated with EBRT + BT compared with EBRT alone (3.9% vs. 5.3%; AHR: 0.73; 95% CI: 0.55-0.95; p = 0.022). Conclusions Brachytherapy boost is associated with a decreased rate of PCSM in some men with high-risk prostate cancer but not among patients with favorable high-risk disease. Our results suggest that the recently-defined “favorable high-risk” category may be used to personalize therapy for men with high-risk disease. PMID:26985191

  18. HIFU therapy for patients with high risk prostate cancer

    NASA Astrophysics Data System (ADS)

    Solovov, V. A.; Vozdvizhenskiy, M. O.; Matysh, Y. S.

    2017-03-01

    Objectives. Patients with high-risk prostate cancer undergoing radical prostatectomy, external beam radiation therapy (EBRT) combined with androgen deprivation therapy (ADT) or ADT alone. The widely accepted definition of high-risk prostate was first proposed by D'Amico based on a pretreatment Gleason score of ≥8, clinical stage T3, PSA level ≥20 ng/mL. There is no trial that compares traditional methods of treatment of such patients with HIFU therapy. Here we explored the effectiveness of the HIFU in multimodal treatment for patients with high risk prostate cancer. Materials & Methods. 701 patients with high risk prostate cancer were treated in our center between September 2007 and December 2013. Gleason score were 8-10, stage T3N0M0, age 69 (58-86) years, mean PSA before treatment 43.3 (22.1-92.9) ng/ml, mean prostate volume - 59.3 (38-123) cc. 248 patients were treated by HIFU. We compare this group of patients with patients who undertook EBRT: number 196, and ADT: number 257. Mean follow-up time 58 months (6-72). Results. The 5-year overall survival rates in patients after HIFU were 73.8 %, after EBRT - 63.0 % and after ADT - 18.1%. Conclusions. Our experience showed that HIFU therapy in combined treatment were successful for high risk prostate cancer.

  19. Inflammatory bowel disease associations with HLA Class II genes

    SciTech Connect

    Castro, R.; Yang, H.; Targan, S.

    1994-09-01

    A PCR-SSOP assay has been used to analyze HLA-Class II DRB1 and DQB1 alleles in 378 Caucasians from a population in Southern California. The data has been analyzed separately for the Ashkenasi Jews and non-Jewish patients (n=286) and controls (n=92). Two common clinical forms of inflammatory bowel disease (IBD) have been studied: ulcerative colitis (UC) and Crohn`s disease (CD). In CD, we observed a susceptible effect with the rare DR1 allele - DRB*0103 [O.R.=4.56; 95% CI (0.96, 42.97); p=0.03]; a trend for an increase in DRB1*0103 was also observed in UC patients. A susceptible effect with DRB1*1502 [O.R.=5.20; 95% CI (1.10, 48.99); p=0.02] was observed in non-Jewish UC patients. This susceptible effect was restricted to UC ANCA-positive (antineutrophil cytoplasmic antibodies) patients. In addition, a significant association with DRB1*1101-DQB1*0301 [O.R.=9.46; 95% CI (1.30, 413.87); p=0.01] was seen with UC among non-Jewish patients: this haplotype was increased with CD among non-Jewish patients. Two protective haplotypes were detected among CD non-Jewish patients: DRB1*1301-DQB1*0603 [O.R.=0.34; 95% CI (0.09, 1.09); p=0.04], and DRB*0404-DQB1*0302 [O.R.=<0.08; 95% CI (0.0, 0.84); p=0.01]. When the same data were analyzed at the serology level, we observed a positive association in UC with DR2 [O.R.6.77; 95% CI (2.47, 22.95); p=2 x 10{sup -4}], and a positive association in CD with DR1 [O.R.=2.63; 95% CI (1.14, 6.62); p=0.01] consistent with previous reports. Thus, some IBD disease associations appear to be common to both UC and CD, while some are unique to one disease.

  20. Polymorphisms and haplotypes of the CYP2B6 detoxification gene in the predisposition of Acute Myeloid Leukemia (AML) and induction of its cytogenetic abnormalities.

    PubMed

    Daraki, Aggeliki; Kakosaiou, Katerina; Zachaki, Sophia; Sambani, Constantina; Aleporou-Marinou, Vassiliki; Kollia, Panagoula; Manola, Kalliopi N

    2016-11-01

    CYP2B6 is a polymorphic detoxification gene which plays a vital role in the degradation of genotoxic compounds. In this study we hypothesized that inadequate detoxification due to CYP2B6 polymorphisms may contribute to AML. To evaluate the potential impact of CYP2B6 polymorphisms on AML development and induction of its specific chromosomal abnormalities we studied C(777)A and A(785)G polymorphisms for the first time in AML. Furthermore, we investigated the co-existence of the above polymorphisms with G(516)T polymorphism to determine the CYP2B6 high-risk haplotypes in AML susceptibility. Our study included 619 AML patients and 430 healthy donors. Concerning C(777)A CYP2B6 polymorphism, no significant difference was found between patients and controls. However, A(785)G CYP2B6 polymorphism showed a statistically higher frequency of the variant genotypes in patients (48.2%), mainly in secondary AML patients (49.1%) than in controls (26.1%). Moreover, an increased frequency of the variant genotypes was found in those with abnormal karyotypes, especially with -7/del(7q), -5/del(5q), +8, inv(16) and t(8;21). The combination of the three CYP2B6 polymorphisms (G(516)T, C(777)A & A(785)G) revealed seven haplotypes. Four out of six haplotypes with at least one mutant allele were significantly associated with an increased risk for AML. Interestingly, T516A777G785 haplotype, where the three mutant alleles co-existed, had ~3-fold increased risk to be found in patients than controls. The association between haplotypes and cytogenetic aberrations revealed a positive correlation between specific CYP2B6 haplotypes and AML cytogenetic abnormalities. Our data suggest that A(785)G CYP2B6 gene polymorphism and specific CYP2B6 haplotypes may contribute to AML and its specific chromosomal aberrations.

  1. Association with Spontaneous Hepatitis C Viral Clearance and Genetic Differentiation of IL28B/IFNL4 Haplotypes in Populations from Mexico

    PubMed Central

    Gonzalez-Aldaco, Karina; Rebello Pinho, João R.; Roman, Sonia; Gleyzer, Ketti; Fierro, Nora A.; Oyakawa, Leticia; Ramos-Lopez, Omar; Ferraz Santana, Rubia A.; Sitnik, Roberta; Panduro, Arturo

    2016-01-01

    Aim To analyze the genetic heterogeneity of the Amerindian and admixed population (Mestizos) based on the IL28B (rs12979860, rs8099917) and IFNL4 (rs368234815) haplotypes, and their association with spontaneous clearance (SC) and liver damage in patients with hepatitis C infection from West Mexico. Methods A total of 711 subjects from West Mexico (181 Amerindians and 530 Mestizos) were studied for the prevalence of IL28B (rs12979860C/T, rs8099917G/T) and IFNL4 (rs368234815∆G/TT) genotypes. A case-control study was performed in 234 treatment-naïve HCV Mestizos (149 chronic hepatitis C and 85 with SC) for the association of haplotypes with SC and liver damage. A real-time PCR assay was used for genotyping, and transitional elastography staged liver damage. Results Significant Fst-values indicated differentiation between the studied populations. The frequencies of the protective C, T, TT alleles were significantly lower in the Amerindians than in Mestizos (p<0.05). The r2 measure of linkage disequilibrium was significant for all variants and the T/G/ΔG risk haplotype predominated in Amerindians and secondly in Mestizos. The protective C/T/TT haplotype was associated with SC (OR = 0.46, 95% IC 0.22–0.95, p = 0.03) and less liver damage (OR = 0.32, 95% IC 0.10–0.97, p = 0.04) in chronic patients. The Structure software analysis demonstrated no significant differences in ancestry among SC and chronic patients. Conclusions West Mexico´s population is genetically heterogeneous at the IL28B/IFNL4 polymorphisms. The T/G/ΔG high-risk haplotype predominated in Amerindians and the beneficial alternative haplotype in Mestizos. The C/T/TT haplotype was associated with SC and less liver damage in chronically infected Mestizo patients. PMID:26741362

  2. First report on the antibody verification of HLA-ABC epitopes recorded in the website-based HLA Epitope Registry.

    PubMed

    Duquesnoy, R J; Marrari, M; Mulder, A; Sousa, L C D da Mata; da Silva, A S; do Monte, S J H

    2014-06-01

    The International Registry of Antibody-Defined HLA Epitopes ( http://www.epregistry.com.br) has been recently established as a tool to understand humoral responses to human leukocyte antigen (HLA) mismatches. These epitopes are defined structurally by three-dimensional molecular modeling and amino acid sequence differences between HLA antigens. So-called eplets represent essential components of HLA epitopes and they are defined by polymorphic residues. A major goal is to identify HLA epitopes that have been verified experimentally with informative antibodies. Our analysis has also included data in many publications. As of 1 November 2013, 95 HLA-ABC antibody-verified epitopes have been recorded, 62 correspond to eplets and 33 are defined by eplets paired with other residue configurations. The Registry is still a work-in-progress and will become a useful resource for HLA professionals interested in histocompatibility testing at the epitope level and investigating antibody responses to HLA mismatches in transplant patients.

  3. Production of human anti-HLA monoclonal antibodies

    SciTech Connect

    Walker, M.C.; Mercier, F.; Roger, J.; Varin, M.

    1986-03-01

    Only 40% of the several hundred anti-HLA murine monoclonal antibodies (MAbs) that have been made detect HLA-A,B,C or DR specificities previously defined by human alloantisera, the range of recognized specificities is very narrow, and few of the MAbs have proven useful as tissue typing reagents. In hopes of obtaining HLA typing reagents, the authors are developing a protocol for the production of human anti-HLA MAbs from HLA-antigen (Ag) immunized peripheral blood B cells of volunteering renal patients, immunized to one or more HLA Ags through therapeutic blood transfusions. A simple enrichment of the donor B cells has not been sufficient for anti-HLA MAb production, the authors are currently delineating the conditions necessary for increasing the number of HLA-specific donor B cells by in vitro stimulation with cells expressing the HLA Ag to which the B cell donor is immunized. For the production of MAbs, the stimulated B cells are transformed with Epstein-Barr virus and subsequently fused with KR-4 lymphoblastoid cells. Hybridomas are selected by HAT and Ouabain. Supernatants are screened for anti-HLA activity against lymphocyte targets expressing the original immunizing HLA Ag by complement mediated /sup 51/Cr release assay. Antibody specificity is determined by the complement-dependent microcytotoxicity test used for HLA typing.

  4. Cloning and Sequencing the First HLA Gene

    PubMed Central

    Jordan, Bertrand R.

