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Sample records for receptor lepr snp

  1. Leptin receptor (LEPR) SNP polymorphisms in HELLP syndrome patients determined by quantitative real-time PCR and melting curve analysis

    PubMed Central

    2010-01-01

    Background Several studies have shown overexpression of leptin in microarray experiments in pre-eclampsia (PE) and in hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. We decided to study four leptin receptor (LEPR) SNP polymorphisms in HELLP syndrome patients by using quantitative real-time PCR and melting curve analysis. Methods DNA was isolated from blood samples from 83 normotensive pregnant women and 75 HELLP syndrome patients. Four SNPs, LEPR c.326A>G (K109), LEPR c.668A>G (Q223R), LEPR c.1968G>C (K656N) and LEPR c.3024A>G (S1008) were determined by quantitative real-time PCR and melting curve analysis. Investigators were blinded to clinical outcomes. Results LEPR c.326A>G, LEPR c.668A>G, LEPR c.1968G>C and LEPR c.3024A>G allele, genotype and haplotype polymorphisms were not different in HELLP syndrome patients and normotensive healthy pregnants. There were strong linkage disequilibrium (LD) between loci c.326A>G and c.6687A>G (D' = 0.974), and c.668A>G and c.1968G>C (D' = 0.934), and c.326A>G and c.1968G>C (D' = 0.885), and c.1968G>C and c.3024A>G (D' = 1.0). However, linkages of c.3024A>G with c.668A>G (D' = 0.111) and c.326A>G (D' = 0.398) were weak. The Hardy-Weinberg equilibrium was observed for all polymorphisms. However the LEPR c.326A>G AG genotype was twice more frequent and the (AG AG GG AG) haplotype was three times more frequent in HELLP syndrome patients. The introduced quantitative real-time PCR combined with melting curve analysis is a fast and reliable method for the determination of LEPR SNPs. Conclusion Although certain LEPR haplotypes are more frequent in HELLP syndrome, we conclude that there is no compelling evidence that the four studied LEPR SNP polymorphisms associated with the development of HELLP syndrome. PMID:20149225

  2. Long form leptin receptor and SNP effect on reproductive traits during embryo attachment in Suzhong sows.

    PubMed

    Fu, Yanfeng; Li, Lan; Li, Bixia; Fang, Xiaomin; Ren, Shouwen

    2016-05-01

    To ascertain whether the long form leptin receptor (LEPR) affects the regulation of embryo attachment and whether there are LEPR Single Nucleotide Polymorphisms (SNPs) associated with reproductive traits in pigs, Real-time qPCR was used to detect relative abundance of LEPR mRNA pattern in different tissues of Suzhong sows during the embryo attachment period (pregnancy day 13, 18 and 24) to the uterus, and PCR-RFLP as well as PCR-sequencing were used to investigate the coding sequence for SNPs of LEPR in a population of 512 Suzhong sows. Real-time qPCR results indicated that LEPR mRNA was present in all 22 tissues of pigs with differences in relative abundance of the LEPR mRNA (P<0.05). Among these tissues, the greatest relative abundance occurred at the endometrial attachment site (P<0.01), followed by the hypothalamus and most reproductive tissues (P<0.05), and there was a lesser relative abundance of the LEPR mRNA in the pituitary. During different embryo attachment periods, LEPR mRNA was greatest on Day 18 (attachment; P<0.05), followed by Day 24 (post-attachment), and relative abundance was least on Day 13 (pre-attachment). The prevalence of the LEPR mRNA in pregnant sows was greater than in non-pregnant sows (P<0.05). At the c.2856C>T locus of LEPR, Chi-square test results demonstrated that allele and genotype frequencies were in Hardy-Weinberg disequilibrium at this locus, PCR-RFLP results revealed that Genotype TT was greater than Genotype CC (P<0.05) for reproductive traits of TNB (Total Number Born) and NBA (Number Born Alive), which suggested that T allele at c.2856C>T locus has advantageous effects on litter size and litter weight in Suzhong pigs. In conclusion, the expression of the LEPR gene might be involved in the regulation of embryo attachment mechanisms in pigs, and the LEPR SNP c.2856C>T could be a molecular marker for improving litter size and litter weight in pig breeding. PMID:27020480

  3. Association between Variants of the Leptin Receptor Gene (LEPR) and Overweight: A Systematic Review and an Analysis of the CoLaus Study

    PubMed Central

    Bender, Nicole; Allemann, Noëmi; Marek, Diana; Vollenweider, Peter; Waeber, Gérard; Mooser, Vincent; Egger, Matthias; Bochud, Murielle

    2011-01-01

    Background Three non-synonymous single nucleotide polymorphisms (Q223R, K109R and K656N) of the leptin receptor gene (LEPR) have been tested for association with obesity-related outcomes in multiple studies, showing inconclusive results. We performed a systematic review and meta-analysis on the association of the three LEPR variants with BMI. In addition, we analysed 15 SNPs within the LEPR gene in the CoLaus study, assessing the interaction of the variants with sex. Methodology/Principal Findings We searched electronic databases, including population-based studies that investigated the association between LEPR variants Q223R, K109R and K656N and obesity- related phenotypes in healthy, unrelated subjects. We furthermore performed meta-analyses of the genotype and allele frequencies in case-control studies. Results were stratified by SNP and by potential effect modifiers. CoLaus data were analysed by logistic and linear regressions and tested for interaction with sex. The meta-analysis of published data did not show an overall association between any of the tested LEPR variants and overweight. However, the choice of a BMI cut-off value to distinguish cases from controls was crucial to explain heterogeneity in Q223R. Differences in allele frequencies across ethnic groups are compatible with natural selection of derived alleles in Q223R and K109R and of the ancient allele in K656N in Asians. In CoLaus, the rs10128072, rs3790438 and rs3790437 variants showed interaction with sex for their association with overweight, waist circumference and fat mass in linear regressions. Conclusions Our systematic review and analysis of primary data from the CoLaus study did not show an overall association between LEPR SNPs and overweight. Most studies were underpowered to detect small effect sizes. A potential effect modification by sex, population stratification, as well as the role of natural selection should be addressed in future genetic association studies. PMID:22028824

  4. The receptor-like kinase SOBIR1 interacts with Brassica napus LepR3 and is required for Leptosphaeria maculans AvrLm1-triggered immunity.

    PubMed

    Ma, Lisong; Borhan, M Hossein

    2015-01-01

    The fungus Leptosphaeria maculans (L. maculans) is the causal agent of blackleg disease of canola/oilseed rape (Brassica napus) worldwide. We previously reported cloning of the B. napus blackleg resistance gene, LepR3, which encodes a receptor-like protein. LepR3 triggers localized cell death upon recognition of its cognate Avr protein, AvrLm1. Here, we exploited the Nicotiana benthamiana model plant to investigate the recognition mechanism of AvrLm1 by LepR3. Co-expression of the LepR3/AvrLm1 gene pair in N. benthamiana resulted in development of a hypersensitive response (HR). However, a truncated AvrLm1 lacking its indigenous signal peptide was compromised in its ability to induce LepR3-mediated HR, indicating that AvrLm1 is perceived by LepR3 extracellularly. Structure-function analysis of the AvrLm1 protein revealed that the C-terminal region of AvrLm1 was required for LepR3-mediated HR in N. benthamiana and for resistance to L. maculans in B. napus. LepR3 was shown to be physically interacting with the B. napus receptor like kinase, SOBIR1 (BnSOBIR1). Silencing of NbSOBIR1 or NbSERK3 (BAK1) compromised LepR3-AvrLm1-dependent HR in N. benthamiana, suggesting that LepR3-mediated resistance to L. maculans in B. napus requires SOBIR1 and BAK1/SERK3. Using this model system, we determined that BnSOBIR1 and SERK3/BAK1 are essential partners in the LepR3 signaling complex and were able to define the AvrLm1 effector domain. PMID:26579176

  5. Genome-wide association study identifies polymorphisms in LEPR as determinants of plasma soluble leptin receptor levels.

    PubMed

    Sun, Qi; Cornelis, Marilyn C; Kraft, Peter; Qi, Lu; van Dam, Rob M; Girman, Cynthia J; Laurie, Cathy C; Mirel, Daniel B; Gong, Huizi; Sheu, Chau-Chyun; Christiani, David C; Hunter, David J; Mantzoros, Christos S; Hu, Frank B

    2010-05-01

    Plasma soluble leptin receptor (sOB-R) levels were inversely associated with diabetes risk factors, including adiposity and insulin resistance, and highly correlated with the expression levels of leptin receptor, which is ubiquitously expressed in most tissues. We conducted a genome-wide association study of sOB-R in 1504 women of European ancestry from the Nurses' Health Study. The initial scan yielded 26 single nucleotide polymorphisms (SNPs) significantly associated with sOB-R levels (P < 5 x 10(-8)); all mapping to the leptin receptor gene (LEPR). Analysis of imputed genotypes on autosomal chromosomes revealed an additional 106 SNPs in and adjacent to this gene that reached genome-wide significance level. Of these 132 SNPs (including two non-synonymous SNPs, rs1137100 and rs1137101), rs2767485, rs1751492 and rs4655555 remained associated with sOB-R levels at the 0.05 level (P = 9.1 x 10(-9), 0.0105 and 0.0267, respectively) after adjustment for other univariately associated SNPs in a forward selection procedure. Significant associations with these SNPs were replicated in an independent sample of young males (n = 875) residing in Cyprus (P < 1 x 10(-4)). These data provide novel evidence revealing the role of polymorphisms in LEPR in modulating plasma levels of sOB-R and may further our understanding of the complex relationships among leptin, leptin receptor and diabetes-related traits. PMID:20167575

  6. Genome-wide association study identifies polymorphisms in LEPR as determinants of plasma soluble leptin receptor levels

    PubMed Central

    Sun, Qi; Cornelis, Marilyn C.; Kraft, Peter; Qi, Lu; van Dam, Rob M.; Girman, Cynthia J.; Laurie, Cathy C.; Mirel, Daniel B.; Gong, Huizi; Sheu, Chau-Chyun; Christiani, David C.; Hunter, David J.; Mantzoros, Christos S.; Hu, Frank B.

    2010-01-01

    Plasma soluble leptin receptor (sOB-R) levels were inversely associated with diabetes risk factors, including adiposity and insulin resistance, and highly correlated with the expression levels of leptin receptor, which is ubiquitously expressed in most tissues. We conducted a genome-wide association study of sOB-R in 1504 women of European ancestry from the Nurses' Health Study. The initial scan yielded 26 single nucleotide polymorphisms (SNPs) significantly associated with sOB-R levels (P < 5 × 10−8); all mapping to the leptin receptor gene (LEPR). Analysis of imputed genotypes on autosomal chromosomes revealed an additional 106 SNPs in and adjacent to this gene that reached genome-wide significance level. Of these 132 SNPs (including two non-synonymous SNPs, rs1137100 and rs1137101), rs2767485, rs1751492 and rs4655555 remained associated with sOB-R levels at the 0.05 level (P = 9.1 × 10−9, 0.0105 and 0.0267, respectively) after adjustment for other univariately associated SNPs in a forward selection procedure. Significant associations with these SNPs were replicated in an independent sample of young males (n = 875) residing in Cyprus (P < 1 × 10−4). These data provide novel evidence revealing the role of polymorphisms in LEPR in modulating plasma levels of sOB-R and may further our understanding of the complex relationships among leptin, leptin receptor and diabetes-related traits. PMID:20167575

  7. Sex Differences in Somatotrope Dependency on Leptin Receptors in Young Mice: Ablation of LEPR Causes Severe Growth Hormone Deficiency and Abdominal Obesity in Males.

    PubMed

    Allensworth-James, Melody L; Odle, Angela; Haney, Anessa; Childs, Gwen

    2015-09-01

    Leptin receptor (LEPR) signaling controls appetite and energy expenditure. Somatotrope-specific deletion of the LEPRb signaling isoform causes GH deficiency and obesity. The present study selectively ablated Lepr exon 1 in somatotropes, which removes the signal peptide, causing the loss of all isoforms of LEPR. Excision of Lepr exon 1 was restricted to the pituitary, and mutant somatotropes failed to respond to leptin. Young (2-3 mo) males showed a severe 84% reduction in serum GH levels and more than 60% reduction in immunolabeled GH cells compared with 41%-42% reductions in GH and GH cells in mutant females. Mutant males (35 d) and females (45 d) weighed less than controls and males had lower lean body mass. Image analysis of adipose tissue by magnetic resonance imaging showed that young males had a 2-fold increase in abdominal fat mass and increased adipose tissue density. Young females had only an overall increase in adipose tissue. Both males and females showed lower energy expenditure and higher respiratory quotient, indicating preferential carbohydrate burning. Young mutant males slept less and were more restless during the dark phase, whereas the opposite was true of females. The effects of a Cre-bearing sire on his non-Cre-recombinase bearing progeny are seen by increased respiratory quotient and reduced litter sizes. These studies elucidate clear sex differences in the extent to which somatotropes are dependent on all isoforms of LEPR. These results, which were not seen with the ablation of Lepr exon 17, highlight the severe consequences of ablation of LEPR in male somatotropes. PMID:26168341

  8. Leptin receptor null mice with reexpression of LepR in GnRHR expressing cells display elevated FSH levels but remain in a prepubertal state.

    PubMed

    Allen, Susan J; Garcia-Galiano, David; Borges, Beatriz C; Burger, Laura L; Boehm, Ulrich; Elias, Carol F

    2016-06-01

    Leptin signals energy sufficiency to the reproductive hypothalamic-pituitary-gonadal (HPG) axis. Studies using genetic models have demonstrated that hypothalamic neurons are major players mediating these effects. Leptin receptor (LepR) is also expressed in the pituitary gland and in the gonads, but the physiological effects of leptin in these sites are still unclear. Female mice with selective deletion of LepR in a subset of gonadotropes show normal pubertal development but impaired fertility. Conditional deletion approaches, however, often result in redundancy or developmental adaptations, which may compromise the assessment of leptin's action in gonadotropes for pubertal maturation. To circumvent these issues, we adopted a complementary genetic approach and assessed if selective reexpression of LepR only in gonadotropes is sufficient to enable puberty and improve fertility of LepR null female mice. We initially assessed the colocalization of gonadotropin-releasing hormone receptor (GnRHR) and LepR in the HPG axis using GnRHR-IRES-Cre (GRIC) and LepR-Cre reporter (tdTomato or enhanced green fluorescent protein) mice. We found that GRIC and leptin-induced phosphorylation of STAT3 are expressed in distinct hypothalamic neurons. Whereas LepR-Cre was observed in theca cells, GRIC expression was rarely found in the ovarian parenchyma. In contrast, a subpopulation of gonadotropes expressed the LepR-Cre reporter gene (tdTomato). We then crossed the GRIC mice with the LepR null reactivable (LepR(loxTB)) mice. These mice showed an increase in FSH levels, but they remained in a prepubertal state. Together with previous findings, our data indicate that leptin-selective action in gonadotropes serves a role in adult reproductive physiology but is not sufficient to allow pubertal maturation in mice. PMID:27101301

  9. Functional consequences of the human leptin receptor (LEPR) Q223R transversion

    PubMed Central

    Stratigopoulos, George; LeDuc, Charles A.; Matsuoka, Naoki; Gutman, Roee; Rausch, Richard; Robertson, Scott A.; Myers, Martin G; Chung, Wendy K; Chua, Streamson C.; Leibel, Rudolph L.

    2010-01-01

    Perturbations in the functional integrity of the leptin axis are obvious candidates for mediation of altered adiposity. In a large number of genetic association studies in humans, the non-conservative LEPR Q223R allele has been inconsistently associated with adiposity. Subtle, long term effects of such genetic variants can be obscured by effects of the environment and other confounders that render definitive inferences difficult to reach. We directly assessed the biological effects of this variant in 129P3/J mice segregating for the humanized Lepr allele at codon 223. No effects of this allele were detected on body weight, composition, or energy expenditure in animals fed diets of varying fat content over periods as long as 235 days. In vitro, Q223R did not affect leptin signaling as reflected by activation of STAT3. We conclude that Q223R is unlikely to play a significant role in regulation of human adiposity. This approach to vetting of human allelic variation might be more widely employed. PMID:18997673

  10. Complementary Effects of Genetic Variations in LEPR on Body Composition and Soluble Leptin Receptor Concentration after 3-Month Lifestyle Intervention in Prepubertal Obese Children

    PubMed Central

    Gajewska, Joanna; Kuryłowicz, Alina; Mierzejewska, Ewa; Ambroszkiewicz, Jadwiga; Chełchowska, Magdalena; Weker, Halina; Puzianowska-Kuźnicka, Monika

    2016-01-01

    In obese individuals, weight loss might be affected by variants of the adipokine-encoding genes. We verified whether selected functional single nucleotide polymorphisms in LEP, LEPR and ADIPOQ are associated with changes in serum levels of the respective adipokines and weight loss in 100 prepubertal obese (SDS-BMI > 2) Caucasian children undergoing lifestyle intervention. Frequencies of the -2548G > A LEP, Q223R LEPR, K656N LEPR, -11377C > G and -11426A > G ADIPOQ polymorphisms were analyzed by restriction fragment length polymorphism. Serum adipokine and soluble leptin receptor (sOB-R) concentrations were measured using the ELISA method. Among the analyzed polymorphisms, only LEPR polymorphisms were associated with changes of SDS-BMI or sOB-R concentrations in children after therapy. Carriers of the wild-type K665N and at least one minor Q223R allele had the greatest likelihood of losing weight (OR = 5.09, p = 0.006), an increase in sOB-R (ptrend = 0.022) and decrease in SDS-BMI correlated with the decrease of fat mass (p < 0.001). In contrast, carrying of the wild-type Q223R and at least one minor K665N allele were associated with a decrease in sOB-R concentrations and a decrease in SDS-BMI correlated with a decrease in fat-free mass (p = 0.002). We suggest that the combination of different LEPR variants, not a single variant, might determine predisposition to weight loss in the prepubertal period. PMID:27240401

  11. Complementary Effects of Genetic Variations in LEPR on Body Composition and Soluble Leptin Receptor Concentration after 3-Month Lifestyle Intervention in Prepubertal Obese Children.

    PubMed

    Gajewska, Joanna; Kuryłowicz, Alina; Mierzejewska, Ewa; Ambroszkiewicz, Jadwiga; Chełchowska, Magdalena; Weker, Halina; Puzianowska-Kuźnicka, Monika

    2016-01-01

    In obese individuals, weight loss might be affected by variants of the adipokine-encoding genes. We verified whether selected functional single nucleotide polymorphisms in LEP, LEPR and ADIPOQ are associated with changes in serum levels of the respective adipokines and weight loss in 100 prepubertal obese (SDS-BMI > 2) Caucasian children undergoing lifestyle intervention. Frequencies of the -2548G > A LEP, Q223R LEPR, K656N LEPR, -11377C > G and -11426A > G ADIPOQ polymorphisms were analyzed by restriction fragment length polymorphism. Serum adipokine and soluble leptin receptor (sOB-R) concentrations were measured using the ELISA method. Among the analyzed polymorphisms, only LEPR polymorphisms were associated with changes of SDS-BMI or sOB-R concentrations in children after therapy. Carriers of the wild-type K665N and at least one minor Q223R allele had the greatest likelihood of losing weight (OR = 5.09, p = 0.006), an increase in sOB-R (ptrend = 0.022) and decrease in SDS-BMI correlated with the decrease of fat mass (p < 0.001). In contrast, carrying of the wild-type Q223R and at least one minor K665N allele were associated with a decrease in sOB-R concentrations and a decrease in SDS-BMI correlated with a decrease in fat-free mass (p = 0.002). We suggest that the combination of different LEPR variants, not a single variant, might determine predisposition to weight loss in the prepubertal period. PMID:27240401

  12. Effect of LEPR, ABCG2 and SCD1 gene polymorphisms on reproductive traits in the Iranian Holstein cattle.

    PubMed

    Asadollahpour Nanaei, H; Ansari Mahyari, S; Edriss, M-A

    2014-10-01

    During the last decades, genetic selection for milk production traits has led to increased fertility and health problems in dairy cattle. The aim of this study was to investigate the impact of three polymorphisms located in the ATP-binding cassette superfamily G member 2 transporter (ABCG2), stearoyl-CoA desaturase 1 (SCD1) and leptin receptor (LEPR) genes on reproductive traits and somatic cell count (SCC). The analysis was conducted on 408 randomly selected cows. The SNPs within the genes (LEPR, ABCG2 and SCD1) were genotyped using the PCR-RFLP method. All three possible genotypes were observed for SCD1-T878C and LEPR-T945M SNPs, but not for ABCG2-Y581S SNP. LEPR-T945M and ABCG2-Y581S SNPs had no statistically significant effect on the studied reproductive traits and SCC. However, SCD1-T878C SNP were negatively and significantly related to pregnancy length, dry days and open days (p < 0.05), which lead to decreased profitability in dairy herds. The results suggest that the T878C SNP of SCD1 might be useful as a DNA marker to decrease reproductive problems and improve production traits in Iranian Holstein dairy cows. PMID:25130486

  13. Data in support of the discovery of alternative splicing variants of quail LEPR and the evolutionary conservation of qLEPRl by nucleotide and amino acid sequences alignment

    PubMed Central

    Wang, Dandan; Xu, Chunlin; Wang, Taian; Li, Hong; Li, Yanmin; Ren, Junxiao; Tian, Yadong; Li, Zhuanjian; Jiao, Yuping; Kang, Xiangtao; Liu, Xiaojun

    2015-01-01

    Leptin receptor (LEPR) belongs to the class I cytokine receptor superfamily which share common structural features and signal transduction pathways. Although multiple LEPR isoforms, which are derived from one gene, were identified in mammals, they were rarely found in avian except the long LEPR. Four alternative splicing variants of quail LEPR (qLEPR) had been cloned and sequenced for the first time (Wang et al., 2015 [1]). To define patterns of the four splicing variants (qLEPRl, qLEPR-a, qLEPR-b and qLEPR-c) and locate the conserved regions of qLEPRl, this data article provides nucleotide sequence alignment of qLEPR and amino acid sequence alignment of representative vertebrate LEPR. The detailed analysis was shown in [1]. PMID:26759819

  14. Data in support of the discovery of alternative splicing variants of quail LEPR and the evolutionary conservation of qLEPRl by nucleotide and amino acid sequences alignment.

    PubMed

    Wang, Dandan; Xu, Chunlin; Wang, Taian; Li, Hong; Li, Yanmin; Ren, Junxiao; Tian, Yadong; Li, Zhuanjian; Jiao, Yuping; Kang, Xiangtao; Liu, Xiaojun

    2016-03-01

    Leptin receptor (LEPR) belongs to the class I cytokine receptor superfamily which share common structural features and signal transduction pathways. Although multiple LEPR isoforms, which are derived from one gene, were identified in mammals, they were rarely found in avian except the long LEPR. Four alternative splicing variants of quail LEPR (qLEPR) had been cloned and sequenced for the first time (Wang et al., 2015 [1]). To define patterns of the four splicing variants (qLEPRl, qLEPR-a, qLEPR-b and qLEPR-c) and locate the conserved regions of qLEPRl, this data article provides nucleotide sequence alignment of qLEPR and amino acid sequence alignment of representative vertebrate LEPR. The detailed analysis was shown in [1]. PMID:26759819

  15. The Impact of LEP G-2548A and LEPR Gln223Arg Polymorphisms on Adiposity, Leptin, and Leptin-Receptor Serum Levels in a Mexican Mestizo Population

    PubMed Central

    Chavarria-Avila, Efraín; Gomez-Bañuelos, Eduardo; Ruiz-Quezada, Sandra-Luz; Castro-Albarran, Jorge; Sánchez-López, Lizeth; Martín-Marquez, Beatriz Teresita; Navarro-Hernández, Rosa-Elena

    2015-01-01

    The polymorphisms in leptin (LEP G-2548A) and leptin-receptor (LEPR Gln223Arg) seem to influence obesity and lipid metabolism among others. The aim of this study was to investigate the effect of these polymorphisms on adiposity, leptin (sLeptin), and leptin-receptor (sLeptin-receptor) serum concentrations as well as inflammation markers. We included 382 adults originally from Western Mexico. They were genotyped by PCR-RFLP. Obese individuals showed higher sLeptin (58.2 ± 31.35 ng/mL) but lower sLeptin-receptor (12.6 ± 3.74 ng/mL) levels than normal weight ones (17.6 ± 14.62 ng/mL, 17.4 ± 4.62 ng/mL, resp.), P < 0.001. Obese subjects carriers of Arg/Arg genotype had more (P = 0.016) sLeptin-receptor (14.7 ± 4.96 ng/mL) and less (P = 0.004) sLeptin (44.0 ± 28.12 ng/mL) levels than Gln/Gln genotype (11.0 ± 2.92 ng/mL, 80.3 ± 33.24 ng/mL, resp.). Body fat mass was lower (P from 0.003 to 0.045) for A/A (36.5% ± 6.80) or Arg/Arg (36.8% ± 6.82) genotypes with respect to G/G (41.3% ± 5.52) and G/A (41.6% ± 5.61) or Gln/Gln (43.7% ± 4.74) and Gln/Arg (41.0% ± 5.52) genotypes carriers. Our results suggest that LEP -2548A and LEPR 223Arg could be genetic markers of less body fat mass accumulation in obese subjects from Western Mexico. PMID:26064921

  16. Novel locus for fibrinogen in 3' region of LEPR gene in island population of Vis (Croatia).

    PubMed

    Tomas, Željka; Petranović, Matea Zajc; Škarić-Jurić, Tatjana; Barešić, Ana; Salihović, Marijana Peričić; Narančić, Nina Smolej

    2014-11-01

    Leptin, a possible mediator between energy homeostasis, inflammation and cardiovascular disease (CVD), acts via leptin receptors. We investigated association of single-nucleotide polymorphisms (SNPs) and haplotypes of the leptin receptor gene (LEPR) with several CVD risk factors: body mass index, waist circumference (WC), serum lipids, fibrinogen and C-reactive protein levels. Thirty-one SNPs in and near LEPR gene were analyzed in 986 inhabitants of the island of Vis, Croatia and 29 SNPs in the inland sample (N=499). We assessed linkage disequilibrium (LD), SNP and haplotype associations with the selected phenotypes. rs4291477 significantly associated with fibrinogen (P=0.003) and rs7539471 marginally significantly with high-density lipoprotein (P=0.004), but only in the Vis sample, while rs10493384 marginally significantly associated with triglyceride levels (P=0.006) in the inland sample. SNPs were grouped into eight LD blocks in Vis and in seven blocks in the inland population. Haplotype A-C-A-A-G-A in block 5 in Vis (rs1782754, rs1171269, rs1022981, rs6673324, rs3790426, rs10493380) and haplotype A-A-A-A in block 4 in the inland data (rs1782754, rs1022981, rs6673324, rs1137100) were nominally associated with WC, P=7.085 × 10(-22) (adjusted P=0.0979) and P=5.496 × 10(-144) (adjusted P=0.1062), respectively. PMID:25296580

  17. A polymorphism in the leptin receptor gene at position 223 is associated with growth hormone replacement therapy responsiveness in idiopathic short stature and growth hormone deficiency patients.

    PubMed

    Su, Pen-Hua; Yang, Shun-Fa; Yu, Ju-Shan; Chen, Suh-Jen; Chen, Jia-Yuh

    2012-12-01

    We hypothesized that responses to growth hormone (GH) therapy by idiopathic short stature (ISS) and growth hormone deficiency (GHD) patients were associated with single nucleotide polymorphisms (SNPs) in the leptin (LEP) and leptin receptor (LEPR) genes. We retrospectively enrolled ISS (n = 32) and GHD (n = 38) patients and forty healthy age-and gender-matched children. They were genotyped for the LEP promoter at nt.-2548, and LEPR K109R and LEPR Q223R polymorphisms. Clinical and laboratory variables were determined before and after 2 years of GH treatment. ISS patients with G/A or A/A genotypes of the LEPR Q223R SNP had a significantly higher height velocity (cm/y) than ISS patients with the G/G genotype at 2 years after GH treatment. For GHD patients, G/A or A/A genotype of the LEPR K109R SNP was associated with higher body weight, higher BMI, and higher weight velocity than patients with the G/G genotype before GH treatment, but not after GH treatment. G/A or A/A genotype of the LEPR Q223R SNP was associated with a significantly higher body weight, higher height velocity before treatment, but not after GH treatment. G/A or A/A genotype of the LEPR Q223R SNP was associated with a significantly higher weight velocity before treatment, but a significantly lower weight velocity was found at 2 years after GH treatment. These results suggest LEPR Q223R SNP (rs1137101) is associated with outcomes of GH replacement therapy in ISS and GHD patients. PMID:23009903

  18. Polymorphisms of the LEP- and LEPR gene and obesity in patients using antipsychotic medication.

    PubMed

    Gregoor, Jochem G; van der Weide, Jan; Mulder, Hans; Cohen, Dan; van Megen, Harold J G M; Egberts, Antoine C G; Heerdink, Eibert R

    2009-02-01

    Weight gain is one of the most serious adverse effects of atypical antipsychotic agents. Genetic factors influence the risk of an individual to gain weight. The objective of our study was to determine whether the LEPR Q223R polymorphism and the LEP promoter 2548G/A polymorphism are associated with obesity in a group of male and female patients using atypical antipsychotic drugs. A cross-sectional study design was used. The study population consisted of 200 patients aged between 18 and 65 years, diagnosed with a psychotic disorder, all of whom had been using an atypical antipsychotic for at least 3 months. The primary outcome measure was the presence of obesity. Determinants were the LEPR Q223R (rs1137101) polymorphism and the LEP promoter 2548G/A single nucleotide polymorphism ([SNP] rs7799039). Of the 200 included patients, 61 (31%) were obese. In females, the LEPR 223QR (adjusted odds ratio, 0.11; 95% confidence interval [CI], 0.02-0.54) and LEPR 223RR (adjusted odds ratio, 0.07; 95% CI, 0.01-0.63) genotypes were associated with a lower risk of obesity. In males, this association was not found. In females, the average body weight was 13.6 kg more (95% CI, 1.11-26.1) in the LEPR 223QQ group compared with the LEPR 223RR group. No significant association was found between the LEP promoter 2548G/A polymorphism and obesity. Taken together, the results of our study show that the LEPR Q223R polymorphism may be associated with obesity in women with a psychotic disorder treated with atypical antipsychotic drugs and stress the importance of stratification for gender when investigating the role of variations of the LEP- and LEPR genes on the metabolic side effects of antipsychotic medications. PMID:19142102

  19. Estrogen, SNP-Dependent Chemokine Expression and Selective Estrogen Receptor Modulator Regulation.

    PubMed

    Ho, Ming-Fen; Bongartz, Tim; Liu, Mohan; Kalari, Krishna R; Goss, Paul E; Shepherd, Lois E; Goetz, Matthew P; Kubo, Michiaki; Ingle, James N; Wang, Liewei; Weinshilboum, Richard M

    2016-03-01

    We previously reported, on the basis of a genome-wide association study for aromatase inhibitor-induced musculoskeletal symptoms, that single-nucleotide polymorphisms (SNPs) near the T-cell leukemia/lymphoma 1A (TCL1A) gene were associated with aromatase inhibitor-induced musculoskeletal pain and with estradiol (E2)-induced TCL1A expression. Furthermore, variation in TCL1A expression influenced the downstream expression of proinflammatory cytokines and cytokine receptors. Specifically, the top hit genome-wide association study SNP, rs11849538, created a functional estrogen response element (ERE) that displayed estrogen receptor (ER) binding and increased E2 induction of TCL1A expression only for the variant SNP genotype. In the present study, we pursued mechanisms underlying the E2-SNP-dependent regulation of TCL1A expression and, in parallel, our subsequent observations that SNPs at a distance from EREs can regulate ERα binding and that ER antagonists can reverse phenotypes associated with those SNPs. Specifically, we performed a series of functional genomic studies using a large panel of lymphoblastoid cell lines with dense genomic data that demonstrated that TCL1A SNPs at a distance from EREs can modulate ERα binding and expression of TCL1A as well as the expression of downstream immune mediators. Furthermore, 4-hydroxytamoxifen or fulvestrant could reverse these SNP-genotype effects. Similar results were found for SNPs in the IL17A cytokine and CCR6 chemokine receptor genes. These observations greatly expand our previous results and support the existence of a novel molecular mechanism that contributes to the complex interplay between estrogens and immune systems. They also raise the possibility of the pharmacological manipulation of the expression of proinflammatory cytokines and chemokines in a SNP genotype-dependent fashion. PMID:26866883

  20. The association between LEPR Q223R polymorphisms and breast cancer risk.

    PubMed

    Wang, Yadong; Yang, Haiyan; Gao, Huiyan; Wang, Haiyu

    2015-05-01

    Recently, we have read with great interest the article entitled "The association between polymorphisms in the leptin receptor (LEPR) gene and risk of breast cancer: a systematic review and pooled analysis" published online by Wang et al. (Breast Cancer Res Treat 136:231-239, 2012). This article suggests that the A allele of LEPR gene rs1137101 variant was low-penetrant risk factor for developing breast cancer. The result is encouraging. Nevertheless, several key issues are worth noticing. PMID:25863476

  1. Common genetic variation in adiponectin, leptin, and leptin receptor and association with breast cancer subtypes

    PubMed Central

    Nyante, Sarah J.; Gammon, Marilie D.; Kaufman, Jay S.; Bensen, Jeannette T.; Lin, Dan Yu; Barnholtz-Sloan, Jill S.; Hu, Yijuan; He, Qianchuan; Luo, Jingchun; Millikan, Robert C.

    2012-01-01

    Adipocytokines are produced by visceral fat, and levels may be associated with breast cancer risk. We investigated whether single nucleotide polymorphisms (SNPs) in adipocytokine genes adiponectin (ADIPOQ), leptin (LEP), and the leptin receptor (LEPR) were associated with basal-like or luminal A breast cancer subtypes. 104 candidate and tag SNPs were genotyped in 1776 of 2022 controls and 1972 (200 basal-like, 679 luminal A) of 2311 cases from the Carolina Breast Cancer Study (CBCS), a population-based case–control study of whites and African Americans. Breast cancer molecular subtypes were determined by immunohistochemistry. Genotype odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. Haplotype ORs and 95% CIs were estimated using Hapstat. Interactions with waist-hip ratio were evaluated using a multiplicative interaction term. Ancestry was estimated from 144 ancestry informative markers (AIMs), and included in models to control for population stratification. Candidate SNPs LEPR K109R (rs1137100) and LEPR Q223R (rs1137101) were positively associated with luminal A breast cancer, whereas ADIPOQ +45 T/G (rs2241766), ADIPOQ +276 G/T (rs1501299), and LEPR K656N (rs8129183) were not associated with either subtype. Few patterns were observed among tag SNPs, with the exception of 3 LEPR SNPs (rs17412175, rs9436746, and rs9436748) that were in moderate LD and inversely associated with basal-like breast cancer. However, no SNP associations were statistically significant after adjustment for multiple comparisons. Haplotypes in LEP and LEPR were associated with both basal-like and luminal A subtypes. There was no evidence of interaction with waist-hip ratio. Data suggest associations between LEPR candidate SNPs and luminal A breast cancer in the CBCS and LEPR intron 2 tag SNPs and basal-like breast cancer. Replication in additional studies where breast cancer subtypes have been defined is necessary to confirm these

  2. Common genetic variation in adiponectin, leptin, and leptin receptor and association with breast cancer subtypes.

    PubMed

    Nyante, Sarah J; Gammon, Marilie D; Kaufman, Jay S; Bensen, Jeannette T; Lin, Dan Yu; Barnholtz-Sloan, Jill S; Hu, Yijuan; He, Qianchuan; Luo, Jingchun; Millikan, Robert C

    2011-09-01

    Adipocytokines are produced by visceral fat, and levels may be associated with breast cancer risk. We investigated whether single nucleotide polymorphisms (SNPs) in adipocytokine genes adiponectin (ADIPOQ), leptin (LEP), and the leptin receptor (LEPR) were associated with basal-like or luminal A breast cancer subtypes. 104 candidate and tag SNPs were genotyped in 1776 of 2022 controls and 1972 (200 basal-like, 679 luminal A) of 2311 cases from the Carolina Breast Cancer Study (CBCS), a population-based case-control study of whites and African Americans. Breast cancer molecular subtypes were determined by immunohistochemistry. Genotype odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. Haplotype ORs and 95% CIs were estimated using Hapstat. Interactions with waist-hip ratio were evaluated using a multiplicative interaction term. Ancestry was estimated from 144 ancestry informative markers (AIMs), and included in models to control for population stratification. Candidate SNPs LEPR K109R (rs1137100) and LEPR Q223R (rs1137101) were positively associated with luminal A breast cancer, whereas ADIPOQ +45 T/G (rs2241766), ADIPOQ +276 G/T (rs1501299), and LEPR K656N (rs8129183) were not associated with either subtype. Few patterns were observed among tag SNPs, with the exception of 3 LEPR SNPs (rs17412175, rs9436746, and rs9436748) that were in moderate LD and inversely associated with basal-like breast cancer. However, no SNP associations were statistically significant after adjustment for multiple comparisons. Haplotypes in LEP and LEPR were associated with both basal-like and luminal A subtypes. There was no evidence of interaction with waist-hip ratio. Data suggest associations between LEPR candidate SNPs and luminal A breast cancer in the CBCS and LEPR intron 2 tag SNPs and basal-like breast cancer. Replication in additional studies where breast cancer subtypes have been defined is necessary to confirm these

  3. SNP genotypes of olfactory receptor genes associated with olfactory ability in German Shepherd dogs.

    PubMed

    Yang, M; Geng, G-J; Zhang, W; Cui, L; Zhang, H-X; Zheng, J-L

    2016-04-01

    To find out the relationship between SNP genotypes of canine olfactory receptor genes and olfactory ability, 28 males and 20 females from German Shepherd dogs in police service were scored by odor detection tests and analyzed using the Beckman GenomeLab SNPstream. The representative 22 SNP loci from the exonic regions of 12 olfactory receptor genes were investigated, and three kinds of odor (human, ice drug and trinitrotoluene) were detected. The results showed that the SNP genotypes at the OR10H1-like:c.632C>T, OR10H1-like:c.770A>T, OR2K2-like:c.518G>A, OR4C11-like:c.511T>G and OR4C11-like:c.692G>A loci had a statistically significant effect on the scenting abilities (P < 0.001). The kind of odor influenced the performances of the dogs (P < 0.001). In addition, there were interactions between genotype and the kind of odor at the following loci: OR10H1-like:c.632C>T, OR10H1-like:c.770A>T, OR4C11-like:c.511T>G and OR4C11-like:c.692G>A (P < 0.001). The dogs with genotype CC at the OR10H1-like:c.632C>T, genotype AA at the OR10H1-like:c.770A>T, genotype TT at the OR4C11-like:c.511T>G and genotype GG at the OR4C11-like:c.692G>A loci did better at detecting the ice drug. We concluded that there was linkage between certain SNP genotypes and the olfactory ability of dogs and that SNP genotypes might be useful in determining dogs' scenting potential. PMID:26582499

  4. Exogenous Parathyroid Hormone-Related Peptide Promotes Fracture Healing in Lepr(-/-) Mice.

    PubMed

    Liu, Anlong; Li, Yishan; Wang, Yinhe; Liu, Li; Shi, Hongfei; Qiu, Yong

    2015-12-01

    Diabetic osteoporosis continues to surge worldwide, increasing the risk of fracture. We have previously demonstrated that haploinsufficiency of endogenous parathyroid hormone-related peptide (PTHrP) impairs fracture healing. However, whether an exogenous supply of PTHrP can repair bone damage and accelerate fracture healing remains unclear. This study aimed to assess the efficacy and safety of PTHrP in healing fractures. Standardized mid-diaphyseal femur fractures were generated in 12-week-old wild-type and leptin receptor null Lepr(-/-) mice. After administration of PTHrP for 2 weeks, callus tissue properties were analyzed by radiography, micro-computed tomography, histology, histochemistry, immunohistochemistry, and molecular biology techniques. At 2 weeks post-fracture, cartilaginous callus areas were reduced, while total callus and bony callus areas were increased in PTHrP-treated Lepr(-/-) animals and control wild-type mice, compared with vehicle-treated Lepr(-/-) mice. The following parameters were enhanced both in Lepr(-/-) mice after treatment with PTHrP and vehicle-treated wild-type animals, compared with vehicle-treated Lepr(-/-) mice: osteoblast numbers; tissue alkaline phosphatase (ALP) and Type I collagen immunopositive areas; mRNA levels of ALP, Type I collagen, osteoprotegerin, and receptor activator for nuclear factor-κ B ligand; protein levels of Runt-related transcription factor 2 and insulin-like growth factor-1; and the number and surface of osteoclasts. In conclusion, exogenous PTHrP by subcutaneous injection promotes fracture repair in Lepr(-/-) mice by increasing callus formation and accelerating cell transformation: upregulated osteoblastic gene and protein expression, increased endochondral bone formation, osteoblastic bone formation, and osteoclastic bone resorption. However, complete repair was not obtained in PTHrP-treated Lepr(-/-) mice as in control wild-type animals. PMID:26314884

  5. The Association of Polymorphisms in Leptin/Leptin Receptor Genes and Ghrelin/Ghrelin Receptor Genes With Overweight/Obesity and the Related Metabolic Disturbances: A Review

    PubMed Central

    Ghalandari, Hamid; Hosseini-Esfahani, Firoozeh; Mirmiran, Parvin

    2015-01-01

    Context: Leptin and ghrelin are two important appetite and energy balance-regulating peptides. Common polymorphisms in the genes coding these peptides and their related receptors are shown to be associated with body weight, different markers of obesity and metabolic abnormalities. This review article aims to investigate the association of common polymorphisms of these genes with overweight/obesity and the metabolic disturbances related to it. Evidence Acquisition: The keywords leptin, ghrelin, polymorphism, single-nucleotide polymorphism (SNP), obesity, overweight, Body Mass Index, metabolic syndrome, and type 2 diabetes mellitus (T2DM) (MeSH headings) were used to search in the following databases: Pubmed, Sciencedirect (Elsevier), and Google scholar. Overall, 24 case-control studies, relevant to our topic, met the criteria and were included in the review. Results: The most prevalent leptin/leptin receptor genes (LEP/LEPR) and ghrelin/ghrelin receptor genes (GHRL/GHSR) single nucleotide polymorphisms studied were LEP G-2548A, LEPR Q223R, and Leu72Met, respectively. Nine studies of the 17 studies on LEP/LEPR, and three studies of the seven studies on GHRL/GHSR showed significant relationships. Conclusions: In general, our study suggests that the association between LEP/LEPR and GHRL/GHSR with overweight/obesity and the related metabolic disturbances is inconclusive. These results may be due to unidentified gene-environment interactions. More investigations are needed to further clarify this association. PMID:26425125

  6. Haplotypic diversity of porcine LEP and LEPR genes involved in growth and fatness regulation.

    PubMed

    Pérez-Montarelo, Dafne; Rodríguez, M Carmen; Fernández, Almudena; Benítez, Rita; García, Fabián; Silió, Luis; Fernández, Ana I

    2015-11-01

    The analysis of structural genetic variability in candidate genes can make it possible to analyse the selection footprint and deepen the understanding of the genetic basis of complex traits. The leptin (LEP) and its receptor (LEPR) porcine genes are involved in food intake and energy homeostasis, and polymorphisms associated to growth and fatness traits have been detected in both genes. The main objective of this study was to explore the genetic variability of the most polymorphic regions of both genes in a variety of pig populations and wild boars from diverse European and Asian origins. In total, 54 animals were included in the analyses, with a remarkable sampling of Spanish wild boars and Iberian pigs. The sequencing allowed the identification of 69 and 26 polymorphisms in LEP and LEPR genes, respectively. Neighbour-joining trees built for the 69 haplotypes identified in the LEP and the 24 haplotypes detected in the LEPR showed the known genetic divergence between European and Asian pig breeds. A high variability of the LEP was detected in the different analysed populations providing new data for the existence of two domestication centres in Asia. In comparison to the LEP gene, the LEPR showed a lower variability, especially in the Iberian breed that showed no variability. Moreover, results of the Hudson-Kreitman-Aguadé neutrality test support a possible selection event of the LEPR gene region in this breed, potentially related with its leptin resistance pattern and good adaptation to a traditional extensive production system with strong seasonal changes of feeding resources. PMID:25910874

  7. Nucleotide Sequencing and SNP Detection of Toll-Like Receptor-4 Gene in Murrah Buffalo (Bubalus bubalis)

    PubMed Central

    Mitra, M.; Taraphder, S.; Sonawane, G. S.; Verma, A.