    2010-01-01

    This Perspectives article recounts the isolation and sequencing of the first human histocompatibility gene (HLA) in 1980–1981. At the time, general knowledge of the molecules of the immune system was already fairly extensive, and gene rearrangements in the immunoglobulin complex (discovered in 1976) had generated much excitement: HLA was quite obviously the next frontier. The author was able to use a homologous murine H-2 cDNA to identify putative human HLA genomic clones in a λ-phage library and thus to isolate and sequence the first human histocompatibility gene. This personal account relates the steps that led to this result, describes the highly competitive international environment, and highlights the role of location, connections, and sheer luck in such an achievement. It also puts this work in perspective with a short description of the current knowledge of histocompatibility genes and, finally, presents some reflections on the meaning of “discovery.” PMID:20457890

  5. HLA and non-HLA genes in Behçet’s disease: a multicentric study in the Spanish population

    PubMed Central

    2013-01-01

    Introduction According to genome wide association (GWA) studies as well as candidate gene approaches, Behçet’s disease (BD) is associated with human leukocyte antigen (HLA)-A and HLA-B gene regions. The HLA-B51 has been consistently associated with the disease, but the role of other HLA class I molecules remains controversial. Recently, variants in non-HLA genes have also been associated with BD. The aims of this study were to further investigate the influence of the HLA region in BD and to explore the relationship with non-HLA genes recently described to be associated in other populations. Methods This study included 304 BD patients and 313 ethnically matched controls. HLA-A and HLA-B low resolution typing was carried out by PCR-SSOP Luminex. Eleven tag single nucleotide polymorphisms (SNPs) located outside of the HLA-region, previously described associated with the disease in GWA studies and having a minor allele frequency in Caucasians greater than 0.15 were genotyped using TaqMan assays. Phenotypic and genotypic frequencies were estimated by direct counting and distributions were compared using the χ2 test. Results In addition to HLA-B*51, HLA-B*57 was found as a risk factor in BD, whereas, B*35 was found to be protective. Other HLA-A and B specificities were suggestive of association with the disease as risk (A*02 and A*24) or protective factors (A*03 and B*58). Regarding the non-HLA genes, the three SNPs located in IL23R and one of the SNPs in IL10 were found to be significantly associated with susceptibility to BD in our population. Conclusion Different HLA specificities are associated with Behçet’s disease in addition to B*51. Other non-HLA genes, such as IL23R and IL-10, play a role in the susceptibility to the disease. PMID:24286189

  6. Fine mapping of disease genes via haplotype clustering.

    PubMed

    Waldron, E R B; Whittaker, J C; Balding, D J

    2006-02-01

    We propose an algorithm for analysing SNP-based population association studies, which is a development of that introduced by Molitor et al. [2003: Am J Hum Genet 73:1368-1384]. It uses clustering of haplotypes to overcome the major limitations of many current haplotype-based approaches. We define a between-haplotype score that is simple, yet appears to capture much of the information about evolutionary relatedness of the haplotypes in the vicinity of a (unobserved) putative causal locus. Haplotype clusters can then be defined via a putative ancestral haplotype and a cut-off distance. The number of an individual's two haplotypes that lie within the cluster predicts the individual's genotype at the causal locus. This predicted genotype can then be investigated for association with the phenotype of interest. We implement our approach within a Markov-chain Monte Carlo algorithm that, in effect, searches over locations and ancestral haplotypes to identify large, case-rich clusters. The algorithm successfully fine-maps a causal mutation in a test analysis using real data, and achieves almost 98% accuracy in predicting the genotype at the causal locus. A simulation study indicates that the new algorithm is substantially superior to alternative approaches, and it also allows us to identify situations in which multi-point approaches can substantially improve over single-SNP analyses. Our algorithm runs quickly and there is scope for extension to a wide range of disease models and genomic scales.

  7. iXora1: exact haplotype inferencing and trait association

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: We address the task of extracting accurate haplotypes from genotype data of individuals of large F1 populations for mapping studies. While methods for inferring parental haplotype assignments on large F1 populations exist in theory, these approaches do not work in practice at high levels...

  8. Reconstruction of N-acetyltransferase 2 haplotypes using PHASE.

    PubMed

    Golka, Klaus; Blaszkewicz, Meinolf; Samimi, Mirabutaleb; Bolt, Hermann M; Selinski, Silvia

    2008-04-01

    The genotyping of N-acetyltransferase 2 (NAT2) by PCR/RFLP methods yields in a considerable percentage ambiguous results. To resolve this methodical problem a statistical approach was applied. PHASE v2.1.1, a statistical program for haplotype reconstruction was used to estimate haplotype pairs from NAT2 genotyping data, obtained by the analysis of seven single nucleotide polymorphisms relevant for Caucasians. In 1,011 out of 2,921 (35%) subjects the haplotype pairs were clearcut by the PCR/RFLP data only. For the majority of the data the applied method resulted in a multiplicity (2-4) of possible haplotype pairs. Haplotype reconstruction using PHASE v2.1.1 cleared this ambiguity in all cases but one, where an alternative haplotype pair was considered with a probability of 0.029. The estimation of the NAT2 haplotype is important because the assignment of the NAT2 alleles *12A, *12B, *12C or *13 to the rapid or slow NAT2 genotype has been discussed controversially. A clear assignment is indispensable in surveys of human bladder cancer caused by aromatic amine exposures. In conclusion, PHASE v2.1.1 software allowed an unambiguous haplotype reconstruction in 2,920 of 2,921 cases (>99.9%).

  9. Prevalent HLA Class II Alleles in Mexico City Appear to Confer Resistance to the Development of Amebic Liver Abscess.

    PubMed

    Hernández, Eric G; Granados, Julio; Partida-Rodríguez, Oswaldo; Valenzuela, Olivia; Rascón, Edgar; Magaña, Ulises; Escamilla-Tilch, Mónica; López-Reyes, Alberto; Nieves-Ramírez, Miriam; González, Enrique; Morán, Patricia; Rojas, Liliana; Valadez, Alicia; Luna, Alexandra; Estrada, Francisco J; Maldonado, Carmen; Ximénez, Cecilia

    2015-01-01

    Amebiasis is an endemic disease and a public health problem throughout Mexico, although the incidence rates of amebic liver abscess (ALA) vary among the geographic regions of the country. Notably, incidence rates are high in the northwestern states (especially Sonora with a rate of 12.57/100,000 inhabitants) compared with the central region (Mexico City with a rate of 0.69/100,000 inhabitants). These data may be related to host genetic factors that are partially responsible for resistance or susceptibility. Therefore, we studied the association of the HLA-DRB1 and HLA-DQB1 alleles with resistance or susceptibility to ALA in two Mexican populations, one each from Mexico City and Sonora. Ninety ALA patients were clinically diagnosed by serology and sonography. Genomic DNA was extracted from peripheral blood mononuclear cells. To establish the genetic identity of both populations, 15 short tandem repeats (STRs) were analyzed with multiplexed PCR, and the allelic frequencies of HLA were studied by PCR-SSO using LUMINEX technology. The allele frequencies obtained were compared to an ethnically matched healthy control group (146 individuals). We observed that both affected populations differed genetically from the control group. We also found interesting trends in the population from Mexico City. HLA-DQB1*02 allele frequencies were higher in ALA patients compared to the control group (0.127 vs 0.047; p= 0.01; pc= NS; OR= 2.9, 95% CI= 1.09-8.3). The less frequent alleles in ALA patients were HLA-DRB1*08 (0.118 vs 0.238 in controls; p= 0.01; pc= NS; OR= 0.42, 95% CI= 0.19-0.87) and HLA-DQB1*04 (0.109 vs 0.214; p= 0.02; pc= NS; OR= 0.40, 95% CI= 0.20-0.94). The haplotype HLA-DRB1*08/-DQB1*04 also demonstrated a protective trend against the development of this disease (0.081 vs. 0.178; p=0.02; pc=NS; OR= 0.40, 95% CI= 0.16-0.93). These trends suggest that the prevalent alleles in the population of Mexico City may be associated with protection against the development of ALA.

  10. Prevalent HLA Class II Alleles in Mexico City Appear to Confer Resistance to the Development of Amebic Liver Abscess

    PubMed Central

    Hernández, Eric G.; Granados, Julio; Partida-Rodríguez, Oswaldo; Valenzuela, Olivia; Rascón, Edgar; Magaña, Ulises; Escamilla-Tilch, Mónica; López-Reyes, Alberto; Nieves-Ramírez, Miriam; González, Enrique; Morán, Patricia; Rojas, Liliana; Valadez, Alicia; Luna, Alexandra; Estrada, Francisco J.; Maldonado, Carmen; Ximénez, Cecilia

    2015-01-01

    Amebiasis is an endemic disease and a public health problem throughout Mexico, although the incidence rates of amebic liver abscess (ALA) vary among the geographic regions of the country. Notably, incidence rates are high in the northwestern states (especially Sonora with a rate of 12.57/100,000 inhabitants) compared with the central region (Mexico City with a rate of 0.69/100,000 inhabitants). These data may be related to host genetic factors that are partially responsible for resistance or susceptibility. Therefore, we studied the association of the HLA-DRB1 and HLA-DQB1 alleles with resistance or susceptibility to ALA in two Mexican populations, one each from Mexico City and Sonora. Ninety ALA patients were clinically diagnosed by serology and sonography. Genomic DNA was extracted from peripheral blood mononuclear cells. To establish the genetic identity of both populations, 15 short tandem repeats (STRs) were analyzed with multiplexed PCR, and the allelic frequencies of HLA were studied by PCR-SSO using LUMINEX technology. The allele frequencies obtained were compared to an ethnically matched healthy control group (146 individuals). We observed that both affected populations differed genetically from the control group. We also found interesting trends in the population from Mexico City. HLA-DQB1*02 allele frequencies were higher in ALA patients compared to the control group (0.127 vs 0.047; p= 0.01; pc= NS; OR= 2.9, 95% CI= 1.09-8.3). The less frequent alleles in ALA patients were HLA-DRB1*08 (0.118 vs 0.238 in controls; p= 0.01; pc= NS; OR= 0.42, 95% CI= 0.19-0.87) and HLA-DQB1*04 (0.109 vs 0.214; p= 0.02; pc= NS; OR= 0.40, 95% CI= 0.20-0.94). The haplotype HLA-DRB1*08/-DQB1*04 also demonstrated a protective trend against the development of this disease (0.081 vs. 0.178; p=0.02; pc=NS; OR= 0.40, 95% CI= 0.16-0.93). These trends suggest that the prevalent alleles in the population of Mexico City may be associated with protection against the development of ALA

  11. Telomerase activation by genomic rearrangements in high-risk neuroblastoma.

    PubMed

    Peifer, Martin; Hertwig, Falk; Roels, Frederik; Dreidax, Daniel; Gartlgruber, Moritz; Menon, Roopika; Krämer, Andrea; Roncaioli, Justin L; Sand, Frederik; Heuckmann, Johannes M; Ikram, Fakhera; Schmidt, Rene; Ackermann, Sandra; Engesser, Anne; Kahlert, Yvonne; Vogel, Wenzel; Altmüller, Janine; Nürnberg, Peter; Thierry-Mieg, Jean; Thierry-Mieg, Danielle; Mariappan, Aruljothi; Heynck, Stefanie; Mariotti, Erika; Henrich, Kai-Oliver; Gloeckner, Christian; Bosco, Graziella; Leuschner, Ivo; Schweiger, Michal R; Savelyeva, Larissa; Watkins, Simon C; Shao, Chunxuan; Bell, Emma; Höfer, Thomas; Achter, Viktor; Lang, Ulrich; Theissen, Jessica; Volland, Ruth; Saadati, Maral; Eggert, Angelika; de Wilde, Bram; Berthold, Frank; Peng, Zhiyu; Zhao, Chen; Shi, Leming; Ortmann, Monika; Büttner, Reinhard; Perner, Sven; Hero, Barbara; Schramm, Alexander; Schulte, Johannes H; Herrmann, Carl; O'Sullivan, Roderick J; Westermann, Frank; Thomas, Roman K; Fischer, Matthias

    2015-10-29

    Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type. In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours.

  12. A haplotype map of the human genome

    PubMed Central

    2007-01-01

    Inherited genetic variation has a critical but as yet largely uncharacterized role in human disease. Here we report a public database of common variation in the human genome: more than one million single nucleotide polymorphisms (SNPs) for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted. These data document the generality of recombination hotspots, a block-like structure of linkage disequilibrium and low haplotype diversity, leading to substantial correlations of SNPs with many of their neighbours. We show how the HapMap resource can guide the design and analysis of genetic association studies, shed light on structural variation and recombination, and identify loci that may have been subject to natural selection during human evolution. PMID:16255080

  13. HLA class II alleles influence rheumatoid arthritis susceptibility and autoantibody status in South Indian Tamil population.

    PubMed

    Mariaselvam, C M; Fortier, C; Charron, D; Krishnamoorthy, R; Tamouza, R; Negi, V S

    2016-11-01

    Rheumatoid arthritis (RA) is a complex multifactorial autoimmune disease characterized by inflammatory arthritis. The precise etiology and pathogenesis of RA remains elusive but evidence points towards stochastic interactions between genetic and environmental factors. This study investigated the distribution of human leucocyte antigen (HLA)-DRB1/DQB1 alleles in South Indian patients with rheumatoid arthritis (RA) and their influence on RA susceptibility and clinical phenotype. Low resolution HLA-DRB1 and -DQB1 typing was performed in 271 RA patients and 233 healthy controls by polymerase chain reaction (PCR) using sequence-specific primers (SSP). HLA-DRB1*10 was found to be more frequent in patients (Pc = 0.004, OR = 2.23, 95% CI = 1.5-3.34) than controls. This difference persisted in RF positive (Pc = 9 × 10(-6) , OR = 2.45, 95% CI = 1.62-3.74), ACPA positive (Pc = 0.007, OR = 2.10, 95% CI = 1.35-3.29), ACPA negative (Pc = 0.001, OR = 2.45, 95% CI = 1.50-3.97) and both RF and ACPA positive subgroup of patients (Pc = 0.003, OR = 2.22, 95% CI = 1.41-3.51). On the contrary, the HLA-DRB1*13 (Pc = 0.01, OR = 0.43, 95% CI = 0.25-0.73) and HLA-DRB1*14 (Pc = 0.003, OR = 0.43, 95% CI = 0.26-0.69) alleles were over-represented in controls than patients. Further, distribution of the prominent Caucasian RA risk allele DRB1*04 did not differ between patients and controls in our study population. We did not find any association between DQB1 alleles and RA susceptibility or autoantibody status. The haplotypes DQB1*05-DRB1*10 (P = 6.8 × 10(-6) , OR = 2.46, 95% CI = 1.63-3.79) and DQB1*06-DRB1*15 (P = 0.03, OR = 1.41, 95% CI = 1.02-1.96) were more frequent in patients while DQB1*05-DRB1*14 (P = 8.4 × 10(-4) , OR = 0.44, 95% CI = 0.26-0.74) and DQB1*06-DRB1*13 (P = 9.5 × 10(-4) , OR = 0.40, 95% CI = 0.21-0.72) were higher in controls. To conclude, HLA-DRB1*10 is associated with RA while HLA-DRB1*13 and HLA-DRB1*14 alleles confer protection in south Indian Tamils.

  14. Haplotype map of sickle cell anemia in Tunisia.

    PubMed

    Moumni, Imen; Ben Mustapha, Maha; Sassi, Sarra; Zorai, Amine; Ben Mansour, Ikbel; Douzi, Kais; Chouachi, Dorra; Mellouli, Fethi; Bejaoui, Mohamed; Abbes, Salem

    2014-01-01

    β-Globin haplotypes are important to establish the ethnic origin and predict the clinical development of sickle cell disease patients (SCD). To determine the chromosomal background of β (S) Tunisian sickle cell patients, in this first study in Tunisia, we have explored four polymorphic regions of β-globin cluster on chromosome 11. It is the 5' region of β-LCR-HS2 site, the intervening sequence II (IVSII) region of two fetal ((G)γ and (A)γ) genes and the 5' region of β-globin gene. The results reveal a high molecular diversity of a microsatellite configuration describing the sequences haplotypes. The linkage disequilibrium analysis showed various haplotype combinations giving 22 "extended haplotypes". These results confirm the utility of the β-globin haplotypes for population studies and contribute to knowledge of the Tunisian gene pool, as well as establishing the role of genetic markers in physiopathology of SCD.

  15. A new mathematical modeling for pure parsimony haplotyping problem.

    PubMed

    Feizabadi, R; Bagherian, M; Vaziri, H R; Salahi, M

    2016-11-01

    Pure parsimony haplotyping (PPH) problem is important in bioinformatics because rational haplotyping inference plays important roles in analysis of genetic data, mapping complex genetic diseases such as Alzheimer's disease, heart disorders and etc. Haplotypes and genotypes are m-length sequences. Although several integer programing models have already been presented for PPH problem, its NP-hardness characteristic resulted in ineffectiveness of those models facing the real instances especially instances with many heterozygous sites. In this paper, we assign a corresponding number to each haplotype and genotype and based on those numbers, we set a mixed integer programing model. Using numbers, instead of sequences, would lead to less complexity of the new model in comparison with previous models in a way that there are neither constraints nor variables corresponding to heterozygous nucleotide sites in it. Experimental results approve the efficiency of the new model in producing better solution in comparison to two state-of-the art haplotyping approaches.

  16. Review of screening for pancreatic cancer in high risk individuals.

    PubMed

    Stoita, Alina; Penman, Ian D; Williams, David B

    2011-05-21

    Pancreatic cancer is difficult to diagnose at an early stage and is associated with a very poor survival. Ten percent of pancreatic cancers result from genetic susceptibility and/or familial aggregation. Individuals from families with multiple affected first-degree relatives and those with a known cancer-causing genetic mutation have been shown to be at much higher risk of developing pancreatic cancer. Recent efforts have focused on detecting disease at an earlier stage to improve survival in these high-risk groups. This article reviews high-risk groups, screening methods, and current screening programs and their results.

  17. Review of screening for pancreatic cancer in high risk individuals

    PubMed Central

    Stoita, Alina; Penman, Ian D; Williams, David B

    2011-01-01

    Pancreatic cancer is difficult to diagnose at an early stage and is associated with a very poor survival. Ten percent of pancreatic cancers result from genetic susceptibility and/or familial aggregation. Individuals from families with multiple affected first-degree relatives and those with a known cancer-causing genetic mutation have been shown to be at much higher risk of developing pancreatic cancer. Recent efforts have focused on detecting disease at an earlier stage to improve survival in these high-risk groups. This article reviews high-risk groups, screening methods, and current screening programs and their results. PMID:21633635

  18. Management of high-risk localized prostate cancer.

    PubMed

    Marciscano, Ariel E; Hardee, Matthew E; Sanfilippo, Nicholas

    2012-01-01

    Traditionally, patients with high-risk localized prostate cancer have been an extremely challenging group to manage due to a significant likelihood of treatment failure and prostate cancer-specific mortality (PCSM). The results of multiple large, prospective, randomized trials have demonstrated that men with high-risk features who are treated in a multimodal fashion at the time of initial diagnosis have improved overall survival. Advances in local treatments such as dose-escalated radiotherapy in conjunction with androgen suppression and postprostatectomy adjuvant radiotherapy have also demonstrated benefits to this subset of patients. However, therapeutic enhancement with the addition of chemotherapy to the primary treatment regimen may help achieve optimal disease control.

  19. Common phenotype and different non-HLA genes in Graves' disease and alopecia areata.

    PubMed

    Taketomo, Yasunori; Noso, Shinsuke; Babaya, Naru; Hiromine, Yoshihisa; Ito, Hiroyuki; Kanto, Kousei; Niwano, Fumimaru; Oiso, Naoki; Kawada, Akira; Kawabata, Yumiko; Ikegami, Hiroshi

    2017-02-01

    Our previous observations clarified that Graves' disease (GD) is the most frequent autoimmune disease in patients with alopecia areata (AA), and 42.7% of patients with AA were positive for thyrotropin receptor antibody (TRAb). A class II HLA haplotype DRB1(∗)15:01-DQB1(∗)06:02 was suggested to contribute to autoimmunity against the thyroid gland in AA. To further clarify the genetic factors contributing to organ specificity in autoimmune diseases, we studied the contribution of non-HLA genes to organ specificity in GD and AA. A high frequency of AA (13.4%) was observed in patients with GD, indicating strong phenotypic association between GD and AA. CTLA4 and TSHR were significantly associated with GD (Pc=0.007 and Pc<0.002, respectively), but not with AA, even in TRAb-positive patients. The difference in the association between GD and AA suggests that the CTLA4 and TSHR are not main factors contributing to determining common genetic basis among GD and AA.