    2012-01-01

    Toll-like receptor-4 (TLR-4) has an important pattern recognition receptor that recognizes endotoxins associated with gram negative bacterial infections. The present investigation was carried out to study nucleotide sequencing and SNP detection by PCR-RFLP analysis of the TLR-4 gene in Murrah buffalo. Genomic DNA was isolated from 102 lactating Murrah buffalo from NDRI herd. The amplified PCR fragments of TLR-4 comprised of exon 1, exon 2, exon 3.1, and exon 3.2 were examined to RFLP. PCR products were obtained with sizes of 165, 300, 478, and 409 bp. TLR-4 gene of investigated Murrah buffaloes was highly polymorphic with AA, AB, and BB genotypes as revealed by PCR-RFLP analysis using Dra I, Hae III, and Hinf I REs. Nucleotide sequencing of the amplified fragment of TLR-4 gene of Murrah buffalo was done. Twelve SNPs were identified. Six SNPs were nonsynonymous resulting in change in amino acids. Murrah is an indigenous Buffalo breed and the presence of the nonsynonymous SNP is indicative of its unique genomic architecture. Sequence alignment and homology across species using BLAST analysis revealed 97%, 97%, 99%, 98%, and 80% sequence homology with Bos taurus, Bos indicus, Ovis aries, Capra hircus, and Homo sapiens, respectively.

  8. ADRB2 and LEPR gene polymorphisms: synergistic effects on the risk of obesity in Japanese.

    PubMed

    Pereira, Tiago V; Mingroni-Netto, Regina C; Yamada, Yoshiji

    2011-07-01

    The objective of the present study was to validate a recently reported synergistic effect between variants located in the leptin receptor (LEPR) gene and in the β-2 adrenergic receptor (ADRB2) gene on the risk of overweight/obesity. We studied a middle-aged/elderly sample of 4,193 nondiabetic Japanese subjects stratified according gender (1,911 women and 2,282 men). The LEPR Gln223Arg (rs1137101) variant as well as both ADRB2 Arg16Gly (rs1042713) and Gln27Glu (rs1042714) polymorphisms were analyzed. The primary outcome was the risk of overweight/obesity defined as BMI ≥25 kg/m(2), whereas secondary outcomes included the risk of a BMI ≥27 kg/m(2) and BMI as a continuous variable. None of the studied polymorphisms showed statistically significant individual effects, regardless of the group or phenotype studied. Haplotype analysis also did not disclose any associations of ADRB2 polymorphisms with BMI. However, dimensionality reduction-based models confirmed significant interactions among the investigated variants for BMI as a continuous variable as well as for the risk of obesity defined as BMI ≥27 kg/m(2). All disclosed interactions were found in men only. Our results provide external validation for a male specific ADRB2-LEPR interaction effect on the risk of overweight/obesity, but indicate that effect sizes associated with these interactions may be smaller in the population studied. PMID:21233812

  9. The Q223R polymorphism in LEPR is associated with obesity in Pacific Islanders.

    PubMed

    Furusawa, Takuro; Naka, Izumi; Yamauchi, Taro; Natsuhara, Kazumi; Kimura, Ryosuke; Nakazawa, Minato; Ishida, Takafumi; Inaoka, Tsukasa; Matsumura, Yasuhiro; Ataka, Yuji; Nishida, Nao; Tsuchiya, Naoyuki; Ohtsuka, Ryutaro; Ohashi, Jun

    2010-03-01

    Various Pacific Island populations have experienced a marked increase in the prevalence of obesity in past decades. This study examined the association of a promoter polymorphism of the leptin gene (LEP), G-2548A (rs7799039), and two non-synonymous single nucleotide polymorphisms of the leptin receptor gene (LEPR), K109R (rs1137100) and Q223R (rs1137101), with body weight, body mass index (BMI) and obesity (BMI > or = 30) in Pacific Islanders. A total of 745 Austronesian (AN)-speaking participants were analyzed after adjusting for age, gender, and population differences. The results revealed that carriers of the 223Q alleles of LEPR had significantly higher body weight (P = 0.0009) and BMI (P = 0.0022) than non-carriers (i.e., 223R homozygotes); furthermore, the 223Q carriers also had a signiWcantly higher risk of obesity in comparison to non-carriers (P = 0.0222). The other two polymorphisms, G-2548A and K109R, were associated with neither body weight, BMI, nor obesity. The 223Q allele was widely found among the AN-speaking study subjects, thus suggesting that the LEPR Q223R polymorphism is one of the factors contributing to the high prevalence of obesity in the Pacific Island populations. PMID:20183928

  10. Common genetic variations in the LEP and LEPR genes, obesity and breast cancer incidence and survival

    PubMed Central

    Cleveland, Rebecca J.; Gammon, Marilie D.; Long, Chang-Min; Gaudet, Mia M.; Eng, Sybil M.; Teitelbaum, Susan L.; Neugut, Alfred I.; Santella, Regina M.

    2013-01-01

    Objective Obesity is a strong risk factor for breast cancer in postmenopausal women and adverse prognostic indicator regardless of menopausal status. Leptin is an important regulator of adipose tissue mass and has been associated with tumor cell growth. Leptin exerts its effects through interaction with the leptin receptor (LEPR). We investigated whether genetic variations in the leptin (LEP) and LEPR genes are associated with risk of breast cancer, or once diagnosed, with survival. Methods The polymorphisms LEP G-2548A and LEPR Q223R were characterized in population-based study consisting of mostly European-American women. The study examined 1,065 women diagnosed with first, primary invasive breast cancer between 1996 and 1997. Controls were 1,108 women frequency matched to the cases by 5-year age group. Results A modest increase in risk of developing breast cancer was associated with the LEP -2548AA genotype when compared to the LEP -2548GG genotype (age-adjusted OR=1.30; 95% CI=1.01–1.66). This association was stronger among postmenopausal women who were obese (OR=1.86; 95% CI=0.95–3.64) although the interaction was of borderline statistical significance (P=0.07). We found no evidence of an association with polymorphisms of either LEP or LEPR in relation to all-cause or breast cancer-specific mortality among women with breast cancer (mean follow-up time=66.7 months). The effects of these genotypes on breast cancer risk and mortality did not vary significantly when stratified by menopausal status. Conclusions In summary, our results show that a common variant in LEP may be associated with the risk of developing breast cancer supporting the hypothesis that leptin is involved in breast carcinogenesis. PMID:19697123

  11. The effect of SCD and LEPR genetic polymorphisms on fat content and composition is maintained throughout fattening in Duroc pigs.

    PubMed

    Henriquez-Rodriguez, E; Bosch, L; Tor, M; Pena, R N; Estany, J

    2016-11-01

    The effects of the stearoyl-CoA desaturase (SCD; AY487830:g.2228T>C) and leptin receptor (LEPR; NM_001024587:g.1987C>T) polymorphisms on fat content and fatty acid (FA) composition were investigated throughout fattening. Samples of Longissimus thoracis (LT) and subcutaneous fat (SF) from 214 Duroc barrows were collected from 160days to slaughter age (220days) using a longitudinal design. Results indicated that the positive effect of the T allele at the SCD gene on monounsaturated FA and of the T allele at the LEPR gene on saturated FA are maintained throughout the growing-finishing period, both in LT and SF. In LEPR, however, compositional changes, particularly in SF, are a result of increased fatness. There is very limited evidence of genotype by age interaction, and thus it is concluded that the combined selection for the SCD T and LEPR C alleles is a good strategy to increase the MUFA/SFA ratio regardless of the age at slaughter. PMID:27240305

  12. The effect of ponderal index at birth on the relationships between common LEP and LEPR polymorphisms and adiposity in adolescents.

    PubMed

    Labayen, Idoia; Ruiz, Jonatan R; Moreno, Luis A; Ortega, Francisco B; Beghin, Laurent; DeHenauw, Stefaan; Benito, Pedro J; Diaz, Ligia E; Ferrari, Marika; Moschonis, George; Kafatos, Anthony; Molnar, Dénes; Widhalm, Kurt; Dallongeville, Jean; Meirhaeghe, Aline; Gottrand, Frédéric

    2011-10-01

    This study examined the effect of ponderal index (PI) at birth on the relationships between eight common polymorphisms of the leptin (LEP) and leptin receptor (LEPR) genes and adiposity in adolescents. A total of 823 European adolescents (45.4% girls) aged 14.8 ± 1.4 years were genotyped for the LEP (rs2167270, rs12706832, rs10244329, rs2071045, and rs3828942) and LEPR (rs1137100, rs1137101, and rs8179183) polymorphisms. The PI was calculated from parental reports of birth weight and length. Fat mass index (FMI) was calculated. Analyses were adjusted for relevant confounders. An "adiposity-risk-allele score" based on genotypes at the three single-nucleotide polymorphisms (SNPs) associated with adolescents' FMI in adolescents within the lower tertile of PI was calculated. The LEP rs10244329 and rs3828942 polymorphisms were associated with higher FMI only in adolescents within the lower PI tertile (+0.55 kg/m(2) per minor T allele, P = 0.040, and +0.58 kg/m(2) per major G allele, P = 0.028, respectively). The LEPR rs8179183 polymorphism was significantly associated with higher FMI in adolescents within the lower PI tertile (+0.87 kg/m(2) per minor C allele, P = 0.006). After correction for multiple comparisons, only the association between the LEPR rs8179183 and FMI persisted. However, each additional risk allele conferred 0.53 kg/m(2) greater FMI in adolescents within the lower tertile of PI (P = 0.008). In conclusion, our results suggest that those adolescents born with lower PI could be more vulnerable to the influence of the LEP rs10244329 and rs3828942 polymorphisms and LEPR rs8179183 polymorphism on total adiposity content. Due to the relatively small sample size, these findings should be replicated in further larger population samples. PMID:21512510

  13. Selective breeding for high anxiety introduces a synonymous SNP that increases neuropeptide S receptor activity.

    PubMed

    Slattery, David A; Naik, Roshan R; Grund, Thomas; Yen, Yi-Chun; Sartori, Simone B; Füchsl, Andrea; Finger, Beate C; Elfving, Betina; Nordemann, Uwe; Guerrini, Remo; Calo, Girolamo; Wegener, Gregers; Mathé, Aleksander A; Singewald, Nicolas; Czibere, Ludwig; Landgraf, Rainer; Neumann, Inga D

    2015-03-18

    Neuropeptide S (NPS) has generated substantial interest due to its anxiolytic and fear-attenuating effects in rodents, while a corresponding receptor polymorphism associated with increased NPS receptor (NPSR1) surface expression and efficacy has been implicated in an increased risk of panic disorder in humans. To gain insight into this paradox, we examined the NPS system in rats and mice bred for high anxiety-related behavior (HAB) versus low anxiety-related behavior, and, thereafter, determined the effect of central NPS administration on anxiety- and fear-related behavior. The HAB phenotype was accompanied by lower basal NPS receptor (Npsr1) expression, which we could confirm via in vitro dual luciferase promoter assays. Assessment of shorter Npsr1 promoter constructs containing a sequence mutation that introduces a glucocorticoid receptor transcription factor binding site, confirmed via oligonucleotide pull-down assays, revealed increased HAB promoter activity-an effect that was prevented by dexamethasone. Analogous to the human NPSR1 risk isoform, functional analysis of a synonymous single nucleotide polymorphism in the coding region of HAB rodents revealed that it caused a higher cAMP response to NPS stimulation. Assessment of the behavioral consequence of these differences revealed that intracerebroventricular NPS reversed the hyperanxiety of HAB rodents as well as the impaired cued-fear extinction in HAB rats and the enhanced fear expression in HAB mice, respectively. These results suggest that alterations in the NPS system, conserved across rodents and humans, contribute to innate anxiety and fear, and that HAB rodents are particularly suited to resolve the apparent discrepancy between the preclinical and clinical findings to date. PMID:25788677

  14. LEPR, ADBR3, IRS-1 and 5-HTT genes polymorphisms do not associate with obesity.

    PubMed

    Mergen, Hatice; Karaaslan, Cağatay; Mergen, Mehmet; Deniz Ozsoy, Ergi; Ozata, Metin

    2007-02-01

    Obesity is a growing problem and is associated with numerous medical conditions. In several genes coding for molecules involved in the regulation of body weight (fat mass) and thermogenesis, polymorphisms have been reported which possibly modify human obesity risk. The aim of this study was to determine the incidence of the following polymorphisms in the following genes in 262 obese (BMI > or = 30) and 138 control (BMI < or = 25) subjects: leptin receptor (LEPR)-Gln223Arg, B3-adrenergic receptor (B3-AR)-Trp64Arg, serotonin transporter (5-HTT)--a 44-base pair insertion/deletion functional polymorphism in the 5-HTTLPR and insulin receptor substrate-1 (IRS-1)-Gly972Arg. Our hypothesis was that these polymorphisms would occur more frequently in the obese population. The polymorphisms were determined by polymerase chain reaction (PCR) and restriction genotyping in study population. In our results, no strong associations were observed between BMI status and these polymorphisms. Weak, though significant, association coefficients obtained with HTT and LEPR loci indicate that the genotype numbers at these loci may depend on BMI status to some extent. PMID:17124363

  15. Selection in the dopamine receptor 2 gene: a candidate SNP study

    PubMed Central

    Fieder, Martin

    2015-01-01

    Dopamine is a major neurotransmitter in the human brain and is associated with various diseases. Schizophrenia, for example, is treated by blocking the dopamine receptors type 2. Shaner, Miller & Mintz (2004) stated that schizophrenia was the low fitness variant of a highly variable mental trait. We therefore explore whether the dopamine receptor 2 gene (DRD2) underwent any selection processes. We acquired genotype data of the 1,000 Genomes project (phase I), which contains 1,093 individuals from 14 populations. We included single nucleotide polymorphisms (SNPs) with two minor allele frequencies (MAFs) in the analysis: MAF over 0.05 and over 0.01. This is equivalent to 151 SNPs (MAF > 0.05) and 246 SNPs (MAF > 0.01) for DRD2. We used two different approaches (an outlier approach and a Bayesian approach) to detect loci under selection. The combined results of both approaches yielded nine (MAF > 0.05) and two candidate SNPs (MAF > 0.01), under balancing selection. We also found weak signs for directional selection on DRD2, but in our opinion these were too weak to draw any final conclusions on directional selection in DRD2. All candidates for balancing selection are in the intronic region of the gene and only one (rs12574471) has been mentioned in the literature. Two of our candidate SNPs are located in specific regions of the gene: rs80215768 lies within a promoter flanking region and rs74751335 lies within a transcription factor binding site. We strongly encourage research on our candidate SNPs and their possible effects. PMID:26290802

  16. Association of rs5888 SNP in the scavenger receptor class B type 1 gene and serum lipid levels

    PubMed Central

    2012-01-01

    Background Bai Ku Yao is a special subgroup of the Yao minority in China. The present study was undertaken to detect the association of rs5888 single nucleotide polymorphism (SNP) in the scavenger receptor class B type 1 (SCARB1) gene and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations. Methods A total of 598 subjects of Bai Ku Yao and 585 subjects of Han Chinese were randomly selected from our stratified randomized cluster samples. Genotypes of the SCARB1 rs5888 SNP were determined by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. Results The levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein (Apo) AI were lower but ApoB was higher in Bai Ku Yao than in Han (P < 0.05-0.001). The frequencies of C and T alleles were 78.3% and 21.7% in Bai Ku Yao, and 73.7% and 26.3% in Han (P < 0.01); respectively. The frequencies of CC, CT and TT genotypes were 60.0%, 36.6% and 3.4% in Bai Ku Yao, and 54.2%, 39.0% and 6.8% in Han (P < 0.01); respectively. The subjects with TT genotype in both ethnic groups had lower HDL-C and ApoAI levels than the subjects with CC or CT genotype (P < 0.05 for all). Subgroup analyses showed that the subjects with TT genotype in Bai Ku Yao had lower HDL-C and ApoAI levels in males than the subjects with CC or CT genotype (P < 0.05 for all), and the T allele carriers had higher TC, LDL-C and ApoB levels in females than the T allele noncarriers (P < 0.05 for all). The participants with TT genotype in Han also had a lower tendency of HDL-C and ApoAI levels in males than the participants with CC or CT genotype, but the difference did not reach statistically significant (P = 0.063 and P = 0.086; respectively). The association of serum HDL-C and ApoAI levels and genotypes was confirmed by

  17. Correlation of leptin and soluble leptin receptor levels with anthropometric parameters in mother-newborn pairs

    PubMed Central

    Marino-Ortega, Linda A; Molina-Bello, Adiel; Polanco-García, Julio C; Muñoz-Valle, José F; Salgado-Bernabé, Aralia B; Guzmán-Guzmán, Iris P; Parra-Rojas, Isela

    2015-01-01

    The aim of this study was to investigate if anthropometric parameters are associated with both leptin and soluble leptin receptor (sLEPR) levels in newborns and their mothers. This cross-sectional study was performed in 118 mother-newborn pairs. The venous blood sample of mothers was taken before delivery and immediately after delivery an umbilical cord blood sample was collected. Levels of leptin and sLEPR in maternal and umbilical cord sera were assessed by ELISA. Maternal serum concentration of leptin and sLEPR (6.2 and 25.7 ng/ml, respectively) were higher than in umbilical cord blood (2.4 and 14.2 ng/ml, respectively). However, the newborns and their mothers had higher sLEPR levels than leptin levels. In mothers was observed that leptin levels increase with weight gain in pregnancy and decreased sLEPR levels. Cord leptin levels correlated with neonatal birth weight and length, the body circumferences, placental weight and maternal leptin levels. Cord sLEPR levels correlated with maternal sLEPR and leptin levels. Maternal serum concentration of leptin correlated with pre-pregnancy BMI, weight gain, cord sLEPR and leptin levels. Maternal sLEPR concentration correlated with cord sLEPR levels. The leptin and sLEPR levels in mother-newborn pairs are related with anthropometric parameters and an inverse correlation between leptin levels and sLEPR was observed in pairs. PMID:26379933

  18. No association of LEPR Gln223Arg polymorphism with leptin, obesity or metabolic disturbances in children

    PubMed Central

    2009-01-01

    Objective The aim of the study was to investigate whether the Gln223Arg in the leptin receptor may influence body weight, leptin concentration, and metabolic parameters in children. Materials and methods The examined group included 101 obese children (58 girls and 43 boys) with BMI 31.41 ± 5.03 kg/m2 (BMI ≥ 2 SDS) and the control group consisted of 41 children with BMI 20.0 ± 0.80 kg/m2 (BMI < 1.0 SDS). Polymorphism identification was performed in total genomic DNA using PCRRFLP method. Results The distribution of genotypes LEPR was the following: in the obese group: AA - 20.8%, AG-55.4%, GG-23.8%; in the control group AA-31.7%, AG-53.65%, GG-14.65%. Comparative analyses between AA homozygous children and carriers of G alleles did not confirm any relation between the analyzed polymorphism and BMI, leptin concentrations, and metabolic disturbances in children with obesity. Conclusion In children with obesity we did not observe association of the LEPR Gln223Arg gene polymorphism with obesity, leptin, insulin resistance, and metabolic abnormalities. PMID:20156757

  19. Association of LEPR and ANKK1 Gene Polymorphisms with Weight Gain in Epilepsy Patients Receiving Valproic Acid

    PubMed Central

    Li, Hongliang; Wang, Xueding; Zhou, Yafang; Ni, Guanzhong; Su, Qibiao; Chen, Ziyi; Chen, Zhuojia; Li, Jiali; Chen, Xinmeng; Hou, Xiangyu; Xie, Wen; Xin, Shuang; Zhou, Liemin

    2015-01-01

    Background: Weight gain is the most frequent adverse effect of valproic acid (VPA) treatment, resulting in poor compliance and many endocrine disturbances. Similarities in the weight change of monozygotic twins receiving VPA strongly suggests that genetic factors are involved in this effect. However, few studies have been conducted to identify the relevant genetic polymorphisms. Additionally, the causal relationship between the VPA concentration and weight gain has been controversial. Thus, we investigated the effects of single nucleotide polymorphisms (SNPs) in several appetite stimulation and energy homeostasis genes and the steady state plasma concentrations (Css) of VPA on the occurrence of weight gain in patients. Methods: A total of 212 epilepsy patients receiving VPA were enrolled. Nineteen SNPs in 11 genes were detected using the Sequenom MassArray iPlex platform, and VPA Css was determined by high-performance liquid chromatography (HPLC). Results: After 6 months of treatment, 20.28% of patients were found to gain a significant amount of weight (weight gained ≥7%). Three SNPs in the leptin receptor (LEPR), ankyrin repeat kinase domain containing 1 (ANKK1), and α catalytic subunit of adenosine monophosphate-activated protein kinase (AMPK) showed significant associations with VPA-induced weight gain (p < 0.001, p = 0.017 and p = 0.020, respectively). After Bonferroni correction for multiple tests, the genotypic association of LEPR rs1137101, the allelic association of LEPR rs1137101, and ANKK1 rs1800497 with weight gain remained significant. However, the VPA Css in patents who gained weight were not significantly different from those who did not gain weight (p = 0.121). Conclusions: LEPR and ANKK1 genetic polymorphisms may have value in predicting VPA-induced weight gain. PMID:25740917

  20. Association between variants in the genes for leptin, leptin receptor, and proopiomelanocortin with chronic heart failure in the Czech population.

    PubMed

    Bienertová-Vasků, Julie Anna; Spinarová, Lenka; Bienert, Petr; Vasků, Anna

    2009-03-01

    Patients with chronic heart failure (CHF) express enhanced catabolic metabolism finally resulting in overall weight loss, whereas adipokines might play a crucial role in signaling among tissues. The aim of this study was to investigate the possible associations of defined variability in leptin (dbSNP ID rs7799039), proopiomelanocortin (dbSNP ID rs3754860 and dbSNP ID rs1009388), and leptin receptor gene (dbSNP rs1137101) with CHF and evaluate their potential as the CHF susceptibility genes. The case-control study comprised a total of 372 patients of Caucasian origin with chronic heart failure (New York Heart Association [NYHA] functional classes II-IV, ejection fraction (EF) <40%) and 407 healthy controls. They were genotyped for the leptin (LEP) -2548 G/A, leptin receptor (LEPR) Gln223Arg, and proopiomelanocortin (POMC) RsaI (5'-untranslated region) and C1032G variants (intron 1) using PCR-based methodology. No case-control differences in genotype as well as allele frequencies were observed between CHF patients and controls. We constructed POMC RsaI/C1032G haplotypes, having found no significant association with body mass index (BMI), left ventricle ejection fraction (LVEF), left ventricle hypertrophy (LVH) and diabetes mellitus (DM). Multivariate regression analyses revealed an approximately 2-fold risk for NYHA class IV associated with the LEPR Gln223Arg (P = 0.0000001, odds ratio [OR] = 2.10, 95% confidence interval [CI] = 1.56-2.84); it also displayed an independent prediction role for LVEF in heart failure cases of all etiologies (P = 0.002, OR = 4.05, 95% CI = 1.36-10.06). In subanalyses according to CHF etiology the LEPR Gln223Arg showed an independent prediction role for NYHA IV in IHD patients (P = 0.0001, OR = 2.50, 95% CI = 1.69-3.82) and both for NYHA IV(P = 0.007, OR = 2.04, 95% CI = 1.20-3.84) and LVEF (P = 0.004, OR = 11.87, 95% CI = 2.08-55.6) in DCMP patients. The role of the polymorphic variants in the genes encoding for adipokines as potential

  1. A functional SNP upstream of the beta-2 adrenergic receptor gene (ADRB2) is associated with obesity in Oceanic populations

    PubMed Central

    Naka, I; Hikami, K; Nakayama, K; Koga, M; Nishida, N; Kimura, R; Furusawa, T; Natsuhara, K; Yamauchi, T; Nakazawa, M; Ataka, Y; Ishida, T; Inaoka, T; Iwamoto, S; Matsumura, Y; Ohtsuka, R; Tsuchiya, N; Ohashi, J

    2013-01-01

    OBJECTIVE: Obesity is a growing health concern in the Oceanic populations. To investigate the genetic factors associated with adult obesity in the Oceanic populations, the association of single nucleotide polymorphisms (SNPs) of the beta-2 adrenergic receptor (ADRB2) gene with obesity was examined in 694 adults living in Tonga and Solomon Islands. RESULTS: A screening for variation in 16 Oceanic subjects detected 17 SNPs in the entire region of ADRB2, of which nine SNPs including two non-synonymous ones, rs1042713 (Arg16Gly) and rs1042714 (Gln27Glu), were further genotyped for all subjects. The rs34623097-A allele, at a SNP located upstream of ADRB2, showed the strongest association with risk for obesity in a logistic regression analysis adjusted for age, sex, and population (P=5.6 × 10−4, odds ratio [OR]=2.5, 95% confidence interval [CI]=1.5–4.2). The 27Glu was also significantly associated with obesity in the single-point association analysis (P=0.013, OR=2.0, 95%CI=1.2–3.4); however, this association was no longer significant after adjustment for rs34623097 since these SNPs were in linkage disequilibrium with each other. A copy of the obesity-risk allele, rs34623097-A, led to a 1.6 kg/m2 increase in body mass index (BMI; defined as weight in kilograms divided by height in meters squared) (P=0.0019). A luciferase reporter assay indicated that rs34623097-A reduced the transcriptional activity of the luciferase reporter gene by approximately 10% compared with rs34623097-G. An electrophoretic mobility shift assay demonstrated that rs34623097 modulated the binding affinity with nuclear factors. An evolutionary analysis implies that a G>A mutation at rs34623097 occurred in the Neandertal genome and then the rs34623097-A allele flowed into the ancestors of present-day humans. CONCLUSION: The present results suggest that rs34623097-A, which would lead to lower expression of ADRB2, contributes to the onset of obesity in the Oceanic populations. PMID:23229733

  2. Plasma Leptin levels, LEPR Q223R Polymorphism and Mammographic Breast Density: a cross-sectional study

    PubMed Central

    Dallal, Cher; Garte, Seymour; Ragin, Camille; Chen, Jiangying; Lloyd, Stacy; Modugno, Francesmary; Weissfeld, Joel; Taioli, Emanuela

    2015-01-01

    Obesity is associated with breast cancer in post-menopausal women, and breast density is a marker of breast cancer risk. Leptin is produced by the adipose tissue, acts through receptors that are polymorphic in nature, and is considered a cancer growth factor. The relationship between Body Mass Index, leptin, leptin receptors and breast density is not well studied. A cross-sectional analysis in 392 post-menopausal healthy women was conducted; participants provided permission to obtain copies of their most recent screening mammogram. Nonfasting plasma leptin levels were determined using a commercially available leptin ELISA kit. The Q223R genotypes of the LEPR gene were performed by polymerase chain reaction followed by restriction fragment length polymorphism analysis using DNA extracted from buffy coat samples. A statistically significant positive relationship was observed between leptin levels and body mass index (P value<0.0001); leptin was significantly positively associated with mammography total breast area and non-dense breast area (P-value<0.0001), while was significantly inversely associated with percent breast density (P-value<0.0001). Leptin levels varied across the LEPR Q223R polymorphism, and were higher in women homozygous for the AA variant. Percent breast density decreased across the LEPR Q223R genotype, with lower percent density in women with the AA genotype. When dense area was considered for quartiles of leptin by LEPR Q223R, a significant inverse trend between leptin levels and dense breast area was observed only among women with the G/G genotype (P-trend<0.001). After adjustment for possible confounders, leptin levels were significantly inversely associated with percent breast density (p=0.01). A significant interaction between body mass index and leptin levels on percent breast density was observed (p=0.03). These findings suggest that the association between leptin and breast density may vary by LEPR Q223R genotype, and that body mass index

  3. Genome-Wide Association Study Singles Out SCD and LEPR as the Two Main Loci Influencing Intramuscular Fat Content and Fatty Acid Composition in Duroc Pigs

    PubMed Central

    Ros-Freixedes, Roger; Gol, Sofia; Pena, Ramona N.; Tor, Marc; Ibáñez-Escriche, Noelia; Dekkers, Jack C. M.; Estany, Joan

    2016-01-01

    Intramuscular fat (IMF) content and fatty acid composition affect the organoleptic quality and nutritional value of pork. A genome-wide association study was performed on 138 Duroc pigs genotyped with a 60k SNP chip to detect biologically relevant genomic variants influencing fat content and composition. Despite the limited sample size, the genome-wide association study was powerful enough to detect the association between fatty acid composition and a known haplotypic variant in SCD (SSC14) and to reveal an association of IMF and fatty acid composition in the LEPR region (SSC6). The association of LEPR was later validated with an independent set of 853 pigs using a candidate quantitative trait nucleotide. The SCD gene is responsible for the biosynthesis of oleic acid (C18:1) from stearic acid. This locus affected the stearic to oleic desaturation index (C18:1/C18:0), C18:1, and saturated (SFA) and monounsaturated (MUFA) fatty acids content. These effects were consistently detected in gluteus medius, longissimus dorsi, and subcutaneous fat. The association of LEPR with fatty acid composition was detected only in muscle and was, at least in part, a consequence of its effect on IMF content, with increased IMF resulting in more SFA, less polyunsaturated fatty acids (PUFA), and greater SFA/PUFA ratio. Marker substitution effects estimated with a subset of 65 animals were used to predict the genomic estimated breeding values of 70 animals born 7 years later. Although predictions with the whole SNP chip information were in relatively high correlation with observed SFA, MUFA, and C18:1/C18:0 (0.48–0.60), IMF content and composition were in general better predicted by using only SNPs at the SCD and LEPR loci, in which case the correlation between predicted and observed values was in the range of 0.36 to 0.54 for all traits. Results indicate that markers in the SCD and LEPR genes can be useful to select for optimum fatty acid profiles of pork. PMID:27023885

  4. CRTAP AND LEPRE1 MUTATIONS IN RECESSIVE OSTEOGENESIS IMPERFECTA

    PubMed Central

    Baldridge, Dustin; Schwarze, Ulrike; Morello, Roy; Lennington, Jennifer; Bertin, Terry K.; Pace, James M.; Pepin, Melanie G.; Weis, MaryAnn; Eyre, David R.; Walsh, Jennifer; Lambert, Deborah; Green, Andrew; Robinson, Haynes; Michelson, Melonie; Houge, Gunnar; Lindman, Carl; Martin, Judith; Ward, Jewell; Lemyre, Emmanuelle; Mitchell, John J.; Krakow, Deborah; Rimoin, David L.; Cohn, Daniel H.; Byers, Peter H.; Lee, Brendan

    2009-01-01

    Autosomal dominant osteogenesis imperfecta (OI) is caused by mutations in the genes (COL1A1 or COL1A2) encoding the chains of type I collagen. Recently, dysregulation of hydroxylation of a single proline residue at position 986 of both the triple-helical domains of type I collagen α1(I) and type II collagen α1(II) chains has been implicated in the pathogenesis of recessive forms of OI. Two proteins, CRTAP, or cartilage-associated protein, and prolyl-3-hydroxylase-1 (P3H1, encoded by the LEPRE1 gene) form a complex that performs the hydroxylation and brings the prolyl cis-trans isomerase cyclophilin-B (CYPB) to the unfolded collagen. In our screen of 78 subjects diagnosed with OI type II or III, we identified three probands with mutations in CRTAP and sixteen with mutations in LEPRE1. The latter group includes a mutation in patients from the Irish Traveller population, a genetically isolated community with increased incidence of OI. The clinical features resulting from CRTAP or LEPRE1 loss of function mutations were difficult to distinguish at birth. Infants in both groups had multiple fractures, decreased bone modeling (affecting especially the femurs), and extremely low bone mineral density. Interestingly, “popcorn” epiphyses may reflect underlying cartilaginous and bone dysplasia in this form of OI. These results expand the range of CRTAP/LEPRE1 mutations that result in recessive OI and emphasize the importance of distinguishing recurrence of severe OI of recessive inheritance from those that result from parental germline mosaicism for COL1A1 or COL1A2 mutations. PMID:18566967

  5. Role of leptin receptors in granulosa cells during ovulation.

    PubMed

    Dupuis, Lisa; Schuermann, Yasmin; Cohen, Tamara; Siddappa, Dayananda; Kalaiselvanraja, Anitha; Pansera, Melissa; Bordignon, Vilceu; Duggavathi, Raj

    2014-02-01

    Leptin is an important hormone influencing reproductive function. However, the mechanisms underpinning the role of leptin in the regulation of reproduction remain to be completely deciphered. In this study, our objective is to understand the mechanisms regulating the expression of leptin receptor (Lepr) and its role in ovarian granulosa cells during ovulation. First, granulosa cells were collected from superovulated mice to profile mRNA expression of Lepr isoforms (LeprA and LeprB) throughout follicular development. Expression of LeprA and LeprB was dramatically induced in the granulosa cells of ovulating follicles at 4 h after human chorionic gonadotropin (hCG) treatment. Relative abundance of both mRNA and protein of CCAAT/enhancer-binding protein β (Cebpβ) increased in granulosa cells from 1 to 7 h post-hCG. Furthermore, chromatin immunoprecipitation assay confirmed the recruitment of Cebpβ to Lepr promoter. Thus, hCG-induced transcription of Lepr appears to be regulated by Cebpβ, which led us to hypothesise that Lepr may play a role during ovulation. To test this hypothesis, we used a recently developed pegylated superactive mouse leptin antagonist (PEG-SMLA) to inhibit Lepr signalling during ovulation. I.p. administration of PEG-SMLA (10 μg/g) to superovulated mice reduced ovulation rate by 65% compared with control treatment. Although the maturation stage of the ovulated oocytes remained unaltered, ovulation genes Ptgs2 and Has2 were downregulated in PEG-SMLA-treated mice compared with control mice. These results demonstrate that Lepr is dramatically induced in the granulosa cells of ovulating follicles and this induction of Lepr expression requires the transcription factor Cebpβ. Lepr plays a critical role in the process of ovulation by regulating, at least in part, the expression of the important genes involved in the preovulatory maturation of follicles. PMID:24256641

  6. Association of LEP G2548A and LEPR Q223R Polymorphisms with Cancer Susceptibility: Evidence from a Meta-Analysis

    PubMed Central

    Shi, Ting-Yan; Zhu, Mei-Ling; Wang, Meng-Yun; Li, Qiao-Xin; Zhou, Xiao-Yan; Qiu, Li-Xin; Wei, Qing-Yi