  20. Genetic susceptibility of eight nonsynonymous polymorphisms in HLA-DRB1 gene to hepatocellular carcinoma in Han Chinese

    PubMed Central

    Shi, Yanhui; Zhai, Weiyu; Wang, Bin; Zhao, Dongmei; Jin, He; Wang, Yuefei; Zhang, Jidong; An, Hongjun; Fu, Zhongze; Zhao, Kun; Lu, Changzhu

    2016-01-01

    Backgrounds and Objective Mounting evidence suggests that human leukocyte antigen (HLA) plays a central role in anti-virus and tumor defense. To test whether genetic variation in HLA-DRB1 gene, a key component of HLA system, can predict its predisposition to hepatocellular carcinoma (HCC), we thereby conducted an association study by genotyping 8 nonsynonymous polymorphisms in HLA-DRB1 gene among 257 HCC patients and 264 controls. Results All polymorphisms respected the Hardy-Weinberg equilibrium. The genotypes and alleles of rs17879599 differed significantly between patients and controls after Bonferroni correction (both P < 0.001), and the power to detect this significance was 94.4%. After adjusting for age, gender, smoking, drinking and hepatitis infection, the mutant allele of rs17879702 was significantly associated with an increased risk for HCC under additive (odds ratio [OR] = 2.12, 95% confidence interval [CI]: 1.20-4.02, P = 0.004) and dominant (OR = 2.51, 95% CI: 1.39–2.96, P = 0.004) models. Haplotype analysis indicated that haplotype A-T-C-T-G-C-T-A (alleles ordered by rs199514452, rs201540428, rs201614260, rs17879702, rs17880292, rs17879599, rs17424145 and rs35445101) was overrepresented in patients and enhanced predisposition to HCC (adjusted OR = 2.72, 95% CI: 1.24–5.78, P = 0.004). In cumulative analysis, carriers of 7–9 unfavorable alleles had a 2.41-fold (95% CI: 1.18–4.92, P = 0.016) increased risk for HCC after adjusting for confounding factors relative to those possessing 4 or less unfavorable alleles. Materials and Methods Genotypes were determined by ligase detection reaction. HCC patients were newly diagnosed, histopathologically confirmed or previously untreated and controls were cancer-free. Conclusions Our findings suggest an independent leading contribution of rs17879599 in the 2nd exon of HLA-DRB1 gene to HCC risk in Han Chinese. PMID:27821814

  1. General Framework for Meta-Analysis of Haplotype Association Tests.

    PubMed

    Wang, Shuai; Zhao, Jing Hua; An, Ping; Guo, Xiuqing; Jensen, Richard A; Marten, Jonathan; Huffman, Jennifer E; Meidtner, Karina; Boeing, Heiner; Campbell, Archie; Rice, Kenneth M; Scott, Robert A; Yao, Jie; Schulze, Matthias B; Wareham, Nicholas J; Borecki, Ingrid B; Province, Michael A; Rotter, Jerome I; Hayward, Caroline; Goodarzi, Mark O; Meigs, James B; Dupuis, Josée

    2016-04-01

    For complex traits, most associated single nucleotide variants (SNV) discovered to date have a small effect, and detection of association is only possible with large sample sizes. Because of patient confidentiality concerns, it is often not possible to pool genetic data from multiple cohorts, and meta-analysis has emerged as the method of choice to combine results from multiple studies. Many meta-analysis methods are available for single SNV analyses. As new approaches allow the capture of low frequency and rare genetic variation, it is of interest to jointly consider multiple variants to improve power. However, for the analysis of haplotypes formed by multiple SNVs, meta-analysis remains a challenge, because different haplotypes may be observed across studies. We propose a two-stage meta-analysis approach to combine haplotype analysis results. In the first stage, each cohort estimate haplotype effect sizes in a regression framework, accounting for relatedness among observations if appropriate. For the second stage, we use a multivariate generalized least square meta-analysis approach to combine haplotype effect estimates from multiple cohorts. Haplotype-specific association tests and a global test of independence between haplotypes and traits are obtained within our framework. We demonstrate through simulation studies that we control the type-I error rate, and our approach is more powerful than inverse variance weighted meta-analysis of single SNV analysis when haplotype effects are present. We replicate a published haplotype association between fasting glucose-associated locus (G6PC2) and fasting glucose in seven studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and we provide more precise haplotype effect estimates.

  2. Frequencies of allele groups HLA-A, HLA-B and HLA-DRB1 in a population from the northwestern region of São Paulo State, Brazil.

    PubMed

    Ayo, C M; da Silveira Camargo, A V; Xavier, D H; Batista, M F; Carneiro, O A; Brandão de Mattos, C C; Ricci, O; de Mattos, L C

    2015-02-01

    The aim of this study was to estimate the HLA-A, HLA-B and HLA-DRB1 allele groups frequencies in a population of 1559 volunteer bone marrow donors from the northwestern region of São Paulo State grouped according to ethnicity. An additional objective was to compare the allele frequencies of the current study with data published for other Brazilian populations. The allele groups were characterized by the PCR-rSSO method using Luminex(®) technology. Twenty HLA-A, 32 HLA-B and 13 HLA-DRB1 allele groups were identified. The most common allele groups in European descent and mixed African and European descent samples were HLA-A*02, HLA-B*35 and HLA-DRB1*13, while HLA-A*02, HLA-B*35 and HLA-DRB1*11 were more common in African descent samples. The HLA-A*23, HLA-A*36, HLA-B*58 and HLA-B*81 allele groups were more common in sample from African descent than European descent, and the HLA-DRB1*08 was more common in mixed African and European descent than in European descent. Allele group frequencies were compared with samples from other Brazilian regions. The HLA-A*30 and HLA-A*23 were more common in this study than in the populations of Rio Grande do Sul and Paraná; and the HLA-A*01, HLA-B*18, HLA-B*57 and HLA-DRB1*11 were more common in this study than in the population of Piauí. The least frequent allele groups were HLA-A*31, HLA-B*15, HLA-B*40 and HLA-DRB1*08 for the population of Piauí, HLA-A*01 and HLA-A*11 for Parana, HLA-A*02 and -A*03 for Rio Grande do Sul and HLA-DRB1*04 for Paraná, Rio Grande do Sul and Piauí. These data provide an overview on the knowledge on HLA diversity in the population of the northwestern region of São Paulo State and show that the genes of this system are useful to distinguish different ethnic groups.

  3. Reflections on HLA Epitope-Based Matching for Transplantation

    PubMed Central

    Duquesnoy, Rene J.

    2016-01-01

    HLA antibodies are primary causes of transplant rejection; they recognize epitopes that can be structurally defined by eplets. There are many reviews about HLA epitope-based matching in transplantation. This article describes some personal reflections about epitopes including a historical perspective of HLA typing at the antigen and allele levels, the repertoires of antibody-verified HLA epitopes, the use of HLAMatchmaker in determining the specificities of antibodies tested in different assays, and, finally, possible strategies to control HLA antibody responses. PMID:27965660

  4. HLA diversity among Nadars, a primitive Dravidian caste of South India.

    PubMed

    Shankarkumar, U; Sridharan, B; Pitchappan, R M

    2003-12-01

    South India is one of the oldest geophysical regions mainly occupied by Dravidian language-speaking people. Here a random panel of 61 unrelated Nadar healthy individual from Tamil Nadu State were analyzed and compared with other populations of India and the world. HLA-A, B and C alleles frequencies and their haplotype frequencies were determined by high-resolution typing of genomic DNA. The analysis revealed that the Nadar caste of South India have several characters shared with East Asian populations consistent with the demographic history of South India, as well as specific features including several unique alleles such as A*03011, A*31011, B*15011, B*3501, B*51011, Cw*02022. In addition, haplotypes such as A*31011-Cw*02022-B*3501, A*03011-Cw*04011-B*4406 and A*2402101-Cw*04011-B*51011 are of high frequency in both these populations but are rare or absent in other populations of India and the world. The study suggests that a comparatively lesser degree of genetic admixture occurred between the South Indian and North Indian racial groups than that between South Indian and East Asian groups.

  5. Distribution of HLA-DRB1 and HLA-DQB1 alleles in Lak population of Iran.

    PubMed

    Varzi, Ali Mohammad; Shahsavar, Farhad; Tarrahi, Mohammad Javad

    2016-07-01

    Human leukocyte antigen (HLA) genes are the most polymorphic loci in the human genome and encode the highly polymorphic molecules critically involved in immune responses. Anthropological studies based on highly polymorphic HLA genes provide useful information for bone marrow donor registry, forensic medicine, disease association studies, as well as designing peptide vaccines against tumors, and infectious or autoimmune diseases. The aim of this study was to determine the HLA-DRB1 and HLA-DQB1 allele frequencies in 100 unrelated Lak individuals from Lorestan province of Iran. Finally, we compared the results with those previously described in four other Iranian populations. Commercial HLA-Type kits were used for determination of the HLA-DRB1 and HLA-DQB1 allele frequencies. Differences between populations in the distribution of HLA-DRB1 and HLA-DQB1 alleles were estimated by χ2 test with Yate's correction and Fisher's exact test. The most frequent HLA-DRB1 alleles were (*)1103=4 (23%), (*)1502 (9.5%), (*)0701 (9%), (*)0301 (8.5%), (*)1101 (7.5%) and (*)1501 (6%) while HLA-DQB1(*)0301 (40%), (*)0201 (15%), (*)0502 (10.5%), (*)0303 (10%), (*)0602=3 (9.5%), and (*)0501 (7.5%) were the most frequent alleles in Lak population. HLA-DRB1(*)0409, (*)0804, (*)1102, (*)1112, (*)1405, and HLA-DQB1(*)0503, (*)0604 were the least observed frequencies in Lak population. Our results based on HLA-DRB1 and HLA-DQB1 allele frequencies showed that the Lak population possesses the previously reported general features of the Lur and Kurd populations but still with unique, decreased or increased frequencies of several alleles. In other words, the Lak population is close to Lurs Khorramabadi and Kurd but far from Lurs Kohkiloyeh/Boyerahmad and Bakhtiari.

  6. An Integrated Tool to Study MHC Region: Accurate SNV Detection and HLA Genes Typing in Human MHC Region Using Targeted High-Throughput Sequencing

    PubMed Central

    Liu, Xiao; Xu, Yinyin; Liang, Dequan; Gao, Peng; Sun, Yepeng; Gifford, Benjamin; D’Ascenzo, Mark; Liu, Xiaomin; Tellier, Laurent C. A. M.; Yang, Fang; Tong, Xin; Chen, Dan; Zheng, Jing; Li, Weiyang; Richmond, Todd; Xu, Xun; Wang, Jun; Li, Yingrui

    2013-01-01

    The major histocompatibility complex (MHC) is one of the most variable and gene-dense regions of the human genome. Most studies of the MHC, and associated regions, focus on minor variants and HLA typing, many of which have been demonstrated to be associated with human disease susceptibility and metabolic pathways. However, the detection of variants in the MHC region, and diagnostic HLA typing, still lacks a coherent, standardized, cost effective and high coverage protocol of clinical quality and reliability. In this paper, we presented such a method for the accurate detection of minor variants and HLA types in the human MHC region, using high-throughput, high-coverage sequencing of target regions. A probe set was designed to template upon the 8 annotated human MHC haplotypes, and to encompass the 5 megabases (Mb) of the extended MHC region. We deployed our probes upon three, genetically diverse human samples for probe set evaluation, and sequencing data show that ∼97% of the MHC region, and over 99% of the genes in MHC region, are covered with sufficient depth and good evenness. 98% of genotypes called by this capture sequencing prove consistent with established HapMap genotypes. We have concurrently developed a one-step pipeline for calling any HLA type referenced in the IMGT/HLA database from this target capture sequencing data, which shows over 96% typing accuracy when deployed at 4 digital resolution. This cost-effective and highly accurate approach for variant detection and HLA typing in the MHC region may lend further insight into immune-mediated diseases studies, and may find clinical utility in transplantation medicine research. This one-step pipeline is released for general evaluation and use by the scientific community. PMID:23894464

  7. Multiple Sclerosis Risk Variant HLA-DRB1*1501 Associates with High Expression of DRB1 Gene in Different Human Populations

    PubMed Central

    Abad-Grau, María del Mar; Fedetz, María; Izquierdo, Guillermo; Lucas, Miguel; Fernández, Óscar; Ndagire, Dorothy; Catalá-Rabasa, Antonio; Ruiz, Agustín; Gayán, Javier; Delgado, Concepción; Arnal, Carmen

    2012-01-01

    The human leukocyte antigen (HLA) DRB1*1501 has been consistently associated with multiple sclerosis (MS) in nearly all populations tested. This points to a specific antigen presentation as the pathogenic mechanism though this does not fully explain the disease association. The identification of expression quantitative trait loci (eQTL) for genes in the HLA locus poses the question of the role of gene expression in MS susceptibility. We analyzed the eQTLs in the HLA region with respect to MS-associated HLA-variants obtained from genome-wide association studies (GWAS). We found that the Tag of DRB1*1501, rs3135388 A allele, correlated with high expression of DRB1, DRB5 and DQB1 genes in a Caucasian population. In quantitative terms, the MS-risk AA genotype carriers of rs3135388 were associated with 15.7-, 5.2- and 8.3-fold higher expression of DQB1, DRB5 and DRB1, respectively, than the non-risk GG carriers. The haplotype analysis of expression-associated variants in a Spanish MS cohort revealed that high expression of DRB1 and DQB1 alone did not contribute to the disease. However, in Caucasian, Asian and African American populations, the DRB1*1501 allele was always highly expressed. In other immune related diseases such as type 1 diabetes, inflammatory bowel disease, ulcerative colitis, asthma and IgA deficiency, the best GWAS-associated HLA SNPs were also eQTLs for different HLA Class II genes. Our data suggest that the DR/DQ expression levels, together with specific structural properties of alleles, seem to be the causal effect in MS and in other immunopathologies rather than specific antigen presentation alone. PMID:22253788

  8. Early Identification of Educationally High Potential and High Risk Children.

    ERIC Educational Resources Information Center

    Keogh, Barbara K.; Smith, Carol E.

    Early identification of educationally high potential and high risk children was investigated by following the same 49 children from kindergarten entrance through grade five of a regular school program. Kindergarten predictive measures were the Bender Gestalt Test and teachers' evaluations; follow-up measures were yearly standard achievement test…

  9. ORGANOPHOSPHATE PESTICIDE EXPOSURES - WHERE ARE THE HIGH RISK CHILDREN?

    EPA Science Inventory

    Methods to identify children at high-risk for organophosphate (OP) pesticide exposure are difficult to develop because biological markers reflect only recent "snapshots" of exposure due to the short half-life of OP compounds (generally about 24 hours). We conducted a series of p...

  10. Environmental Influences and Perinatal Risk Factors in High Risk Children.

    ERIC Educational Resources Information Center

    Lindgren, Scott D.; And Others

    Children in a longitudinal high-risk infant follow-up program were evaluated at age 5 to determine whether they demonstrated behavior problems or cognitive deficits exceeding expectations based on conditions in their home environments. Normal expectations were determined through regression analyses on a group of age-matched controls. All high-risk…

  11. Intervening with High-Risk Families via Infant Daycare.

    ERIC Educational Resources Information Center

    Ramey, Craig T.; Farran, Dale C.

    A longitudinal study was conducted at the Frank Porter Graham Center NC to explore the use of educational day care and related services as a mechanism for preparing socially disadvantaged children for success in later public schooling. Infant children of mothers who met a criterion score on a high risk index were randomly assigned to either an…

  12. The High-Risk (Disturbed and Disturbing) College Student

    ERIC Educational Resources Information Center

    Hollingsworth, Kathy R.; Dunkle, John H.; Douce, Louise

    2009-01-01

    The disturbed and disturbing college student causes the most vexing concerns for student affairs administrators. The Assessment-Intervention of Student Problems (AISP) model offers a useful and easily understood framework for dealing with the various challenges of this high-risk student population. This chapter focuses on changes that have…

  13. Process Writing for High-Risk and Learning Disabled Students.

    ERIC Educational Resources Information Center

    Zaragoza, Nina

    1987-01-01

    Discusses the major elements of writing process instruction and the positive influence they have on learning-disabled and inner-city high-risk students. Argues that such process-writing programs might serve as a preventative measure for children likely to be categorized as learning disabled in the future. (HTH)

  14. Big Books from Little Voices: Reaching High Risk Beginning Readers.

    ERIC Educational Resources Information Center

    Trachtenburg, Phyllis; Ferruggia, Ann

    1989-01-01

    Discusses how interactive, whole class techniques (using a student-generated Big Book adaptation of "Corduroy") improved the reading skills of high risk first grade readers. Describes several activities, including sight word strategies, decoding techniques, and word processing, and suggests 27 Big Books for use with these activities. (MM)

  15. Staying Alive! Training High-Risk Teams for Self Correction

    NASA Technical Reports Server (NTRS)

    Slack, Kelley; Noe, Raymond; Weaver, Sallie

    2011-01-01

    Research examining teams working in high-risk operations has been lacking. The present symposium showcases research on team training that helps to optimize team performance in environments characterized by life or death situations arising spontaneously after long periods of mundane activity by pulling experts from diverse areas of industry: space flight, health care, and medical simulation.

  16. High Risk Drinking among Non-Affiliated College Students

    ERIC Educational Resources Information Center

    Smith, Margaret; Finneran, John; Droppa, Marj

    2014-01-01

    This study investigated the high risk drinking practices of unaffiliated college students who are not involved in formal athletics, fraternities, or sororities. Using a qualitative research design, the investigators interviewed students at a northeast public college in fall 2010 to learn about unaffiliated students' drinking experiences and their…

  17. Genomic analysis of high-risk smoldering multiple myeloma

    PubMed Central

    López-Corral, Lucía; Mateos, María Victoria; Corchete, Luis A.; Sarasquete, María Eugenia; de la Rubia, Javier; de Arriba, Felipe; Lahuerta, Juan-José; García-Sanz, Ramón; San Miguel, Jesús F.; Gutiérrez, Norma C.

    2012-01-01

    Smoldering myeloma is an asymptomatic plasma cell dyscrasia with a heterogeneous propensity to progress to active myeloma. In order to investigate the biology of smoldering myeloma patients with high risk of progression, we analyzed the genomic characteristics by FISH, SNP-arrays and gene expression profile of a group of patients with high-risk smoldering myeloma included in a multicenter randomized trial. Chromosomal abnormalities detected by FISH and SNP-arrays at diagnosis were not associated to risk of progression to symptomatic myeloma. However, the overexpression of four SNORD genes (SNORD25, SNORD27, SNORD30 and SNORD31) was correlated with shorter time to progression (P<0.03). When plasma cells from high-risk smoldering patients who progressed to symptomatic myeloma were sequentially analyzed, newly acquired lesions together with an increase in the proportion of plasma cells carrying a given abnormality were observed. These findings suggest that gene expression profiling is a valuable technique to identify smoldering myeloma patients with high risk of progression. (Clinical Trials NCT00443235) PMID:22331267

  18. A Bridge Course for High-Risk Freshman: Evaluating Outcomes.

    ERIC Educational Resources Information Center

    Hardy, Dorothy C.; Karathanos, Demetrius

    1992-01-01

    Examines outcomes of a "bridge" course for first-year college students that emphasizes personal and psychological adjustment to the university experience to enhance the likelihood of academic success. Findings from 59 high-risk students who completed course suggest that goal of enhancing likelihood of academic success for such students was…

  19. Troubled Relationships: High-Risk Latina Adolescents and Nonresident Fathers

    ERIC Educational Resources Information Center

    Lopez, Vera; Corona, Rosalie

    2012-01-01

    This qualitative study explored 18 high-risk adolescent Latinas' perceptions of their relationships with nonresident fathers. A number of interrelated factors--early childhood memories, mothers' interpretations, and fathers' behaviors--shaped girls' perceptions, which in turn, influenced how they interacted with fathers. Some girls struggled to…

  20. Explorations in High-Risk Stimulation: Two Modalities in Mothering.

    ERIC Educational Resources Information Center

    Gochman, Eva R. Grubler; Aisenstein, Clara

    An exploratory study of high-risk mothers' interactions with their infants studied modalities of stimulation; vestibular and auditory. It was hypothesized that stimulation would be lower for non-paranoid than for paranoid types, and than for control mothers. Mothers recruited from inner city gynecological clinics were screened for probable…

  1. Cumulative Experiences of Violence among High-Risk Urban Youth

    ERIC Educational Resources Information Center

    Taylor, Catherine A.; Boris, Neil W.; Heller, Sherryl Scott; Clum, Gretchen A.; Rice, Janet C.; Zeanah, Charles H.

    2008-01-01

    This study examines type-specific and cumulative experiences of violence among a vulnerable population of youth. Sixty high-risk, shelter-dwelling, urban youth were interviewed regarding their history of childhood maltreatment, exposure to community violence (ECV), and experience with intimate partner violence (IPV). Results show a high prevalence…

  2. Sociobiology and HLA genetic polymorphism in hill tribes, the Irula of the Nilgiri hills and the Malayali of the Shevroy hills, south India.