    2013-01-01

    Background Numerous epidemiological studies have examined associations of genetic variations in LEP (G2548A, -2548 nucleotide upstream of the ATG start site) and LEPR (Q223R, nonsynonymous SNP in exon 6) with cancer susceptibility; however, the findings are inconsistent. Therefore, we performed a meta-analysis to comprehensively evaluate such associations. Methods We searched published literature from MEDLINE, EMBASE, Web of Science and CBM for eligible publications. We also assessed genotype-based mRNA expression data from HapMap for rs7799039 (G2548A) and rs1137101 (Q223R) in normal cell lines derived from 270 subjects with different ethnicities. Results The final analysis included 16 published studies of 6569 cases and 8405 controls for the LEP G2548A and 19 studies of 7504 cases and 9581 controls for the LEPR Q223R. Overall, LEP G2548A was statistically significantly associated with an increased risk of overall cancer (AA vs. GG: OR=1.27, 95% CI=1.05-1.54; recessive model: OR=1.19, 95% CI=1.00-1.41). Further stratifications by cancer type showed an increased risk for prostate cancer (recessive model: OR=1.26, 95% CI=1.05-1.51) but not for other cancers. For LEPR Q223R, no statistical evidence for an association with risk of cancer was found for all; however, further stratification by ethnicity showed an increased risk for Africans but not for other ethnicities. No significantly differences in LEP and LEPR mRNA expression were found among genotypes or by ethnicity. Conclusions Despite some limitations, this meta-analysis found some statistical evidence for an association between the LEP 2548AA genotype and overall risk of cancer, particularly for prostate cancer, but given this variant did not have an effect on mRNA expression, this association warrants additional validation in large and well-designed studies. PMID:24146750

  7. Measurement of the levels of leptin, BDNF associated with polymorphisms LEP G2548A, LEPR Gln223Arg and BDNF Val66Met in Thai with metabolic syndrome

    PubMed Central

    2014-01-01

    Background Metabolic syndrome is a cluster of metabolic risk factors including dyslipidemia, impaired glucose tolerance, hypertension and central obesity. BDNF (Brain-derived neurotrophic factor) and leptin have been implied in the energy homeostasis. The purposes of this study were to examine concentrations of leptin, BDNF and biochemical parameters in metabolic-syndrome subjects and healthy controls, and also to search for associations of leptin gene (LEP) G2548A, leptin receptor gene (LEPR) Gln223Arg, and BDNF gene (BDNF) Val66Met polymorphisms with leptin levels, BDNF levels and metabolic syndrome among Thais. Methods The case-controlled design was performed using 322 Thai volunteers (160 metabolic-syndrome subjects; 162 controls) during the health screening program. Metabolic syndrome was assessed by using the modified National Cholesterol Education Program, Adult Treatment Panel III criteria. The levels of leptin, BDNF, insulin, glucose and lipids were measured in samples. Genotyping of LEP G2548A, LEPR Gln223Arg and BDNF Val66Met was carried out using polymerase chain reaction-restriction fragment length polymorphism technique. Results Serum leptin levels were significantly higher in the metabolic-syndrome group than the control group (p < 0.01), but the BDNF difference between them was not significant. Significant associations of LEPR Gln223Arg polymorphism were found with leptin and glucose levels (p < 0.05), after adjusting for potential covariates. This LEPR polymorphism in the metabolic-syndrome group was also significantly more frequent than in the control group (p < 0.05). However, other gene polymorphisms, LEP G2548A and BDNF Val66Met, showed no significant relationship with leptin levels, BDNF levels or metabolic syndrome. Conclusion These findings suggest leptin levels are linked with metabolic syndrome. LEPR Gln223Arg polymorphism impacted leptin concentrations, and this gene polymorphism may influence susceptibility to metabolic syndrome among

  8. Creating leptin-like biofunctions by active immunization against chicken leptin receptor in growing chickens.

    PubMed

    Lei, M M; Wu, S Q; Shao, X B; Li, X W; Chen, Z; Ying, S J; Shi, Z D

    2015-01-01

    In this study, immunization against chicken leptin receptor (cLEPR) extracellular domain (ECD) was applied to investigate leptin regulation and LEPR biofunction in growing chicken pullets. A recombinant protein (cLEPR ECD) based on the cLEPR complemenary DNA sequence corresponding to the 582nd to 796th amino acid residues of cLEPR mature peptide was prepared and used as antigen. Immunization against cLEPR ECD in growing chickens increased anti-cLEPR ECD antibody titers in blood, enhanced proportions of phosphorylated janus kinase 2 (JAK2) and served as signal transducer and activator of transcription 3 (STAT3) protein in liver tissue. Chicken live weight gain and abdominal fat mass were significantly decreased (P < 0.05), but feed intake was stimulated by cLEPR ECD immunization (P < 0.05). The treatment also upregulated the gene expression levels of lepR, AMP-activated protein kinase (AMPK), acetyl CoA carboxylase-2 (ACC2), and uncoupling protein 3 (UCP3) in liver, abdominal fat, and breast muscle (P < 0.05) but decreased fasn expression levels (P < 0.01). Apart from that of lepR, the expression of appetite-regulating genes, such as orexigenic genes, agouti-related peptide (AgRP) and neuropeptide Y (NPY), were upregulated (P < 0.01), whereas the anorexigenic gene proopiomelanocortin (POMC) was downregulated in the hypothalamic tissue of cLEPR-immunized pullets (P < 0.01). Blood concentrations of metabolic molecules, such as glucose, triglycerides, and very-low-density lipoprotein, were significantly decreased in cLEPR-immunized pullets but those of cholesterol, high-density lipoprotein, and low-density lipoprotein increased. These results demonstrate that antibodies to membrane proximal cLEPR ECD enhance cLEPR signal transduction, which stimulates metabolism and reduces fat deposition in chickens. PMID:25447880

  9. The Influence of LepR Tyrosine Site Mutations on Mouse Ovary Development and Related Gene Expression Changes

    PubMed Central

    Tu, Xiaoyu; Kuang, Zhichao; Gong, Xia; Shi, Yan; Yu, Lin; Shi, Huijuan; Wang, Jian; Sun, Zhaogui

    2015-01-01

    Leptin exerts many biological functions, such as in metabolism and reproduction, through binding to and activating the leptin receptor, LepRb, which is expressed in many regions of the brain. To better understand the roles of LepR downstream signaling pathways, Y123F mice, which expressed mutant leptin receptors with phenylalanine (F) substituted for three tyrosines (Y) (Tyr985, Tyr1077 and Tyr1138), were generated. The body weight and abdominal fat deposits of Y123F homozygous mice (HOM) were higher than those of wild-type mice (WT). HOM ovaries were atrophic and the follicles developed abnormally; however, the HOM ovaries did not exhibit polycystic phenotypes. Moreover, Y123F HOM adults had no estrous cycle and the blood estrogen concentration remained stable at a low level below detection limit of 5 pg/ml. LepR expression in HOM ovaries was higher than in WT ovaries. Using cDNA Microarrays, the mRNA expressions of 41 genes were increased, and 100 were decreased in HOM vs. WT ovaries, and many signaling pathways were evaluated to be involved significantly. The expressions of 19 genes were validated by real-time quantitative PCR, most of which were consistent with the microarray results. Thus, Y123F HOM mice were suggested as a new animal model of PCOS for research that mainly emphasizes metabolic disorders and anovulation, but not the polycystic phenotype. Meanwhile, using the model, we found that JAK-STAT and hormone biosynthesis pathways were involved in the follicular development and ovulation disorders caused by LepR deficiency in ovaries, although we could not exclude indirect actions from the brain. PMID:26529315

  10. Analysis of 10 independent samples provides evidence for association between schizophrenia and a SNP flanking fibroblast growth factor receptor 2 (FGFR2)

    PubMed Central

    O’Donovan, M.C.; Norton, N.; Williams, H.; Peirce, T.; Moskvina, V.; Nikolov, I.; Hamshere, M.; Carroll, L.; Georgieva, L.; Dwyer, S; Holmans, P.; Marchini, J. L.; Spencer, C.C.A.; Howie, B.; Leung, H-T.; Giegling, I.; Hartmann, A.M.; Möller, H.-J.; Morris, D.W.; Shi, Y.; Feng, G.; Hoffmann, P.; Propping, P.; Vasilescu, C.; Maier, W.; Rietschel, M.; Zammit, S.; Schumacher, J.; Quinn, E.M.; Schulze, T.G.; Iwata, N.; Ikeda, M.; Darvasi, A.; Shifman, S.; He, L.; Duan, J.; Sanders, A.R.; Levinson, D.F.; Adolfsson, R.; Ösby, U.; Terenius, Lars; Jönsson, Erik G; Cichon, S.; Nöthen, M. M.; Gill, M.; Corvin, A.P.; Rujescu, D.; Gejman, P.V.; Kirov, G.; Craddock, N.; Williams, N.M.; Owen, M.J.

    2010-01-01

    We and others have previously reported linkage to schizophrenia on chromosome 10q25-q26 but, to date, a susceptibility gene in the region has not been identified. We examined data from 3606 SNPs mapping to 10q25-q26 that had been typed in a genome-wide association study (GWAS) of schizophrenia (479 UK cases/2937 controls). SNPs with p<0.01 (n=40) were genotyped in an additional 163 UK cases and those markers that remained nominally significant at p<0.01 (n=22) were genotyped in replication samples from Ireland, Germany and Bulgaria consisting of a total of 1664 cases with schizophrenia and 3541 controls. Only one SNP, rs17101921, was nominally significant after meta-analyses across the replication samples and this was genotyped in an additional six samples from the US/Australia, Germany, China, Japan, Israel and Sweden (n= 5142 cases/ 6561 controls). Across all replication samples, the allele at rs17101921 that was associated in the GWAS showed evidence for association independent of the original data (OR 1.17 (95% CI 1.06-1.29), p=0.0009). The SNP maps 85kb from the nearest gene encoding fibroblast growth factor receptor 2 (FGFR2) making this a potential susceptibility gene for schizophrenia. PMID:18813210

  11. DNA microarray analysis identifies CKS2 and LEPR as potential markers of meningioma recurrence.

    PubMed

    Menghi, Francesca; Orzan, Francesca N; Eoli, Marica; Farinotti, Mariangela; Maderna, Emanuela; Pisati, Federica; Bianchessi, Donatella; Valletta, Lorella; Lodrini, Sandro; Galli, Giuseppe; Anghileri, Elena; Pellegatta, Serena; Pollo, Bianca; Finocchiaro, Gaetano

    2011-01-01

    Meningiomas are the most frequent intracranial tumors. Surgery can be curative, but recurrences are possible. We performed gene expression analyses and loss of heterozygosity (LOH) studies looking for new markers predicting the recurrence risk. We analyzed expression profiles of 23 meningiomas (10 grade I, 10 grade II, and 3 grade III) and validated the data using quantitative polymerase chain reaction (qPCR). We performed LOH analysis on 40 meningiomas, investigating chromosomal regions on 1p, 9p, 10q, 14q, and 22q. We found 233 and 268 probe sets to be significantly down- and upregulated, respectively, in grade II or III meningiomas. Genes downregulated in high-grade meningiomas were overrepresented on chromosomes 1, 6, 9, 10, and 14. Based on functional enrichment analysis, we selected LIM domain and actin binding 1 (LIMA1), tissue inhibitor of metalloproteinases 3 (TIMP3), cyclin-dependent kinases regulatory subunit 2 (CKS2), leptin receptor (LEPR), and baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) for validation using qPCR and confirmed their differential expression in the two groups of tumors. We calculated ΔCt values of CKS2 and LEPR and found that their differential expression (C-L index) was significantly higher in grade I than in grade II or III meningiomas (p < .0001). Interestingly, the C-L index of nine grade I meningiomas from patients who relapsed in <5 years was significantly lower than in grade I meningiomas from patients who did not relapse. These findings indicate that the C-L index may be relevant to define the progression risk in meningioma patients, helping guide their clinical management. A prospective analysis on a larger number of cases is warranted. PMID:21948653

  12. Variations in the Obesity Gene "LEPR" Contribute to Risk of Type 2 Diabetes Mellitus: Evidence from a Meta-Analysis.

    PubMed

    Yang, Ming Ming; Wang, Jun; Fan, Jiao Jie; Ng, Tsz Kin; Sun, Dian Jun; Guo, Xin; Teng, Yan; Li, Yan-Bo

    2016-01-01

    Leptin is a hormone protein regulating food intake and energy expenditure. A number of studies have evaluated the genetic effect of leptin (LEP) and leptin receptor (LEPR) genes on T2DM. This study aimed to investigate the association between these gene polymorphisms and T2DM by a systematic review and meta-analysis. Published studies were identified through extensive search in PubMed and EMBASE. A total of 5143 T2DM cases and 5021 controls from 14 articles were included in this study. Five functional variants in LEPR were well evaluated. Meta-analysis showed that rs1137101 (p.R223Q) was significantly associated with T2DM in all genetic models: allele model (OR = 1.27, 95% confidence interval (CI) = 1.13-1.42), dominant model (OR = 1.19, 95% CI = 1.05-1.35), homozygote model (OR = 1.82, 95% CI = 1.38-2.39), and recessive model (OR = 1.75, 95% CI = 1.35-2.28), with minimal heterogeneity and no indication of publication bias. Similar associations with T2DM were also found for rs62589000 (p.P1019P) and 3'UTR ins/del, although the data was obtained from a small number of studies. For the other two polymorphisms rs1137100 (p.R109K) and rs8179183 (p.K656N), they were not significantly associated with T2DM. Our results provide robust evidences for the genetic association of rs1137101 (p.R223Q) in LEPR with T2DM susceptibility. PMID:27195302

  13. Associations of Candidate SNP on Age, Leptin Concentration, Backfat, and Body Weight at Puberty in Gilts

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Body weight (BW), backfat thickness (BF), and leptin play important roles in livestock reproduction. The objective of this study was to determine whether polymorphisms in the leptin (LEP), leptin receptor (LEPR), PAX5, and POMC genes were associated with age, leptin concentration, body condition as ...

  14. Polymorphism in LEP and LEPR May Modify Leptin Levels and Represent Risk Factors for Thyroid Cancer

    PubMed Central

    Marcello, Marjory Alana; Calixto, Antonio Ramos; de Almeida, Jacqueline Fatima Martins; Cunha, Lucas Leite; Cavalari, Camila Ayume Amano; Etchebehere, Elba C. S.; da Assumpção, Ligia Vera Montalli; Geloneze, Bruno; Carvalho, Andre Lopes; Ward, Laura Sterian

    2015-01-01

    Purpose. To understand the role of polymorphisms in the LEP (rs7799039 and rs2167270) and LEPR (rs1137101 and rs1137100) genes in DTC susceptibility and their effect on leptin levels. Methods. We studied 153 patients with DTC and 234 controls through TaqMan SNP Genotyping and ELISA, comparing these data to the clinicopathological data of patients with DTC. Results. Patients with AA genotype of rs7799039 had higher levels of serum leptin (9.22 ± 0.98 ng/mL) than those with AG genotype (10.07 ± 0.60 ng/mL; P = 0.005). Individuals with AG genotype of rs2167270 also produced higher serum leptin levels (10.05 ± 0.59 ng/mL) than the subjects with GG genotype (9.52 ± 0.79 ng/mL; P < 0.05). A multivariate logistic regression adjusted for gender, age, and BMI showed that the AG genotype of rs7799039 was an independent risk for DTC (OR, 11.689; P = 0.0183; 95% CI, 1.516–90.119). Similarly, AG and GG genotypes of rs1137101 increased the susceptibility to DTC (OR, 3.747; P = 0.027; 95% CI, 1.161–12.092 and OR, 5.437; P = 0.013; 95% CI, 1.426–20.729). Conclusions. We demonstrated that rs7799039 and rs2167270 polymorphisms modify the serum leptin concentrations in patients with DTC. Furthermore, polymorphisms rs7799039 and rs1137101 increase the risk of DTC development, although they do not correlate with tumor aggressiveness. PMID:25810718

  15. Polymorphism in LEP and LEPR May Modify Leptin Levels and Represent Risk Factors for Thyroid Cancer.

    PubMed

    Marcello, Marjory Alana; Calixto, Antonio Ramos; de Almeida, Jacqueline Fatima Martins; Martins, Mariana Bonjiorno; Cunha, Lucas Leite; Cavalari, Camila Ayume Amano; Etchebehere, Elba C S; da Assumpção, Ligia Vera Montalli; Geloneze, Bruno; Carvalho, Andre Lopes; Ward, Laura Sterian

    2015-01-01

    Purpose. To understand the role of polymorphisms in the LEP (rs7799039 and rs2167270) and LEPR (rs1137101 and rs1137100) genes in DTC susceptibility and their effect on leptin levels. Methods. We studied 153 patients with DTC and 234 controls through TaqMan SNP Genotyping and ELISA, comparing these data to the clinicopathological data of patients with DTC. Results. Patients with AA genotype of rs7799039 had higher levels of serum leptin (9.22 ± 0.98 ng/mL) than those with AG genotype (10.07 ± 0.60 ng/mL; P = 0.005). Individuals with AG genotype of rs2167270 also produced higher serum leptin levels (10.05 ± 0.59 ng/mL) than the subjects with GG genotype (9.52 ± 0.79 ng/mL; P < 0.05). A multivariate logistic regression adjusted for gender, age, and BMI showed that the AG genotype of rs7799039 was an independent risk for DTC (OR, 11.689; P = 0.0183; 95% CI, 1.516-90.119). Similarly, AG and GG genotypes of rs1137101 increased the susceptibility to DTC (OR, 3.747; P = 0.027; 95% CI, 1.161-12.092 and OR, 5.437; P = 0.013; 95% CI, 1.426-20.729). Conclusions. We demonstrated that rs7799039 and rs2167270 polymorphisms modify the serum leptin concentrations in patients with DTC. Furthermore, polymorphisms rs7799039 and rs1137101 increase the risk of DTC development, although they do not correlate with tumor aggressiveness. PMID:25810718

  16. Conditional Expression of Pomc in the Lepr-Positive Subpopulation of POMC Neurons Is Sufficient for Normal Energy Homeostasis and Metabolism

    PubMed Central

    Lam, Daniel D.; Attard, Courtney A.; Mercer, Aaron J.; Myers, Martin G.; Rubinstein, Marcelo

    2015-01-01

    Peptides derived from the proopiomelanocortin (POMC) precursor are critical for the normal regulation of many physiological parameters, and POMC deficiency results in severe obesity and metabolic dysfunction. Conversely, augmentation of central nervous system melanocortin function is a promising therapeutic avenue for obesity and diabetes but is confounded by detrimental cardiovascular effects including hypertension. Because the hypothalamic population of POMC-expressing neurons is neurochemically and neuroanatomically heterogeneous, there is interest in the possible dissociation of functionally distinct POMC neuron subpopulations. We used a Cre recombinase-dependent and hypothalamus-specific reactivatable PomcNEO allele to restrict Pomc expression to hypothalamic neurons expressing leptin receptor (Lepr) in mice. In contrast to mice with total hypothalamic Pomc deficiency, which are severely obese, mice with Lepr-restricted Pomc expression displayed fully normal body weight, food consumption, glucose homeostasis, and locomotor activity. Thus, Lepr+ POMC neurons, which constitute approximately two-thirds of the total POMC neuron population, are sufficient for normal regulation of these parameters. This functional dissociation approach represents a promising avenue for isolating therapeutically relevant POMC neuron subpopulations. PMID:25594696

  17. Evaluation of leptin receptor expression on buffalo leukocytes.

    PubMed

    De Matteis, Giovanna; Grandoni, Francesco; Scatà, Maria Carmela; Catizone, Angela; Reale, Anna; Crisà, Alessandra; Moioli, Bianca

    2016-09-01

    Experimental evidences support a direct role for leptin in immunity. Besides controlling food intake and energy expenditure, leptin was reported to be involved in the regulation of the immune system in ruminants. The aim of this work was to highlight the expression of leptin receptor (LEPR) on Bubalus bubalis immune cells using a multi-approach assessment: flow cytometry, confocal microscopy and gene expression analysis. Flow cytometric analysis of LEPR expression showed that peripheral blood monocytes were the predominant cells expressing LEPR. This result was corroborated by confocal microscopy and RT-PCR analysis. Moreover, among lymphocytes, LEPR was mainly expressed by B lymphocytes and Natural Killer cells. Evidence of LEPR expression on buffalo blood leukocytes showed to be a good indicator of the responsivity of these cells to leptin, so confirming the involvement of leptin in buffalo immune response. PMID:27436440

  18. Leptin receptor polymorphisms interact with polyunsaturated fatty acids to augment risk of insulin resistance and metabolic syndrome in adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The leptin receptor (LEPR) is associated with insulin resistance, a key feature of metabolic syndrome (MetS). Gene-fatty acid interactions may affect MetS risk. The objective was to investigate the relationship among LEPR polymorphisms, insulin resistance, andMetSrisk and whether plasma fatty acids,...

  19. The methylation of the LEPR/LEPROT genotype at the promoter and body regions influence concentrations of leptin in girls and BMI at age 18 years if their mother smoked during pregnancy

    PubMed Central

    Yousefi, Mitra; Karmaus, Wilfried; Zhang, Hongmei; Ewart, Susan; Arshad, Hasan; Holloway, John W

    2013-01-01

    To determine whether DNA methylation (DNA-M) of the leptin receptor genotype (LEPR/LEPROT) links gestational smoking and leptin serum levels and BMI later in life, we focused on female offspring, 18 years of age, from the Isle of Wight Birth Cohort (IOWBC). Leptin binds to the leptin receptor encoded by the LEPR/LEPROT genotype. Using general linear models, we tested a two-stage model. First, we investigated whether single nucleotide polymorphisms (SNPs) acting as methylation quantitative trait loci (methQTLs) depending on gestational smoking were related to differentially methylated cytosine-phosphate-guanine (CpG) sites. In stage 2, we tested whether the selected CpG sites, in interaction with other SNPs (modifiable genetic variants, modGV), are associated with serum leptin and BMI (stage 2). Children from the IOWBC were followed from birth to age 18. Information on gestational smoking was gathered upon delivery. SNPs tagging LEPR and LEPROT genes were genotyped. Data on LEPR/LEPROT DNA-M and leptin were obtained from blood samples drawn at age 18; to determine BMI, height and weight were ascertained. Blood samples were provided by 238 girls. Of the 21 CpG sites, interactions between gestational smoking and SNPs were detected for 16 CpGs. Methylation of seven of the 16 CpGs were, in interaction with modGVs, associated with leptin levels at age 18 years. Two CpGs survived a multiple testing penalty and were also associated with BMI. This two-stage model may explain why maternal smoking has a long-term effect on leptin levels and BMI in girls at age 18 years. PMID:23875062

  20. SNP-VISTA

    SciTech Connect

    Shah, Nameeta; Teplitsky, Michael; Minovitsky, Simon; Dubchak, Inna

    2005-11-07

    SNP-VISTA aids in analyses of the following types of data: A. Large-scale re-sequence data of disease-related genes for discovery of associated and/or causative alleles (GeneSNP-VISTA). B. Massive amounts of ecogenomics data for studying homologous recombination in microbial populations (EcoSNP-VISTA). The main features and capabilities of SNP-VISTA are: 1) Mapping of SNPs to gene structure; 2) classification of SNPs, based on their location in the gene, frequency of occurrence in samples and allele composition; 3) clustering, based on user-defined subsets of SNPs, highlighting haplotypes as well as recombinant sequences; 4) integration of protein conservation visualization; and 5) display of automatically calculated recombination points that are user-editable. The main strength of SNP-VISTA is its graphical interface and use of visual representations, which support interactive exploration and hence better understanding of large-scale SNPs data.

  1. IGF2, LEPR, POMC, PPARG, and PPARGC1 gene variants are associated with obesity-related risk phenotypes in Brazilian children and adolescents

    PubMed Central

    Queiroz, E.M.; Cândido, A.P.C.; Castro, I.M.; Bastos, A.Q.A.; Machado-Coelho, G.L.L.; Freitas, R.N.

    2015-01-01

    Association studies of genetic variants and obesity and/or obesity-related risk factors have yielded contradictory results. The aim of the present study was to determine the possible association of five single-nucleotide polymorphisms (SNPs) located in the IGF2, LEPR, POMC, PPARG, and PPARGC1genes with obesity or obesity-related risk phenotypes. This case-control study assessed overweight (n=192) and normal-weight (n=211) children and adolescents. The SNPs were analyzed using minisequencing assays, and variables and genotype distributions between the groups were compared using one-way analysis of variance and Pearson's chi-square or Fisher's exact tests. Logistic regression analysis adjusted for age and gender was used to calculate the odds ratios (ORs) for selected phenotype risks in each group. No difference in SNP distribution was observed between groups. In children, POMC rs28932472(C) was associated with lower diastolic blood pressure (P=0.001), higher low-density lipoprotein (LDL) cholesterol (P=0.014), and higher risk in overweight children of altered total cholesterol (OR=7.35, P=0.006). In adolescents, IGF2 rs680(A) was associated with higher glucose (P=0.012) and higher risk in overweight adolescents for altered insulin (OR=10.08, P=0.005) and homeostasis model of insulin resistance (HOMA-IR) (OR=6.34, P=0.010). PPARG rs1801282(G) conferred a higher risk of altered insulin (OR=12.31, P=0.003), and HOMA-IR (OR=7.47, P=0.005) in overweight adolescents. PARGC1 rs8192678(A) was associated with higher triacylglycerols (P=0.005), and LEPR rs1137101(A) was marginally associated with higher LDL cholesterol (P=0.017). LEPR rs1137101(A) conferred higher risk for altered insulin, and HOMA-IR in overweight adolescents. The associations observed in this population suggested increased risk for cardiovascular diseases and/or type 2 diabetes later in life for individuals carrying these alleles. PMID:25923461

  2. IGF2, LEPR, POMC, PPARG, and PPARGC1 gene variants are associated with obesity-related risk phenotypes in Brazilian children and adolescents.

    PubMed

    Queiroz, E M; Cândido, A P C; Castro, I M; Bastos, A Q A; Machado-Coelho, G L L; Freitas, R N

    2015-07-01

    Association studies of genetic variants and obesity and/or obesity-related risk factors have yielded contradictory results. The aim of the present study was to determine the possible association of five single-nucleotide polymorphisms (SNPs) located in the IGF2, LEPR, POMC, PPARG, and PPARGC1 genes with obesity or obesity-related risk phenotypes. This case-control study assessed overweight (n=192) and normal-weight (n=211) children and adolescents. The SNPs were analyzed using minisequencing assays, and variables and genotype distributions between the groups were compared using one-way analysis of variance and Pearson's chi-square or Fisher's exact tests. Logistic regression analysis adjusted for age and gender was used to calculate the odds ratios (ORs) for selected phenotype risks in each group. No difference in SNP distribution was observed between groups. In children, POMC rs28932472(C) was associated with lower diastolic blood pressure (P=0.001), higher low-density lipoprotein (LDL) cholesterol (P=0.014), and higher risk in overweight children of altered total cholesterol (OR=7.35, P=0.006). In adolescents, IGF2 rs680(A) was associated with higher glucose (P=0.012) and higher risk in overweight adolescents for altered insulin (OR=10.08, P=0.005) and homeostasis model of insulin resistance (HOMA-IR) (OR=6.34, P=0.010). PPARG rs1801282(G) conferred a higher risk of altered insulin (OR=12.31, P=0.003), and HOMA-IR (OR=7.47, P=0.005) in overweight adolescents. PARGC1 rs8192678(A) was associated with higher triacylglycerols (P=0.005), and LEPR rs1137101(A) was marginally associated with higher LDL cholesterol (P=0.017). LEPR rs1137101(A) conferred higher risk for altered insulin, and HOMA-IR in overweight adolescents. The associations observed in this population suggested increased risk for cardiovascular diseases and/or type 2 diabetes later in life for individuals carrying these alleles. PMID:25923461

  3. Transcriptional Characterization of Porcine Leptin and Leptin Receptor Genes.

    PubMed

    Pérez-Montarelo, Dafne; Fernández, Almudena; Barragán, Carmen; Noguera, Jose L; Folch, Josep M; Rodríguez, M Carmen; Ovilo, Cristina; Silió, Luis; Fernández, Ana I

    2013-01-01

    The leptin (LEP) and its receptor (LEPR) regulate food intake and energy balance through hypothalamic signaling. However, the LEP-LEPR axis seems to be more complex and its expression regulation has not been well described. In pigs, LEP and LEPR genes have been widely studied due to their relevance. Previous studies reported significant effects of SNPs located in both genes on growth and fatness traits. The aim of this study was to determine the expression profiles of LEP and LEPR across hypothalamic, adipose, hepatic and muscle tissues in Iberian x Landrace backcrossed pigs and to analyze the effects of gene variants on transcript abundance. To our knowledge, non porcine LEPR isoforms have been described rather than LEPRb. A short porcine LEPR isoform (LEPRa), that encodes a protein lacking the intracellular residues responsible of signal transduction, has been identified for the first time. The LEPRb isoform was only quantifiable in hypothalamus while LEPRa appeared widely expressed across tissues, but at higher levels in liver, suggesting that both isoforms would develop different roles. The unique LEP transcript showed expression in backfat and muscle. The effects of gene variants on transcript expression revealed interesting results. The LEPRc.1987C>T polymorphism showed opposite effects on LEPRb and LEPRa hypothalamic expression. In addition, one out of the 16 polymorphisms identified in the LEPR promoter region revealed high differential expression in hepatic LEPRa. These results suggest a LEPR isoform-specific regulation at tissue level. Conversely, non-differential expression of LEP conditional on the analyzed polymorphisms could be detected, indicating that its regulation is likely affected by other mechanisms rather than gene sequence variants. The present study has allowed a transcriptional characterization of LEP and LEPR isoforms on a range of tissues. Their expression patterns seem to indicate that both molecules develop peripheral roles apart from

  4. Leptin receptor expression and Gln223Arg polymorphism as prognostic markers in oral and oropharyngeal cancer.

    PubMed

    Rodrigues, P R S; Maia, L L; Santos, M; Peterle, G T; Alves, L U; Takamori, J T; Souza, R P; Barbosa, W M; Mercante, A M C; Nunes, F D; Carvalho, M B; Tajara, E H; Louro, I D; Silva-Conforti, A M A

    2015-01-01

    The leptin gene product is released into the blood stream, passes through the blood-brain barrier, and finds the leptin receptor (LEPR) in the central nervous system. This hormone regulates food intake, hematopoiesis, inflammation, immunity, differentiation, and cell proliferation. The LEPR Gln223Arg polymorphism has been reported to alter receptor function and expression, both of which have been related with prognostics in several tumor types. Furthermore, several studies have shown a relationship between the Gln223Arg polymorphism and tumor development, and its role in oral and oropharyngeal squamous cell carcinoma is now well understood. In this study, 315 DNA samples were used for LEPR Gln223Arg genotyping and 87 primary oral and oropharyngeal squamous cell carcinomas were used for immunohistochemical expression analysis, such that a relationship between these and tumor development and prognosis could be established. Homozygous LEPR Arg223 was found to be associated with a 2-fold reduction in oral and oropharyngeal cancer risk. In contrast, the presence of the Arg223 allele in tumors was associated with worse disease-free and disease-specific survival. Low LEPR expression was found to be an independent risk factor, increasing the risk for lymph node metastasis 4-fold. In conclusion, the Gln223Arg polymorphism and LEPR expression might be valuable markers for oral and oropharyngeal cancer, suggesting that LEPR might serve as a potential target for future therapies. PMID:26634459

  5. Family-Based Association Study Between SLC2A1, HK1, and LEPR Polymorphisms With Myelomeningocele in Chile

    PubMed Central

    Suazo, José; Castillo, Silvia; Martin, Luz Maria; Rojas, Francisca; Santos, José Luis; Rotter, Karin; Solar, Margarita; Tapia, Eva

    2013-01-01

    Obese/diabetic mothers present a higher risk to develop offspring with myelomeningocele (MM), evidence supporting the role of energy homeostasis-related genes in neural tube defects. Using polymerase chain reaction–restriction fragment length polymorphism, we have genotyped SLC2A1, HK1, and LEPR single-nucleotide polymorphisms in 105 Chilean patients with MM and their parents in order to evaluate allele–phenotype associations by means of allele/haplotype transmission test (TDT) and parent-of-origin effects. We detected an undertransmission for the SLC2A1 haplotype T-A (rs710218-rs2229682; P = .040), which was not significant when only lower MM (90% of the cases) was analyzed. In addition, the leptin receptor rs1137100 G allele showed a significant increase in the risk of MM for maternal-derived alleles in the whole sample (2.43-fold; P = .038) and in lower MM (3.20-fold; P = .014). Our results support the role of genes involved in energy homeostasis in the risk of developing MM, thus sustaining the hypothesis of diverse pathways and genetic mechanisms acting in the expression of such birth defect. PMID:23427181

  6. SNP-VISTA

    Energy Science and Technology Software Center (ESTSC)

    2005-11-07

    SNP-VISTA aids in analyses of the following types of data: A. Large-scale re-sequence data of disease-related genes for discovery of associated and/or causative alleles (GeneSNP-VISTA). B. Massive amounts of ecogenomics data for studying homologous recombination in microbial populations (EcoSNP-VISTA). The main features and capabilities of SNP-VISTA are: 1) Mapping of SNPs to gene structure; 2) classification of SNPs, based on their location in the gene, frequency of occurrence in samples and allele composition; 3) clustering,more » based on user-defined subsets of SNPs, highlighting haplotypes as well as recombinant sequences; 4) integration of protein conservation visualization; and 5) display of automatically calculated recombination points that are user-editable. The main strength of SNP-VISTA is its graphical interface and use of visual representations, which support interactive exploration and hence better understanding of large-scale SNPs data.« less

  7. Leptin Receptor Promotes Adipogenesis and Reduces Osteogenesis by Regulating Mesenchymal Stromal Cells in Adult Bone Marrow.

    PubMed

    Yue, Rui; Zhou, Bo O; Shimada, Issei S; Zhao, Zhiyu; Morrison, Sean J

    2016-06-01

    Skeletal stem cells (SSCs) that are the major source of osteoblasts and adipocytes in adult bone marrow express leptin receptor (LepR). To test whether LepR regulates SSC function, we conditionally deleted Lepr from limb bone marrow stromal cells, but not from the axial skeleton or hypothalamic neurons, using Prx1-Cre. Prx1-Cre;Lepr(fl/fl) mice exhibited normal body mass and normal hematopoiesis. However, limb bones from Prx1-Cre;Lepr(fl/fl) mice exhibited increased osteogenesis, decreased adipogenesis, and accelerated fracture healing. Leptin increased adipogenesis and reduced osteogenesis by activating Jak2/Stat3 signaling in bone marrow stromal cells. A high-fat diet increased adipogenesis and reduced osteogenesis in limb bones from wild-type mice, but not from Prx1-Cre;Lepr(fl/fl) mice. This reflected local effects of LepR on osteogenesis and adipogenesis by bone marrow stromal cells and systemic effects on bone resorption. Leptin/LepR signaling regulates adipogenesis and osteogenesis by mesenchymal stromal cells in the bone marrow in response to diet and adiposity. PMID:27053299

  8. Allelic background of LEPRE1 mutations that cause recessive forms of osteogenesis imperfecta in different populations

    PubMed Central

    Pepin, Melanie G; Schwarze, Ulrike; Singh, Virendra; Romana, Marc; Jones-LeCointe, Altheia; Byers, Peter H

    2013-01-01

    Biallelic mutations in LEPRE1 result in recessively inherited forms of osteogenesis imperfecta (OI) that are often lethal in the perinatal period. A mutation (c.1080+1G>T, IVS5+1G>T) in African Americans has a carrier frequency of about 1/240. The mutant allele originated in West Africa in tribes of Ghana and Nigeria where the carrier frequencies are 2% and 5%. By examining 200 samples from an African-derived population in Tobago and reviewing hospital neonatal death records, we determined that the carrier frequency of c.1080+1G>T was about one in 200 and did not contribute to the neonatal deaths recorded over a 3-year period of time in Trinidad. In the course of sequence analysis, we found surprisingly high LEPRE1 allelic diversity in the Tobago DNA samples in which there were 11 alleles distinguished by a single basepair variant in or near exon 5. All the alleles found in the Tobago population that were within the sequence analysis region were found in the African American population in the Exome Variant Project. This diversity appeared to reflect the geographic origin of the original population in Tobago. In 44 individuals with biallelic LEPRE1 mutations identified by clinical diagnostic testing, we found the sequence alterations occurred on seven of the 11 variant alleles. All but one of the mutations identified resulted in mRNA or protein instability for the majority of the transcripts from the altered allele. These findings suggest that the milder end of the clinical spectrum could be due to as yet unidentified missense mutations in LEPRE1. PMID:24498616

  9. SNP panels/Imputation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Participants from thirteen countries discussed services that Interbull can perform or recommendations that Interbull can make to promote harmonization and assist member countries in improving their genomic evaluations in regard to SNP panels and imputation. The panel recommended: A mechanism to shar...