    PubMed

    Pitchappan, R M; Balakrishnan, K; Sudarsen, V; Brahmajothi, V; Mahendran, V; Amalraj, S; Santhakumari, R; Vijayakumar, K; Sivalingam, P; Ramasamy, S

    1997-02-01

    Two endogamous tribes of Tamil Nadu, South India, the Irula of the Nilgiri hills and the Malayali of the Shevroy hills, were studied for their sociobiology and HLA polymorphism. For sociobiological studies 166 marriages in the Irula and 368 marriages in the Malayali were recorded. The number and spatial distribution of patrilineal clans and their marriageable range (number of clans from which the brides came) were studied. Eight clans in the Irula and 16 clans in the Malayali were identified. Of these the Kuppar of the Irula and the Malayan of Malayali were the largest clans, and both of them had the greatest marriageable range. The numerical strength and the resultant spatial distribution correlated well with the marriageable range. HLA-A, B, and DR polymorphism was studied on 191 Irula and 42 Malayali following standard procedures. HLA typing revealed high frequencies (> 10%) of alleles HLA-A2, A9, A11, B17, B35, B40, DR2, and DR7 in both tribes, but the Irula had elevated HLA-A10, B8, and DR8 frequencies and the Malayali had elevated HLA-A31, B7, DR4, and DR5 frequencies. Two-locus haplotypes A10-B8 and A2-B5 were identified in both tribes, but A11-B40 and A2-B53 were present only in the Irula and A33-B44 and B15-DR6 were present only in the Malayali. The sociobiology of the Irula was correlated to the HLA genetic profile. The Irula sample was stratified based on clan and HLA data; The Kuppar clan was closer to the Kalkatti, the second largest clan, than to the Pungar and the Sambar clans. Thus the numerical strength and spatial distribution of various exogamous clans, presumably a result of migration during different periods of history, is reflected in the marriageable range and thus in the genetic distance. In studying HLA or any other genetic polymorphism of an endogamous tribe or caste, one needs to consider the social structure, spatial distribution, and marriageable range.

  3. Humanized birth in high risk pregnancy: barriers and facilitating factors.

    PubMed

    Behruzi, Roxana; Hatem, Marie; Goulet, Lise; Fraser, William; Leduc, Nicole; Misago, Chizuru

    2010-02-01

    The medical model of childbearing assumes that a pregnancy always has the potential to turn into a risky procedure. In order to advocate humanized birth in high risk pregnancy, an important step involves the enlightenment of the professional's preconceptions on humanized birth in such a situation. The goal of this paper is to identify the professionals' perception of the potential obstacles and facilitating factors for the implementation of humanized care in high risk pregnancies. Twenty-one midwives, obstetricians, and health administrator professionals from the clinical and academic fields were interviewed in nine different sites in Japan from June through August 2008. The interviews were audio taped, and transcribed with the participants' consent. Data was subsequently analyzed using content analysis qualitative methods. Professionals concurred with the concept that humanized birth is a changing and promising process, and can often bring normality to the midst of a high obstetric risk situation. No practice guidelines can be theoretically defined for humanized birth in a high risk pregnancy, as there is no conflict between humanized birth and medical intervention in such a situation. Barriers encountered in providing humanized birth in a high risk pregnancy include factors such as: the pressure of being responsible for the safety of the mother and the fetus, lack of the women's active involvement in the decision making process and the heavy burden of responsibility on the physician's shoulders, potential legal issues, and finally, the lack of midwifery authority in providing care at high risk pregnancy. The factors that facilitate humanized birth in a high risk include: the sharing of decision making and other various responsibilities between the physicians and the women; being caring; stress management, and the fact that the evolution of a better relationship and communication between the health professional and the patient will lead to a stress

  4. The structure of HLA-DR52c: Comparison to other HLA-DRB3 alleles

    SciTech Connect

    Dai, Shaodong; Crawford, Frances; Marrack, Philippa; Kappler, John W.

    2008-09-05

    Class II major histocompatibility complex (MHCII) molecules present antigens to CD4{sup +} T cells. In addition to the most commonly studied human MHCII isotype, HLA-DR, whose {beta} chain is encoded by the HLA-DRB1 locus, several other isotypes that use the same {alpha} chain but have {beta} chains encoded by other genes. These other DR molecules also are expressed in antigen-presenting cells and are known to participate in peptide presentation to T cells and to be recognized as alloantigens by other T cells. Like some of the HLA-DRB1 alleles, several of these alternate DR molecules have been associated with specific autoimmune diseases and T cell hypersensitivity. Here we present the structure of an HLA-DR molecule (DR52c) containing one of these alternate {beta} chains (HLA-DRB3*0301) bound to a self-peptide derived from the Tu elongation factor. The molecule shares structurally conserved elements with other MHC class II molecules but has some unique features in the peptide-binding groove. Comparison of the three major HLA-DBR3 alleles (DR52a, b, and c) suggests that they were derived from one another by recombination events that scrambled the four major peptide-binding pockets at peptide positions 1, 4, 6, and 9 but left virtually no polymorphisms elsewhere in the molecules.

  5. Biological Markers of Pseudomonas aeruginosa Epidemic High-Risk Clones

    PubMed Central

    Mulet, Xavier; Cabot, Gabriel; Ocampo-Sosa, Alain A.; Domínguez, M. Angeles; Zamorano, Laura; Juan, Carlos; Tubau, Fe; Rodríguez, Cristina; Moyà, Bartolomé; Peña, Carmen; Martínez-Martínez, Luis

    2013-01-01

    A limited number of Pseudomonas aeruginosa genotypes (mainly ST-111, ST-175, and ST-235), known as high-risk clones, are responsible for epidemics of nosocomial infections by multidrug-resistant (MDR) or extensively drug-resistant (XDR) strains worldwide. We explored the potential biological parameters that may explain the success of these clones. A total of 20 isolates from each of 4 resistance groups (XDR, MDR, ModR [resistant to 1 or 2 classes], and MultiS [susceptible to all antipseudomonals]), recovered from a multicenter study of P. aeruginosa bloodstream infections performed in 10 Spanish hospitals, were analyzed. A further set of 20 XDR isolates belonging to epidemic high-risk clones (ST-175 [n = 6], ST-111 [n = 7], and ST-235 [n = 7]) recovered from different geographical locations was also studied. When unknown, genotypes were documented through multilocus sequence typing. The biological parameters evaluated included twitching, swimming, and swarming motility, biofilm formation, production of pyoverdine and pyocyanin, spontaneous mutant frequencies, and the in vitro competition index (CI) obtained with a flow cytometry assay. All 20 (100%) XDR, 8 (40%) MDR, and 1 (5%) ModR bloodstream isolate from the multicenter study belonged to high-risk clones. No significant differences were observed between clonally diverse ModR and MultiS isolates for any of the parameters. In contrast, MDR/XDR high-risk clones showed significantly increased biofilm formation and mutant frequencies but significantly reduced motility (twitching, swimming, and swarming), production of pyoverdine and pyocyanin, and fitness. The defined biological markers of high-risk clones, which resemble those resulting from adaptation to chronic infections, could be useful for the design of specific treatment and infection control strategies. PMID:23979744

  6. A novel HLA-B allele, B*58:01:12, detected in a Taiwanese volunteer bone marrow stem cell donor using sequence-based typing method.

    PubMed

    Yang, K L; Lee, S K; Kao, R H; Lin, C L; Lin, P Y

    2013-08-01

    Human leukocyte antigen-B*58:01:12, a novel rare allele of HLA-B*58:01 variant, was found in a Taiwanese volunteer bone marrow donor by SBT (sequence-based typing) method. The DNA sequence of B*58:01:12 is identical to the sequence of B*58:01:01 in exons 2, 3 and 4 except at nucleotide position 483 where nucleotide C is substituted by T (at codon 137; GAC GAT). Due to the silent point mutation, the amino acid sequence of B*58:01:12 is identical to the sequence of B*58:01:01. The HLA haplotype in association with B*58:01:12 may be deduced as A*33:03-B*58:01:12-DRB1*03:01. The discovery of B*58:01:12 adds further polymorphism of B*58:01 in Taiwanese population.

  7. Towards understanding the origin and dispersal of Austronesians in the Solomon Sea: HLA class II polymorphism in eight distinct populations of Asia-Oceania.

    PubMed

    Zimdahl, H; Schiefenhövel, W; Kayser, M; Roewer, L; Nagy, M

    1999-12-01

    HLA class II nucleotide sequence polymorphisms were examined in eight ethnic groups of Asia-Oceania using DNA typing methods. Allele frequencies and characteristic DR/DQ haplotypes were determined and compared with those of other populations of Asia-Oceania. Genetic distances were measured to show the genetic relationship within the studied populations as well as between the studied populations and previously published populations. Phylogenetic trees were constructed based on HLA allele frequencies using the neighbour-joining method. The populations, mainly Trobriand Islanders, Roro, Tolai, Western Samoans and Taiwanese Aborigines, are characterized by a reduced diversity at the HLA loci examined, especially for DPB1. The high frequency of the 'Asian'-specific DPB1*0501 allele in Trobrianders and Roro, but also in Western Samoans and Taiwanese Aborigines, was the most striking result. The prevalence of DPB1*0501 and the short genetic distance from Trobriander and Roro to Taiwanese Aborigines provide evidence that the origin of the Austronesian odyssey is south-east Asia, and Taiwan could be an important part of it. The relatedness of Trobrianders to the Polynesian population from Western Samoa indicates a probable recent common ancestor. The observed lack of diversity may reflect bottleneck(s) and/or limited diversity of the founding population. Analysis of HLA class I antigens, together with mt-DNA and Y-chromosomal studies, will give us further information about the settlement of the Trobriand and other islands during the colonization of the Pacific.

  8. Genotypic diversity of the Killer Cell Immunoglobulin-like Receptors (KIR) and their HLA class I Ligands in a Saudi population

    PubMed Central

    Omar, Suliman Y. Al; Alkuriji, Afrah; Alwasel, Saleh; Dar, javid Ahmed; Alhammad, Alwaleed; Christmas, Stephen; Mansour, Lamjed

    2016-01-01

    Abstract Killer Cell Immunoglobulin-like Receptors (KIR) have been used as good markers for the study of genetic predisposition in many diseases and in human genetic population dynamics. In this context, we have investigated the genetic diversity of KIR genes and their main HLA class I ligands in Saudi population and compared the data with other studies of neighboring populations. One hundred and fourteen randomly selected healthy Saudi subjects were genotyped for the presence or absence of 16 KIR genes and their HLA-C1, -C2, -Bw4Thr80 and Bw4Ile80 groups, using a PCR-SSP technique. The results show the occurrence of the framework genes (3DL2, 3DL3 and 2DL4) and the pseudogenes (2DP1 and 3DP1) at highest frequencies. All inhibitory KIR (iKIR) genes appeared at higher frequencies than activating genes (aKIR), except for 2DS4 with a frequency of 90.35%. A total of 55 different genotypes were observed appearing at different frequencies, where 12 are considered novel. Two haplotypes were characterized, AA and Bx (BB and AB), which were observed in 24.5% and 75.5% respectively of the studied group. The frequencies of iKIR + HLA associations were found to be much higher than aKIR + HLA. KIR genes frequencies in the Saudi population are comparable with other Middle Eastern and North African populations. PMID:27007893

  9. Serum antibodies to human leucocyte antigen (HLA)-E, HLA-F and HLA-G in patients with systemic lupus erythematosus (SLE) during disease flares: Clinical relevance of HLA-F autoantibodies.