  10. Discovery and functional characterization of leptin and its receptors in Japanese quail (Coturnix japonica).

    PubMed

    Wang, Dandan; Xu, Chunlin; Wang, Taian; Li, Hong; Li, Yanmin; Ren, Junxiao; Tian, Yadong; Li, Zhuanjian; Jiao, Yuping; Kang, Xiangtao; Liu, Xiaojun

    2016-01-01

    Leptin is an important endocrine regulation factor of food intake and energy homeostasis in mammals; however, the existence of a poultry leptin gene (LEP) is still debated. Here, for the first time, we report the cloning of a partial exon 3 sequence of LEP (qLEP) and four different leptin receptor splicing variants, including a long receptor (qLEPRl) and three soluble receptors (qLEPR-a, qLEPR-b and qLEPR-c) in Japanese quail (Coturnix japonica). The qLEP gene had high GC content (64%), which is similar to other reported avian leptin genes. The encoded qLEP protein possessed the conserved pair of cysteine residues that are required to form a lasso knot for full biological activity, but shared relatively low identities with LEPs of other vertebrates. The translated qLEPRl protein contained 1143 amino acids and shared high amino acid sequence identity with a chicken homolog (89% identity). qLEPRl also contained all the motifs, domains, and basic tyrosine residues that are conserved in the LEPRl proteins of other vertebrates. qRT-PCR analysis showed that LEP and the four LEPR variants were expressed extensively in all tissues examined; the expression levels of LEP were relatively high in hypothalamus, skeletal muscle, and pancreas, while the expression levels of the LEPRs were highest in the pituitary. Compared with the expression levels of juvenile qLEP and total qLEPR (including all LEPR variants), the expression levels of mature qLEP and total qLEPR were up-regulated in the hypothalamus and pituitary, and down-regulated in the ovary. The expressions of LEP/LEPR increased when fasting and decreased when refeeding in the brain and peripheral tissues of juvenile quail, which suggested that the LEP/LEPR system modulated food intake and energy expenditure, although, unlike in mammals, LEP may actually act to inhibit food intake during fasting, at least in juvenile quail. The results indicate that qLEP and qLEPR have unique expression patterns and that the encoded

  11. Osteogenesis imperfecta due to compound heterozygosity for the LEPRE1 gene.

    PubMed

    Moul, Adrienne; Alladin, Amanda; Navarrete, Cristina; Abdenour, George; Rodriguez, Maria M

    2013-10-01

    Osteogenesis imperfecta is a rare connective tissue disorder characterized by bone fragility and low bone density. Most cases are caused by an autosomal dominant mutation in either COL1A1 or COL1A2 gene encoding type I collagen. However, autosomal recessive forms have been identified. We present a patient with severe respiratory distress due to osteogenesis imperfecta simulating type II, born to a non-consanguineous couple with mixed African-American and African-Hispanic ethnicity. Cultured skin fibroblasts demonstrated compound heterozygosity for mutations in the LEPRE1 gene encoding prolyl 3-hydroxylase 1 confirming the diagnosis of autosomal recessive osteogenesis imperfecta type VIII, perinatal lethal type. PMID:23301918

  12. Leptin Receptor Gene Polymorphism may Affect Subclinical Atherosclerosis in Patients with Acromegaly

    PubMed Central

    Turgut, Sebahat; Topsakal, Senay; Ata, Melek Tunç; Herek, Duygu; Akın, Fulya; Özkan, Şeyma; Turgut, Günfer

    2016-01-01

    Background: Acromegaly is associated with increased morbidity and mortality related to cardiovascular diseases. Leptin (LEP) and Leptin Receptor (LEPR) gene polymorphisms can increase cardiovascular risks. The aim of this study was to investigate association between the frequencies of LEP and LEPR gene polymorphisms and subclinical atherosclerosis in acromegalic patients. Methods: Forty-four acromegalic patients and 30 controls were admitted to study. The polymorphisms were identified by using polymerase chain reaction from peripheral blood samples. The levels of systolic and diastolic blood pressure, BMI, fasting plasma glucose, fasting insulin, IGF-I, GH, IGFBP3, leptin, triglyceride, carotid Intima Media Thickness (cIMT) and HDL and LDL cholesterol concentrations were evaluated. Results: There was statistically significant difference between the LEPR genotypes of acromegalic patients (GG 11.4%, GA 52.3%, and AA 36.4%) and controls (GG 33.3%, GA 50%, and AA 16.7%) although their LEP genotype distribution was similar. In addition, the prevalence of the LEPR gene G and A alleles was significantly different between patients and controls. No significant difference was found among the G(-2548) A leptin genotypes of groups in terms of the clinical parameters. cIMT significantly increased homozygote LEPR GG genotype group compared to AA subjects in patients. But the other parameters were not different between LEPR genotypes groups of patients and controls. Conclusion: It can be said that the LEPR gene polymorphism may affect cIMT in patients. The reason is that LEPR GG genotype carriers may have more risk than other genotypes in the development of subclinical atherosclerosis in acromegaly. PMID:27563428

  13. Human-Specific SNP in Obesity Genes, Adrenergic Receptor Beta2 (ADRB2), Beta3 (ADRB3), and PPAR γ2 (PPARG), during Primate Evolution

    PubMed Central

    Takenaka, Akiko; Nakamura, Shin; Mitsunaga, Fusako; Inoue-Murayama, Miho; Udono, Toshifumi; Suryobroto, Bambang

    2012-01-01

    Adrenergic-receptor beta2 (ADRB2) and beta3 (ADRB3) are obesity genes that play a key role in the regulation of energy balance by increasing lipolysis and thermogenesis. The Glu27 allele in ADRB2 and the Arg64 allele in ADRB3 are associated with abdominal obesity and early onset of non-insulin-dependent diabetes mellitus (NIDDM) in many ethnic groups. Peroxisome proliferator-activated receptor γ (PPARG) is required for adipocyte differentiation. Pro12Ala mutation decreases PPARG activity and resistance to NIDDM. In humans, energy-expense alleles, Gln27 in ADRB2 and Trp64 in ADRB3, are at higher frequencies than Glu27 and Arg64, respectively, but Ala12 in PPARG is at lower frequency than Pro12. Adaptation of humans for lipolysis, thermogenesis, and reduction of fat accumulation could be considered by examining which alleles in these genes are dominant in non-human primates (NHP). All NHP (P. troglodytes, G. gorilla, P. pygmaeus, H. agilis and macaques) had energy-thrifty alleles, Gly16 and Glu27 in ADRB2, and Arg64 in ADRB3, but did not have energy-expense alleles, Arg16, Gln27 and Trp64 alleles. In PPARG gene, all NHP had large adipocyte accumulating type, the Pro12 allele. Conclusions These results indicate that a tendency to produce much more heat through the energy-expense alleles developed only in humans, who left tropical rainforests for savanna and developed new features in their heat-regulation systems, such as reduction of body hair and increased evaporation of water, and might have helped the protection of entrails from cold at night, especially in glacial periods. PMID:22937051

  14. Common Variants of IL6, LEPR, and PBEF1 Are Associated With Obesity in Indian Children

    PubMed Central

    Tabassum, Rubina; Mahendran, Yuvaraj; Dwivedi, Om Prakash; Chauhan, Ganesh; Ghosh, Saurabh; Marwaha, Raman K.; Tandon, Nikhil; Bharadwaj, Dwaipayan

    2012-01-01

    The increasing prevalence of obesity in urban Indian children is indicative of an impending crisis of metabolic disorders. Although perturbations in the secretion of adipokines and inflammatory molecules in childhood obesity are well documented, the contribution of common variants of genes encoding them is not well investigated. We assessed the association of 125 common variants from 21 genes, encoding adipocytokines and inflammatory markers in 1,325 urban Indian children (862 normal weight [NW group] and 463 overweight/obese [OW/OB group]) and replicated top loci in 1,843 Indian children (1,399 NW children and 444 OW/OB children). Variants of four genes (PBEF1 [rs3801266] [P = 4.5 × 10−4], IL6 [rs2069845] [P = 8.7 × 10−4], LEPR [rs1137100] [P = 1.8 × 10−3], and IL6R [rs7514452] [P = 2.1 × 10−3]) were top signals in the discovery sample. Associations of rs2069845, rs1137100, and rs3801266 were replicated (P = 7.9 × 10−4, 8.3 × 10−3, and 0.036, respectively) and corroborated in meta-analysis (P = 2.3 × 10−6, 3.9 × 10−5, and 4.3 × 10−4, respectively) that remained significant after multiple testing corrections. These variants also were associated with quantitative measures of adiposity (weight, BMI, and waist and hip circumferences). Allele dosage analysis of rs2069845, rs1137100, and rs3801266 revealed that children with five to six risk alleles had an approximately four times increased risk of obesity than children with less than two risk alleles (P = 1.2 × 10−7). In conclusion, our results demonstrate the association of the common variants of IL6, LEPR, and PBEF1 with obesity in Indian children. PMID:22228719

  15. Differences in metabolomic profiles of male db/db and s/s, leptin receptor mutant mice

    PubMed Central

    Saadat, Nadia; IglayReger, Heidi B.; Myers, Martin G.; Bodary, Peter

    2012-01-01

    Leptin, a protein hormone secreted by adipose tissue, plays an important role in regulating energy metabolism and the immune response. Despite similar extremes of adiposity, mutant mouse models, db/db, carrying spontaneous deletion of the active form of the leptin receptor (LEPR-B) intracellular signaling domain, and the s/s, carrying a specific point mutation leading to a dysfunctional LEPR-B-STAT3 signaling pathway, have been shown to have robust differences in glucose homeostasis. This suggests specific effects of leptin, mediated by non-STAT3 LEPR-B pathways. Differences in the LEPR-B signaling pathways in these two LEPR-B mutant mice models are expected to lead to differences in metabolism. In the current study, the hypothesized differences in metabolism were investigated using the metabolomics approach. Proton nuclear magnetic resonance spectroscopy (1HNMR) was conducted on 24 h urine samples in deuterium oxide using a 500 MHz instrument at 25°C. Principle Component Analysis showed clear separation of urine NMR spectra between the groups (P < 0.05). The CHENOMX metabolite database was used to identify several metabolites that differed between the two mouse models. Significant differences (P < 0.05) in metabolites associated with the glycine, serine, and homocysteine metabolism were observed. The results demonstrate that the metabolomic profile of db/db and s/s mice are fundamentally different and provide insight into the unique metabolic effects of leptin exerted through non-STAT3 LEPR-B pathways. PMID:22318992

  16. SNP-VISTA: An interactive SNP visualization tool

    PubMed Central

    Shah, Nameeta; Teplitsky, Michael V; Minovitsky, Simon; Pennacchio, Len A; Hugenholtz, Philip; Hamann, Bernd; Dubchak, Inna L

    2005-01-01

    Background Recent advances in sequencing technologies promise to provide a better understanding of the genetics of human disease as well as the evolution of microbial populations. Single Nucleotide Polymorphisms (SNPs) are established genetic markers that aid in the identification of loci affecting quantitative traits and/or disease in a wide variety of eukaryotic species. With today's technological capabilities, it has become possible to re-sequence a large set of appropriate candidate genes in individuals with a given disease in an attempt to identify causative mutations. In addition, SNPs have been used extensively in efforts to study the evolution of microbial populations, and the recent application of random shotgun sequencing to environmental samples enables more extensive SNP analysis of co-occurring and co-evolving microbial populations. The program is available at [1]. Results We have developed and present two modifications of an interactive visualization tool, SNP-VISTA, to aid in the analyses of the following types of data: A. Large-scale re-sequence data of disease-related genes for discovery of associated and/or causative alleles (GeneSNP-VISTA). B. Massive amounts of ecogenomics data for studying homologous recombination in microbial populations (EcoSNP-VISTA). The main features and capabilities of SNP-VISTA are: 1) mapping of SNPs to gene structure; 2) classification of SNPs, based on their location in the gene, frequency of occurrence in samples and allele composition; 3) clustering, based on user-defined subsets of SNPs, highlighting haplotypes as well as recombinant sequences; 4) integration of protein evolutionary conservation visualization; and 5) display of automatically calculated recombination points that are user-editable. Conclusion The main strength of SNP-VISTA is its graphical interface and use of visual representations, which support interactive exploration and hence better understanding of large-scale SNP data by the user. PMID

  17. Leptin receptor signaling in T cells is required for Th17 differentiation

    PubMed Central

    Reis, Bernardo S; Lee, Kihyun; Fanok, Melania H; Mascaraque, Cristina; Amoury, Manal; Cohn, Lillian; Rogoz, Aneta; Dallner, Olof S; Moraes-Vieira, Pedro M; Domingos, Ana I; Mucida, Daniel

    2015-01-01

    The hormone leptin plays a key role in energy homeostasis, and the absence of either leptin or its receptor (lepR) leads to severe obesity and metabolic disorders. To avoid indirect effects and to address the cell-intrinsic role of leptin signaling in the immune system, we conditionally targeted lepR in T cells. In contrast to pleiotropic immune disorders reported in obese mice with leptin or lepR deficiency, we found that lepR deficiency in CD4+ T cells resulted in a selective defect in both autoimmune and protective Th17 responses. Reduced capacity for differentiation towards a Th17 phenotype by lepr-deficient T cells was attributed to reduced activation of the signal transducer and activator of transcription 3 (STAT3) and its downstream targets. This study establishes cell-intrinsic roles for leptin receptor signaling in the immune system and suggests that leptin signaling during T cell differentiation plays a crucial role in T cell peripheral effector function. PMID:25917102

  18. Transcriptomic analysis of aggressive meningiomas identifies PTTG1 and LEPR as prognostic biomarkers independent of WHO grade

    PubMed Central

    Jungk, Christine; Sahm, Felix; Ull, Anna Theresa; Warta, Rolf; Lamszus, Katrin; Gousias, Konstantinos; Ketter, Ralf; Roesch, Saskia; Rapp, Carmen; Schefzyk, Sebastian; Urbschat, Steffi; Lahrmann, Bernd; Kessler, Almuth F.; Löhr, Mario; Senft, Christian; Grabe, Niels; Reuss, David; Beckhove, Philipp; Westphal, Manfred; von Deimling, Andreas; Unterberg, Andreas

    2016-01-01

    Meningiomas are frequent central nervous system tumors. Although most meningiomas are benign (WHO grade I) and curable by surgery, WHO grade II and III tumors remain therapeutically challenging due to frequent recurrence. Interestingly, relapse also occurs in some WHO grade I meningiomas. Hence, we investigated the transcriptional features defining aggressive (recurrent, malignantly progressing or WHO grade III) meningiomas in 144 cases. Meningiomas were categorized into non-recurrent (NR), recurrent (R), and tumors undergoing malignant progression (M) in addition to their WHO grade. Unsupervised transcriptomic analysis in 62 meningiomas revealed transcriptional profiles lining up according to WHO grade and clinical subgroup. Notably aggressive subgroups (R+M tumors and WHO grade III) shared a large set of differentially expressed genes (n=332; p<0.01, FC>1.25). In an independent multicenter validation set (n=82), differential expression of 10 genes between WHO grades was confirmed. Additionally, among WHO grade I tumors differential expression between NR and aggressive R+M tumors was affirmed for PTTG1, AURKB, ECT2, UBE2C and PRC1, while MN1 and LEPR discriminated between NR and R+M WHO grade II tumors. Univariate survival analysis revealed a significant association with progression-free survival for PTTG1, LEPR, MN1, ECT2, PRC1, COX10, UBE2C expression, while multivariate analysis identified a prediction for PTTG1 and LEPR mRNA expression independent of gender, WHO grade and extent of resection. Finally, stainings of PTTG1 and LEPR confirmed malignancy-associated protein expression changes. In conclusion, based on the so far largest study sample of WHO grade III and recurrent meningiomas we report a comprehensive transcriptional landscape and two prognostic markers. PMID:26894859

  19. Duplicated Leptin Receptors in Two Species of Eel Bring New Insights into the Evolution of the Leptin System in Vertebrates

    PubMed Central

    Morini, Marina; Pasquier, Jérémy; Dirks, Ron; van den Thillart, Guido; Tomkiewicz, Jonna; Rousseau, Karine; Dufour, Sylvie; Lafont, Anne-Gaëlle

    2015-01-01

    Since its discovery in mammals as a key-hormone in reproduction and metabolism, leptin has been identified in an increasing number of tetrapods and teleosts. Tetrapods possess only one leptin gene, while most teleosts possess two leptin genes, as a result of the teleost third whole genome duplication event (3R). Leptin acts through a specific receptor (LEPR). In the European and Japanese eels, we identified two leptin genes, and for the first time in vertebrates, two LEPR genes. Synteny analyses indicated that eel LEPRa and LEPRb result from teleost 3R. LEPRb seems to have been lost in the teleost lineage shortly after the elopomorph divergence. Quantitative PCRs revealed a wide distribution of leptins and LEPRs in the European eel, including tissues involved in metabolism and reproduction. Noticeably, leptin1 was expressed in fat tissue, while leptin2 in the liver, reflecting subfunctionalization. Four-month fasting had no impact on the expression of leptins and LEPRs in control European eels. This might be related to the remarkable adaptation of silver eel metabolism to long-term fasting throughout the reproductive oceanic migration. In contrast, sexual maturation induced differential increases in the expression of leptins and LEPRs in the BPG-liver axis. Leptin2 was strikingly upregulated in the liver, the central organ of the reproductive metabolic challenge in teleosts. LEPRs were differentially regulated during sexual maturation, which may have contributed to the conservation of the duplicated LEPRs in this species. This suggests an ancient and positive role of the leptin system in the vertebrate reproductive function. This study brings new insights on the evolutionary history of the leptin system in vertebrates. Among extant vertebrates, the eel represents a unique case of duplicated leptins and leptin receptors as a result of 3R. PMID:25946034

  20. Duplicated leptin receptors in two species of eel bring new insights into the evolution of the leptin system in vertebrates.

    PubMed

    Morini, Marina; Pasquier, Jérémy; Dirks, Ron; van den Thillart, Guido; Tomkiewicz, Jonna; Rousseau, Karine; Dufour, Sylvie; Lafont, Anne-Gaëlle

    2015-01-01

    Since its discovery in mammals as a key-hormone in reproduction and metabolism, leptin has been identified in an increasing number of tetrapods and teleosts. Tetrapods possess only one leptin gene, while most teleosts possess two leptin genes, as a result of the teleost third whole genome duplication event (3R). Leptin acts through a specific receptor (LEPR). In the European and Japanese eels, we identified two leptin genes, and for the first time in vertebrates, two LEPR genes. Synteny analyses indicated that eel LEPRa and LEPRb result from teleost 3R. LEPRb seems to have been lost in the teleost lineage shortly after the elopomorph divergence. Quantitative PCRs revealed a wide distribution of leptins and LEPRs in the European eel, including tissues involved in metabolism and reproduction. Noticeably, leptin1 was expressed in fat tissue, while leptin2 in the liver, reflecting subfunctionalization. Four-month fasting had no impact on the expression of leptins and LEPRs in control European eels. This might be related to the remarkable adaptation of silver eel metabolism to long-term fasting throughout the reproductive oceanic migration. In contrast, sexual maturation induced differential increases in the expression of leptins and LEPRs in the BPG-liver axis. Leptin2 was strikingly upregulated in the liver, the central organ of the reproductive metabolic challenge in teleosts. LEPRs were differentially regulated during sexual maturation, which may have contributed to the conservation of the duplicated LEPRs in this species. This suggests an ancient and positive role of the leptin system in the vertebrate reproductive function. This study brings new insights on the evolutionary history of the leptin system in vertebrates. Among extant vertebrates, the eel represents a unique case of duplicated leptins and leptin receptors as a result of 3R. PMID:25946034

  1. Leptin receptor gene polymorphisms in severely pre-eclamptic women.

    PubMed

    Rigó, János; Szendei, György; Rosta, Klára; Fekete, Andrea; Bögi, Krisztina; Molvarec, Attila; Rónai, Zsolt; Vér, Agota

    2006-09-01

    Variants of the leptin receptor gene (LEPR) may modulate the effect of elevated serum leptin levels in pre-eclampsia. The aim of our study was to evaluate the LEPR gene polymorphisms Lys109Arg (A109G) and Gln223Arg (A223G) in severely pre-eclamptic women. In a case-control study, we analyzed blood samples from 124 severely pre-eclamptic patients and 107 healthy control women by the polymerase chain reaction-restriction fragment length polymorphism method. The Pearson chi2 test was used to estimate odds ratios (OR) and 95% confidence intervals (CI). The association was adjusted for maternal age, pre-pregnancy body mass index and primiparity with logistic regression analysis. Pregnant women with the LEPR 223G allele (223A/G or 223G/G genotype) had almost double the risk of developing severe pre-eclampsia compared with patients with the 223A/A genotype (adjusted OR = 1.92, 95% CI: 1.07-3.41). Genotype variants of LEPR A109G alone did not affect the risk of severe pre-eclampsia. Haplotype estimation of A109G and A223G polymorphisms of the LEPR gene revealed that the G-A haplotype versus other pooled haplotypes was significantly less common in the pre-eclamptic group (p < 0.01), while the G-G haplotype versus others was overrepresented among severely pre-eclamptic patients (p < 0.01), compared with controls. In conclusion, our data indicate that LEPR A223G polymorphism may individually modify the risk of severe pre-eclampsia. PMID:17071538

  2. SNP genotyping by heteroduplex analysis.

    PubMed

    Paniego, Norma; Fusari, Corina; Lia, Verónica; Puebla, Andrea

    2015-01-01

    Heteroduplex-based genotyping methods have proven to be technologically effective and economically efficient for low- to medium-range throughput single-nucleotide polymorphism (SNP) determination. In this chapter we describe two protocols that were successfully applied for SNP detection and haplotype analysis of candidate genes in association studies. The protocols involve (1) enzymatic mismatch cleavage with endonuclease CEL1 from celery, associated with fragment separation using capillary electrophoresis (CEL1 cleavage), and (2) differential retention of the homo/heteroduplex DNA molecules under partial denaturing conditions on ion pair reversed-phase liquid chromatography (dHPLC). Both methods are complementary since dHPLC is more versatile than CEL1 cleavage for identifying multiple SNP per target region, and the latter is easily optimized for sequences with fewer SNPs or small insertion/deletion polymorphisms. Besides, CEL1 cleavage is a powerful method to localize the position of the mutation when fragment resolution is done using capillary electrophoresis. PMID:25373754

  3. The association between polymorphisms in the leptin receptor gene and risk of breast cancer: a systematic review and pooled analysis.

    PubMed

    Wang, Li-qiang; Shen, Wei; Xu, Lan; Chen, Min-Bin; Gong, Ting; Lu, Pei-Hua; Tao, Guo-Qing

    2012-11-01

    Many epidemiological studies have found that leptin correlates to body fat extent and breast cancer. Leptin exerts its physiological action through the leptin receptor (LEPR). However, published data on the association between LEPR alleles and breast cancer occurrence have led to in contradictory results. A total of 10 studies were identified to the meta-analysis, including 4,644 cases and 5,485 controls for LEPR rs1137101 polymorphism, 5 studies with 2,759 cases and 4,464 controls for rs1137100 polymorphism, and 2 studies for rs8051542, rs8051542, and rs8051542 polymorphisms. The pooled odds ratios (OR) with 95 % confidence intervals (CI) for breast cancer risk associated with LEPR genotypes were estimated. Elevated breast cancer risk was associated with LEPR rs1137101 polymorphism when all studies were pooled in the meta-analysis (allele contrast model: OR = 0.71, 95 % CI = 0.551-0.997). In the stratified analysis by ethnicity, significantly increased risks were also found among Asians for allele contrast model (OR 0.414, 95 % CI 0.312-0.550) and dominant model (OR 0.537, 95 % CI 0.370-0.781); for Africans, significantly increased risks were also found for allele contrast model (OR 0.716, 95 % CI 0.595-0.861), homozygote codominant (OR 0.537, 95 % CI 0.370-0.781) and dominant model (OR 1.595, 95 % CI 1.207-2.108). And significantly elevated breast cancer risk was associated with LEPR rs1137100 polymorphism for allele contrast (OR = 0.666, 95 % CI = 0.603-0.720) and homozygote codominant models (OR = 0.344, 95 % CI = 0.282-0.421). For LEPR rs8179183, rs4655537, and rs3762274 polymorphisms, no significant associations were detected in all comparison models. This pooled analysis suggested that rs1137101 and rs1137100 polymorphisms were significantly correlated with breast cancer risk and the A allele of LEPR rs1137101 variant and the G allele of LEPR rs1137100 variant were low-penetrant risk factors for developing breast cancer. Further, no

  4. Variants in the LEPR gene are nominally associated with higher BMI and lower 24 hour energy expenditure in Pima Indians

    PubMed Central

    Traurig, Michael; Perez, Jessica; Ma, Lijun; Bian, Li; Kobes, Sayuko; Hanson, Robert L.; Knowler, William C.; Krakoff, Jonathan; Bogardus, Clifton; Baier, Leslie J.

    2012-01-01

    Genome-wide association studies (GWASs) have been used to search for susceptibility genes for type 2 diabetes and obesity in the Pima Indians, a population with high a prevalence of both diseases. In these studies, a variant (rs2025804) in the LEPR gene was nominally associated with BMI in 1082 subjects (P=0.03 adjusted for age, sex, birth year, and family membership). Therefore the LEPR and leptin overlapping transcript (LEPROT) genes were selected for further sequencing and genotyping in larger population-based samples for association analyses with obesity-related phenotypes. Selected variants (n=80) spanning these genes were genotyped in a sample of full-heritage Pima Indians (n=2842) and several common variants including rs2025804 were nominally associated with BMI (P=0.05-0.003 adjusted for age, sex, birth year, and family membership). Four common tag variants associated with BMI in the full-heritage Pima Indian sample were genotyped in a second sample of mixed-heritage Native Americans (n=2969) and 3 of the variants showed nominal replication (P=0.03-0.006 adjusted as above and additionally for Indian heritage). Combining both samples provided the strongest evidence for association (adjusted P=0.0003-0.0001). A subset of these individuals (n=403) had been metabolically characterized for predictors of obesity and the BMI risk alleles for the variants tagged by rs2025804 were also associated with lower 24 hour energy expenditure as assessed in a human respiratory chamber (P=0.0007 adjusted for age, sex, fat mass, fat free mass, activity, and family membership). We conclude that common non-coding variation in the LEPR gene is associated with higher BMI and lower energy expenditure in Native Americans. PMID:22810975

  5. Correlation of leptin receptor expression with BMI in differential grades of human meningiomas

    PubMed Central

    RUTKOWSKI, ROBERT; RESZEC, JOANNA; HERMANOWICZ, ADAM; CHRZANOWSKI, ROBERT; LYSON, TOMASZ; MARIAK, ZENON; CHYCZEWSKI, LECH

    2016-01-01

    Meningioma is one of the most common primary brain tumor, especially in postmenopausal women. The most important risk factors include radiation, primary head injury or genetic alterations, however it is currently unclear why postmenopausal women are predominantly affected. The aim of the present study was to evaluate leptin receptor (LEPR) expression and body mass index (BMI) in patients with meningiomas of differential grades. Specimens of 158 meningiomas were classified as either G1 (low-grade meningiomas, n=114) or G2/G3 (high-grade meningiomas, n=44). Immunohistochemistry was performed to assess LEPR expression. The mean BMIs of the female and male patient groups were 28.43±5.29 and 23.93±4.66, respectively. Mean BMI was significantly higher in the female group, by ~4.50 kg/m2. Patient age significantly correlated with LEPR expression, with the highly positive (++) and positive (+) groups having mean ages of 62.3±12.07 and 52.3±13.04, respectively. A strong positive correlation (r=0.73) was observed between leptin receptor expression and BMI, with the LEPR (++) group having a mean BMI of 30.11±4.49, compared to 22.12±2.48 for the LEPR (+) group. Furthermore, in the low-grade meningioma group, mean BMI was higher in female patients than male patients (28.13±5.54 and 25.38±4.57, respectively; P=0.01). Additionally, there was strong positive correlation between BMI and leptin receptor expression in the low-grade meningioma group (r=0.69). For the high-grade meningioma group, mean BMI was 29.49±4.26 and 21.76±3.98 in female and male patients, respectively, and LEPR expression strongly correlated with BMI in this group (r=0.80). The present study demonstrates a correlation between patient BMI, age, and LEPR expression status in low- and high-grade meningiomas. Our results indicate that in addition to endogenous hormones, such as estrogen or progesterone, or fatty tissue-associated proinflammatory cytokines, LEPR expression status may be a risk factor for

  6. Leptin and leptin receptor genes in relation to premenopausal breast cancer incidence and grade in Caucasian women.

    PubMed

    Gu, Fangyi; Kraft, Peter; Rice, Megan; Michels, Karin B

    2012-01-01

    Body mass is inversely related to breast cancer risk among premenopausal women. Leptin, an essential cytokine regulating food intake, energy expenditure, glucose, and fat metabolism may be part of the mechanistic pathway. We investigated 50 tagging and candidate SNPs in the leptin (LEP) and leptin receptor (LEPR) genes for associations with premenopausal breast cancer incidence using 405 cases and 810 controls nested within the Nurses' Health Study II. We also examined associations between these SNPs and circulating leptin (among 910 women) and breast cancer grade (among 267 patients). Permutation tests were performed to adjust for multiple testing. We did not detect a significant association between SNPs in the LEP or LEPR gene and either breast cancer incidence or plasma leptin levels. Among cases, 14 SNPs of the LEPR gene were significantly associated with cancer grade, and rs1137101 (Q223R) survived multiple testing adjustment (adjusted P = 0.04). The G carriers of rs1137101 were more likely to have poorly differentiated than well-differentiated cancers. Our data suggest that common genetic variation in the LEP or LEPR gene has no strong association with premenopausal breast cancer risk. The LEPR gene might be associated with breast cancer grade. PMID:21947707

  7. Leptin and leptin receptor genes in relation to premenopausal breast cancer incidence and grade in Caucasian women

    PubMed Central

    Gu, Fangyi; Kraft, Peter; Rice, Megan; Michels, Karin B.

    2012-01-01

    Body mass is inversely related to breast cancer risk among premenopausal women. Leptin, an essential cytokine regulating food intake, energy expenditure, glucose, and fat metabolism may be part of the mechanistic pathway. We investigated 50 tagging and candidate SNPs in the leptin (LEP) and leptin receptor (LEPR) genes for associations with premenopausal breast cancer incidence using 405 cases and 810 controls nested within the Nurses’ Health Study II. We also examined associations between these SNPs and circulating leptin (among 910 women) and breast cancer grade (among 267 patients). Permutation tests were performed to adjust for multiple testing. We did not detect a significant association between SNPs in the LEP or LEPR gene and either breast cancer incidence or plasma leptin levels. Among cases, 14 SNPs of the LEPR gene were significantly associated with cancer grade, and rs1137101 (Q223R) survived multiple testing adjustment (adjusted P = 0.04). The G carriers of rs1137101 were more likely to have poorly differentiated than well-differentiated cancers. Our data suggest that common genetic variation in the LEP or LEPR gene has no strong association with premenopausal breast cancer risk. The LEPR gene might be associated with breast cancer grade. PMID:21947707

  8. SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival.

    PubMed

    Jamshidi, Maral; Fagerholm, Rainer; Khan, Sofia; Aittomäki, Kristiina; Czene, Kamila; Darabi, Hatef; Li, Jingmei; Andrulis, Irene L; Chang-Claude, Jenny; Devilee, Peter; Fasching, Peter A; Michailidou, Kyriaki; Bolla, Manjeet K; Dennis, Joe; Wang, Qin; Guo, Qi; Rhenius, Valerie; Cornelissen, Sten; Rudolph, Anja; Knight, Julia A; Loehberg, Christian R; Burwinkel, Barbara; Marme, Frederik; Hopper, John L; Southey, Melissa C; Bojesen, Stig E; Flyger, Henrik; Brenner, Hermann; Holleczek, Bernd; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Van Dyck, Laurien; Nevelsteen, Ines; Couch, Fergus J; Olson, Janet E; Giles, Graham G; McLean, Catriona; Haiman, Christopher A; Henderson, Brian E; Winqvist, Robert; Pylkäs, Katri; Tollenaar, Rob A E M; García-Closas, Montserrat; Figueroa, Jonine; Hooning, Maartje J; Martens, John W M; Cox, Angela; Cross, Simon S; Simard, Jacques; Dunning, Alison M; Easton, Douglas F; Pharoah, Paul D P; Hall, Per; Blomqvist, Carl; Schmidt, Marjanka K; Nevanlinna, Heli

    2015-11-10

    In breast cancer, constitutive activation of NF-κB has been reported, however, the impact of genetic variation of the pathway on patient prognosis has been little studied. Furthermore, a combination of genetic variants, rather than single polymorphisms, may affect disease prognosis. Here, in an extensive dataset (n = 30,431) from the Breast Cancer Association Consortium, we investigated the association of 917 SNPs in 75 genes in the NF-κB pathway with breast cancer prognosis. We explored SNP-SNP interactions on survival using the likelihood-ratio test comparing multivariate Cox' regression models of SNP pairs without and with an interaction term. We found two interacting pairs associating with prognosis: patients simultaneously homozygous for the rare alleles of rs5996080 and rs7973914 had worse survival (HRinteraction 6.98, 95% CI=3.3-14.4, P=1.42E-07), and patients carrying at least one rare allele for rs17243893 and rs57890595 had better survival (HRinteraction 0.51, 95% CI=0.3-0.6, P = 2.19E-05). Based on in silico functional analyses and literature, we speculate that the rs5996080 and rs7973914 loci may affect the BAFFR and TNFR1/TNFR3 receptors and breast cancer survival, possibly by disturbing both the canonical and non-canonical NF-κB pathways or their dynamics, whereas, rs17243893-rs57890595 interaction on survival may be mediated through TRAF2-TRAIL-R4 interplay. These results warrant further validation and functional analyses. PMID:26317411

  9. SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival

    PubMed Central

    Jamshidi, Maral; Fagerholm, Rainer; Khan, Sofia; Aittomäki, Kristiina; Czene, Kamila; Darabi, Hatef; Li, Jingmei; Andrulis, Irene L.; Chang-Claude, Jenny; Devilee, Peter; Fasching, Peter A.; Michailidou, Kyriaki; Bolla, Manjeet K.; Dennis, Joe; Wang, Qin; Guo, Qi; Rhenius, Valerie; Cornelissen, Sten; Rudolph, Anja; Knight, Julia A.; Loehberg, Christian R.; Burwinkel, Barbara; Marme, Frederik; Hopper, John L.; Southey, Melissa C.; Bojesen, Stig E.; Flyger, Henrik; Brenner, Hermann; Holleczek, Bernd; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Dyck, Laurien Van; Nevelsteen, Ines; Couch, Fergus J.; Olson, Janet E.; Giles, Graham G.; McLean, Catriona; Haiman, Christopher A.; Henderson, Brian E.; Winqvist, Robert; Pylkäs, Katri; Tollenaar, Rob A.E.M.; García-Closas, Montserrat; Figueroa, Jonine; Hooning, Maartje J.; Martens, John W.M.; Cox, Angela; Cross, Simon S.; Simard, Jacques; Dunning, Alison M.; Easton, Douglas F.; Pharoah, Paul D.P.; Hall, Per; Blomqvist, Carl; Schmidt, Marjanka K.; Nevanlinna, Heli

    2015-01-01

    In breast cancer, constitutive activation of NF-κB has been reported, however, the impact of genetic variation of the pathway on patient prognosis has been little studied. Furthermore, a combination of genetic variants, rather than single polymorphisms, may affect disease prognosis. Here, in an extensive dataset (n = 30,431) from the Breast Cancer Association Consortium, we investigated the association of 917 SNPs in 75 genes in the NF-κB pathway with breast cancer prognosis. We explored SNP-SNP interactions on survival using the likelihood-ratio test comparing multivariate Cox’ regression models of SNP pairs without and with an interaction term. We found two interacting pairs associating with prognosis: patients simultaneously homozygous for the rare alleles of rs5996080 and rs7973914 had worse survival (HRinteraction 6.98, 95% CI=3.3-14.4, P = 1.42E-07), and patients carrying at least one rare allele for rs17243893 and rs57890595 had better survival (HRinteraction 0.51, 95% CI=0.3-0.6, P = 2.19E-05). Based on in silico functional analyses and literature, we speculate that the rs5996080 and rs7973914 loci may affect the BAFFR and TNFR1/TNFR3 receptors and breast cancer survival, possibly by disturbing both the canonical and non-canonical NF-κB pathways or their dynamics, whereas, rs17243893-rs57890595 interaction on survival may be mediated through TRAF2-TRAIL-R4 interplay. These results warrant further validation and functional analyses. PMID:26317411

  10. Association of leptin receptor gene Gln223Arg polymorphism with susceptibility to colorectal cancer

    PubMed Central

    Arkani, Maral; Safaei, Akram; Pourhoseingholi, Mohamad Amin; Mohebbi, Seyed Reza; Fatemi, Seyed Reza; Vafaei, Mohammad

    2011-01-01

    Aim Leptin is a 16 kDa polypeptide hormone which secreted by adipose tissue and has an important role in energy balance, insulin pathway and inflammation, because of that it may play an important role in colorectal cancer (CRC). Leptin exerts its effect through the leptin receptor (LEPR) a member of the class I cytokine receptor family. Background We have investigated whether glutamine to arginine substitution (Gln223Arg) in exon 6 of the leptin receptor gene, has implications for susceptibility to CRC. Patients and methods Polymerase chain reaction (PCR) and restriction enzyme digestion (RFLP) was performed to evaluate the association between the Gln223Arg polymorphism of the LEPR and CRC risk in a case-control study in 346 subjects involving 173 cases with CRC and 173 controls. Results There was no statistically evidence of significant difference in genotype and allele frequencies between the cases with CRC and controls for the Gln223Arg polymorphism of LEPR, before or after adjusting for confounders (age, BMI, sex, and smoking status). Furthermore, no significant difference was observed between the CRC cases and controls by BMI, sex and smoking status. Conclusion Our findings suggest that the LEPR Gln223Arg polymorphism is not associated with the risk of CRC in Iranian population. PMID:24834182

  11. The Expression of LEP, LEPR, IGF1 and IL10 in Obesity and the Relationship with microRNAs

    PubMed Central

    Viesti A. Collares, Renata; Salgado, Wilson; Pretti da Cunha Tirapelli, Daniela; dos Santos, José Sebastião

    2014-01-01

    Obesity is a multifactorial disease, with epigenetic alterations. Have been described modifications in the expression of some microRNAs, and some proteins related to obesity. The objective was to determine and correlate, in obese patients, the gene expression of LEP, LEPR, IGF1, IL10 and of miR-27a, miR-27b, miR-143 and miR-145. RNA was extracted from biopsies of subcutaneous fat, liver and visceral fat of 15 obese subjects submitted to bariatric surgery and of 15 non-obese subjects submitted to cholecystectomy for cDNA synthesis and for RT-PCR. The microRNAs were chosen using the TargetScan software. An increased expression of LEP and IGF1 was detected in the subcutaneous fat of the obese group compared to control, while the expression of IGF1 was higher in the control group than in the obese one. MiRNA-27a had a higher expression in the omentum of the obese patients and there was also a correlation in the expression of miRNA-145 and LEPR in the omentum of this group. PMID:24690978

  12. Genetic modifiers of Lepr{sup fa} associated with variability in insulin production and susceptibility to NIDDM

    SciTech Connect

    Chung, W.K.; Zheng, M.; Chua, M.

    1997-05-01

    In an attempt to identify the genetic basis for susceptibility to non-insulin-dependent diabetes mellitus within the context of obesity, we generated 401 genetically obese Lepr{sup fa}/Lepr{sup fa} F2 WKY13M intercross rats that demonstrated wide variation in multiple phenotypic measures related to diabetes, including plasma glucose concentration, percentage of glycosylated hemoglobin, plasma insulin concentration, and pancreatic islet morphology. Using selective genotyping genome scanning approaches, we have identified three quantitative trait loci (QTLs) on Chr. 1 (LOD 7.1 for pancreatic morpholology), Chr. 12 (LOD 5.1 for body mass index and LOD 3.4 for plasma glucose concentration), and Chr. 16 (P < 0.001 for genotype effect on plasma glucose concentration). The obese F2 progeny demonstrated sexual dimorphism for these traits, with increased diabetes susceptibility in the males appearing at approximately 6 weeks of age, as sexual maturation occurred. For each of the QTLs, the linked phenotypes demonstrated sexual dimorphism (more severe affection in males). The QTL on Chr. 1 maps to a region vicinal to that previously linked to adiposity in studies of diabetes susceptibility in the nonobese Goto-Kakizaki rat, which is genetically closely related to the Wistar counterstrain we employed. Several candidate genes, including tubby (tub), multigenic obesity 1 (Mob1), adult obesity and diabetes (Ad), and insulin-like growth factor-2 (Igf2), map to murine regions homologous to the QTL region identified on rat Chr. 1. 60 refs., 5 figs., 4 tabs.

  13. SNP-SNP interactions in breast cancer susceptibility

    PubMed Central

    Onay, Venüs Ümmiye; Briollais, Laurent; Knight, Julia A; Shi, Ellen; Wang, Yuanyuan; Wells, Sean; Li, Hong; Rajendram, Isaac; Andrulis, Irene L; Ozcelik, Hilmi

    2006-01-01

    Background Breast cancer predisposition genes identified to date (e.g., BRCA1 and BRCA2) are responsible for less than 5% of all breast cancer cases. Many studies have shown that the cancer risks associated with individual commonly occurring single nucleotide polymorphisms (SNPs) are incremental. However, polygenic models suggest that multiple commonly occurring low to modestly penetrant SNPs of cancer related genes might have a greater effect on a disease when considered in combination. Methods In an attempt to identify the breast cancer risk conferred by SNP interactions, we have studied 19 SNPs from genes involved in major cancer related pathways. All SNPs were genotyped by TaqMan 5'nuclease assay. The association between the case-control status and each individual SNP, measured by the odds ratio and its corresponding 95% confidence interval, was estimated using unconditional logistic regression models. At the second stage, two-way interactions were investigated using multivariate logistic models. The robustness of the interactions, which were observed among SNPs with stronger functional evidence, was assessed using a bootstrap approach, and correction for multiple testing based on the false discovery rate (FDR) principle. Results None of these SNPs contributed to breast cancer risk individually. However, we have demonstrated evidence for gene-gene (SNP-SNP) interaction among these SNPs, which were associated with increased breast cancer risk. Our study suggests cross talk between the SNPs of the DNA repair and immune system (XPD-[Lys751Gln] and IL10-[G(-1082)A]), cell cycle and estrogen metabolism (CCND1-[Pro241Pro] and COMT-[Met108/158Val]), cell cycle and DNA repair (BARD1-[Pro24Ser] and XPD-[Lys751Gln]), and within carcinogen metabolism (GSTP1-[Ile105Val] and COMT-[Met108/158Val]) pathways. Conclusion The importance of these pathways and their communication in breast cancer predisposition has been emphasized previously, but their biological interactions

  14. Leptin and its receptors.

    PubMed

    Wada, Nobuhiro; Hirako, Satoshi; Takenoya, Fumiko; Kageyama, Haruaki; Okabe, Mai; Shioda, Seiji

    2014-11-01

    Leptin is mainly produced in the white adipose tissue before being secreted into the blood and transported across the blood-brain barrier. Leptin binds to a specific receptor (LepR) that has numerous subtypes (LepRa, LepRb, LepRc, LepRd, LepRe, and LepRf). LepRb, in particular, is expressed in several brain nuclei, including the arcuate nucleus, the paraventricular nucleus, and the dorsomedial, lateral and ventromedial regions of the hypothalamus. LepRb is also co-expressed with several neuropeptides, including proopiomelanocortin, neuropeptide Y, galanin, galanin-like peptide, gonadotropin-releasing hormone, tyrosine hydroxylase and neuropeptide W. Functionally, LepRb induces activation of the JAK2/ERK, /STAT3, /STAT5 and IRS/PI3 kinase signaling cascades, which are important for the regulation of energy homeostasis and appetite in mammals. In this review, we discuss the structure, genetics and distribution of the leptin receptors, and their role in cell signaling mechanisms. PMID:25218975

  15. Gene-gene interactions among CX3CL1, LEPR and IL-6 related to coronary artery disease in Chinese Han population

    PubMed Central

    Jin, Song-Gen; Chen, Guo-Lin; Yang, Song-Liu; Zhao, Ming-Yan

    2015-01-01

    Objective: The purpose of this study was to investigate the impact of the interactions among CX3CL1 (rs170364 and rs614230), LEPR (rs6700896), and IL-6 (rs2066992) polymorphisms on the risk of coronary artery disease (CAD) in Chinese Han population. Methods: 120 CAD patients and 109 healthy controls were enrolled in the study. Polymerase chain reaction (PCR) and direct sequencing methods were used to analyze the genotypes of CX3CL1, LEPR, and IL-6 polymorphisms. Multifactor dimensionality reduction (MDR) software was utilized to analyze gene-gene interactions. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used for evaluating the association between gene polymorphisms or gene-gene interactions and CAD risk. Results: In the study, TT genotype of rs170364 in CX3CL1 might decrease the CAD risk (OR=0.39, 95% CI=0.16-0.98). No significant correlation was found between T allele of rs170364 and CAD risk (P>0.05). CC genotype and C allele in rs614230 (CX3CL1) were significantly related with decreased risk of CAD (OR=0.38, 95% CI=0.17-0.86; OR=0.66, 95% CI=0.45-0.97). For IL-6 rs2066992 polymorphism. GG genotype could increase the risk of CAD (OR=2.32, 95% CI=1.04-5.17). Whereas, no significant correlation was observed between LEPR rs6700896 and CAD susceptibility. MDR analysis showed that CX3CL1, LEPR and IL-6 genes might jointly promote the occurrence of CAD. Conclusions: The interactions of CX3CL1, LEPR and IL-6 genes might increase the risk of CAD. PMID:26191329

  16. BM-SNP: A Bayesian Model for SNP Calling Using High Throughput Sequencing Data.

    PubMed

    Xu, Yanxun; Zheng, Xiaofeng; Yuan, Yuan; Estecio, Marcos R; Issa, Jean-Pierre; Qiu, Peng; Ji, Yuan; Liang, Shoudan

    2014-01-01

    A single-nucleotide polymorphism (SNP) is a sole base change in the DNA sequence and is the most common polymorphism. Detection and annotation of SNPs are among the central topics in biomedical research as SNPs are believed to play important roles on the manifestation of phenotypic events, such as disease susceptibility. To take full advantage of the next-generation sequencing (NGS) technology, we propose a Bayesian approach, BM-SNP, to identify SNPs based on the posterior inference using NGS data. In particular, BM-SNP computes the posterior probability of nucleotide variation at each covered genomic position using the contents and frequency of the mapped short reads. The position with a high posterior probability of nucleotide variation is flagged as a potential SNP. We apply BM-SNP to two cell-line NGS data, and the results show a high ratio of overlap ( >95 percent) with the dbSNP database. Compared with MAQ, BM-SNP identifies more SNPs that are in dbSNP, with higher quality. The SNPs that are called only by BM-SNP but not in dbSNP may serve as new discoveries. The proposed BM-SNP method integrates information from multiple aspects of NGS data, and therefore achieves high detection power. BM-SNP is fast, capable of processing whole genome data at 20-fold average coverage in a short amount of time. PMID:26357041

  17. Leptin receptor polymorphisms interact with polyunsaturated fatty acids to augment risk of insulin resistance and metabolic syndrome in adults.

    PubMed

    Phillips, Catherine M; Goumidi, Louisa; Bertrais, Sandrine; Field, Martyn R; Ordovas, Jose M; Cupples, L Adrienne; Defoort, Catherine; Lovegrove, Julie A; Drevon, Christian A; Blaak, Ellen E; Gibney, Michael J; Kiec-Wilk, Beata; Karlstrom, Britta; Lopez-Miranda, Jose; McManus, Ross; Hercberg, Serge; Lairon, Denis; Planells, Richard; Roche, Helen M

    2010-02-01

    The leptin receptor (LEPR) is associated with insulin resistance, a key feature of metabolic syndrome (MetS). Gene-fatty acid interactions may affect MetS risk. The objective was to investigate the relationship among LEPR polymorphisms, insulin resistance, and MetS risk and whether plasma fatty acids, a biomarker of dietary fatty acids, modulate this. LEPR polymorphisms (rs10493380, rs1137100, rs1137101, rs12067936, rs1805096, rs2025805, rs3790419, rs3790433, rs6673324, and rs8179183), biochemical measurements, and plasma fatty acid profiles were determined in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n = 1754). LEPR rs3790433 GG homozygotes had increased MetS risk compared with the minor A allele carriers [odds ratio (OR) = 1.65; 95% CI: 1.05-2.57; P = 0.028], which may be accounted for by their increased risk of elevated insulin concentrations (OR 2.40; 95% CI: 1.28-4.50; P = 0.006) and insulin resistance (OR = 2.15; 95% CI: 1.18-3.90; P = 0.012). Low (less than median) plasma (n-3) and high (n-6) PUFA status exacerbated the genetic risk conferred by GG homozygosity to hyperinsulinemia (OR 2.92-2.94) and insulin resistance (OR 3.40-3.47). Interestingly, these associations were abolished against a high (n-3) or low (n-6) PUFA background. Importantly, we replicated some of these findings in an independent cohort. Homozygosity for the LEPR rs3790433 G allele was associated with insulin resistance, which may predispose to increased MetS risk. Novel gene-nutrient interactions between LEPR rs3790433 and PUFA suggest that these genetic influences were more evident in individuals with low plasma (n-3) or high plasma (n-6) PUFA. PMID:20032477

  18. Selective Deletion of Leptin Receptors in Gonadotropes Reveals Activin and GnRH-Binding Sites as Leptin Targets in Support of Fertility

    PubMed Central

    Akhter, Noor; CarlLee, Tyler; Syed, Mohsin M.; Odle, Angela K.; Cozart, Michael A.; Haney, Anessa C.; Allensworth-James, Melody L.; Beneš, Helen

    2014-01-01

    The adipokine, leptin (LEP), is a hormonal gateway, signaling energy stores to appetite-regulatory neurons, permitting reproduction when stores are sufficient. Dual-labeling for LEP receptors (LEPRs) and gonadotropins or GH revealed a 2-fold increase in LEPR during proestrus, some of which was seen in LH gonadotropes. We therefore investigated LEPR functions in gonadotropes with Cre-LoxP technology, deleting the signaling domain of the LEPR (Lepr-exon 17) with Cre-recombinase driven by the rat LH-β promoter (Lhβ-cre). Selectivity of the deletion was validated by organ genotyping and lack of LEPR and responses to LEP by mutant gonadotropes. The mutation had no impact on growth, body weight, the timing of puberty, or pregnancy. Mutant females took 36% longer to produce their first litter and had 50% fewer pups/litter. When the broad impact of the loss of gonadotrope LEPR on all pituitary hormones was studied, mutant diestrous females had reduced serum levels of LH (40%), FSH (70%), and GH (54%) and mRNA levels of Fshβ (59%) and inhibin/activin β A and β B (25%). Mutant males had reduced serum levels of GH (74%), TSH (31%), and prolactin (69%) and mRNA levels of Gh (31%), Ghrhr (30%), Fshβ (22%), and glycoprotein α-subunit (Cga) (22%). Serum levels of LEP and ACTH and mRNA levels of Gnrhr were unchanged. However, binding to GnRH receptors was reduced in LEPR-null LH or FSH gonadotropes by 82% or 89%, respectively, in females (P < .0001) and 27% or 53%, respectively, in males (P < .03). This correlated with reductions in GnRH receptor protein immunolabeling, suggesting that LEP's actions may be posttranscriptional. Collectively, these studies highlight the importance of LEP to gonadotropes with GnRH-binding sites and activin as potential targets. LEP may modulate population growth, adjusting the number of offspring to the availability of food supplies. PMID:25057790

  19. The Acute-Phase Protein Orosomucoid Regulates Food Intake and Energy Homeostasis via Leptin Receptor Signaling Pathway.

    PubMed

    Sun, Yang; Yang, Yili; Qin, Zhen; Cai, Jinya; Guo, Xiuming; Tang, Yun; Wan, Jingjing; Su, Ding-Feng; Liu, Xia

    2016-06-01

    The acute-phase protein orosomucoid (ORM) exhibits a variety of activities in vitro and in vivo, notably modulation of immunity and transportation of drugs. We found in this study that mice lacking ORM1 displayed aberrant energy homeostasis characterized by increased body weight and fat mass. Further investigation found that ORM, predominantly ORM1, is significantly elevated in sera, liver, and adipose tissues from the mice with high-fat diet (HFD)-induced obesity and db/db mice that develop obesity spontaneously due to mutation in the leptin receptor (LepR). Intravenous or intraperitoneal administration of exogenous ORM decreased food intake in C57BL/6, HFD, and leptin-deficient ob/ob mice, which was absent in db/db mice and was significantly reduced in mice with arcuate nucleus (ARC) LepR knockdown, whereas enforced expression of ORM1 in ARC significantly decreased food intake, body weight, and serum insulin level. Furthermore, we found that ORM is able to bind directly to LepR and activate the receptor-mediated JAK2-STAT3 signaling in hypothalamus tissue and GT1-7 cells, which was derived from hypothalamic tumor. These data indicated that ORM could function through LepR to regulate food intake and energy homeostasis in response to nutrition status. Modulating the expression of ORM is a novel strategy for the management of obesity and related metabolic disorders. PMID:27207522

  20. Detecting Susceptibility to Breast Cancer with SNP-SNP Interaction Using BPSOHS and Emotional Neural Networks.

    PubMed

    Wang, Xiao; Peng, Qinke; Fan, Yue

    2016-01-01

    Studies for the association between diseases and informative single nucleotide polymorphisms (SNPs) have received great attention. However, most of them just use the whole set of useful SNPs and fail to consider the SNP-SNP interactions, while these interactions have already been proven in biology experiments. In this paper, we use a binary particle swarm optimization with hierarchical structure (BPSOHS) algorithm to improve the effective of PSO for the identification of the SNP-SNP interactions. Furthermore, in order to use these SNP interactions in the susceptibility analysis, we propose an emotional neural network (ENN) to treat SNP interactions as emotional tendency. Different from the normal architecture, just as the emotional brain, this architecture provides a specific path to treat the emotional value, by which the SNP interactions can be considered more quickly and directly. The ENN helps us use the prior knowledge about the SNP interactions and other influence factors together. Finally, the experimental results prove that the proposed BPSOHS_ENN algorithm can detect the informative SNP-SNP interaction and predict the breast cancer risk with a much higher accuracy than existing methods. PMID:27294121

  1. Detecting Susceptibility to Breast Cancer with SNP-SNP Interaction Using BPSOHS and Emotional Neural Networks

    PubMed Central

    Wang, Xiao; Fan, Yue

    2016-01-01

    Studies for the association between diseases and informative single nucleotide polymorphisms (SNPs) have received great attention. However, most of them just use the whole set of useful SNPs and fail to consider the SNP-SNP interactions, while these interactions have already been proven in biology experiments. In this paper, we use a binary particle swarm optimization with hierarchical structure (BPSOHS) algorithm to improve the effective of PSO for the identification of the SNP-SNP interactions. Furthermore, in order to use these SNP interactions in the susceptibility analysis, we propose an emotional neural network (ENN) to treat SNP interactions as emotional tendency. Different from the normal architecture, just as the emotional brain, this architecture provides a specific path to treat the emotional value, by which the SNP interactions can be considered more quickly and directly. The ENN helps us use the prior knowledge about the SNP interactions and other influence factors together. Finally, the experimental results prove that the proposed BPSOHS_ENN algorithm can detect the informative SNP-SNP interaction and predict the breast cancer risk with a much higher accuracy than existing methods. PMID:27294121

  2. A novel application of pattern recognition for accurate SNP and indel discovery from high-throughput data: targeted resequencing of the glucocorticoid receptor co-chaperone FKBP5 in a Caucasian population.

    PubMed

    Pelleymounter, Linda L; Moon, Irene; Johnson, Julie A; Laederach, Alain; Halvorsen, Matt; Eckloff, Bruce; Abo, Ryan; Rossetti, Sandro

    2011-12-01

    The detection of single nucleotide polymorphisms (SNPs) and insertion/deletions (indels) with precision from high-throughput data remains a significant bioinformatics challenge. Accurate detection is necessary before next-generation sequencing can routinely be used in the clinic. In research, scientific advances are inhibited by gaps in data, exemplified by the underrepresented discovery of rare variants, variants in non-coding regions and indels. The continued presence of false positives and false negatives prevents full automation and requires additional manual verification steps. Our methodology presents applications of both pattern recognition and sensitivity analysis to eliminate false positives and aid in the detection of SNP/indel loci and genotypes from high-throughput data. We chose FK506-binding protein 51(FKBP5) (6p21.31) for our clinical target because of its role in modulating pharmacological responses to physiological and synthetic glucocorticoids and because of the complexity of the genomic region. We detected genetic variation across a 160 kb region encompassing FKBP5. 613 SNPs and 57 indels, including a 3.3 kb deletion were discovered. We validated our method using three independent data sets and, with Sanger sequencing and Affymetrix and Illumina microarrays, achieved 99% concordance. Furthermore we were able to detect 267 novel rare variants and assess linkage disequilibrium. Our results showed both a sensitivity and specificity of 98%, indicating near perfect classification between true and false variants. The process is scalable and amenable to automation, with the downstream filters taking only 1.5h to analyze 96 individuals simultaneously. We provide examples of how our level of precision uncovered the interactions of multiple loci, their predicted influences on mRNA stability, perturbations of the hsp90 binding site, and individual variation in FKBP5 expression. Finally we show how our discovery of rare variants may change current

  3. Leptin and Leptin Receptor Genetic Variants Associate with Habitual Physical Activity and the Arm Body Composition Response to Resistance Training

    PubMed Central

    Walsh, S; Haddad, CJ; Kostek, MA; Angelopoulos, TJ; Clarkson, PM; Gordon, PM; Moyna, NM; Visich, PS; Zoeller, RF; Seip, RL; Bilbie, S; Thompson, PD; Devaney, J; Gordish-Dressman, H; Hoffman, EP; Price, Thomas B.; Pescatello, LS

    2012-01-01

    PURPOSE We investigated the influence of Leptin (LEP) and leptin receptor (LEPR) SNPs on habitual physical activity (PA) and body composition response to a unilateral, upper body resistance training (RT) program. METHODS European-derived American volunteers (men=111, women=131, 23.4±5.4 yr, 24.4±4.6 kg·m−2) were genotyped for LEP 19 G>A (rs2167270), and LEPR 326 A>G (rs1137100), 668 A>G (rs1137101), 3057 G>A (rs1805096), and 1968 G>C (rs8179183). They completed the Paffenbarger PA Questionnaire. Arm muscle and subcutaneous fat volumes were measured before and after 12wk of supervised RT with MRI. Multivariate and repeated measures ANCOVA tested differences among phenotypes by genotype and gender with age and body mass index as covariates. RESULTS Adults with the LEP 19 GG genotype reported more kcal/wk in vigorous intensity PA (1273.3±176.8, p=0.017) and sports/recreation (1922.8±226.0, p<0.04) than A allele carriers (718.0±147.2, 1328.6±188.2, respectively). Those with the LEP 19 GG genotype spent more hr/wk in light intensity PA (39.7±1.6) than A allele carriers (35.0±1.4, p=0.03). In response to RT, adults with the LEPR 668 G allele gained greater arm muscle volume (67687.05±3186.7 vs. 52321.87±5125.05 mm3, p=0.01) and subcutaneous fat volume (10599.89±3683.57 vs. −5224.73±5923.98 mm3, p=0.02) than adults with the LEPR 668 AA genotype, respectively. CONCLUSION LEP19 G>A and LEPR 668 A>G associated with habitual PA and the body composition response to RT. These LEP and LEPR SNPs are located in coding exons likely influencing LEP and LEPR function. Further investigation is needed to confirm our findings and establish mechanisms for LEP and LEPR genotype and PA and body composition associations we observed. PMID:22975643

  4. SNP genotyping by DNA photoligation: application to SNP detection of genes from food crops

    NASA Astrophysics Data System (ADS)

    Yoshimura, Yoshinaga; Ohtake, Tomoko; Okada, Hajime; Ami, Takehiro; Tsukaguchi, Tadashi; Fujimoto, Kenzo

    2009-06-01

    We describe a simple and inexpensive single-nucleotide polymorphism (SNP) typing method, using DNA photoligation with 5-carboxyvinyl-2'-deoxyuridine and two fluorophores. This SNP-typing method facilitates qualitative determination of genes from indica and japonica rice, and showed a high degree of single nucleotide specificity up to 10 000. This method can be used in the SNP typing of actual genomic DNA samples from food crops.

  5. SNP Arrays for Species Identification in Salmonids.

    PubMed

    Wenne, Roman; Drywa, Agata; Kent, Matthew; Sundsaasen, Kristil Kindem; Lien, Sigbjørn

    2016-01-01

    The use of SNP genotyping microarrays, developed in one species to analyze a closely related species for which genomic sequence information is scarce, enables the rapid development of a genomic resource (SNP information) without the need to develop new species-specific markers. Using large numbers of microarray SNPs offers the best chance to detect informative markers in nontarget species, markers that can very often be assayed using a lower throughput platform as is described in this paper. PMID:27460372

  6. Leptin Receptor Gene Polymorphisms and the Risk of Non-Alcoholic Fatty Liver Disease and Coronary Atherosclerosis in the Chinese Han Population

    PubMed Central

    An, Bai-Quan; Lu, Lin-Lin; Yuan, Chen; Xin, Yong-Ning; Xuan, Shi-Ying

    2016-01-01

    Background Leptin receptor (LEPR) polymorphisms have been reported to be associated with lipid metabolism and insulin resistance in various populations. However, whether LEPR polymorphisms are associated with the risks of non-alcoholic fatty liver disease (NAFLD) and coronary atherosclerosis in the Chinese Han population remains unknown. Objectives To investigate the association of LEPR polymorphisms at Q223R and K109R with the risks of NAFLD and coronary atherosclerosis in the Chinese Han population. Patients and Methods Genotypes of LEPR Q223R and K109R were determined by polymerase chain reaction followed by sequencing in patients with NAFLD (n = 554), coronary atherosclerosis (n = 421), and healthy controls (n = 550). Serum lipid profiles were determined using biochemical methods. Pearson’s χ2 test was used to check for Hardy-Weinberg equilibrium and to analyze the distributions of genotypes’ alleles between groups. Baseline characteristics were analyzed using student’s t-test, paired-samples t-test, or the χ2 test where appropriate. Results The LEPR Q223R A allele significantly reduced the risks of both NAFLD and coronary atherosclerosis (OR = 0.683, 95% CI: 0.527 - 0.884, P = 0.004 and OR = 0.724, 95% CI: 0.548 - 0.955, P = 0.022, respectively). Compared to controls, no significant differences in the genotype and allele frequencies of K109R were found in the NAFLD and coronary atherosclerosis populations, respectively. However, there was a significantly increased risk of coronary atherosclerosis in NAFLD patients who carried the K109R A allele (OR = 2.283, 95% CI: 1.556 - 3.348, P < 0.001). Conclusions LEPR Q223R polymorphisms may confer a significant risk of NAFLD and coronary atherosclerosis. The A allele in the K109R polymorphism might be considered an independent risk factor for coronary atherosclerosis in NAFLD patients. PMID:27257426

  7. Genome-wide SNP detection, validation, and development of an 8K SNP array for apple

    Technology Transfer Automated Retrieval System (TEKTRAN)

    As high-throughput genetic marker screening systems are essential for a range of genetics studies and plant breeding applications, the International RosBREED SNP Consortium (IRSC) has utilized the Illumina Infinium® II system to develop a medium- to high-throughput SNP screening tool for genome-wide...

  8. SNPMeta: SNP annotation and SNP metadata collection without a reference genome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The increase in availability of resequencing data is greatly accelerating SNP discovery and has facilitated the development of SNP genotyping assays. This, in turn, is increasing interest in annotation of individual SNPs. Currently, these data are only available through curation, or comparison to a ...

  9. Neuropeptide Y and Agouti-Related Peptide Mediate Complementary Functions of Hyperphagia and Reduced Energy Expenditure in Leptin Receptor Deficiency

    PubMed Central

    Luo, Na; Marcelin, Genevieve; Liu, Shun Mei; Schwartz, Gary

    2011-01-01

    Neuropeptide Y (NPY) and agouti-related peptide (AGRP) can produce hyperphagia, reduce energy expenditure, and promote triglyceride deposition in adipose depots. As these two neuropeptides are coexpressed within the hypothalamic arcuate nucleus and mediate a major portion of the obesity caused by leptin signaling deficiency, we sought to determine whether the two neuropeptides mediated identical or complementary actions. Because of separate neuropeptide receptors and signal transduction mechanisms, there is a possibility of distinct encoding systems for the feeding and energy expenditure aspects of leptin-regulated metabolism. We have genetically added NPY deficiency and/or AGRP deficiency to LEPR deficiency isolated to AGRP cells. Our results indicate that the obesity of LEPR deficiency in AGRP/NPY neurons can produce obesity with either AGRP or NPY alone with AGRP producing hyperphagia while NPY promotes reduced energy expenditure. The absence of both NPY and AGRP prevents the development of obesity attributable to isolated LEPR deficiency in AGRP/NPY neurons. Operant behavioral testing indicated that there were no alterations in the reward for a food pellet from the AGRP-specific LEPR deficiency. PMID:21285324

  10. Rapid and efficient identification of the mouse leptin receptor mutation (C57BL/KsJ-db/db) by tetra-primer amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) analysis.

    PubMed

    Jung, Harry; Nam, Hajin; Suh, Jun-Gyo

    2016-03-01

    The C57BLKS/J-Lepr(db) mouse has a point mutation in the leptin receptor gene and is one of the most useful animal model for non-insulin dependent diabetes mellitus in human. Since the homozygote of C57BLKS/J-Lepr(db) mouse is infertile, detection of point mutation in the leptin receptor gene is important for efficient maintaining strains as well as mass production of homozygotes. To develop a rapid and efficient genotyping method for C57BLKS/J-Lepr(db) mouse, the tetra-primer amplification-refractory mutation system polymerase chain reaction (ARMS-PCR) was used. The 407 and 199 bp PCR products were amplified from normal (+/+) mice; while the 407 and 268 bp PCR products were amplified from homozygotes (db/db) mice; and the 407, 268, and 199 bp PCR products were amplified from heterozygotes (db/+) mice. This result showed that the tetra-primer ARMS-PCR analysis by us is suitable to detect point mutation of the leptin receptor gene. Taken together, our method will dramatically reduce animal use for maintenance of strains as well as production of homozygote in the C57BLKS/J-Lepr(db) strains. PMID:27051445

  11. SNP Discovery Using Next Generation Transcriptomic Sequencing.

    PubMed

    De Wit, Pierre

    2016-01-01

    In this chapter, I will guide the user through methods to find new SNP markers from expressed sequence (RNA-Seq) data, focusing on the sample preparation and also on the bioinformatic analyses needed to sort through the immense flood of data from high-throughput sequencing machines. The general steps included are as follows: sample preparation, sequencing, quality control of data, assembly, mapping, SNP discovery, filtering, validation. The first few steps are traditional laboratory protocols, whereas steps following the sequencing are of bioinformatic nature. The bioinformatics described herein are by no means exhaustive, rather they serve as one example of a simple way of analyzing high-throughput sequence data to find SNP markers. Ideally, one would like to run through this protocol several times with a new dataset, while varying software parameters slightly, in order to determine the robustness of the results. The final validation step, although not described in much detail here, is also quite critical as that will be the final test of the accuracy of the assumptions made in silico.There is a plethora of downstream applications of a SNP dataset, not covered in this chapter. For an example of a more thorough protocol also including differential gene expression and functional enrichment analyses, BLAST annotation and downstream applications of SNP markers, a good starting point could be the "Simple Fool's Guide to population genomics via RNA-Seq," which is available at http://sfg.stanford.edu . PMID:27460371

  12. A mutation in the leptin receptor is associated with Entamoeba histolytica infection in children

    PubMed Central

    Duggal, Priya; Guo, Xiaoti; Haque, Rashidul; Peterson, Kristine M.; Ricklefs, Stacy; Mondal, Dinesh; Alam, Faisal; Noor, Zannatun; Verkerke, Hans P.; Marie, Chelsea; Leduc, Charles A.; Jr., Streamson C. Chua; Jr., Martin G. Myers; Leibel, Rudolph L.; Houpt, Eric; Gilchrist, Carol A.; Sher, Alan; Porcella, Stephen F.; Jr., William A. Petri

    2011-01-01

    Malnutrition substantially increases susceptibility to Entamoeba histolytica in children. Leptin is a hormone produced by adipocytes that inhibits food intake, influences the immune system, and is suppressed in malnourished children. Therefore we hypothesized that diminished leptin function may increase susceptibility to E. histolytica infection. We prospectively observed a cohort of children, beginning at preschool age, for infection by the parasite E. histolytica every other day over 9 years and evaluated them for genetic variants in leptin (LEP) and the leptin receptor (LEPR). We found increased susceptibility to intestinal infection by this parasite associated with an amino acid substitution in the cytokine receptor homology domain 1 of LEPR. Children carrying the allele for arginine (223R) were nearly 4 times more likely to have an infection compared with those homozygous for the ancestral glutamine allele (223Q). An association of this allele with amebic liver abscess was also determined in an independent cohort of adult patients. In addition, mice carrying at least 1 copy of the R allele of Lepr were more susceptible to infection and exhibited greater levels of mucosal destruction and intestinal epithelial apoptosis after amebic infection. These findings suggest that leptin signaling is important in mucosal defense against amebiasis and that polymorphisms in the leptin receptor explain differences in susceptibility of children in the Bangladesh cohort to amebiasis. PMID:21393862

  13. Panax notoginseng saponins ameliorate impaired arterial vasodilation in SHRSP.Z-Lepr(fa) /lzmDmcr rats with metabolic syndrome.

    PubMed

    Wu, Ting; Sun, Jianning; Kagota, Satomi; Maruyama, Kana; Wakuda, Hirokazu; Shinozuka, Kazumasa

    2016-04-01

    Panax notoginseng saponins (PNS) are major components of Panax notoginseng, a herb with established clinical efficacy against vascular diseases. SHRSP.Z-Lepr(fa) /IzmDmcr (SHRSP.ZF) rats, a new animal model for metabolic syndrome, display an impaired vasorelaxation response in aortas and mesenteric arteries that is mediated by nitric oxide (NO). This study investigated whether PNS and its components can ameliorate this vascular dysfunction in SHRSP.ZF rats. In an in vitro study, in the presence or absence of PNS and its components, vasodilation in response to nitroprusside was determined from myographs under isometric tension conditions in aortas and mesenteric arteries from male SHRSP.ZF rats at 18-20 weeks of age. In an in vivo study, PNS (30 mg/kg per day) was orally administered to SHRSP.ZF rats from 8 to 20 weeks of age. In vitro treatment with PNS and Ginsenoside Rb1 increased nitroprusside-induced relaxation of aortas and mesenteric arteries in SHRSP.ZF rats. The PNS-induced increase was not affected by a nitric oxide (NO) synthase inhibitor or endothelium denudation. Relaxation in response to a cell-permeable cGMP analogue was increased by PNS, but cGMP accumulation by nitroprusside was not altered. In vivo treatment with PNS in SHRSP.ZF rats lowered blood pressure and increased relaxation and the expression of soluble guanylyl cyclase protein in arteries, without affecting metabolic abnormalities. These results indicate that PNS causes an increase in vasodilation in response to NO and a decrease in blood pressure, resulting in protection against vascular dysfunction in SHRSP.ZF rats. PNS might be beneficial in alleviating impaired vasodilation in metabolic syndrome. PMID:26784885

  14. SNP Array in Hematopoietic Neoplasms: A Review

    PubMed Central

    Song, Jinming; Shao, Haipeng

    2015-01-01

    Cytogenetic analysis is essential for the diagnosis and prognosis of hematopoietic neoplasms in current clinical practice. Many hematopoietic malignancies are characterized by structural chromosomal abnormalities such as specific translocations, inversions, deletions and/or numerical abnormalities that can be identified by karyotype analysis or fluorescence in situ hybridization (FISH) studies. Single nucleotide polymorphism (SNP) arrays offer high-resolution identification of copy number variants (CNVs) and acquired copy-neutral loss of heterozygosity (LOH)/uniparental disomy (UPD) that are usually not identifiable by conventional cytogenetic analysis and FISH studies. As a result, SNP arrays have been increasingly applied to hematopoietic neoplasms to search for clinically-significant genetic abnormalities. A large numbers of CNVs and UPDs have been identified in a variety of hematopoietic neoplasms. CNVs detected by SNP array in some hematopoietic neoplasms are of prognostic significance. A few specific genes in the affected regions have been implicated in the pathogenesis and may be the targets for specific therapeutic agents in the future. In this review, we summarize the current findings of application of SNP arrays in a variety of hematopoietic malignancies with an emphasis on the clinically significant genetic variants. PMID:27600067

  15. The SNP Consortium website: past, present and future.

    PubMed

    Thorisson, Gudmundur A; Stein, Lincoln D

    2003-01-01

    The SNP Consortium website (http://snp.cshl.org) has undergone many changes since its initial conception three years ago. The database back end has been changed from the venerable ACeDB to the more scalable MySQL engine. Users can access the data via gene or single nucleotide polymorphism (SNP) keyword searches and browse or dump SNP data to textfiles. A graphical genome browsing interface shows SNPs mapped onto the genome assembly in the context of externally available gene predictions and other features. SNP allele frequency and genotype data are available via FTP-download and on individual SNP report web pages. SNP linkage maps are available for download and for browsing in a comparative map viewer. All software components of the data coordinating center (DCC) website (http://snp.cshl.org) are open source. PMID:12519964

  16. An Improved Opposition-Based Learning Particle Swarm Optimization for the Detection of SNP-SNP Interactions

    PubMed Central

    Shang, Junliang; Sun, Yan; Li, Shengjun; Liu, Jin-Xing; Zheng, Chun-Hou; Zhang, Junying

    2015-01-01

    SNP-SNP interactions have been receiving increasing attention in understanding the mechanism underlying susceptibility to complex diseases. Though many works have been done for the detection of SNP-SNP interactions, the algorithmic development is still ongoing. In this study, an improved opposition-based learning particle swarm optimization (IOBLPSO) is proposed for the detection of SNP-SNP interactions. Highlights of IOBLPSO are the introduction of three strategies, namely, opposition-based learning, dynamic inertia weight, and a postprocedure. Opposition-based learning not only enhances the global explorative ability, but also avoids premature convergence. Dynamic inertia weight allows particles to cover a wider search space when the considered SNP is likely to be a random one and converges on promising regions of the search space while capturing a highly suspected SNP. The postprocedure is used to carry out a deep search in highly suspected SNP sets. Experiments of IOBLPSO are performed on both simulation data sets and a real data set of age-related macular degeneration, results of which demonstrate that IOBLPSO is promising in detecting SNP-SNP interactions. IOBLPSO might be an alternative to existing methods for detecting SNP-SNP interactions. PMID:26236727

  17. Polymorphisms of the porcine cathepsins, growth hormone-releasing hormone and leptin receptor genes and their association with meat quality traits in Ukrainian Large White breed.

    PubMed

    Balatsky, Viktor; Bankovska, Irina; Pena, Ramona N; Saienko, Artem; Buslyk, Tetyana; Korinnyi, Sergii; Doran, Olena

    2016-06-01

    Cathepsins, growth hormone-releasing hormone (GHRH) and leptin receptor (LEPR) genes have been receiving increasing attention as potential markers for meat quality and pig performance traits. This study investigated the allele variants in four cathepsin genes (CTSB, CTSK, CTSL, CTSS), GHRH and LEPR in pure-bred Ukrainian Large White pigs and evaluated effects of the allele variants on meat quality characteristics. The study was conducted on 72 pigs. Genotyping was performed using PCR-RFLP technique. Meat quality characteristics analysed were intramuscular fat content, tenderness, total water content, ultimate pH, crude protein and ashes. A medium level of heterozygosity values was established for GHRH and LEPR genes which corresponded to very high levels of informativeness indexes. Cathepsins CTSL, CTSB and CTSK had a low level of heterozygosity, and CTSS did not segregate in this breed. Association studies established that intramuscular fat content and tenderness were affected by the allele variance in GHRH and LEPR but not by CTSB and CTSL genes. The GHRH results could be particularly relevant for the production of lean prime cuts as the A allele is associated with both, a lower meat fat content and better tenderness values, which are two attributes highly regarded by consumers. Results of this study suggest that selective breeding towards GHRH/AA genotype would be particularly useful for improving meat quality characteristics in the production systems involving lean Large White lines, which typically have less than 2 % intramuscular fat content. PMID:27075656

  18. Interactions between SNP alleles at multiple loci contribute to skin color differences between caucasoid and mongoloid subjects.

    PubMed

    Anno, Sumiko; Abe, Takashi; Yamamoto, Takushi

    2008-01-01

    This study aimed to identify single nucleotide polymorphism (SNP) alleles at multiple loci associated with racial differences in skin color using SNP genotyping. A total of 122 Caucasians in Toledo, Ohio and 100 Mongoloids in Japan were genotyped for 20 SNPs in 7 candidate genes, encoding the Agouti signaling protein (ASIP), tyrosinase-related protein 1 (TYRP1), tyrosinase (TYR), melanocortin 1 receptor (MC1R), oculocutaneous albinism II (OCA2), microphthalmia-associated transcription factor (MITF), and myosin VA (MYO5A). Data were used to analyze associations between the 20 SNP alleles using linkage disequilibrium (LD). Combinations of SNP alleles were jointly tested under LD for associations with racial groups by performing a chi(2) test for independence. Results showed that SNP alleles at multiple loci can be considered the haplotype that contributes to significant differences between the two population groups and suggest a high probability of LD. Confirmation of these findings requires further study with other ethnic groups to analyze the associations between SNP alleles at multiple loci and skin color variation among races. PMID:18392143

  19. Exhaustive Genome-Wide Search for SNP-SNP Interactions Across 10 Human Diseases.

    PubMed

    Murk, William; DeWan, Andrew T

    2016-01-01

    The identification of statistical SNP-SNP interactions may help explain the genetic etiology of many human diseases, but exhaustive genome-wide searches for these interactions have been difficult, due to a lack of power in most datasets. We aimed to use data from the Resource for Genetic Epidemiology Research on Adult Health and Aging (GERA) study to search for SNP-SNP interactions associated with 10 common diseases. FastEpistasis and BOOST were used to evaluate all pairwise interactions among approximately N = 300,000 single nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) ≥ 0.15, for the dichotomous outcomes of allergic rhinitis, asthma, cardiac disease, depression, dermatophytosis, type 2 diabetes, dyslipidemia, hemorrhoids, hypertensive disease, and osteoarthritis. A total of N = 45,171 subjects were included after quality control steps were applied. These data were divided into discovery and replication subsets; the discovery subset had > 80% power, under selected models, to detect genome-wide significant interactions (P < 10(-12)). Interactions were also evaluated for enrichment in particular SNP features, including functionality, prior disease relevancy, and marginal effects. No interaction in any disease was significant in both the discovery and replication subsets. Enrichment analysis suggested that, for some outcomes, interactions involving SNPs with marginal effects were more likely to be nominally replicated, compared to interactions without marginal effects. If SNP-SNP interactions play a role in the etiology of the studied conditions, they likely have weak effect sizes, involve lower-frequency variants, and/or involve complex models of interaction that are not captured well by the methods that were utilized. PMID:27185397

  20. Exhaustive Genome-Wide Search for SNP-SNP Interactions Across 10 Human Diseases

    PubMed Central

    Murk, William; DeWan, Andrew T.

    2016-01-01

    The identification of statistical SNP-SNP interactions may help explain the genetic etiology of many human diseases, but exhaustive genome-wide searches for these interactions have been difficult, due to a lack of power in most datasets. We aimed to use data from the Resource for Genetic Epidemiology Research on Adult Health and Aging (GERA) study to search for SNP-SNP interactions associated with 10 common diseases. FastEpistasis and BOOST were used to evaluate all pairwise interactions among approximately N = 300,000 single nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) ≥ 0.15, for the dichotomous outcomes of allergic rhinitis, asthma, cardiac disease, depression, dermatophytosis, type 2 diabetes, dyslipidemia, hemorrhoids, hypertensive disease, and osteoarthritis. A total of N = 45,171 subjects were included after quality control steps were applied. These data were divided into discovery and replication subsets; the discovery subset had > 80% power, under selected models, to detect genome-wide significant interactions (P < 10−12). Interactions were also evaluated for enrichment in particular SNP features, including functionality, prior disease relevancy, and marginal effects. No interaction in any disease was significant in both the discovery and replication subsets. Enrichment analysis suggested that, for some outcomes, interactions involving SNPs with marginal effects were more likely to be nominally replicated, compared to interactions without marginal effects. If SNP-SNP interactions play a role in the etiology of the studied conditions, they likely have weak effect sizes, involve lower-frequency variants, and/or involve complex models of interaction that are not captured well by the methods that were utilized. PMID:27185397

  1. A novel approach to analyzing fMRI and SNP data via parallel independent component analysis

    NASA Astrophysics Data System (ADS)

    Liu, Jingyu; Pearlson, Godfrey; Calhoun, Vince; Windemuth, Andreas

    2007-03-01

    There is current interest in understanding genetic influences on brain function in both the healthy and the disordered brain. Parallel independent component analysis, a new method for analyzing multimodal data, is proposed in this paper and applied to functional magnetic resonance imaging (fMRI) and a single nucleotide polymorphism (SNP) array. The method aims to identify the independent components of each modality and the relationship between the two modalities. We analyzed 92 participants, including 29 schizophrenia (SZ) patients, 13 unaffected SZ relatives, and 50 healthy controls. We found a correlation of 0.79 between one fMRI component and one SNP component. The fMRI component consists of activations in cingulate gyrus, multiple frontal gyri, and superior temporal gyrus. The related SNP component is contributed to significantly by 9 SNPs located in sets of genes, including those coding for apolipoprotein A-I, and C-III, malate dehydrogenase 1 and the gamma-aminobutyric acid alpha-2 receptor. A significant difference in the presences of this SNP component is found between the SZ group (SZ patients and their relatives) and the control group. In summary, we constructed a framework to identify the interactions between brain functional and genetic information; our findings provide new insight into understanding genetic influences on brain function in a common mental disorder.