    PubMed

    Jucaud, V; Ravindranath, M H; Terasaki, P I; Morales-Buenrostro, L E; Hiepe, F; Rose, T; Biesen, R

    2016-03-01

    T lymphocyte hyperactivity and progressive inflammation in systemic lupus erythematosus (SLE) patients results in over-expression of human leucocyte antigen (HLA)-Ib on the surface of lymphocytes. These are shed into the circulation upon inflammation, and may augment production of antibodies promoting pathogenicity of the disease. The objective was to evaluate the association of HLA-Ib (HLA-E, HLA-F and HLA-G) antibodies to the disease activity of SLE. The immunoglobulin (Ig)G/IgM reactivity to HLA-Ib and β2m in the sera of 69 German, 29 Mexican female SLE patients and 17 German female controls was measured by multiplex Luminex(®)-based flow cytometry. The values were expressed as mean flourescence intensity (MFI). Only the German SLE cohort was analysed in relation to the clinical disease activity. In the controls, anti-HLA-G IgG predominated over other HLA-Ib antibodies, whereas SLE patients had a preponderance of anti-HLA-F IgG over the other HLA-Ib antibodies. The disease activity index, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)-2000, was reflected only in the levels of anti-HLA-F IgG. Anti-HLA-F IgG with MFI level of 500-1999 was associated with active SLE, whereas inactive SLE revealed higher MFI (>2000). When anti-HLA-F IgG were cross-reactive with other HLA-Ib alleles, their reactivity was reflected in the levels of anti-HLA-E and -G IgG. The prevalence of HLA-F-monospecific antibodies in SLE patients was also associated with the clinical disease activity. Anti-HLA-F IgG is possibly involved in the clearance of HLA-F shed from lymphocytes and inflamed tissues to lessen the disease's severity, and thus emerges as a beneficial immune biomarker. Therefore, anti-HLA-Ib IgG should be considered as a biomarker in standard SLE diagnostics.

  10. Large scale replication study of the association between HLA class II/BTNL2 variants and osteoarthritis of the knee in European-descent populations.

    PubMed

    Valdes, Ana M; Styrkarsdottir, Unnur; Doherty, Michael; Morris, David L; Mangino, Massimo; Tamm, Agu; Doherty, Sally A; Kisand, Kalle; Kerna, Irina; Tamm, Ann; Wheeler, Margaret; Maciewicz, Rose A; Zhang, Weiya; Muir, Kenneth R; Dennison, Elaine M; Hart, Deborah J; Metrustry, Sarah; Jonsdottir, Ingileif; Jonsson, Gudbjorn F; Jonsson, Helgi; Ingvarsson, Thorvaldur; Cooper, Cyrus; Vyse, Timothy J; Spector, Tim D; Stefansson, Kari; Arden, Nigel K

    2011-01-01

    Osteoarthritis (OA) is the most common form of arthritis and a major cause of disability. This study evaluates the association in Caucasian populations of two single nucleotide polymorphisms (SNPs) mapping to the Human Leukocyte Antigen (HLA) region and deriving from a genome wide association scan (GWAS) of knee OA in Japanese populations. The frequencies for rs10947262 were compared in 36,408 controls and 5,749 knee OA cases from European-descent populations. rs7775228 was tested in 32,823 controls and 1,837 knee OA cases of European descent. The risk (major) allele at rs10947262 in Caucasian samples was not significantly associated with an odds ratio (OR)  = 1.07 (95%CI 0.94 -1.21; p = 0.28). For rs7775228 the meta-analysis resulted in OR = 0.94 (95%CI 0.81-1.09; p = 0.42) for the allele associated with risk in the Japanese GWAS. In Japanese individuals these two SNPs are in strong linkage disequilibrium (LD) (r(2) = 0.86) with the HLA class II haplotype DRB1*1502 DQA1*0103 DQB1*0601 (frequency 8%). In Caucasian and Chinese samples, using imputed data, these SNPs appear not to be in LD with that haplotype (r(2)<0.07). The rs10947262 and rs7775228 variants are not associated with risk of knee OA in European descent populations and they do not appear tag the same HLA class II haplotype as they do in Japanese individuals.

  11. Accounting for haplotype phase uncertainty in linkage disequilibrium estimation.

    PubMed

    Kulle, B; Frigessi, A; Edvardsen, H; Kristensen, V; Wojnowski, L

    2008-02-01

    The characterization of linkage disequilibrium (LD) is applied in a variety of studies including the identification of molecular determinants of the local recombination rate, the migration and population history of populations, and the role of positive selection in adaptation. LD suffers from the phase uncertainty of the haplotypes used in its calculation, which reflects limitations of the algorithms used for haplotype estimation. We introduce a LD calculation method, which deals with phase uncertainty by weighting all possible haplotype pairs according to their estimated probabilities as evaluated by PHASE. In contrast to the expectation-maximization (EM) algorithm as implemented in the HAPLOVIEW and GENETICS packages, our method considers haplotypes based on the entire genetic information available for the candidate region. We tested the method using simulated and real genotyping data. The results show that, for all practical purposes, the new method is advantageous in comparison with algorithms that calculate LD using only the most probable haplotype or bilocus haplotypes based on the EM algorithm. The new method deals especially well with low LD regions, which contribute strongly to phase uncertainty. Altogether, the method is an attractive alternative to standard LD calculation procedures, including those based on the EM algorithm. We implemented the method in the software suite R, together with an interface to the popular haplotype calculation package PHASE.

  12. Human dopamine transporter gene: differential regulation of 18-kb haplotypes

    PubMed Central

    Zhao, Ying; Xiong, Nian; Liu, Yang; Zhou, Yanhong; Li, Nuomin; Qing, Hong; Lin, Zhicheng

    2013-01-01

    Aim Since previous functional studies of short haplotypes and polymorphic sites of SLC6A3 have shown variant-dependent and drug-sensitive promoter activity, this study aimed to understand whether a large SLC6A3 regulatory region, containing these small haplotypes and polymorphic sites, can display haplotype-dependent promoter activity in a drug-sensitive and pathway-related manner. Materials & methods By creating and using a single copy number luciferase-reporter vector, we examined regulation of two different SLC6A3 haplotypes (A and B) of the 5′ 18-kb promoter and two known downstream regulatory variable number tandem repeats by 17 drugs in four different cellular models. Results The two regulatory haplotypes displayed up to 3.2-fold difference in promoter activity. The regulations were drug selective (37.5% of the drugs showed effects), and both haplotype and cell type dependent. Pathway analysis revealed at least 13 main signaling hubs targeting SLC6A3, including histone deacetylation, AKT, PKC and CK2 α-chains. Conclusion SLC6A3 may be regulated via either its promoter or the variable number tandem repeats independently by specific signaling pathways and in a haplotype-dependent manner. Furthermore, we have developed the first pathway map for SLC6A3 regulation. These findings provide a framework for understanding complex and variant-dependent regulations of SLC6A3. PMID:24024899

  13. Imputing Variants in HLA-DR Beta Genes Reveals That HLA-DRB1 Is Solely Associated with Rheumatoid Arthritis and Systemic Lupus Erythematosus

    PubMed Central

    Kim, Kwangwoo; Bang, So-Young; Yoo, Dae Hyun; Cho, Soo-Kyung; Choi, Chan-Bum; Sung, Yoon-Kyoung; Kim, Tae-Hwan; Jun, Jae-Bum; Kang, Young Mo; Suh, Chang-Hee; Shim, Seung-Cheol; Lee, Shin-Seok; Lee, Jisoo; Chung, Won Tae; Kim, Seong-Kyu; Choe, Jung-Yoon; Nath, Swapan K.; Lee, Hye-Soon; Bae, Sang-Cheol

    2016-01-01

    The genetic association of HLA-DRB1 with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) is well documented, but association with other HLA-DR beta genes (HLA-DRB3, HLA-DRB4 and HLA-DRB5) has not been thoroughly studied, despite their similar functions and chromosomal positions. We examined variants in all functional HLA-DR beta genes in RA and SLE patients and controls, down to the amino-acid level, to better understand disease association with the HLA-DR locus. To this end, we improved an existing HLA reference panel to impute variants in all protein-coding HLA-DR beta genes. Using the reference panel, HLA variants were inferred from high-density SNP data of 9,271 RA-control subjects and 5,342 SLE-control subjects. Disease association tests were performed by logistic regression and log-likelihood ratio tests. After imputation using the newly constructed HLA reference panel and statistical analysis, we observed that HLA-DRB1 variants better accounted for the association between MHC and susceptibility to RA and SLE than did the other three HLA-DRB variants. Moreover, there were no secondary effects in HLA-DRB3, HLA-DRB4, or HLA-DRB5 in RA or SLE. Of all the HLA-DR beta chain paralogs, those encoded by HLA-DRB1 solely or dominantly influence susceptibility to RA and SLE. PMID:26919467

  14. The Immunogenicity of HLA Class II Mismatches: The Predicted Presentation of Nonself Allo-HLA-Derived Peptide by the HLA-DR Phenotype of the Recipient Is Associated with the Formation of DSA

    PubMed Central

    2017-01-01

    The identification of permissible HLA class II mismatches can prevent DSA in mismatched transplantation. The HLA-DR phenotype of recipients contributes to DSA formation by presenting allo-HLA-derived peptides to T-helper cells, which induces the differentiation of B cells into plasma cells. Comparing the binding affinity of self and nonself allo-HLA-derived peptides for recipients' HLA class II antigens may distinguish immunogenic HLA mismatches from nonimmunogenic ones. The binding affinities of allo-HLA-derived peptides to recipients' HLA-DR and HLA-DQ antigens were predicted using the NetMHCIIpan 3.1 server. HLA class II mismatches were classified based on whether they induced DSA and whether self or nonself peptide was predicted to bind with highest affinity to recipients' HLA-DR and HLA-DQ. Other mismatch characteristics (eplet, hydrophobic, electrostatic, and amino acid mismatch scores and PIRCHE-II) were evaluated. A significant association occurred between DSA formation and the predicted HLA-DR presentation of nonself peptides (P = 0.0169; accuracy = 80%; sensitivity = 88%; specificity = 63%). In contrast, mismatch characteristics did not differ significantly between mismatches that induced DSA and the ones that did not, except for PIRCHE-II (P = 0.0094). This methodology predicts DSA formation based on HLA mismatches and recipients' HLA-DR phenotype and may identify permissible HLA mismatches to help optimize HLA matching and guide donor selection. PMID:28331856

  15. HLA-G and classical HLA class I expression in primary colorectal cancer and associated liver metastases.

    PubMed

    Swets, Marloes; König, Marion H; Zaalberg, Anniek; Dekker-Ensink, Neeltje G; Gelderblom, Hans; van de Velde, Cornelis J H; van den Elsen, Peter J; Kuppen, Peter J K

    2016-09-01

    De novo expression of HLA-G has been demonstrated in colorectal cancer. HLA-G, amongst others, inhibits natural killer cell function, contributing to host immune defense evasion. Another mechanism to escape anti-tumor immunity is loss of HLA class I. Therefore, we determined HLA-G and HLA class I expression on primary colorectal tumors and associated liver metastases, in order to get insight in the metastasizing process regarding escaping anti-tumor immunity. HLA-G expression was evaluated using three mAbs; 4H84, MEM-G/1 and MEM-G/2. In total 81 colorectal cancer patients were evaluated. Formalin-fixed paraffin-embedded tissue sections of primary tumors and associated liver metastases, were immunohistochemically stained. A concordance between expression or loss/downregulation in the primary tumor and associated liver metastasis regarding HLA class I expression was observed in 80% of the cases. In contrast with the hypothesis of escaping NK cell-killing, we demonstrated for each HLA-G detecting mAbs used in this study, that the majority of the primary tumors that positively stained for HLA-G did not express HLA-G in the associated liver metastasis. Furthermore, we revealed the existence of non-specific binding and in addition we found that the different epitopes of HLA-G detected by 4H84, MEM-G/1 and MEM-G/2 mAbs were expressed differentially in colorectal tumor tissues.