  2. A Bayesian Framework for SNP Identification

    SciTech Connect

    Webb-Robertson, Bobbie-Jo M.; Havre, Susan L.; Payne, Deborah A.

    2005-07-01

    Current proteomics techniques, such as mass spectrometry, focus on protein identification, usually ignoring most types of modifications beyond post-translational modifications, with the assumption that only a small number of peptides have to be matched to a protein for a positive identification. However, not all proteins are being identified with current techniques and improved methods to locate points of mutation are becoming a necessity. In the case when single-nucleotide polymorphisms (SNPs) are observed, brute force is the most common method to locate them, quickly becoming computationally unattractive as the size of the database associated with the model organism grows. We have developed a Bayesian model for SNPs, BSNP, incorporating evolutionary information at both the nucleotide and amino acid levels. Formulating SNPs as a Bayesian inference problem allows probabilities of interest to be easily obtained, for example the probability of a specific SNP or specific type of mutation over a gene or entire genome. Three SNP databases were observed in the evaluation of the BSNP model; the first SNP database is a disease specific gene in human, hemoglobin, the second is also a disease specific gene in human, p53, and the third is a more general SNP database for multiple genes in mouse. We validate that the BSNP model assigns higher posterior probabilities to the SNPs defined in all three separate databases than can be attributed to chance under specific evolutionary information, for example the amino acid model described by Majewski and Ott in conjunction with either the four-parameter nucleotide model by Bulmer or seven-parameter nucleotide model by Majewski and Ott.

  3. METU-SNP: an integrated software system for SNP-complex disease association analysis.

    PubMed

    Ustünkar, Gürkan; Aydın Son, Yeşim

    2011-01-01

    Recently, there has been increasing research to discover genomic biomarkers, haplotypes, and potentially other variables that together contribute to the development of diseases. Single Nucleotide Polymorphisms (SNPs) are the most common form of genomic variations and they can represent an individual’s genetic variability in greatest detail. Genome-wide association studies (GWAS) of SNPs, high-dimensional case-control studies, are among the most promising approaches for identifying disease causing variants. METU-SNP software is a Java based integrated desktop application specifically designed for the prioritization of SNP biomarkers and the discovery of genes and pathways related to diseases via analysis of the GWAS case-control data. Outputs of METU-SNP can easily be utilized for the downstream biomarkers research to allow the prediction and the diagnosis of diseases and other personalized medical approaches. Here, we introduce and describe the system functionality and architecture of the METU-SNP. We believe that the METU-SNP will help researchers with the reliable identification of SNPs that are involved in the etiology of complex diseases, ultimately supporting the development of personalized medicine approaches and targeted drug discoveries. PMID:22156365

  4. eSNPO: An eQTL-based SNP Ontology and SNP functional enrichment analysis platform.

    PubMed

    Li, Jin; Wang, Limei; Jiang, Tao; Wang, Jizhe; Li, Xue; Liu, Xiaoyan; Wang, Chunyu; Teng, Zhixia; Zhang, Ruijie; Lv, Hongchao; Guo, Maozu

    2016-01-01

    Genome-wide association studies (GWASs) have mined many common genetic variants associated with human complex traits like diseases. After that, the functional annotation and enrichment analysis of significant SNPs are important tasks. Classic methods are always based on physical positions of SNPs and genes. Expression quantitative trait loci (eQTLs) are genomic loci that contribute to variation in gene expression levels and have been proven efficient to connect SNPs and genes. In this work, we integrated the eQTL data and Gene Ontology (GO), constructed associations between SNPs and GO terms, then performed functional enrichment analysis. Finally, we constructed an eQTL-based SNP Ontology and SNP functional enrichment analysis platform. Taking Parkinson Disease (PD) as an example, the proposed platform and method are efficient. We believe eSNPO will be a useful resource for SNP functional annotation and enrichment analysis after we have got significant disease related SNPs. PMID:27470167

  5. eSNPO: An eQTL-based SNP Ontology and SNP functional enrichment analysis platform

    PubMed Central

    Li, Jin; Wang, Limei; Jiang, Tao; Wang, Jizhe; Li, Xue; Liu, Xiaoyan; Wang, Chunyu; Teng, Zhixia; Zhang, Ruijie; Lv, Hongchao; Guo, Maozu

    2016-01-01

    Genome-wide association studies (GWASs) have mined many common genetic variants associated with human complex traits like diseases. After that, the functional annotation and enrichment analysis of significant SNPs are important tasks. Classic methods are always based on physical positions of SNPs and genes. Expression quantitative trait loci (eQTLs) are genomic loci that contribute to variation in gene expression levels and have been proven efficient to connect SNPs and genes. In this work, we integrated the eQTL data and Gene Ontology (GO), constructed associations between SNPs and GO terms, then performed functional enrichment analysis. Finally, we constructed an eQTL-based SNP Ontology and SNP functional enrichment analysis platform. Taking Parkinson Disease (PD) as an example, the proposed platform and method are efficient. We believe eSNPO will be a useful resource for SNP functional annotation and enrichment analysis after we have got significant disease related SNPs. PMID:27470167

  6. SNP sets and reading ability: testing confirmation of a 10-SNP set in a population sample.

    PubMed

    Luciano, Michelle; Montgomery, Grant W; Martin, Nicholas G; Wright, Margaret J; Bates, Timothy C

    2011-06-01

    A set of 10 SNPs associated with reading ability in 7-year-olds was reported based on initial pooled analyses of 100K SNP chip data, with follow-up testing stages using pooling and individual testing. Here we examine this association in an adolescent population sample of Australian twins and siblings (N = 1177) aged 12 to 25 years. One (rs1842129) of the 10 SNPs approached significance (P = .05) but no support was found for the remaining 9 SNPs or the SNP set itself. Results indicate that these SNPs are not associated with reading ability in an Australian population. The results are interpreted as supporting use of much larger SNP sets in common disorders where effects are small. PMID:21623652

  7. Identification of genes with nonsynonymous SNP in Jeju horse by whole-genome resequencing reveals a functional role for immune response.

    PubMed

    Lee, J-H; Song, K-D; Kim, J-M; Leem, H-K; Park, K-D

    2016-03-01

    Jeju horse (Natural Monument number 347) is a breed of horse that has experienced long-term isolation and domestication in Jeju Island, South Korea. We evaluated genetic features of this breed, including SNP, by whole-genome resequencing using an Illumina HiSeq 2000. A total of 5,986,852 SNP were identified in 4 Jeju horses and were divided into homozygous and heterozygous SNP (2,357,099 and 3,629,753 SNP, respectively). It revealed that 63.8% of these SNP resided in intergenic regions. Immune response genes with nonsynonymous SNP were overrepresented in Jeju horses as evidenced by Gene Ontology clustering. Among these genes, Toll-like receptors (TLR) are highly enriched. Comparing TLR genes between Jeju horses and the Przewalski's horse, and genes showed "possibly damaging" mutations in several regions by analysis with PolyPhen-2. These results provide a framework for further genetic studies in Jeju horse by domestication. Furthermore, research on functions of SNP-associated genes would aid in understanding the molecular genetic variation of horse breeds. PMID:27065251

  8. Smarter clustering methods for SNP genotype calling

    PubMed Central

    Lin, Yan; Tseng, George C.; Cheong, Soo Yeon; Bean, Lora J. H.; Sherman, Stephanie L.; Feingold, Eleanor

    2008-01-01

    Motivation: Most genotyping technologies for single nucleotide polymorphism (SNP) markers use standard clustering methods to ‘call’ the SNP genotypes. These methods are not always optimal in distinguishing the genotype clusters of a SNP because they do not take advantage of specific features of the genotype calling problem. In particular, when family data are available, pedigree information is ignored. Furthermore, prior information about the distribution of the measurements for each cluster can be used to choose an appropriate model-based clustering method and can significantly improve the genotype calls. One special genotyping problem that has never been discussed in the literature is that of genotyping of trisomic individuals, such as individuals with Down syndrome. Calling trisomic genotypes is a more complicated problem, and the addition of external information becomes very important. Results: In this article, we discuss the impact of incorporating external information into clustering algorithms to call the genotypes for both disomic and trisomic data. We also propose two new methods to call genotypes using family data. One is a modification of the K-means method and uses the pedigree information by updating all members of a family together. The other is a likelihood-based method that combines the Gaussian or beta-mixture model with pedigree information. We compare the performance of these two methods and some other existing methods using simulation studies. We also compare the performance of these methods on a real dataset generated by the Illumina platform (www.illumina.com). Availability: The R code for the family-based genotype calling methods (SNPCaller) is available to be downloaded from the following website: http://watson.hgen.pitt.edu/register. Contact: liny@upmc.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:18826959

  9. Linkage mapping bovine EST-based SNP

    PubMed Central

    Snelling, Warren M; Casas, Eduardo; Stone, Roger T; Keele, John W; Harhay, Gregory P; Bennett, Gary L; Smith, Timothy PL

    2005-01-01

    Background Existing linkage maps of the bovine genome primarily contain anonymous microsatellite markers. These maps have proved valuable for mapping quantitative trait loci (QTL) to broad regions of the genome, but more closely spaced markers are needed to fine-map QTL, and markers associated with genes and annotated sequence are needed to identify genes and sequence variation that may explain QTL. Results Bovine expressed sequence tag (EST) and bacterial artificial chromosome (BAC)sequence data were used to develop 918 single nucleotide polymorphism (SNP) markers to map genes on the bovine linkage map. DNA of sires from the MARC reference population was used to detect SNPs, and progeny and mates of heterozygous sires were genotyped. Chromosome assignments for 861 SNPs were determined by twopoint analysis, and positions for 735 SNPs were established by multipoint analyses. Linkage maps of bovine autosomes with these SNPs represent 4585 markers in 2475 positions spanning 3058 cM . Markers include 3612 microsatellites, 913 SNPs and 60 other markers. Mean separation between marker positions is 1.2 cM. New SNP markers appear in 511 positions, with mean separation of 4.7 cM. Multi-allelic markers, mostly microsatellites, had a mean (maximum) of 216 (366) informative meioses, and a mean 3-lod confidence interval of 3.6 cM Bi-allelic markers, including SNP and other marker types, had a mean (maximum) of 55 (191) informative meioses, and were placed within a mean 8.5 cM 3-lod confidence interval. Homologous human sequences were identified for 1159 markers, including 582 newly developed and mapped SNP. Conclusion Addition of these EST- and BAC-based SNPs to the bovine linkage map not only increases marker density, but provides connections to gene-rich physical maps, including annotated human sequence. The map provides a resource for fine-mapping quantitative trait loci and identification of positional candidate genes, and can be integrated with other data to guide and

  10. pfSNP: An integrated potentially functional SNP resource that facilitates hypotheses generation through knowledge syntheses.

    PubMed

    Wang, Jingbo; Ronaghi, Mostafa; Chong, Samuel S; Lee, Caroline G L

    2011-01-01

    Currently, >14,000,000 single nucleotide polymorphisms (SNPs) are reported. Identifying phenotype-affecting SNPs among these many SNPs pose significant challenges. Although several Web resources are available that can inform about the functionality of SNPs, these resources are mainly annotation databases and are not very comprehensive. In this article, we present a comprehensive, well-annotated, integrated pfSNP (potentially functional SNPs) Web resource (http://pfs.nus.edu.sg/), which is aimed to facilitate better hypothesis generation through knowledge syntheses mediated by better data integration and a user-friendly Web interface. pfSNP integrates >40 different algorithms/resources to interrogate >14,000,000 SNPs from the dbSNP database for SNPs of potential functional significance based on previous published reports, inferred potential functionality from genetic approaches as well as predicted potential functionality from sequence motifs. Its query interface has the user-friendly "auto-complete, prompt-as-you-type" feature and is highly customizable, facilitating different combination of queries using Boolean-logic. Additionally, to facilitate better understanding of the results and aid in hypotheses generation, gene/pathway-level information with text clouds highlighting enriched tissues/pathways as well as detailed-related information are also provided on the results page. Hence, the pfSNP resource will be of great interest to scientists focusing on association studies as well as those interested to experimentally address the functionality of SNPs. PMID:20672376

  11. KinSNP software for homozygosity mapping of disease genes using SNP microarrays.

    PubMed

    Amir, El-Ad David; Bartal, Ofer; Morad, Efrat; Nagar, Tal; Sheynin, Jony; Parvari, Ruti; Chalifa-Caspi, Vered

    2010-08-01

    Consanguineous families affected with a recessive genetic disease caused by homozygotisation of a mutation offer a unique advantage for positional cloning of rare diseases. Homozygosity mapping of patient genotypes is a powerful technique for the identification of the genomic locus harbouring the causing mutation. This strategy relies on the observation that in these patients a large region spanning the disease locus is also homozygous with high probability. The high marker density in single nucleotide polymorphism (SNP) arrays is extremely advantageous for homozygosity mapping. We present KinSNP, a user-friendly software tool for homozygosity mapping using SNP arrays. The software searches for stretches of SNPs which are homozygous to the same allele in all ascertained sick individuals. User-specified parameters control the number of allowed genotyping 'errors' within homozygous blocks. Candidate disease regions are then reported in a detailed, coloured Excel file, along with genotypes of family members and healthy controls. An interactive genome browser has been included which shows homozygous blocks, individual genotypes, genes and further annotations along the chromosomes, with zooming and scrolling capabilities. The software has been used to identify the location of a mutated gene causing insensitivity to pain in a large Bedouin family. KinSNP is freely available from. PMID:20846928

  12. SNP marker detection and genotyping in tilapia.

    PubMed

    Van Bers, N E M; Crooijmans, R P M A; Groenen, M A M; Dibbits, B W; Komen, J

    2012-09-01

    We have generated a unique resource consisting of nearly 175 000 short contig sequences and 3569 SNP markers from the widely cultured GIFT (Genetically Improved Farmed Tilapia) strain of Nile tilapia (Oreochromis niloticus). In total, 384 SNPs were selected to monitor the wider applicability of the SNPs by genotyping tilapia individuals from different strains and different geographical locations. In all strains and species tested (O. niloticus, O. aureus and O. mossambicus), the genotyping assay was working for a similar number of SNPs (288-305 SNPs). The actual number of polymorphic SNPs was, as expected, highest for individuals from the GIFT population (255 SNPs). In the individuals from an Egyptian strain and in individuals caught in the wild in the basin of the river Volta, 197 and 163 SNPs were polymorphic, respectively. A pairwise calculation of Nei's genetic distance allowed the discrimination of the individual strains and species based on the genotypes determined with the SNP set. We expect that this set will be widely applicable for use in tilapia aquaculture, e.g. for pedigree reconstruction. In addition, this set is currently used for assaying the genetic diversity of native Nile tilapia in areas where tilapia is, or will be, introduced in aquaculture projects. This allows the tracing of escapees from aquaculture and the monitoring of effects of introgression and hybridization. PMID:22524158

  13. Single Nucleotide Polymorphism (SNP) in the Adiponectin Gene and Cardiovascular Disease.

    PubMed

    Chirumbolo, Salvatore

    2016-07-01

    by others[9] or a direct marker for CAD affected patients[10]. The paper by Mohammadzadeh et al.[1] assesses data coming elsewhere from literature but raises important concerns about the suitability of ADIPOQ SNPs in diagnosing susceptibility to CAD and the relationship with plasma adiponectin level. In normal, non diabetic, normoglycemic subject, this relationship does not seem to work. Therefore the question is how much predictive this SNP haplotype may be to foresee metabolic syndrome and CAD onset risk in young health subjects? Maybe, the role of adiponectin in cardiovascular physiology depends on its ability to target adiponectin receptors and to negatively regulate obesity. Some authors reported in healthy volunteers an absence of correlation between circulating adiponectin levels and biochemical markers, particularly lipoproteins and suggested that SNP +276G>T was related to an independent effect on adiponectin levels and on lipoprotein metabolism[11]. On the contrary, adiponectin genetic variants and SNP +276G>T was associated with increasing susceptibility of type 2 diabetes and plasma glucose impairment[12]. The interesting study by Mohammadzadeh et al.[1] suggests that SNP of ADIPOQ +276G>T should be related to susceptibility to glucose metabolism, while indirectly to lipid metabolism and fat-related cardiovascular damage. PMID:26884098

  14. Imputation of KIR Types from SNP Variation Data.

    PubMed

    Vukcevic, Damjan; Traherne, James A; Næss, Sigrid; Ellinghaus, Eva; Kamatani, Yoichiro; Dilthey, Alexander; Lathrop, Mark; Karlsen, Tom H; Franke, Andre; Moffatt, Miriam; Cookson, William; Trowsdale, John; McVean, Gil; Sawcer, Stephen; Leslie, Stephen

    2015-10-01

    Large population studies of immune system genes are essential for characterizing their role in diseases, including autoimmune conditions. Of key interest are a group of genes encoding the killer cell immunoglobulin-like receptors (KIRs), which have known and hypothesized roles in autoimmune diseases, resistance to viruses, reproductive conditions, and cancer. These genes are highly polymorphic, which makes typing expensive and time consuming. Consequently, despite their importance, KIRs have been little studied in large cohorts. Statistical imputation methods developed for other complex loci (e.g., human leukocyte antigen [HLA]) on the basis of SNP data provide an inexpensive high-throughput alternative to direct laboratory typing of these loci and have enabled important findings and insights for many diseases. We present KIR∗IMP, a method for imputation of KIR copy number. We show that KIR∗IMP is highly accurate and thus allows the study of KIRs in large cohorts and enables detailed investigation of the role of KIRs in human disease. PMID:26430804

  15. Imputation of KIR Types from SNP Variation Data

    PubMed Central

    Vukcevic, Damjan; Traherne, James A.; Næss, Sigrid; Ellinghaus, Eva; Kamatani, Yoichiro; Dilthey, Alexander; Lathrop, Mark; Karlsen, Tom H.; Franke, Andre; Moffatt, Miriam; Cookson, William; Trowsdale, John; McVean, Gil; Sawcer, Stephen; Leslie, Stephen

    2015-01-01

    Large population studies of immune system genes are essential for characterizing their role in diseases, including autoimmune conditions. Of key interest are a group of genes encoding the killer cell immunoglobulin-like receptors (KIRs), which have known and hypothesized roles in autoimmune diseases, resistance to viruses, reproductive conditions, and cancer. These genes are highly polymorphic, which makes typing expensive and time consuming. Consequently, despite their importance, KIRs have been little studied in large cohorts. Statistical imputation methods developed for other complex loci (e.g., human leukocyte antigen [HLA]) on the basis of SNP data provide an inexpensive high-throughput alternative to direct laboratory typing of these loci and have enabled important findings and insights for many diseases. We present KIR∗IMP, a method for imputation of KIR copy number. We show that KIR∗IMP is highly accurate and thus allows the study of KIRs in large cohorts and enables detailed investigation of the role of KIRs in human disease. PMID:26430804

  16. Large-Scale SNP Marker Development and Genotyping in Oat

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In this study, our goals are to develop genome-wide SNP markers using next generation sequencing technologies and to apply a highly parallel SNP genotyping system developed by Illumina for genetics and breeding applications in oat. The large amount of DNA sequence sources generated from cDNAs and Di...

  17. SNPConvert: SNP Array Standardization and Integration in Livestock Species

    PubMed Central

    Nicolazzi, Ezequiel Luis; Marras, Gabriele; Stella, Alessandra

    2016-01-01

    One of the main advantages of single nucleotide polymorphism (SNP) array technology is providing genotype calls for a specific number of SNP markers at a relatively low cost. Since its first application in animal genetics, the number of available SNP arrays for each species has been constantly increasing. However, conversely to that observed in whole genome sequence data analysis, SNP array data does not have a common set of file formats or coding conventions for allele calling. Therefore, the standardization and integration of SNP array data from multiple sources have become an obstacle, especially for users with basic or no programming skills. Here, we describe the difficulties related to handling SNP array data, focusing on file formats, SNP allele coding, and mapping. We also present SNPConvert suite, a multi-platform, open-source, and user-friendly set of tools to overcome these issues. This tool, which can be integrated with open-source and open-access tools already available, is a first step towards an integrated system to standardize and integrate any type of raw SNP array data. The tool is available at: https://github. com/nicolazzie/SNPConvert.git. PMID:27600083

  18. SNPConvert: SNP Array Standardization and Integration in Livestock Species.

    PubMed

    Nicolazzi, Ezequiel Luis; Marras, Gabriele; Stella, Alessandra

    2016-01-01

    One of the main advantages of single nucleotide polymorphism (SNP) array technology is providing genotype calls for a specific number of SNP markers at a relatively low cost. Since its first application in animal genetics, the number of available SNP arrays for each species has been constantly increasing. However, conversely to that observed in whole genome sequence data analysis, SNP array data does not have a common set of file formats or coding conventions for allele calling. Therefore, the standardization and integration of SNP array data from multiple sources have become an obstacle, especially for users with basic or no programming skills. Here, we describe the difficulties related to handling SNP array data, focusing on file formats, SNP allele coding, and mapping. We also present SNPConvert suite, a multi-platform, open-source, and user-friendly set of tools to overcome these issues. This tool, which can be integrated with open-source and open-access tools already available, is a first step towards an integrated system to standardize and integrate any type of raw SNP array data. The tool is available at: https://github. com/nicolazzie/SNPConvert.git. PMID:27600083

  19. Accelerating genetic improvement with SNP chips and DNA sequencing

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The development of high-density single nucleotide polymorphism (SNP) assays is expected to have a profound impact on genetic progress in the U.S. dairy industry. In the 16 months since its initial availability, the Illumina BovineSNP50 BeadChip has been used to genotype nearly 20,000 Holsteins. Thes...

  20. Atomic Force Microscopy for DNA SNP Identification

    NASA Astrophysics Data System (ADS)

    Valbusa, Ugo; Ierardi, Vincenzo

    The knowledge of the effects of single-nucleotide polymorphisms (SNPs) in the human genome greatly contributes to better comprehension of the relation between genetic factors and diseases. Sequence analysis of genomic DNA in different individuals reveals positions where variations that involve individual base substitutions can occur. Single-nucleotide polymorphisms are highly abundant and can have different consequences at phenotypic level. Several attempts were made to apply atomic force microscopy (AFM) to detect and map SNP sites in DNA strands. The most promising approach is the study of DNA mutations producing heteroduplex DNA strands and identifying the mismatches by means of a protein that labels the mismatches. MutS is a protein that is part of a well-known complex of mismatch repair, which initiates the process of repairing when the MutS binds to the mismatched DNA filament. The position of MutS on the DNA filament can be easily recorded by means of AFM imaging.

  1. Germline Mutation of the CCK Receptor: A Novel Biomarker for Pancreas Cancer

    PubMed Central

    Alsubai, Jelal; Matters, Gail L; McGovern, Christopher O; Liao, Jiangang; Gilius, Evan L; Smith, Jill P

    2016-01-01

    Objectives: Today, genetic biomarkers have been demonstrated to play an important role in identifying at-risk subjects for familial or inherited cancers. We have identified a single-nucleotide polymorphism (SNP) that results in missplicing of the cholecystokinin (CCK) receptor gene and expressing a larger mutated receptor in pancreatic cancer. The purpose of this study was to evaluate the significance and specificity of this SNP as a potential biomarker in patients with pancreatic cancer compared with other gastrointestinal (GI) cancers that also have CCK receptors. Methods: DNA was isolated and genotyped for the CCK receptor SNP from frozen tumor tissue from banked specimens of patients with pancreas, gastric, or colon cancer and from human cancer cell lines. Genotype and allelic frequencies were compared between the cancer cohort and two normal control databases using Fisher's exact test and odds ratio (OR). The Kaplan–Meier method was used to estimate the survival for patients with the CCK-B receptor SNP compared with those with the wild-type genotype. Immunohistochemical staining of cancer cells was done to detect the mutated receptor. Results: Colon and gastric cancer patients had similar genotype frequencies for the CCK receptor SNP as that reported in the normal population. In contrast, the prevalence of the SNP in subjects with pancreatic cancer was twice that of controls and other GI cancers. Survival was adversely affected by the presence of the SNP only in those with pancreatic cancer. Immunoreactivity for the mutated receptor was positive in pancreatic cancer tissues with the SNP but absent in other GI cancers. Conclusions: A SNP of the CCK receptor is significantly increased in patients with pancreatic cancer but not in those with other GI malignancies. Therefore, this SNP may be a potential biomarker for pancreatic cancer. PMID:26741064

  2. Analysis of Gln223Agr Polymorphism of Leptin Receptor Gene in Type II Diabetic Mellitus Subjects among Malaysians

    PubMed Central

    Etemad, Ali; Ramachandran, Vasudevan; Pishva, Seyyed Reza; Heidari, Farzad; Aziz, Ahmad Fazli Abdul; Yusof, Ahmad Khairuddin Mohamed; Pei, Chong Pei; Ismail, Patimah

    2013-01-01

    Leptin is known as the adipose peptide hormone. It plays an important role in the regulation of body fat and inhibits food intake by its action. Moreover, it is believed that leptin level deductions might be the cause of obesity and may play an important role in the development of Type 2 Diabetes Mellitus (T2DM), as well as in cardiovascular diseases (CVD). The Leptin Receptor (LEPR) gene and its polymorphisms have not been extensively studied in relation to the T2DM and its complications in various populations. In this study, we have determined the association of Gln223Agr loci of LEPR gene in three ethnic groups of Malaysia, namely: Malays, Chinese and Indians. A total of 284 T2DM subjects and 281 healthy individuals were recruited based on International Diabetes Federation (IDF) criteria. Genomic DNA was extracted from the buccal specimens of the subjects. The commercial polymerase chain reaction (PCR) method was carried out by proper restriction enzyme MSP I to both amplify and digest the Gln223Agr polymorphism. The p-value among the three studied races was 0.057, 0.011 and 0.095, respectively. The values such as age, WHR, FPG, HbA1C, LDL, HDL, Chol and Family History were significantly different among the subjects with Gln223Agr polymorphism of LEPR (p < 0.05). PMID:24051404

  3. Analysis of Gln223Agr polymorphism of Leptin Receptor Gene in type II diabetic mellitus subjects among Malaysians.

    PubMed

    Etemad, Ali; Ramachandran, Vasudevan; Pishva, Seyyed Reza; Heidari, Farzad; Aziz, Ahmad Fazli Abdul; Yusof, Ahmad Khairuddin Mohamed; Pei, Chong Pei; Ismail, Patimah

    2013-01-01

    Leptin is known as the adipose peptide hormone. It plays an important role in the regulation of body fat and inhibits food intake by its action. Moreover, it is believed that leptin level deductions might be the cause of obesity and may play an important role in the development of Type 2 Diabetes Mellitus (T2DM), as well as in cardiovascular diseases (CVD). The Leptin Receptor (LEPR) gene and its polymorphisms have not been extensively studied in relation to the T2DM and its complications in various populations. In this study, we have determined the association of Gln223Agr loci of LEPR gene in three ethnic groups of Malaysia, namely: Malays, Chinese and Indians. A total of 284 T2DM subjects and 281 healthy individuals were recruited based on International Diabetes Federation (IDF) criteria. Genomic DNA was extracted from the buccal specimens of the subjects. The commercial polymerase chain reaction (PCR) method was carried out by proper restriction enzyme MSP I to both amplify and digest the Gln223Agr polymorphism. The p-value among the three studied races was 0.057, 0.011 and 0.095, respectively. The values such as age, WHR, FPG, HbA1C, LDL, HDL, Chol and Family History were significantly different among the subjects with Gln223Agr polymorphism of LEPR (p < 0.05). PMID:24051404

  4. Leptin and leptin receptor gene polymorphisms and their association with plasma leptin levels and obesity in a multi-ethnic Malaysian suburban population

    PubMed Central

    2014-01-01

    Background This study was to investigate the prevalence of single nucleotide polymorphisms (SNPs) in leptin gene LEP (A19G and G2548A) and leptin receptor gene LEPR (K109R and Q223R) and their association with fasting plasma leptin level (PLL) and obesity in a Malaysian suburban population in Kampar, Perak. Methods Convenience sampling was performed with informed consents, and the study sample was drawn from patients who were patrons of the Kampar Health Clinic. A total of 408 subjects (mean age, 52.4 ± 13.7 years; 169 men, 239 women; 190 obese, 218 non-obese; 148 Malays, 177 ethnic Chinese, 83 ethnic Indians) participated. Socio-demographic data and anthropometric measurements were taken, and genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results The LEP A19G, G2548A and LEPR K109R, Q223R variant allele frequencies were 0.74, 0.67 and 0.61, 0.79, respectively. The genotype and allele distributions of these gene variants were significantly different among ethnic groups, but not among body mass index (BMI) classes. Subjects with LEPR K109 and Q223 allele had significantly higher systolic blood pressure and adiposity indices after adjustment for ethnicity (higher BMI, total body and subcutaneous fat; lower skeletal muscle percentage). Subjects with LEPR 109R allele had lower PLL than their wild-type allele counterparts. The influence of LEP A19G and G2548A SNPs on blood pressures, anthropometrics, and PLL was not evident. Interestingly, synergistic effect of the LEP and LEPR SNPs was observed as subjects homozygous for all four SNPs studied exhibited significantly higher subcutaneous fat and PLL than those with other genotype combinations. Conclusions The LEP and LEPR SNPs in this study may not be an obesity marker among Malaysians in this population, but were associated with ethnicity. Our findings suggest that each of these SNPs contributes to minor but significant variation in obesity

  5. SNP variation in ADRB3 gene reflects the breed difference of sheep populations.

    PubMed

    Wu, Jianliang; Qiao, Liying; Liu, Jianhua; Yuan, Yanan; Liu, Wenzhong

    2012-08-01

    The β3-adrenergic receptor (ADRB3), a G-protein coupled receptor, plays a major role in energy metabolism and regulation of lipolysis and homeostasis. We detect the single nucleotide polymorphism (SNP) variation in full-length sequence of ovine ADRB3 gene in 12 domestic sheep populations within four types by polymerase chain reaction-single strand conformation polymorphism and sequencing to reveal the breed difference. Twenty-two SNPs, 12 of which in the exon 1 and ten in the intron, were detected, and 12 new exonic and four new intronic SNPs were found. Most SNPs presented in Shanxi Dam Line and least ones in Dorset. The average SNP number in both meat and dual purpose for meat and wool breeds was significantly higher than general and dual purpose breeds for wool and meat. Frequency of each SNP in studied breeds or types was different. The 18C Del and 1617T Ins majorly existed in dual purpose breeds for wool and meat. The 25A Del, 119C>G and 130C>T were mostly found in the meat and dual purpose for meat and wool breeds. The 1764C>A more frequently presented in meat than in other types. The majority of variations came from within the populations as suggested by analysis of molecular variance. Close relationship presented among the Chinese and western breeds, respectively. In conclusion, SNPs of ovine ADRB3 gene can reflect the breed difference and within- and between-population variations, and to a great extent, the breed relationship. PMID:22711302

  6. Omega-3 fatty acids protect renal functions by increasing docosahexaenoic acid-derived metabolite levels in SHR.Cg-Lepr(cp)/NDmcr rats, a metabolic syndrome model.

    PubMed

    Katakura, Masanori; Hashimoto, Michio; Inoue, Takayuki; Al Mamun, Abdullah; Tanabe, Yoko; Iwamoto, Ryo; Arita, Makoto; Tsuchikura, Satoru; Shido, Osamu

    2014-01-01

    The omega-3 polyunsaturated fatty acids (ω-3 PUFAs) docosahexaenoic acid (DHA) and/or eicosapentaenoic acid (EPA) protect against diabetic nephropathy by inhibiting inflammation. The aim of this study was to assess the effects of highly purified DHA and EPA or EPA only administration on renal function and renal eicosanoid and docosanoid levels in an animal model of metabolic syndrome, SHR.Cg-Lepr(cp)/NDmcr (SHRcp) rats. Male SHRcp rats were divided into 3 groups. Control (5% arabic gum), TAK-085 (300 mg/kg/day, containing 467 mg/g EPA and 365 mg/g DHA), or EPA (300 mg/kg/day) was orally administered for 20 weeks. The urinary albumin to creatinine ratio in the TAK-085-administered group was significantly lower than that in other groups. The glomerular sclerosis score in the TAK-085-administered group was significantly lower than that in the other groups. Although DHA levels were increased in total kidney fatty acids, the levels of nonesterified DHA were not significantly different among the 3 groups, whereas the levels of protectin D1, resolvin D1, and resolvin D2 were significantly increased in the TAK-085-administered group. The results show that the use of combination therapy with DHA and EPA in SHRcp rats improved or prevented renal failure associate with metabolic syndrome with decreasing triglyceride levels and increasing ω-3 PUFA lipid mediators. PMID:24642910

  7. The Perils of SNP Microarray Testing: Uncovering Unexpected Consanguinity

    PubMed Central

    Tarini, Beth A.; Konczal, Laura; Goldenberg, Aaron J.; Goldman, Edward B.; McCandless, Shawn E.

    2013-01-01

    Background While single nucleotide polymorphism (SNP) chromosomal microarrays identify areas of small genetic deletions/duplications, they can also reveal regions of homozygosity indicative of consanguinity. As more non-geneticists order SNP microarrays, they must prepare for the potential ethical, legal and social issues that result from revelation of unanticipated consanguinity. Patient An infant with multiple congenital anomalies underwent SNP microarray testing. Results The results of the SNP microarray revealed several large regions of homozygosity that indicated identity by descent most consistent with a second or third degree relative mating (e.g., uncle/ niece, half brother/sister, first cousins). Mother was not aware of the test's potential to reveal consanguinity. When informed of the test results, she reluctantly admitted to being raped by her half-brother around the time of conception. Conclusions During the pre-testing consent process, providers should inform parents that SNP microarray testing could reveal consanguinity. Providers must also understand the psychological implications, as well as the legal and moral obligations, that accompany SNP microarray results that indicate consanguinity. PMID:23827427

  8. Relationships between plasma leptin levels, leptin G2548A, leptin receptor Gln223Arg polymorphisms and gestational diabetes mellitus in Chinese population

    PubMed Central

    Yang, Mei; Peng, Songxu; Li, Wei; Wan, Zhihua; Fan, Linlin; Du, Yukai

    2016-01-01

    The purposes of this study were to examine concentrations of leptin and biochemical parameters in gestational diabetes mellitus (GDM) patients and normal glucose tolerance (NGT) individuals, and also to explore the links of leptin (LEP) G2548A and leptin receptor (LEPR) Gln223Arg polymorphisms with leptin levels and GDM risk among Chinese. Our study included 357 GDM and 355 NGT individuals who were at 24~30 gestational weeks. Plasma leptin and insulin levels were analyzed by ELISA. Gene polymorphisms were genotyped using TaqMan real-time polymerase chain reaction assay. The results showed that plasma leptin levels were significantly higher in the impaired fasting glucose (IFG) group than NGT group (34.35 (26.54, 56.48) ng/mL vs 26.31 (17.99, 37.87) ng/mL, P < 0.05). Plasma leptin levels correlated with plasma fasting insulin levels, pre-pregnant body mass index, homeostasis model assessment-insulin resistance and quantitative insulin sensitivity check index both in GDM and NGT group (P < 0.05). However, neither LEP G2548A nor LEPR Gln223Arg polymorphisms were significantly associated with GDM risk and plasma leptin levels (P > 0.05). Our findings showed that high leptin level was associated with GDM. And larger and more rigorous researches were needed to further explore the association of LEP and LEPR gene polymorphisms and GDM among Chinese population. PMID:27034205

  9. Leptin Receptor Gene Gln223Arg Polymorphism Is Not Associated with Hypertension: A Preliminary Population-Based Cross-Sectional Study

    PubMed Central

    Pena, Geórgia das Graças; Guimarães, Andre L. S.; Veloso, Rosângela R.; Reis, Tatiana C.; Gomes, Crizian S.; Neto, João F. R.; Velasquez-Melendez, Gustavo

    2014-01-01

    Hypertension is responsible for high morbidity and mortality as one of the most important cardiometabolic risk factors. The aim of the study was to investigate whether the Gln223Arg in the leptin receptor (LEPR) influences the prevalence of hypertension. A cross-sectional study was carried out in individuals aged ≥ 18 years. Polymorphism identification was performed using PCR-RFLP analysis. Participants with blood pressure ≥ 140/90 mmHg or medication use were considered hypertensive. Frequencies, means, cross-tabulations, and multivariate models were produced to study differences in hypertension prevalence by genotypes. The study includes 470 participants. The frequency of GG polymorphism variant was 10.43%, 46.81% AG, and 42.77% AA. The distribution of hypertension frequency by LEPR genotypes was the following: AA 43.8%, AG 40.4%, and GG 40.8%; there were no significant differences between groups. Comparative analysis which used multivariate Poisson regression adjusted by many potential confounders (age, sex, schooling, smoking, alcohol intake, obesity, and family history of parental obesity) did not modify this result. In this large sample of population-based study, the association of the LEPR Gln223Arg gene polymorphism with hypertension was not observed. PMID:24772364

  10. Leptin and leptin receptor genotypes and colon cancer: Gene–gene and gene–lifestyle interactions

    PubMed Central

    Slattery, Martha L.; Wolff, Roger K.; Herrick, Jennifer; Caan, Bette J.; Potter, John D.