  16. General Framework for Meta‐Analysis of Haplotype Association Tests

    PubMed Central

    Wang, Shuai; Zhao, Jing Hua; An, Ping; Guo, Xiuqing; Jensen, Richard A.; Marten, Jonathan; Huffman, Jennifer E.; Meidtner, Karina; Boeing, Heiner; Campbell, Archie; Rice, Kenneth M.; Scott, Robert A.; Yao, Jie; Schulze, Matthias B.; Wareham, Nicholas J.; Borecki, Ingrid B.; Province, Michael A.; Rotter, Jerome I.; Hayward, Caroline; Goodarzi, Mark O.; Meigs, James B.

    2016-01-01

    ABSTRACT For complex traits, most associated single nucleotide variants (SNV) discovered to date have a small effect, and detection of association is only possible with large sample sizes. Because of patient confidentiality concerns, it is often not possible to pool genetic data from multiple cohorts, and meta‐analysis has emerged as the method of choice to combine results from multiple studies. Many meta‐analysis methods are available for single SNV analyses. As new approaches allow the capture of low frequency and rare genetic variation, it is of interest to jointly consider multiple variants to improve power. However, for the analysis of haplotypes formed by multiple SNVs, meta‐analysis remains a challenge, because different haplotypes may be observed across studies. We propose a two‐stage meta‐analysis approach to combine haplotype analysis results. In the first stage, each cohort estimate haplotype effect sizes in a regression framework, accounting for relatedness among observations if appropriate. For the second stage, we use a multivariate generalized least square meta‐analysis approach to combine haplotype effect estimates from multiple cohorts. Haplotype‐specific association tests and a global test of independence between haplotypes and traits are obtained within our framework. We demonstrate through simulation studies that we control the type‐I error rate, and our approach is more powerful than inverse variance weighted meta‐analysis of single SNV analysis when haplotype effects are present. We replicate a published haplotype association between fasting glucose‐associated locus (G6PC2) and fasting glucose in seven studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and we provide more precise haplotype effect estimates. PMID:27027517

  17. Maximum-likelihood estimation of haplotype frequencies in nuclear families.

    PubMed

    Becker, Tim; Knapp, Michael

    2004-07-01

    The importance of haplotype analysis in the context of association fine mapping of disease genes has grown steadily over the last years. Since experimental methods to determine haplotypes on a large scale are not available, phase has to be inferred statistically. For individual genotype data, several reconstruction techniques and many implementations of the expectation-maximization (EM) algorithm for haplotype frequency estimation exist. Recent research work has shown that incorporating available genotype information of related individuals largely increases the precision of haplotype frequency estimates. We, therefore, implemented a highly flexible program written in C, called FAMHAP, which calculates maximum likelihood estimates (MLEs) of haplotype frequencies from general nuclear families with an arbitrary number of children via the EM-algorithm for up to 20 SNPs. For more loci, we have implemented a locus-iterative mode of the EM-algorithm, which gives reliable approximations of the MLEs for up to 63 SNP loci, or less when multi-allelic markers are incorporated into the analysis. Missing genotypes can be handled as well. The program is able to distinguish cases (haplotypes transmitted to the first affected child of a family) from pseudo-controls (non-transmitted haplotypes with respect to the child). We tested the performance of FAMHAP and the accuracy of the obtained haplotype frequencies on a variety of simulated data sets. The implementation proved to work well when many markers were considered and no significant differences between the estimates obtained with the usual EM-algorithm and those obtained in its locus-iterative mode were observed. We conclude from the simulations that the accuracy of haplotype frequency estimation and reconstruction in nuclear families is very reliable in general and robust against missing genotypes.

  18. Validation of the High-Risk Pregnancy Stress Scale in a sample of hospitalized Greek high-risk pregnant women.

    PubMed

    Gourounti, Kleanthi; Karpathiotaki, Natassa; Karapanou, Vassiliki; Antzaklis, Panos; Daskalakis, Georgios

    2016-01-01

    The aim of the authors in this study was to determine the psychometric properties of the Greek adaptation of the High-Risk Pregnancy Stress Scale (HRPSS) in a sample of high-risk hospitalized pregnant women. The sample consisted of 133 high-risk pregnant women with gestational age from 9 to 37 weeks. Data were collected between February and June of 2014. HRPSS was "forward-backward" translated from English to Greek. Principal axis factoring with promax rotation was used to test the factor structure of the HRPSS. Measures of state anxiety (STAI) and depressive symptoms (EPDS) were used to assess the convergent validity of the HRPSS. Exploratory factor analysis suggested three factors: concerns of pregnancy, movement restriction, and isolation and restriction of external activities. Construct validity was confirmed by computing correlations between the HRPSS and constructions of anxiety and depressive symptoms. Internal consistency reliability was satisfactory (α = 0.813). The original factor structure of the HRPSS was only partly replicated. The results of the exploratory factor analysis suggested that a three-factor solution instead of a two-factor solution would be the most adequate. The HRPSS is an appropriate measure for assessing the levels of concerns regarding pregnancy outcome, movement restriction, isolation, and external activity restrictions in Greek high-risk pregnant women.

  19. Comparison of the power of haplotype-based versus single- and multilocus association methods for gene × environment (gene × sex) interactions and application to gene × smoking and gene × sex interactions in rheumatoid arthritis

    PubMed Central

    Dempfle, Astrid; Hein, Rebecca; Beckmann, Lars; Scherag, André; Nguyen, Thuy Trang; Schäfer, Helmut; Chang-Claude, Jenny

    2007-01-01

    Accounting for interactions with environmental factors in association studies may improve the power to detect genetic effects and may help identifying important environmental effect modifiers. The power of unphased genotype-versus haplotype-based methods in regions with high linkage disequilibrium (LD), as measured by D', for analyzing gene × environment (gene × sex) interactions was compared using the Genetic Analysis Workshop 15 (GAW15) simulated data on rheumatoid arthritis with prior knowledge of the answers. Stepwise and regular conditional logistic regression (CLR) was performed using a matched case-control sample for a HLA region interacting with sex. Haplotype-based analyses were performed using a haplotype-sharing-based Mantel statistic and a test for haplotype-trait association in a general linear model framework. A step-down minP algorithm was applied to derive adjusted p-values and to allow for power comparisons. These methods were also applied to the GAW15 real data set for PTPN22. For markers in strong LD, stepwise CLR performed poorly because of the correlation/collinearity between the predictors in the model. The power was high for detecting genetic main effects using simple CLR models and haplotype-based methods and for detecting joint effects using CLR and Mantel statistics. Only the haplotype-trait association test had high power to detect the gene × sex interaction. In the PTPN22 region with markers characterized by strong LD, all methods indicated a significant genotype × sex interaction in a sample of about 1000 subjects. The previously reported R620W single-nucleotide polymorphism was identified using logistic regression, but the haplotype-based methods did not provide any precise location information. PMID:18466575

  20. A single endoplasmic reticulum aminopeptidase-1 protein allotype is a strong risk factor for Behçet’s disease in HLA-B*51 carriers

    PubMed Central

    Takeuchi, Masaki; Ombrello, Michael J; Kirino, Yohei; Erer, Burak; Tugal-Tutkun, Ilknur; Seyahi, Emire; Özyazgan, Yilmaz; Watts, Norman; Gül, Ahmet; Kastner, Daniel L.; Remmers, Elaine F

    2016-01-01

    Introduction Endoplasmic reticulum aminopeptidase 1 (ERAP1) protein is highly polymorphic with numerous missense amino acid variants. We sought to determine the naturally occurring ERAP1 protein allotypes and their contribution to Behçet’s disease. Methods Genotypes of all reported missense ERAP1 gene variants with 1000 Genomes EUR super-population frequency greater than 1% were determined in 1,900 Behçet’s disease cases and 1,779 controls from Turkey. ERAP1 protein allotypes and their contributions to Behçet’s disease risk were determined by haplotype identification and disease association analyses. Results One ERAP1 protein allotype with 5 non-ancestral amino acids was recessively associated with disease (P = 3.13 × 10−6, odds ratio 2.55, 95% CI 1.70 to 3.82). The ERAP1 association was absent in individuals who lacked HLA-B*51. Individuals who carry HLA-B*51 and who are also homozygous for the haplotype had an increased disease odds compared with those with neither risk factor (P = 4.80 × 10−20, odds ratio 10.96, 95% CI 5.91 to 20.32). Discussion The Behçet’s disease-associated ERAP1 protein allotype was previously shown to have poor peptide trimming activity. Combined with its requirement for HLA-B*51, these data suggest that a hypoactive ERAP1 allotype contributes to Behçet’s disease risk by altering the peptides available for binding to HLA-B*51. PMID:27217550

  1. The A3 allele of the HLA-DQA1 locus is associated with susceptibility to type 1 diabetes in Japanese.

    PubMed Central

    Todd, J A; Fukui, Y; Kitagawa, T; Sasazuki, T

    1990-01-01

    Analysis of the frequencies of class II HLA-DR and HLA-DQ alleles by serological and DNA typing in 49 Japanese patients with type 1 (insulin-dependent) diabetes and 31 Japanese controls indicates the following. (i) Susceptibility is more strongly associated with the HLA-DQ subregion than with the HLA-DR subregion. (ii) Of the class II alleles detected, the A3 allele of the DQA1 locus was the most strongly associated with disease. Ninety-six percent of the patients were positive for the A3 allele compared to 53% of the controls (P = 0.001; relative risk = 19.7; confidence limits = 3.72-188.64)