    2008-01-01

    Leptin may play an important role in colorectal cancer because of its role in energy balance, insulin and inflammation. We evaluated the LEP rs2167270 (19 G > A) and rs7799039 (−2548 G > A) polymorphisms and the leptin receptor, LEPR rs6588147 (located in intron 2), polymorphism with risk of developing colon cancer in a study of 1,567 cases and 1,965 controls. We evaluated the effects of the polymorphisms with body mass index (BMI), recent use of aspirin/NSAIDs and genetic variations in genes related to insulin signaling pathways including insulin-like growth factor 1 (IGF1), insulin-like growth factor binding protein 3 (IGFBP3), and insulin- related substrates 1 and 2 (IRS1, IRS2) and the vitamin D receptor (VDR). We observed a slight reduction in colon cancer risk with the AA LEP rs2167270 genotype (OR 0.79 95% CI 0.64, 0.98) and although not reaching statistical significance, with the combined GG LEP rs2167270 and GG LEPR rs6588147 (OR 0.70, 95% CI 0.49, 1.02) genotypes. BMI did not interact with any of these polymorphisms to alter colon cancer risk. However, recent aspirin/NSAID use significantly interacted with both LEP polymorphisms. Likewise, variants of IGF1 and IRS2 interacted with the LEP rs2167270 polymorphism. VDR polymorphisms interacted with all LEP and LEPR polymorphisms. These data support an association between LEP and colon cancer. They also suggest that the mechanisms linking leptin to colon cancer may be independent of energy balance. PMID:18059035

  11. A SNP resource for Douglas-fir: de novo transcriptome assembly and SNP detection and validation

    PubMed Central

    2013-01-01

    Background Douglas-fir (Pseudotsuga menziesii), one of the most economically and ecologically important tree species in the world, also has one of the largest tree breeding programs. Although the coastal and interior varieties of Douglas-fir (vars. menziesii and glauca) are native to North America, the coastal variety is also widely planted for timber production in Europe, New Zealand, Australia, and Chile. Our main goal was to develop a SNP resource large enough to facilitate genomic selection in Douglas-fir breeding programs. To accomplish this, we developed a 454-based reference transcriptome for coastal Douglas-fir, annotated and evaluated the quality of the reference, identified putative SNPs, and then validated a sample of those SNPs using the Illumina Infinium genotyping platform. Results We assembled a reference transcriptome consisting of 25,002 isogroups (unique gene models) and 102,623 singletons from 2.76 million 454 and Sanger cDNA sequences from coastal Douglas-fir. We identified 278,979 unique SNPs by mapping the 454 and Sanger sequences to the reference, and by mapping four datasets of Illumina cDNA sequences from multiple seed sources, genotypes, and tissues. The Illumina datasets represented coastal Douglas-fir (64.00 and 13.41 million reads), interior Douglas-fir (80.45 million reads), and a Yakima population similar to interior Douglas-fir (8.99 million reads). We assayed 8067 SNPs on 260 trees using an Illumina Infinium SNP genotyping array. Of these SNPs, 5847 (72.5%) were called successfully and were polymorphic. Conclusions Based on our validation efficiency, our SNP database may contain as many as ~200,000 true SNPs, and as many as ~69,000 SNPs that could be genotyped at ~20,000 gene loci using an Infinium II array—more SNPs than are needed to use genomic selection in tree breeding programs. Ultimately, these genomic resources will enhance Douglas-fir breeding and allow us to better understand landscape-scale patterns of genetic variation

  12. Denaturing high performance liquid chromatography: high throughput mutation screening in familial hypertrophic cardiomyopathy and SNP genotyping in motor neurone disease

    PubMed Central

    Yu, B; Sawyer, N A; Caramins, M; Yuan, Z G; Saunderson, R B; Pamphlett, R; Richmond, D R; Jeremy, R W; Trent, R J

    2005-01-01

    Aims: To evaluate the usefulness of denaturing high performance liquid chromatography (DHPLC) as a high throughput tool in: (1) DNA mutation detection in familial hypertrophic cardiomyopathy (FHC), and (2) single nucleotide polymorphism (SNP) discovery and validation in sporadic motor neurone disease (MND). Methods: The coding sequence and intron–exon boundaries of the cardiac β myosin heavy chain gene (MYH7) were screened by DHPLC for mutation identification in 150 unrelated patients diagnosed with FHC. One hundred and forty patients with sporadic MND were genotyped for the A67T SNP in the poliovirus receptor gene. All DHPLC positive signals were confirmed by conventional methods. Results: Mutation screening of MYH7 covered 10 kb with a total of 5700 amplicons, and more than 6750 DHPLC injections were completed within 35 days. The causative mutation was identified in 14% of FHC cases, including seven novel missense mutations (L227V, E328G, K351E, V411I, M435T, E894G, and E927K). Genotyping of the A67T SNP was performed at two different temperatures both in MND cases and 280 controls. This coding SNP was found more frequently in MND cases (13.6%) than in controls (6.8%). Furthermore, 19 and two SNPs were identified in MYH7 and the poliovirus receptor gene, respectively, during DHPLC screening. Conclusions: DHPLC is a high throughput, sensitive, specific, and robust platform for the detection of DNA variants, such as disease causing mutations or SNPs. It enables rapid and accurate screening of large genomic regions. PMID:15858117

  13. DoGSD: the dog and wolf genome SNP database.

    PubMed

    Bai, Bing; Zhao, Wen-Ming; Tang, Bi-Xia; Wang, Yan-Qing; Wang, Lu; Zhang, Zhang; Yang, He-Chuan; Liu, Yan-Hu; Zhu, Jun-Wei; Irwin, David M; Wang, Guo-Dong; Zhang, Ya-Ping

    2015-01-01

    The rapid advancement of next-generation sequencing technology has generated a deluge of genomic data from domesticated dogs and their wild ancestor, grey wolves, which have simultaneously broadened our understanding of domestication and diseases that are shared by humans and dogs. To address the scarcity of single nucleotide polymorphism (SNP) data provided by authorized databases and to make SNP data more easily/friendly usable and available, we propose DoGSD (http://dogsd.big.ac.cn), the first canidae-specific database which focuses on whole genome SNP data from domesticated dogs and grey wolves. The DoGSD is a web-based, open-access resource comprising ∼ 19 million high-quality whole-genome SNPs. In addition to the dbSNP data set (build 139), DoGSD incorporates a comprehensive collection of SNPs from two newly sequenced samples (1 wolf and 1 dog) and collected SNPs from three latest dog/wolf genetic studies (7 wolves and 68 dogs), which were taken together for analysis with the population genetic statistics, Fst. In addition, DoGSD integrates some closely related information including SNP annotation, summary lists of SNPs located in genes, synonymous and non-synonymous SNPs, sampling location and breed information. All these features make DoGSD a useful resource for in-depth analysis in dog-/wolf-related studies. PMID:25404132

  14. DoGSD: the dog and wolf genome SNP database

    PubMed Central

    Bai, Bing; Zhao, Wen-Ming; Tang, Bi-Xia; Wang, Yan-Qing; Wang, Lu; Zhang, Zhang; Yang, He-Chuan; Liu, Yan-Hu; Zhu, Jun-Wei; Irwin, David M.; Wang, Guo-Dong; Zhang, Ya-Ping

    2015-01-01

    The rapid advancement of next-generation sequencing technology has generated a deluge of genomic data from domesticated dogs and their wild ancestor, grey wolves, which have simultaneously broadened our understanding of domestication and diseases that are shared by humans and dogs. To address the scarcity of single nucleotide polymorphism (SNP) data provided by authorized databases and to make SNP data more easily/friendly usable and available, we propose DoGSD (http://dogsd.big.ac.cn), the first canidae-specific database which focuses on whole genome SNP data from domesticated dogs and grey wolves. The DoGSD is a web-based, open-access resource comprising ∼19 million high-quality whole-genome SNPs. In addition to the dbSNP data set (build 139), DoGSD incorporates a comprehensive collection of SNPs from two newly sequenced samples (1 wolf and 1 dog) and collected SNPs from three latest dog/wolf genetic studies (7 wolves and 68 dogs), which were taken together for analysis with the population genetic statistics, Fst. In addition, DoGSD integrates some closely related information including SNP annotation, summary lists of SNPs located in genes, synonymous and non-synonymous SNPs, sampling location and breed information. All these features make DoGSD a useful resource for in-depth analysis in dog-/wolf-related studies. PMID:25404132

  15. Substantial SNP-based heritability estimates for working memory performance

    PubMed Central

    Vogler, C; Gschwind, L; Coynel, D; Freytag, V; Milnik, A; Egli, T; Heck, A; de Quervain, D J-F; Papassotiropoulos, A

    2014-01-01

    Working memory (WM) is an important endophenotype in neuropsychiatric research and its use in genetic association studies is thought to be a promising approach to increase our understanding of psychiatric disease. As for any genetically complex trait, demonstration of sufficient heritability within the specific study context is a prerequisite for conducting genetic studies of that trait. Recently developed methods allow estimating trait heritability using sets of common genetic markers from genome-wide association study (GWAS) data in samples of unrelated individuals. Here we present single-nucleotide polymorphism (SNP)-based heritability estimates (h2SNP) for a WM phenotype. A Caucasian sample comprising a total of N=2298 healthy and young individuals was subjected to an N-back WM task. We calculated the genetic relationship between all individuals on the basis of genome-wide SNP data and performed restricted maximum likelihood analyses for variance component estimation to derive the h2SNP estimates. Heritability estimates for three 2-back derived WM performance measures based on all autosomal chromosomes ranged between 31 and 41%, indicating a substantial SNP-based heritability for WM traits. These results indicate that common genetic factors account for a prominent part of the phenotypic variation in WM performance. Hence, the application of GWAS on WM phenotypes is a valid method to identify the molecular underpinnings of WM. PMID:25203169

  16. Conditions for the validity of SNP-based heritability estimation

    PubMed Central

    2014-01-01

    The heritability of a trait (h2) is the proportion of its population variance caused by genetic differences, and estimates of this parameter are important for interpreting the results of genome-wide association studies (GWAS). In recent years, researchers have adopted a novel method for estimating a lower bound on heritability directly from GWAS data that uses realized genetic similarities between nominally unrelated individuals. The quantity estimated by this method is purported to be the contribution to heritability that could in principle be recovered from association studies employing the given panel of SNPs (hSNP2). Thus far, the validity of this approach has mostly been tested empirically. Here, we provide a mathematical explication and show that the method should remain a robust means of obtaining hSNP2 SNP under circumstances wider than those under which it has so far been derived. PMID:24744256

  17. Whole genome SNP scanning of snow sheep (Ovis nivicola).

    PubMed

    Deniskova, T E; Okhlopkov, I M; Sermyagin, A A; Gladyr', E A; Bagirov, V A; Sölkner, J; Mamaev, N V; Brem, G; Zinov'eva, N A

    2016-07-01

    This is the first report performing the whole genome SNP scanning of snow sheep (Ovis nivicola). Samples of snow sheep (n = 18) collected in six different regions of the Republic of Sakha (Yakutia) from 64° to 71° N. For SNP genotyping, we applied Ovine 50K SNP BeadChip (Illumina, United States), designed for domestic sheep. The total number of genotyped SNPs (call rate 90%) was 47796 (88.1% of total SNPs), wherein 1006 SNPs were polymorphic (2.1%). Principal component analysis (PCA) showed the clear differentiation within the species O. nivicola: studied individuals were distributed among five distinct arrays corresponding to the geographical locations of sampling points. Our results demonstrate that the DNA chip designed for domestic sheep can be successfully used to study the allele pool and the genetic structure of snow sheep populations. PMID:27599514

  18. Detection of copy number variation by SNP-allelotyping.

    PubMed

    Parker, Brett; Alexander, Ryan; Wu, Xingyao; Feely, Shawna; Shy, Michael; Schnetz-Boutaud, Nathalie; Li, Jun

    2015-03-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by an abnormal copy number variation (CNV) with a trisomy of chromosome 17p12. The increase of the DNA-segment copy number is expected to alter the allele frequency of single nucleotide polymorphism (SNP) within the duplicated region. We tested whether SNP allele frequency determined by a Sequenom MassArray can be used to detect the CMT1A mutation. Our results revealed distinct patterns of SNP allele frequency distribution, which reliably differentiated CMT1A patients from controls. This finding suggests that this technique may serve as an alternative approach to identifying CNV in certain diseases, including CMT1A. PMID:24830919

  19. A robust SNP barcode for typing Mycobacterium tuberculosis complex strains

    PubMed Central

    Coll, Francesc; McNerney, Ruth; Guerra-Assunção, José Afonso; Glynn, Judith R.; Perdigão, João; Viveiros, Miguel; Portugal, Isabel; Pain, Arnab; Martin, Nigel; Clark, Taane G.

    2014-01-01

    Strain-specific genomic diversity in the Mycobacterium tuberculosis complex (MTBC) is an important factor in pathogenesis that may affect virulence, transmissibility, host response and emergence of drug resistance. Several systems have been proposed to classify MTBC strains into distinct lineages and families. Here, we investigate single-nucleotide polymorphisms (SNPs) as robust (stable) markers of genetic variation for phylogenetic analysis. We identify ~92k SNP across a global collection of 1,601 genomes. The SNP-based phylogeny is consistent with the gold-standard regions of difference (RD) classification system. Of the ~7k strain-specific SNPs identified, 62 markers are proposed to discriminate known circulating strains. This SNP-based barcode is the first to cover all main lineages, and classifies a greater number of sublineages than current alternatives. It may be used to classify clinical isolates to evaluate tools to control the disease, including therapeutics and vaccines whose effectiveness may vary by strain type. PMID:25176035

  20. A 48 SNP set for grapevine cultivar identification

    PubMed Central

    2011-01-01

    Background Rapid and consistent genotyping is an important requirement for cultivar identification in many crop species. Among them grapevine cultivars have been the subject of multiple studies given the large number of synonyms and homonyms generated during many centuries of vegetative multiplication and exchange. Simple sequence repeat (SSR) markers have been preferred until now because of their high level of polymorphism, their codominant nature and their high profile repeatability. However, the rapid application of partial or complete genome sequencing approaches is identifying thousands of single nucleotide polymorphisms (SNP) that can be very useful for such purposes. Although SNP markers are bi-allelic, and therefore not as polymorphic as microsatellites, the high number of loci that can be multiplexed and the possibilities of automation as well as their highly repeatable results under any analytical procedure make them the future markers of choice for any type of genetic identification. Results We analyzed over 300 SNP in the genome of grapevine using a re-sequencing strategy in a selection of 11 genotypes. Among the identified polymorphisms, we selected 48 SNP spread across all grapevine chromosomes with allele frequencies balanced enough as to provide sufficient information content for genetic identification in grapevine allowing for good genotyping success rate. Marker stability was tested in repeated analyses of a selected group of cultivars obtained worldwide to demonstrate their usefulness in genetic identification. Conclusions We have selected a set of 48 stable SNP markers with a high discrimination power and a uniform genome distribution (2-3 markers/chromosome), which is proposed as a standard set for grapevine (Vitis vinifera L.) genotyping. Any previous problems derived from microsatellite allele confusion between labs or the need to run reference cultivars to identify allele sizes disappear using this type of marker. Furthermore, because SNP

  1. SNP marker discovery in koala TLR genes.

    PubMed

    Cui, Jian; Frankham, Greta J; Johnson, Rebecca N; Polkinghorne, Adam; Timms, Peter; O'Meally, Denis; Cheng, Yuanyuan; Belov, Katherine

    2015-01-01

    Toll-like receptors (TLRs) play a crucial role in the early defence against invading pathogens, yet our understanding of TLRs in marsupial immunity is limited. Here, we describe the characterisation of nine TLRs from a koala immune tissue transcriptome and one TLR from a draft sequence of the koala genome and the subsequent development of an assay to study genetic diversity in these genes. We surveyed genetic diversity in 20 koalas from New South Wales, Australia and showed that one gene, TLR10 is monomorphic, while the other nine TLR genes have between two and 12 alleles. 40 SNPs (16 non-synonymous) were identified across the ten TLR genes. These markers provide a springboard to future studies on innate immunity in the koala, a species under threat from two major infectious diseases. PMID:25799012

  2. SNP Marker Discovery in Koala TLR Genes

    PubMed Central

    Cui, Jian; Frankham, Greta J.; Johnson, Rebecca N.; Polkinghorne, Adam; Timms, Peter; O’Meally, Denis; Cheng, Yuanyuan; Belov, Katherine

    2015-01-01

    Toll-like receptors (TLRs) play a crucial role in the early defence against invading pathogens, yet our understanding of TLRs in marsupial immunity is limited. Here, we describe the characterisation of nine TLRs from a koala immune tissue transcriptome and one TLR from a draft sequence of the koala genome and the subsequent development of an assay to study genetic diversity in these genes. We surveyed genetic diversity in 20 koalas from New South Wales, Australia and showed that one gene, TLR10 is monomorphic, while the other nine TLR genes have between two and 12 alleles. 40 SNPs (16 non-synonymous) were identified across the ten TLR genes. These markers provide a springboard to future studies on innate immunity in the koala, a species under threat from two major infectious diseases. PMID:25799012

  3. Do you really know where this SNP goes?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The release of build 10.2 of the swine genome was a marked improvement over previous builds and has proven extremely useful. However, as most know, there are regions of the genome that this particular build does not accurately represent. For instance, nearly 25% of the 62,162 SNP on the Illumina Por...

  4. Analysis of genetic diversity using SNP markers in oat

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A large-scale single nucleotide polymorphism (SNP) discovery was carried out in cultivated oat using Roche 454 sequencing methods. DNA sequences were generated from cDNAs originating from a panel of 20 diverse oat cultivars, and from Diversity Array Technology (DArT) genomic complexity reductions fr...

  5. Genetic mapping in grapevine using a SNP microarray: intensity values

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genotyping microarrays are widely used for genome wide association studies, but in high-diversity organisms, the quality of SNP calls can be diminished by genetic variation near the assayed nucleotide. To address this limitation in grapevine, we developed a simple heuristic that uses hybridization i...

  6. SNP marker diversity in common bean (Phaseolus vulgaris L.).

    PubMed

    Cortés, Andrés J; Chavarro, Martha C; Blair, Matthew W

    2011-09-01

    Single nucleotide polymorphism (SNP) markers have become a genetic technology of choice because of their automation and high precision of allele calls. In this study, our goal was to develop 94 SNPs and test them across well-chosen common bean (Phaseolus vulgaris L.) germplasm. We validated and accessed SNP diversity at 84 gene-based and 10 non-genic loci using KASPar technology in a panel of 70 genotypes that have been used as parents of mapping populations and have been previously evaluated for SSRs. SNPs exhibited high levels of genetic diversity, an excess of middle frequency polymorphism, and a within-genepool mismatch distribution as expected for populations affected by sudden demographic expansions after domestication bottlenecks. This set of markers was useful for distinguishing Andean and Mesoamerican genotypes but less useful for distinguishing within each gene pool. In summary, slightly greater polymorphism and race structure was found within the Andean gene pool than within the Mesoamerican gene pool but polymorphism rate between genotypes was consistent with genepool and race identity. Our survey results represent a baseline for the choice of SNP markers for future applications because gene-associated SNPs could themselves be causative SNPs for traits. Finally, we discuss that the ideal genetic marker combination with which to carry out diversity, mapping and association studies in common bean should consider a mix of both SNP and SSR markers. PMID:21785951

  7. SNP Discovery through Next-Generation Sequencing and Its Applications

    PubMed Central

    Kumar, Santosh; Banks, Travis W.; Cloutier, Sylvie

    2012-01-01

    The decreasing cost along with rapid progress in next-generation sequencing and related bioinformatics computing resources has facilitated large-scale discovery of SNPs in various model and nonmodel plant species. Large numbers and genome-wide availability of SNPs make them the marker of choice in partially or completely sequenced genomes. Although excellent reviews have been published on next-generation sequencing, its associated bioinformatics challenges, and the applications of SNPs in genetic studies, a comprehensive review connecting these three intertwined research areas is needed. This paper touches upon various aspects of SNP discovery, highlighting key points in availability and selection of appropriate sequencing platforms, bioinformatics pipelines, SNP filtering criteria, and applications of SNPs in genetic analyses. The use of next-generation sequencing methodologies in many non-model crops leading to discovery and implementation of SNPs in various genetic studies is discussed. Development and improvement of bioinformatics software that are open source and freely available have accelerated the SNP discovery while reducing the associated cost. Key considerations for SNP filtering and associated pipelines are discussed in specific topics. A list of commonly used software and their sources is compiled for easy access and reference. PMID:23227038

  8. Software solutions for the livestock genomics SNP array revolution.

    PubMed

    Nicolazzi, E L; Biffani, S; Biscarini, F; Orozco Ter Wengel, P; Caprera, A; Nazzicari, N; Stella, A

    2015-08-01

    Since the beginning of the genomic era, the number of available single nucleotide polymorphism (SNP) arrays has grown considerably. In the bovine species alone, 11 SNP chips not completely covered by intellectual property are currently available, and the number is growing. Genomic/genotype data are not standardized, and this hampers its exchange and integration. In addition, software used for the analyses of these data usually requires not standard (i.e. case specific) input files which, considering the large amount of data to be handled, require at least some programming skills in their production. In this work, we describe a software toolkit for SNP array data management, imputation, genome-wide association studies, population genetics and genomic selection. However, this toolkit does not solve the critical need for standardization of the genotypic data and software input files. It only highlights the chaotic situation each researcher has to face on a daily basis and gives some helpful advice on the currently available tools in order to navigate the SNP array data complexity. PMID:25907889

  9. Association of selected SNP with carcass and taste panel assessed meat quality traits in a commercial population of Aberdeen Angus-sired beef cattle

    PubMed Central

    Gill, Jennifer L; Bishop, Stephen C; McCorquodale, Caroline; Williams, John L; Wiener, Pamela

    2009-01-01

    Background The purpose of this study was to evaluate the effects of eight single nucleotide polymorphisms (SNP), previously associated with meat and milk quality traits in cattle, in a population of 443 commercial Aberdeen Angus-cross beef cattle. The eight SNP, which were located within five genes: μ-calpain (CAPN1), calpastatin (CAST), leptin (LEP), growth hormone receptor (GHR) and acylCoA:diacylglycerol acyltransferase 1 (DGAT1), are included in various commercial tests for tenderness, fatness, carcass composition and milk yield/quality. Methods A total of 27 traits were examined, 19 relating to carcass quality, such as carcass weight and fatness, one mechanical measure of tenderness, and the remaining seven were sensory traits, such as flavour and tenderness, assessed by a taste panel. Results An SNP in the CAPN1 gene, CAPN316, was significantly associated with tenderness measured by both the tenderometer and the taste panel as well as the weight of the hindquarter, where animals inheriting the CC genotype had more tender meat and heavier hindquarters. An SNP in the leptin gene, UASMS2, significantly affected overall liking, where animals with the TT genotype were assigned higher scores by the panellists. The SNP in the GHR gene was significantly associated with odour, where animals inheriting the AA genotype produced steaks with an intense odour when compared with the other genotypes. Finally, the SNP in the DGAT1 gene was associated with sirloin weight after maturation and fat depth surrounding the sirloin, with animals inheriting the AA genotype having heavier sirloins and more fat. Conclusion The results of this study confirm some previously documented associations. Furthermore, novel associations have been identified which, following validation in other populations, could be incorporated into breeding programmes to improve meat quality. PMID:19555501

  10. Association of Atherosclerotic Peripheral Arterial Disease with Adiponectin Genes SNP+45 and SNP+276: A Case-Control Study

    PubMed Central

    Gherman, Claudia D.; Bolboacă, Sorana D.

    2013-01-01

    Objectives. We hypothesized that adiponectin gene SNP+45 (rs2241766) and SNP+276 (rs1501299) would be associated with atherosclerotic peripheral arterial disease (PAD). Furthermore, the association between circulating adiponectin levels, fetuin-A, and tumoral necrosis factor-alpha (TNF-α) in patients with atherosclerotic peripheral arterial disease was investigated. Method. Several blood parameters (such as adiponectin, fetuin-A, and TNF-α) were measured in 346 patients, 226 with atherosclerotic peripheral arterial disease (PAD) and 120 without symptomatic PAD (non-PAD). Two common SNPs of the ADIPOQ gene represented by +45T/G 2 and +276G/T were also investigated. Results. Adiponectin concentrations showed lower circulating levels in the PAD patients compared to non-PAD patients (P < 0.001). Decreasing adiponectin concentration was associated with increasing serum levels of fetuin-A in the PAD patients. None of the investigated adiponectin SNPs proved to be associated with the subjects' susceptibility to PAD (P > 0.05). Conclusion. The results of our study demonstrated that neither adiponectin SNP+45 nor SNP+276 is associated with the risk of PAD. PMID:23819115

  11. High throughput SNP discovery and validation in the pig: towards the development of a high density swine SNP chip

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Recent developments in sequencing technology have allowed the generation of millions of short read sequences in a fast and inexpensive way. This enables the cost effective large scale identification of hundreds of thousands of SNPs needed for the development of high density SNP arrays. Currently, a ...

  12. Large-Scale SNP Discovery through RNA Sequencing and SNP Genotyping by Targeted Enrichment Sequencing in Cassava (Manihot esculenta Crantz)

    PubMed Central

    Pootakham, Wirulda; Shearman, Jeremy R.; Ruang-areerate, Panthita; Sonthirod, Chutima; Sangsrakru, Duangjai; Jomchai, Nukoon; Yoocha, Thippawan; Triwitayakorn, Kanokporn; Tragoonrung, Somvong; Tangphatsornruang, Sithichoke

    2014-01-01

    Cassava (Manihot esculenta Crantz) is one of the most important crop species being the main source of dietary energy in several countries. Marker-assisted selection has become an essential tool in plant breeding. Single nucleotide polymorphism (SNP) discovery via transcriptome sequencing is an attractive strategy for genome complexity reduction in organisms with large genomes. We sequenced the transcriptome of 16 cassava accessions using the Illumina HiSeq platform and identified 675,559 EST-derived SNP markers. A subset of those markers was subsequently genotyped by capture-based targeted enrichment sequencing in 100 F1 progeny segregating for starch viscosity phenotypes. A total of 2,110 non-redundant SNP markers were used to construct a genetic map. This map encompasses 1,785 cM and consists of 19 linkage groups. A major quantitative trait locus (QTL) controlling starch pasting properties was identified and shown to coincide with the QTL previously reported for this trait. With a high-density SNP-based linkage map presented here, we also uncovered a novel QTL associated with starch pasting time on LG 10. PMID:25551642

  13. Regulation of the seasonal leptin and leptin receptor expression profile during early sexual maturation and feed restriction in male Atlantic salmon, Salmo salar L., parr.

    PubMed

    Trombley, Susanne; Mustafa, Arshi; Schmitz, Monika

    2014-08-01

    In mammals, leptin acts as an adiposity signal and is a crucial link between nutritional status and the reproductive axis. So far the link between leptin and energy balance during sexual maturation in teleosts has been poorly investigated. In this study, seasonal gene expression changes in two leptin genes (lepa1 and lepa2) and the leptin receptor were investigated during early sexual maturation in male Atlantic salmon parr under fully fed (control) and feed restricted conditions from April through September. Both Atlantic salmon lepa1 and lepa2 in the liver and lepr in the brain were significantly down-regulated in non-maturing control males in early spring, coinciding with the start of the growth and fat accumulation. In maturing control males, hepatic leptin expression increased during mid-spermatogenesis and lepa1 and lepa2 mRNA levels were up-regulated by 7.7 and 49 times respectively during final maturation. For the first time in a fish species, a significant up-regulation of lepr expression was observed in the testis throughout mid to late spermatogenesis. Feed restriction decreased the incidence of sexual maturation by 53% and highly up-regulated both leptin genes in the liver and the leptin receptor in the pituitary. This study shows that hepatic lepa1 and lepa2 expression and lepr expression in the testis is affected by early sexual maturation in male Atlantic salmon parr. Fast growth and high fat stores are associated with low leptin levels while feed restriction has a stimulatory effect on hepatic leptin and leptin receptor gene expression in the pituitary, suggesting a role for leptin other than that as an adiposity signal. PMID:24818969

  14. High-throughput SNP genotyping for breeding applications in rice using the BeadXpress platform

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Multiplexed single nucleotide polymorphism (SNP) markers have the potential to increase the speed and cost-effectiveness of genotyping, provided that an optimal SNP density is used for each application. To test the efficiency of multiplexed SNP genotyping for diversity, mapping and breeding applicat...

  15. Multiple SNP Set Analysis for Genome-Wide Association Studies Through Bayesian Latent Variable Selection.

    PubMed

    Lu, Zhao-Hua; Zhu, Hongtu; Knickmeyer, Rebecca C; Sullivan, Patrick F; Williams, Stephanie N; Zou, Fei

    2015-12-01

    The power of genome-wide association studies (GWAS) for mapping complex traits with single-SNP analysis (where SNP is single-nucleotide polymorphism) may be undermined by modest SNP effect sizes, unobserved causal SNPs, correlation among adjacent SNPs, and SNP-SNP interactions. Alternative approaches for testing the association between a single SNP set and individual phenotypes have been shown to be promising for improving the power of GWAS. We propose a Bayesian latent variable selection (BLVS) method to simultaneously model the joint association mapping between a large number of SNP sets and complex traits. Compared with single SNP set analysis, such joint association mapping not only accounts for the correlation among SNP sets but also is capable of detecting causal SNP sets that are marginally uncorrelated with traits. The spike-and-slab prior assigned to the effects of SNP sets can greatly reduce the dimension of effective SNP sets, while speeding up computation. An efficient Markov chain Monte Carlo algorithm is developed. Simulations demonstrate that BLVS outperforms several competing variable selection methods in some important scenarios. PMID:26515609

  16. The development and characterization of a 57K SNP array for rainbow trout

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In this paper we describe the development and characterization of the first high density single nucleotide polymorphism (SNP) genotyping array for rainbow trout. The SNP array is publically available from a commercial vendor. The SNP genotyping quality was high and validation rate was close to 90%...

  17. Development of Single Nucleotide Polymorphism (SNP) Markers for Use in Commercial Maize (Zea Mays L.) Germplasm

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The development of single nucleotide polymorphism (SNP) markers in maize offer the opportunity to utilize DNA markers in many new areas of population genetics, gene discovery, plant breeding, and germplasm identification. However, the steps from sequencing and SNP discovery to SNP marker design and ...

  18. Influence of MDM2 SNP309 and SNP285 status on the risk of cancer in the breast, prostate, lung and colon.

    PubMed

    Gansmo, Liv B; Knappskog, Stian; Romundstad, Pål; Hveem, Kristian; Vatten, Lars; Lønning, Per E

    2015-07-01

    MDM2 is a key regulator of the p53 tumor suppressor protein and is overexpressed in many human cancers. Two single nucleotide polymorphisms (SNPs) located in the MDM2 intronic promoter (P2) have been found to exert biological function. The G-allele of SNP309T>G; rs2279744 increases MDM2 transcription and has been linked to increased cancer risk. In contrast, the less frequent SNP285G>C; rs117039649, which is in complete linkage disequilibrium with SNP309 (generating a SNP285C/309G variant haplotype), has been related to reduced MDM2 transcription and to reduced risk of breast, endometrial and ovarian cancer. In this large population-based case-control study, we genotyped SNP309 and SNP285 in 10,830 individuals, including cases with cancer of the breast (n=1,717), colon (n=1,532), lung (n=1,331) and prostate (n=2,501), as well as 3,749 non-cancer controls. We found a slightly reduced risk for lung cancer among individuals harboring the SNP309TG/GG genotypes compared to the SNP309TT genotype (OR= 0.86; CI = 0.67-0.98), but this association was restricted to women (OR = 0.77; CI = 0.63-0.95) and was not present among men (OR = 0.91; CI = 0.77-1.08). Consistent with previous findings, we found a reduced risk for breast cancer among individuals carrying the SNP285GC/309GG genotype versus the SNP285GG/309GG genotype (OR = 0.55; CI = 0.33-0.93). In conclusion, our data support the hypothesis that the effects of both SNP285 and SNP309 status are tissue dependent. PMID:25431177

  19. SNP analysis of follistatin gene associated with polycystic ovarian syndrome

    PubMed Central

    Panneerselvam, Palanisamy; Sivakumari, Kanakarajan; Jayaprakash, Ponmani; Srikanth, Ramanathan

    2010-01-01

    Follistatin has been reported as a candidate gene for polycystic ovarian syndrome (PCOS) based on linkage and association studies. In this study, investigation of polymorphisms in the FST gene was done to determine if genetic variation is associated with susceptibility to PCOS. The nucleotide sequence of human follistatin and the protein sequence of human follistatin were retrieved from the NCBI database using Entrez. The follistatin protein of human was retrieved from the Swiss-Prot database. There are 344 amino acids and the molecular weight is 38,007 Da. The ProtParam analysis shows that the isoelectric point is 5.53 and the aliphatic index is 61.25. The hydropathicity is −0.490. The domains in FST protein are as follows: Pfam-B 5005 domain from 1 to 92; EGF-like subdomain from 93 to 116; Kazal 1 domain, occurred in three places, namely, 118–164, 192–239, and 270–316. There are 31 single-nucleotide polymorphisms (SNPs) for this gene. Some are nonsynonymous, some occur in the intron region, and some in an untranslated region. Two nonsynonymous SNPs, namely, rs11745088 and rs1127760, were taken for analysis. In the SNP rs11745088, the change is E152Q. Likewise, in rs1127760, the change is C239S. SIFT (Sorting Intolerant from Tolerant) showed positions of amino acids and the single letter code of amino acids that can be tolerated or deleterious for each position. There were six SNP results and each result had links to it. The dbSNP id, primary database id, and the type of mutation whether silent and if occurring in coding region are given as phenotype alterations. The FASTA format of protein was given to the nsSNP Analyzer tool, and the variation E152Q and C239S were given as inputs in the SNP data field. E152Q change was neutral and C239S causes disease. Using PANTHER for evolutionary analysis of coding SNPs, the protein sequence was given as input and analyzed for the E152Q and C239S SNPs for deleterious effect on protein function. The genetic association

  20. SNP analysis of follistatin gene associated with polycystic ovarian syndrome.

    PubMed

    Panneerselvam, Palanisamy; Sivakumari, Kanakarajan; Jayaprakash, Ponmani; Srikanth, Ramanathan

    2010-01-01

    Follistatin has been reported as a candidate gene for polycystic ovarian syndrome (PCOS) based on linkage and association studies. In this study, investigation of polymorphisms in the FST gene was done to determine if genetic variation is associated with susceptibility to PCOS. The nucleotide sequence of human follistatin and the protein sequence of human follistatin were retrieved from the NCBI database using Entrez. The follistatin protein of human was retrieved from the Swiss-Prot database. There are 344 amino acids and the molecular weight is 38,007 Da. The ProtParam analysis shows that the isoelectric point is 5.53 and the aliphatic index is 61.25. The hydropathicity is -0.490. The domains in FST protein are as follows: Pfam-B 5005 domain from 1 to 92; EGF-like subdomain from 93 to 116; Kazal 1 domain, occurred in three places, namely, 118-164, 192-239, and 270-316. There are 31 single-nucleotide polymorphisms (SNPs) for this gene. Some are nonsynonymous, some occur in the intron region, and some in an untranslated region. Two nonsynonymous SNPs, namely, rs11745088 and rs1127760, were taken for analysis. In the SNP rs11745088, the change is E152Q. Likewise, in rs1127760, the change is C239S. SIFT (Sorting Intolerant from Tolerant) showed positions of amino acids and the single letter code of amino acids that can be tolerated or deleterious for each position. There were six SNP results and each result had links to it. The dbSNP id, primary database id, and the type of mutation whether silent and if occurring in coding region are given as phenotype alterations. The FASTA format of protein was given to the nsSNP Analyzer tool, and the variation E152Q and C239S were given as inputs in the SNP data field. E152Q change was neutral and C239S causes disease. Using PANTHER for evolutionary analysis of coding SNPs, the protein sequence was given as input and analyzed for the E152Q and C239S SNPs for deleterious effect on protein function. The genetic association

  1. Investigating single nucleotide polymorphism (SNP) density in the human genome and its implications for molecular evolution.

    PubMed

    Zhao, Zhongming; Fu, Yun-Xin; Hewett-Emmett, David; Boerwinkle, Eric

    2003-07-17

    We investigated the single nucleotide polymorphism (SNP) density across the human genome and in different genic categories using two SNP databases: Celera's CgsSNP, which includes SNPs identified by comparing genomic sequences, and Celera's RefSNP, which includes SNPs from a variety of sources and is biased toward disease-associated genes. Based on CgsSNP, the average numbers of SNPs per 10 kb was 8.33, 8.44, and 8.09 in the human genome, in intergenic regions, and in genic regions, respectively. In genic regions, the SNP density in intronic, exonic and adjoining untranslated regions was 8.21, 5.28, and 7.51 SNPs per 10 kb, respectively. The pattern of SNP density based on RefSNP was different from that based on CgsSNP, emphasizing its utility for genotype-phenotype association studies but not for most population genetic studies. The number of SNPs per chromosome was correlated with chromosome length, but the density of SNPs estimated by CgsSNP was not significantly correlated with the GC content of the chromosome. Based on CgsSNP, the ratio of nonsense to missense mutations (0.027), the ratio of missense to silent mutations (1.15), and the ratio of non-synonymous to synonymous mutations (1.18) was less than half of that expected in a human protein coding sequence under the neutral mutation theory, reflecting a role for natural selection, especially purifying selection. PMID:12909357

  2. Multiple SNP-sets Analysis for Genome-wide Association Studies through Bayesian Latent Variable Selection

    PubMed Central

    Lu, Zhaohua; Zhu, Hongtu; Knickmeyer, Rebecca C; Sullivan, Patrick F.; Stephanie, Williams N.; Zou, Fei

    2015-01-01

    The power of genome-wide association studies (GWAS) for mapping complex traits with single SNP analysis may be undermined by modest SNP effect sizes, unobserved causal SNPs, correlation among adjacent SNPs, and SNP-SNP interactions. Alternative approaches for testing the association between a single SNP-set and individual phenotypes have been shown to be promising for improving the power of GWAS. We propose a Bayesian latent variable selection (BLVS) method to simultaneously model the joint association mapping between a large number of SNP-sets and complex traits. Compared to single SNP-set analysis, such joint association mapping not only accounts for the correlation among SNP-sets, but also is capable of detecting causal SNP-sets that are marginally uncorrelated with traits. The spike-slab prior assigned to the effects of SNP-sets can greatly reduce the dimension of effective SNP-sets, while speeding up computation. An efficient MCMC algorithm is developed. Simulations demonstrate that BLVS outperforms several competing variable selection methods in some important scenarios. PMID:26515609

  3. Introgression browser: high-throughput whole-genome SNP visualization.

    PubMed

    Aflitos, Saulo Alves; Sanchez-Perez, Gabino; de Ridder, Dick; Fransz, Paul; Schranz, Michael E; de Jong, Hans; Peters, Sander A

    2015-04-01

    Breeding by introgressive hybridization is a pivotal strategy to broaden the genetic basis of crops. Usually, the desired traits are monitored in consecutive crossing generations by marker-assisted selection, but their analyses fail in chromosome regions where crossover recombinants are rare or not viable. Here, we present the Introgression Browser (iBrowser), a bioinformatics tool aimed at visualizing introgressions at nucleotide or SNP (Single Nucleotide Polymorphisms) accuracy. The software selects homozygous SNPs from Variant Call Format (VCF) information and filters out heterozygous SNPs, multi-nucleotide polymorphisms (MNPs) and insertion-deletions (InDels). For data analysis iBrowser makes use of sliding windows, but if needed it can generate any desired fragmentation pattern through General Feature Format (GFF) information. In an example of tomato (Solanum lycopersicum) accessions we visualize SNP patterns and elucidate both position and boundaries of the introgressions. We also show that our tool is capable of identifying alien DNA in a panel of the closely related S. pimpinellifolium by examining phylogenetic relationships of the introgressed segments in tomato. In a third example, we demonstrate the power of the iBrowser in a panel of 597 Arabidopsis accessions, detecting the boundaries of a SNP-free region around a polymorphic 1.17 Mbp inverted segment on the short arm of chromosome 4. The architecture and functionality of iBrowser makes the software appropriate for a broad set of analyses including SNP mining, genome structure analysis, and pedigree analysis. Its functionality, together with the capability to process large data sets and efficient visualization of sequence variation, makes iBrowser a valuable breeding tool. PMID:25704554

  4. Detection of homologous horizontal gene transfer in SNP data

    Energy Science and Technology Software Center (ESTSC)

    2012-07-23

    We study the detection of mutations, sequencing errors, and homologous horizontal gene transfers (HGT) in a set of closely related microbial genomes. We base the model on single nucleotide polymorphisms (SNP's) and break the genomes into blocks to handle the rearrangement problem. Then we apply a synamic programming algorithm to model whether changes within each block are likely a result of mutations, sequencing errors, or HGT.

  5. Genetic heterogeneity in rhabdomyosarcoma revealed by SNP array analysis.

    PubMed

    Walther, Charles; Mayrhofer, Markus; Nilsson, Jenny; Hofvander, Jakob; Jonson, Tord; Mandahl, Nils; Øra, Ingrid; Gisselsson, David; Mertens, Fredrik

    2016-01-01

    Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents. Alveolar (ARMS) and embryonal (ERMS) histologies predominate, but rare cases are classified as spindle cell/sclerosing (SRMS). For treatment stratification, RMS is further subclassified as fusion-positive (FP-RMS) or fusion-negative (FN-RMS), depending on whether a gene fusion involving PAX3 or PAX7 is present or not. We investigated 19 cases of pediatric RMS using high resolution single-nucleotide polymorphism (SNP) array. FP-ARMS displayed, on average, more structural rearrangements than ERMS; the single FN-ARMS had a genomic profile similar to ERMS. Apart from previously known amplification (e.g., MYCN, CDK4, and MIR17HG) and deletion (e.g., NF1, CDKN2A, and CDKN2B) targets, amplification of ERBB2 and homozygous loss of ASCC3 or ODZ3 were seen. Combining SNP array with cytogenetic data revealed that most cases were polyploid, with at least one case having started as a near-haploid tumor. Further bioinformatic analysis of the SNP array data disclosed genetic heterogeneity, in the form of subclonal chromosomal imbalances, in five tumors. The outcome was worse for patients with FP-ARMS than ERMS or FN-ARMS (6/8 vs. 1/9 dead of disease), and the only children with ERMS showing intratumor diversity or with MYOD1 mutation-positive SRMS also died of disease. High resolution SNP array can be useful in evaluating genomic imbalances in pediatric RMS. PMID:26482321

  6. Robust Demographic Inference from Genomic and SNP Data

    PubMed Central

    Excoffier, Laurent; Dupanloup, Isabelle; Huerta-Sánchez, Emilia; Sousa, Vitor C.; Foll, Matthieu

    2013-01-01

    We introduce a flexible and robust simulation-based framework to infer demographic parameters from the site frequency spectrum (SFS) computed on large genomic datasets. We show that our composite-likelihood approach allows one to study evolutionary models of arbitrary complexity, which cannot be tackled by other current likelihood-based methods. For simple scenarios, our approach compares favorably in terms of accuracy and speed with , the current reference in the field, while showing better convergence properties for complex models. We first apply our methodology to non-coding genomic SNP data from four human populations. To infer their demographic history, we compare neutral evolutionary models of increasing complexity, including unsampled populations. We further show the versatility of our framework by extending it to the inference of demographic parameters from SNP chips with known ascertainment, such as that recently released by Affymetrix to study human origins. Whereas previous ways of handling ascertained SNPs were either restricted to a single population or only allowed the inference of divergence time between a pair of populations, our framework can correctly infer parameters of more complex models including the divergence of several populations, bottlenecks and migration. We apply this approach to the reconstruction of African demography using two distinct ascertained human SNP panels studied under two evolutionary models. The two SNP panels lead to globally very similar estimates and confidence intervals, and suggest an ancient divergence (>110 Ky) between Yoruba and San populations. Our methodology appears well suited to the study of complex scenarios from large genomic data sets. PMID:24204310

  7. PanSNPdb: The Pan-Asian SNP Genotyping Database

    PubMed Central

    Ngamphiw, Chumpol; Assawamakin, Anunchai; Xu, Shuhua; Shaw, Philip J.; Yang, Jin Ok; Ghang, Ho; Bhak, Jong; Liu, Edison; Tongsima, Sissades

    2011-01-01

    The HUGO Pan-Asian SNP consortium conducted the largest survey to date of human genetic diversity among Asians by sampling 1,719 unrelated individuals among 71 populations from China, India, Indonesia, Japan, Malaysia, the Philippines, Singapore, South Korea, Taiwan, and Thailand. We have constructed a database (PanSNPdb), which contains these data and various new analyses of them. PanSNPdb is a research resource in the analysis of the population structure of Asian peoples, including linkage disequilibrium patterns, haplotype distributions, and copy number variations. Furthermore, PanSNPdb provides an interactive comparison with other SNP and CNV databases, including HapMap3, JSNP, dbSNP and DGV and thus provides a comprehensive resource of human genetic diversity. The information is accessible via a widely accepted graphical interface used in many genetic variation databases. Unrestricted access to PanSNPdb and any associated files is available at: http://www4a.biotec.or.th/PASNP. PMID:21731755

  8. Development of a forensic identity SNP panel for Indonesia.

    PubMed

    Augustinus, Daniel; Gahan, Michelle E; McNevin, Dennis

    2015-07-01

    Genetic markers included in forensic identity panels must exhibit Hardy-Weinberg and linkage equilibrium (HWE and LE). "Universal" panels designed for global use can fail these tests in regional jurisdictions exhibiting high levels of genetic differentiation such as the Indonesian archipelago. This is especially the case where a single DNA database is required for allele frequency estimates to calculate random match probabilities (RMPs) and associated likelihood ratios (LRs). A panel of 65 single nucleotide polymorphisms (SNPs) and a reduced set of 52 SNPs have been selected from 15 Indonesian subpopulations in the HUGO Pan Asian SNP database using a SNP selection strategy that could be applied to any panel of forensic identity markers. The strategy consists of four screening steps: (1) application of a G test for HWE; (2) ranking for high heterozygosity; (3) selection for LE; and (4) selection for low inbreeding depression. SNPs in our Indonesian panel perform well in comparison to some other universal SNP and short tandem repeat (STR) panels as measured by Fisher's exact test for HWE and LE and Wright's F statistics. PMID:25104323

  9. Multiplex Detection and SNP Genotyping in a Single Fluorescence Channel

    PubMed Central

    Fu, Guoliang; Miles, Andrea; Alphey, Luke

    2012-01-01

    Probe-based PCR is widely used for SNP (single nucleotide polymorphism) genotyping and pathogen nucleic acid detection due to its simplicity, sensitivity and cost-effectiveness. However, the multiplex capability of hydrolysis probe-based PCR is normally limited to one target (pathogen or allele) per fluorescence channel. Current fluorescence PCR machines typically have 4–6 channels. We present a strategy permitting the multiplex detection of multiple targets in a single detection channel. The technique is named Multiplex Probe Amplification (MPA). Polymorphisms of the CYP2C9 gene (cytochrome P450, family 2, subfamily C, polypeptide 9, CYP2C9*2) and human papillomavirus sequences HPV16, 18, 31, 52 and 59 were chosen as model targets for testing MPA. The allele status of the CYP2C9*2 determined by MPA was entirely concordant with the reference TaqMan® SNP Genotyping Assays. The four HPV strain sequences could be independently detected in a single fluorescence detection channel. The results validate the multiplex capacity, the simplicity and accuracy of MPA for SNP genotyping and multiplex detection using different probes labeled with the same fluorophore. The technique offers a new way to multiplex in a single detection channel of a closed-tube PCR. PMID:22272339

  10. Multiplex detection and SNP genotyping in a single fluorescence channel.

    PubMed

    Fu, Guoliang; Miles, Andrea; Alphey, Luke

    2012-01-01

    Probe-based PCR is widely used for SNP (single nucleotide polymorphism) genotyping and pathogen nucleic acid detection due to its simplicity, sensitivity and cost-effectiveness. However, the multiplex capability of hydrolysis probe-based PCR is normally limited to one target (pathogen or allele) per fluorescence channel. Current fluorescence PCR machines typically have 4-6 channels. We present a strategy permitting the multiplex detection of multiple targets in a single detection channel. The technique is named Multiplex Probe Amplification (MPA). Polymorphisms of the CYP2C9 gene (cytochrome P450, family 2, subfamily C, polypeptide 9, CYP2C9*2) and human papillomavirus sequences HPV16, 18, 31, 52 and 59 were chosen as model targets for testing MPA. The allele status of the CYP2C9*2 determined by MPA was entirely concordant with the reference TaqMan® SNP Genotyping Assays. The four HPV strain sequences could be independently detected in a single fluorescence detection channel. The results validate the multiplex capacity, the simplicity and accuracy of MPA for SNP genotyping and multiplex detection using different probes labeled with the same fluorophore. The technique offers a new way to multiplex in a single detection channel of a closed-tube PCR. PMID:22272339

  11. How far from the SNP may the causative genes be?

    PubMed

    Brodie, Aharon; Azaria, Johnathan Roy; Ofran, Yanay

    2016-07-27

    While GWAS identify many disease-associated SNPs, using them to decipher disease mechanisms is hindered by the difficulty in mapping SNPs to genes. Most SNPs are in non-coding regions and it is often hard to identify the genes they implicate. To explore how far the SNP may be from the affected genes we used a pathway-based approach. We found that affected genes are often up to 2 Mbps away from the associated SNP, and are not necessarily the closest genes to the SNP. Existing approaches for mapping SNPs to genes leave many SNPs unmapped to genes and reveal only 86 significant phenotype-pathway associations for all known GWAS hits combined. Using the pathway-based approach we propose here allows mapping of virtually all SNPs to genes and reveals 435 statistically significant phenotype-pathway associations. In search for mechanisms that may explain the relationships between SNPs and distant genes, we found that SNPs that are mapped to distant genes have significantly more large insertions/deletions around them than other SNPs, suggesting that these SNPs may sometimes be markers for large insertions/deletions that may affect large genomic regions. PMID:27269582

  12. Population distribution and ancestry of the cancer protective MDM2 SNP285 (rs117039649).

    PubMed

    Knappskog, Stian; Gansmo, Liv B; Dibirova, Khadizha; Metspalu, Andres; Cybulski, Cezary; Peterlongo, Paolo; Aaltonen, Lauri; Vatten, Lars; Romundstad, Pål; Hveem, Kristian; Devilee, Peter; Evans, Gareth D; Lin, Dongxin; Van Camp, Guy; Manolopoulos, Vangelis G; Osorio, Ana; Milani, Lili; Ozcelik, Tayfun; Zalloua, Pierre; Mouzaya, Francis; Bliznetz, Elena; Balanovska, Elena; Pocheshkova, Elvira; Kučinskas, Vaidutis; Atramentova, Lubov; Nymadawa, Pagbajabyn; Titov, Konstantin; Lavryashina, Maria; Yusupov, Yuldash; Bogdanova, Natalia; Koshel, Sergey; Zamora, Jorge; Wedge, David C; Charlesworth, Deborah; Dörk, Thilo; Balanovsky, Oleg; Lønning, Per E

    2014-09-30

    The MDM2 promoter SNP285C is located on the SNP309G allele. While SNP309G enhances Sp1 transcription factor binding and MDM2 transcription, SNP285C antagonizes Sp1 binding and reduces the risk of breast-, ovary- and endometrial cancer. Assessing SNP285 and 309 genotypes across 25 different ethnic populations (>10.000 individuals), the incidence of SNP285C was 6-8% across European populations except for Finns (1.2%) and Saami (0.3%). The incidence decreased towards the Middle-East and Eastern Russia, and SNP285C was absent among Han Chinese, Mongolians and African Americans. Interhaplotype variation analyses estimated SNP285C to have originated about 14,700 years ago (95% CI: 8,300 - 33,300). Both this estimate and the geographical distribution suggest SNP285C to have arisen after the separation between Caucasians and modern day East Asians (17,000 - 40,000 years ago). We observed a strong inverse correlation (r = -0.805; p < 0.001) between the percentage of SNP309G alleles harboring SNP285C and the MAF for SNP309G itself across different populations suggesting selection and environmental adaptation with respect to MDM2 expression in recent human evolution. In conclusion, we found SNP285C to be a pan-Caucasian variant. Ethnic variation regarding distribution of SNP285C needs to be taken into account when assessing the impact of MDM2 SNPs on cancer risk. PMID:25327560

  13. Population distribution and ancestry of the cancer protective MDM2 SNP285 (rs117039649)

    PubMed Central

    Knappskog, Stian; Gansmo, Liv B.; Dibirova, Khadizha; Metspalu, Andres; Cybulski, Cezary; Peterlongo, Paolo; Aaltonen, Lauri; Vatten, Lars; Romundstad, Pål; Hveem, Kristian; Devilee, Peter; Evans, Gareth D.; Lin, Dongxin; Camp, Guy Van; Manolopoulos, Vangelis G.; Osorio, Ana; Milani, Lili; Ozcelik, Tayfun; Zalloua, Pierre; Mouzaya, Francis; Bliznetz, Elena; Balanovska, Elena; Pocheshkova, Elvira; Kučinskas, Vaidutis; Atramentova, Lubov; Nymadawa, Pagbajabyn; Titov, Konstantin; Lavryashina, Maria; Yusupov, Yuldash; Bogdanova, Natalia; Koshel, Sergey; Zamora, Jorge; Wedge, David C.; Charlesworth, Deborah; Dörk, Thilo; Balanovsky, Oleg; Lønning, Per E.

    2014-01-01

    The MDM2 promoter SNP285C is located on the SNP309G allele. While SNP309G enhances Sp1 transcription factor binding and MDM2 transcription, SNP285C antagonizes Sp1 binding and reduces the risk of breast-, ovary- and endometrial cancer. Assessing SNP285 and 309 genotypes across 25 different ethnic populations (>10.000 individuals), the incidence of SNP285C was 6-8% across European populations except for Finns (1.2%) and Saami (0.3%). The incidence decreased towards the Middle-East and Eastern Russia, and SNP285C was absent among Han Chinese, Mongolians and African Americans. Interhaplotype variation analyses estimated SNP285C to have originated about 14,700 years ago (95% CI: 8,300 – 33,300). Both this estimate and the geographical distribution suggest SNP285C to have arisen after the separation between Caucasians and modern day East Asians (17,000 - 40,000 years ago). We observed a strong inverse correlation (r = -0.805; p < 0.001) between the percentage of SNP309G alleles harboring SNP285C and the MAF for SNP309G itself across different populations suggesting selection and environmental adaptation with respect to MDM2 expression in recent human evolution. In conclusion, we found SNP285C to be a pan-Caucasian variant. Ethnic variation regarding distribution of SNP285C needs to be taken into account when assessing the impact of MDM2 SNPs on cancer risk. PMID:25327560

  14. Mouse SNP Miner: an annotated database of mouse functional single nucleotide polymorphisms

    PubMed Central

    Reuveni, Eli; Ramensky, Vasily E; Gross, Cornelius

    2007-01-01

    Background The mapping of quantitative trait loci in rat and mouse has been extremely successful in identifying chromosomal regions associated with human disease-related phenotypes. However, identifying the specific phenotype-causing DNA sequence variations within a quantitative trait locus has been much more difficult. The recent availability of genomic sequence from several mouse inbred strains (including C57BL/6J, 129X1/SvJ, 129S1/SvImJ, A/J, and DBA/2J) has made it possible to catalog DNA sequence differences within a quantitative trait locus derived from crosses between these strains. However, even for well-defined quantitative trait loci (<10 Mb) the identification of candidate functional DNA sequence changes remains challenging due to the high density of sequence variation between strains. Description To help identify functional DNA sequence variations within quantitative trait loci we have used the Ensembl annotated genome sequence to compile a database of mouse single nucleotide polymorphisms (SNPs) that are predicted to cause missense, nonsense, frameshift, or splice site mutations (available at ). For missense mutations we have used the PolyPhen and PANTHER algorithms to predict whether amino acid changes are likely to disrupt protein function. Conclusion We have developed a database of mouse SNPs predicted to cause missense, nonsense, frameshift, and splice-site mutations. Our analysis revealed that 20% and 14% of missense SNPs are likely to be deleterious according to PolyPhen and PANTHER, respectively, and 6% are considered deleterious by both algorithms. The database also provides gene expression and functional annotations from the Symatlas, Gene Ontology, and OMIM databases to further assess candidate phenotype-causing mutations. To demonstrate its utility, we show that Mouse SNP Miner successfully finds a previously identified candidate SNP in the taste receptor, Tas1r3, that underlies sucrose preference in the C57BL/6J strain. We also use Mouse

  15. No evidence that GATA3 rs570613 SNP modifies breast cancer risk

    PubMed Central

    Johnatty, Sharon E.; Couch, Fergus J.; Fredericksen, Zachary; Tarrell, Robert; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Gschwantler-Kaulich, Daphne; Singer, Christian F.; Fuerhauser, Christine; Fink-Retter, Anneliese; Domchek, Susan M.; Nathanson, Katherine L.; Pankratz, Vernon S.; Lindor, Noralane M.; Godwin, Andrew K.; Caligo, Maria A.; Hopper, John; Southey, Melissa C.; Giles, Graham G.; Justenhoven, Christina; Brauch, Hiltrud; Hamann, Ute; Ko, Yon-Dschun; Heikkinen, Tuomas; Aaltonen, Kirsimari; Aittomäki, Kristiina; Blomqvist, Carl; Nevanlinna, Heli; Hall, Per; Czene, Kamila; Liu, Jianjun; Peock, Susan; Cook, Margaret; Platte, Radka; Evans, D. Gareth; Lalloo, Fiona; Eeles, Rosalind; Pichert, Gabriella; Eccles, Diana; Davidson, Rosemarie; Cole, Trevor; Cook, Jackie; Douglas, Fiona; Chu, Carol; Hodgson, Shirley; Paterson, Joan; Hogervorst, Frans B.L.; Rookus, Matti A.; Seynaeve, Caroline; Wijnen, Juul; Vreeswijk, Maaike; Ligtenberg, Marjolijn; Luijt, Rob B. van der; van Os, Theo A.M.; Gille, Hans J.P.; Blok, Marinus J.; Issacs, Claudine; Humphreys, Manjeet K.; McGuffog, Lesley; Healey, Sue; Sinilnikova, Olga; Antoniou, Antonis C.; Easton, Douglas F.; Chenevix-Trench, Georgia

    2009-01-01

    GATA-binding protein 3 (GATA3) is a transcription factor that is crucial to mammary gland morphogenesis and differentiation of progenitor cells, and has been suggested to have a tumor suppressor function. The rs570613 single nucleotide polymorphism (SNP) in intron 4 of GATA3 was previously found to be associated with a reduction in breast cancer risk in the Cancer Genetic Markers of Susceptibility project and in pooled analysis of two case-control studies from Norway and Poland (Ptrend =0.004), with some evidence for a stronger association with estrogen receptor (ER) negative tumours [1]. We genotyped GATA3 rs570613 in 6,388 cases and 4,995 controls from the Breast Cancer Association Consortium (BCAC) and 5,617 BRCA1 and BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). We found no association between this SNP and breast cancer risk in BCAC cases overall (ORper-allele = 1.00, 95% CI 0.94 − 1.05), in ER negative BCAC cases (ORper-allele = 1.02, 95% CI 0.91−1.13), in BRCA1 mutation carriers RRper-allele = 0.99, 95% CI 0.90−1.09) or BRCA2 mutation carriers (RRper-allele = 0.93, 95% CI 0.80−1.07). We conclude that there is no evidence that either GATA3 rs570613, or any variant in strong linkage disequilibrium with it, is associated with breast cancer risk in women. PMID:19082709

  16. Exploration of SNP variants affecting hair colour prediction in Europeans.

    PubMed

    Söchtig, Jens; Phillips, Chris; Maroñas, Olalla; Gómez-Tato, Antonio; Cruz, Raquel; Alvarez-Dios, Jose; de Cal, María-Ángeles Casares; Ruiz, Yarimar; Reich, Kristian; Fondevila, Manuel; Carracedo, Ángel; Lareu, María V

    2015-09-01

    DNA profiling is a key tool for forensic analysis; however, current methods identify a suspect either by direct comparison or from DNA database searches. In cases with unidentified suspects, prediction of visible physical traits e.g. pigmentation or hair distribution of the DNA donors can provide important probative information. This study aimed to explore single nucleotide polymorphism (SNP) variants for their effect on hair colour prediction. A discovery panel of 63 SNPs consisting of already established hair colour markers from the HIrisPlex hair colour phenotyping assay as well as additional markers for which associations to human pigmentation traits were previously identified was used to develop multiplex assays based on SNaPshot single-base extension technology. A genotyping study was performed on a range of European populations (n = 605). Hair colour phenotyping was accomplished by matching donor's hair to a graded colour category system of reference shades and photography. Since multiple SNPs in combination contribute in varying degrees to hair colour predictability in Europeans, we aimed to compile a compact marker set that could provide a reliable hair colour inference from the fewest SNPs. The predictive approach developed uses a naïve Bayes classifier to provide hair colour assignment probabilities for the SNP profiles of the key SNPs and was embedded into the Snipper online SNP classifier ( http://mathgene.usc.es/snipper/ ). Results indicate that red, blond, brown and black hair colours are predictable with informative probabilities in a high proportion of cases. Our study resulted in the identification of 12 most strongly associated SNPs to hair pigmentation variation in six genes. PMID:26162598

  17. Computational tradeoffs in multiplex PCR assay design for SNP genotyping

    PubMed Central

    Rachlin, John; Ding, Chunming; Cantor, Charles; Kasif, Simon

    2005-01-01

    Background Multiplex PCR is a key technology for detecting infectious microorganisms, whole-genome sequencing, forensic analysis, and for enabling flexible yet low-cost genotyping. However, the design of a multiplex PCR assays requires the consideration of multiple competing objectives and physical constraints, and extensive computational analysis must be performed in order to identify the possible formation of primer-dimers that can negatively impact product yield. Results This paper examines the computational design limits of multiplex PCR in the context of SNP genotyping and examines tradeoffs associated with several key design factors including multiplexing level (the number of primer pairs per tube), coverage (the % of SNP whose associated primers are actually assigned to one of several available tube), and tube-size uniformity. We also examine how design performance depends on the total number of available SNPs from which to choose, and primer stringency criterial. We show that finding high-multiplexing/high-coverage designs is subject to a computational phase transition, becoming dramatically more difficult when the probability of primer pair interaction exceeds a critical threshold. The precise location of this critical transition point depends on the number of available SNPs and the level of multiplexing required. We also demonstrate how coverage performance is impacted by the number of available snps, primer selection criteria, and target multiplexing levels. Conclusion The presence of a phase transition suggests limits to scaling Multiplex PCR performance for high-throughput genomics applications. Achieving broad SNP coverage rapidly transitions from being very easy to very hard as the target multiplexing level (# of primer pairs per tube) increases. The onset of a phase transition can be "delayed" by having a larger pool of SNPs, or loosening primer selection constraints so as to increase the number of candidate primer pairs per SNP, though the latter

  18. Silica nanoparticles activate purinergic signaling via P2X7 receptor in dendritic cells, leading to production of pro-inflammatory cytokines.

    PubMed

    Nakanishi, Kana; Tsukimoto, Mitsutoshi; Tanuma, Sei-Ichi; Takeda, Ken; Kojima, Shuji

    2016-09-01

    We examined the mechanism of SNP-mediated stimulation of IL-1β and IL-18 production via P2R-mediated pathways in mouse bone marrow dendritic cells (mBMDCs). Examination of uptake of SNPs with diameters of 30, 70, and 300nm (SNP30, SNP70, and SNP300, respectively) by lipopolysaccharide-matured mBMDCs revealed that significant uptake of SNP30 occurred within as short a time as 1h. Production of IL-1β and IL-18 by cells exposed to SNPs increased dose-dependently, and was highest in cells exposed to SNP30. The SNP30-induced cytokine production was significantly inhibited by ATPase (apyrase) and by P2X7 receptor antagonist (A438079). ATP release was also highest in SNP30-exposed cells. Treatment of mBMDCs with exogenous ATP induced release of high levels of IL-1β and IL-18, and this release was also significantly inhibited by apyrase and A438079. The order of effectiveness of the three SNPs for inducing intracellular reactive oxygen species (ROS) production accorded well with those of cytokine production and ATP release. ROS production was inhibited by diphenyleneiodonium chloride (DPI). SNPs, especially SNP30, activate purinergic signaling in matured mBMDCs by inducing ATP release via P2X7 receptor. ATP induces ROS production via NADPH oxidase, and ROS activate inflammasomes, leading to caspase-1-dependent processing of pro-cytokines and release of IL-1β and IL-18. PMID:27311643

  19. QuantiSNP: an Objective Bayes Hidden-Markov Model to detect and accurately map copy number variation using SNP genotyping data.

    PubMed

    Colella, Stefano; Yau, Christopher; Taylor, Jennifer M; Mirza, Ghazala; Butler, Helen; Clouston, Penny; Bassett, Anne S; Seller, Anneke; Holmes, Christopher C; Ragoussis, Jiannis

    2007-01-01

    Array-based technologies have been used to detect chromosomal copy number changes (aneuploidies) in the human genome. Recent studies identified numerous copy number variants (CNV) and some are common polymorphisms that may contribute to disease susceptibility. We developed, and experimentally validated, a novel computational framework (QuantiSNP) for detecting regions of copy number variation from BeadArray SNP genotyping data using an Objective Bayes Hidden-Markov Model (OB-HMM). Objective Bayes measures are used to set certain hyperparameters in the priors using a novel re-sampling framework to calibrate the model to a fixed Type I (false positive) error rate. Other parameters are set via maximum marginal likelihood to prior training data of known structure. QuantiSNP provides probabilistic quantification of state classifications and significantly improves the accuracy of segmental aneuploidy identification and mapping, relative to existing analytical tools (Beadstudio, Illumina), as demonstrated by validation of breakpoint boundaries. QuantiSNP identified both novel and validated CNVs. QuantiSNP was developed using BeadArray SNP data but it can be adapted to other platforms and we believe that the OB-HMM framework has widespread applicability in genomic research. In conclusion, QuantiSNP is a novel algorithm for high-resolution CNV/aneuploidy detection with application to clinical genetics, cancer and disease association studies. PMID:17341461

  20. Prognostic significance of interleukin-6 single nucleotide polymorphism genotypes in neuroblastoma: rs1800795 (promoter) and rs8192284 (receptor)

    PubMed Central

    Lagmay, Joanne P.; London, Wendy B.; Gross, Thomas G.; Termuhlen, Amanda; Sullivan, Nicholas; Axel, Amy; Mundy, Bethany; Ranalli, Mark; Canner, Jason; McGrady, Patrick; Hall, Brett

    2009-01-01

    Purpose Neuroblastoma is a childhood cancer of the sympathetic nervous system and many patients present with high risk disease. Risk stratification, based on pathology and tumor-derived biomarkers, has improved prediction of clinical outcomes, but overall survival rates remain unfavorable and new therapeutic targets are needed. Some studies suggest a link between interleukin-6 and more aggressive behavior in neuroblastoma tumor cells. Therefore, we examined the impact of two IL-6 single nucleotide polymorphisms (SNP) on neuroblastoma disease progression. Experimental design DNA samples from 96 high risk neuroblastoma patients were screened for two SNP that are known to regulate the serum levels of IL-6 and the soluble IL-6 receptor (IL-6R), rs1800795 and rs8192284 respectively. The genotype for each SNP was determined in a blinded fashion and independent statistical analysis was performed to determine SNP-related event free survival (EFS) and overall survival (OS) rates. Results The rs1800795 IL-6 promoter SNP is an independent prognostic factor for EFS and OS in -high risk neuroblastoma patients. In contrast, the rs8192284 IL-6 receptor SNP revealed no prognostic value. Conclusions The rs1800795 SNP (-174 IL-6 (G>C) represents a novel and independent prognostic marker for both EFS and OS in high risk neuroblastoma. Since the rs1800795 SNP (-174 IL-6 (G>C) has been shown to correlate with production of IL-6, this cytokine may represent a target for development of new therapies in neuroblastoma. PMID:19671870

  1. PCR amplification of SNP loci from crude DNA for large-scale genotyping of oomycetes.

    PubMed

    Hu, Jian; Lyon, Rebecca; Zhou, Yuxin; Lamour, Kurt

    2014-01-01

    Similar to other eukaryotes, single nucleotide polymorphism (SNP) markers are abundant in many oomycete plant pathogen genomes. High resolution DNA melting analysis (HR-DMA) is a cost-effective method for SNP genotyping, but like many SNP marker technologies, is limited by the amount and quality of template DNA. We describe PCR preamplification of Phytophthora and Peronospora SNP loci from crude DNA extracted from a small amount of mycelium and/or infected plant tissue to produce sufficient template to genotype at least 10 000 SNPs. The approach is fast, inexpensive, requires minimal biological material and should be useful for many organisms in a variety of contexts. PMID:24871597

  2. Accuracy of direct genomic values in Holstein bulls and cows using subsets of SNP markers

    PubMed Central

    2010-01-01

    Background At the current price, the use of high-density single nucleotide polymorphisms (SNP) genotyping assays in genomic selection of dairy cattle is limited to applications involving elite sires and dams. The objective of this study was to evaluate the use of low-density assays to predict direct genomic value (DGV) on five milk production traits, an overall conformation trait, a survival index, and two profit index traits (APR, ASI). Methods Dense SNP genotypes were available for 42,576 SNP for 2,114 Holstein bulls and 510 cows. A subset of 1,847 bulls born between 1955 and 2004 was used as a training set to fit models with various sets of pre-selected SNP. A group of 297 bulls born between 2001 and 2004 and all cows born between 1992 and 2004 were used to evaluate the accuracy of DGV prediction. Ridge regression (RR) and partial least squares regression (PLSR) were used to derive prediction equations and to rank SNP based on the absolute value of the regression coefficients. Four alternative strategies were applied to select subset of SNP, namely: subsets of the highest ranked SNP for each individual trait, or a single subset of evenly spaced SNP, where SNP were selected based on their rank for ASI, APR or minor allele frequency within intervals of approximately equal length. Results RR and PLSR performed very similarly to predict DGV, with PLSR performing better for low-density assays and RR for higher-density SNP sets. When using all SNP, DGV predictions for production traits, which have a higher heritability, were more accurate (0.52-0.64) than for survival (0.19-0.20), which has a low heritability. The gain in accuracy using subsets that included the highest ranked SNP for each trait was marginal (5-6%) over a common set of evenly spaced SNP when at least 3,000 SNP were used. Subsets containing 3,000 SNP provided more than 90% of the accuracy that could be achieved with a high-density assay for cows, and 80% of the high-density assay for young bulls

  3. Lack of association between MDM2 promoter SNP309 and clinical outcome in patients with neuroblastoma.

    PubMed

    Rihani, Ali; Van Maerken, Tom; De Wilde, Bram; Zeka, Fjoralba; Laureys, Geneviève; Norga, Koen; Tonini, Gian Paolo; Coco, Simona; Versteeg, Rogier; Noguera, Rosa; Schulte, Johannes H; Eggert, Angelika; Stallings, Raymond L; Speleman, Frank; Vandesompele, Jo

    2014-10-01

    While a polymorphism located within the promoter region of the MDM2 proto-oncogene, SNP309 (T > G), has previously been associated with increased risk and aggressiveness of neuroblastoma and other tumor entities, a protective effect has also been reported in certain other cancers. In this study, we evaluated the association of MDM2 SNP309 with outcome in 496 patients with neuroblastoma and its effect on MDM2 expression. No significant difference in overall or event-free survival was observed among patients with neuroblastoma with or without MDM2 SNP309. The presence of SNP309 does not affect MDM2 expression in neuroblastoma. PMID:24391119

  4. Genome-wide SNP discovery in walnut with an AGSNP pipeline updated for SNP discovery in allogamous organisms

    PubMed Central

    2012-01-01

    Background A genome-wide set of single nucleotide polymorphisms (SNPs) is a valuable resource in genetic research and breeding and is usually developed by re-sequencing a genome. If a genome sequence is not available, an alternative strategy must be used. We previously reported the development of a pipeline (AGSNP) for genome-wide SNP discovery in coding sequences and other single-copy DNA without a complete genome sequence in self-pollinating (autogamous) plants. Here we updated this pipeline for SNP discovery in outcrossing (allogamous) species and demonstrated its efficacy in SNP discovery in walnut (Juglans regia L.). Results The first step in the original implementation of the AGSNP pipeline was the construction of a reference sequence and the identification of single-copy sequences in it. To identify single-copy sequences, multiple genome equivalents of short SOLiD reads of another individual were mapped to shallow genome coverage of long Sanger or Roche 454 reads making up the reference sequence. The relative depth of SOLiD reads was used to filter out repeated sequences from single-copy sequences in the reference sequence. The second step was a search for SNPs between SOLiD reads and the reference sequence. Polymorphism within the mapped SOLiD reads would have precluded SNP discovery; hence both individuals had to be homozygous. The AGSNP pipeline was updated here for using SOLiD or other type of short reads of a heterozygous individual for these two principal steps. A total of 32.6X walnut genome equivalents of SOLiD reads of vegetatively propagated walnut scion cultivar ‘Chandler’ were mapped to 48,661 ‘Chandler’ bacterial artificial chromosome (BAC) end sequences (BESs) produced by Sanger sequencing during the construction of a walnut physical map. A total of 22,799 putative SNPs were initially identified. A total of 6,000 Infinium II type SNPs evenly distributed along the walnut physical map were selected for the construction of an Infinium Bead

  5. RNASEL and MIR146A SNP-SNP Interaction as a Susceptibility Factor for Non-Melanoma Skin Cancer

    PubMed Central

    Farzan, Shohreh F.; Karagas, Margaret R.; Christensen, Brock C.; Li, Zhongze; Kuriger, Jacquelyn K.; Nelson, Heather H.

    2014-01-01

    Immunity and inflammatory pathways are important in the genesis of non-melanoma skin cancers (NMSC). Functional genetic variation in immune modulators has the potential to affect disease etiology. We investigated associations between common variants in two key regulators, MIR146A and RNASEL, and their relation to NMSCs. Using a large population-based case-control study of basal cell (BCC) and squamous cell carcinoma (SCC), we investigated the impact of MIR146A SNP rs2910164 on cancer risk, and interaction with a SNP in one of its putative targets (RNASEL, rs486907). To examine associations between genotype and BCC and SCC, occurrence odds ratios (OR) and 95% confidence intervals (95%CI) were calculated using unconditional logistic regression, accounting for multiple confounding factors. We did not observe an overall change in the odds ratios for SCC or BCC among individuals carrying either of the RNASEL or MIR146A variants compared with those who were wild type at these loci. However, there was a sex-specific association between BCC and MIR146A in women (ORGC = 0.73, [95%CI = 0.52–1.03]; ORCC = 0.29, [95% CI = 0.14–0.61], p-trend<0.001), and a reduction in risk, albeit not statistically significant, associated with RNASEL and SCC in men (ORAG = 0.88, [95%CI = 0.65–1.19]; ORAA = 0.68, [95%CI = 0.43–1.08], p-trend = 0.10). Most striking was the strong interaction between the two genes. Among individuals carrying variant alleles of both rs2910164 and rs486907, we observed inverse relationships with SCC (ORSCC = 0.56, [95%CI = 0.38–0.81], p-interaction = 0.012) and BCC (ORBCC = 0.57, [95%CI = 0.40–0.80], p-interaction = 0.005). Our results suggest that genetic variation in immune and inflammatory regulators may influence susceptibility to NMSC, and novel SNP-SNP interaction for a microRNA and its target. These data suggest that RNASEL, an enzyme involved in RNA turnover, is controlled by miR-146a

  6. RNASEL and MIR146A SNP-SNP interaction as a susceptibility factor for non-melanoma skin cancer.

    PubMed

    Farzan, Shohreh F; Karagas, Margaret R; Christensen, Brock C; Li, Zhongze; Kuriger, Jacquelyn K; Nelson, Heather H

    2014-01-01

    Immunity and inflammatory pathways are important in the genesis of non-melanoma skin cancers (NMSC). Functional genetic variation in immune modulators has the potential to affect disease etiology. We investigated associations between common variants in two key regulators, MIR146A and RNASEL, and their relation to NMSCs. Using a large population-based case-control study of basal cell (BCC) and squamous cell carcinoma (SCC), we investigated the impact of MIR146A SNP rs2910164 on cancer risk, and interaction with a SNP in one of its putative targets (RNASEL, rs486907). To examine associations between genotype and BCC and SCC, occurrence odds ratios (OR) and 95% confidence intervals (95%CI) were calculated using unconditional logistic regression, accounting for multiple confounding factors. We did not observe an overall change in the odds ratios for SCC or BCC among individuals carrying either of the RNASEL or MIR146A variants compared with those who were wild type at these loci. However, there was a sex-specific association between BCC and MIR146A in women (ORGC = 0.73, [95%CI = 0.52-1.03]; ORCC = 0.29, [95% CI = 0.14-0.61], p-trend<0.001), and a reduction in risk, albeit not statistically significant, associated with RNASEL and SCC in men (ORAG = 0.88, [95%CI = 0.65-1.19]; ORAA = 0.68, [95%CI = 0.43-1.08], p-trend = 0.10). Most striking was the strong interaction between the two genes. Among individuals carrying variant alleles of both rs2910164 and rs486907, we observed inverse relationships with SCC (ORSCC = 0.56, [95%CI = 0.38-0.81], p-interaction = 0.012) and BCC (ORBCC = 0.57, [95%CI = 0.40-0.80], p-interaction = 0.005). Our results suggest that genetic variation in immune and inflammatory regulators may influence susceptibility to NMSC, and novel SNP-SNP interaction for a microRNA and its target. These data suggest that RNASEL, an enzyme involved in RNA turnover, is controlled by miR-146a and may be important in NMSC etiology. PMID:24699816

  7. Eigenanalysis of SNP data with an identity by descent interpretation.

    PubMed

    Zheng, Xiuwen; Weir, Bruce S

    2016-02-01

    Principal component analysis (PCA) is widely used in genome-wide association studies (GWAS), and the principal component axes often represent perpendicular gradients in geographic space. The explanation of PCA results is of major interest for geneticists to understand fundamental demographic parameters. Here, we provide an interpretation of PCA based on relatedness measures, which are described by the probability that sets of genes are identical-by-descent (IBD). An approximately linear transformation between ancestral proportions (AP) of individuals with multiple ancestries and their projections onto the principal components is found. In addition, a new method of eigenanalysis "EIGMIX" is proposed to estimate individual ancestries. EIGMIX is a method of moments with computational efficiency suitable for millions of SNP data, and it is not subject to the assumption of linkage equilibrium. With the assumptions of multiple ancestries and their surrogate ancestral samples, EIGMIX is able to infer ancestral proportions (APs) of individuals. The methods were applied to the SNP data from the HapMap Phase 3 project and the Human Genome Diversity Panel. The APs of individuals inferred by EIGMIX are consistent with the findings of the program ADMIXTURE. In conclusion, EIGMIX can be used to detect population structure and estimate genome-wide ancestral proportions with a relatively high accuracy. PMID:26482676

  8. SNP Markers and Their Impact on Plant Breeding

    PubMed Central

    Mammadov, Jafar; Aggarwal, Rajat; Buyyarapu, Ramesh; Kumpatla, Siva

    2012-01-01

    The use of molecular markers has revolutionized the pace and precision of plant genetic analysis which in turn facilitated the implementation of molecular breeding of crops. The last three decades have seen tremendous advances in the evolution of marker systems and the respective detection platforms. Markers based on single nucleotide polymorphisms (SNPs) have rapidly gained the center stage of molecular genetics during the recent years due to their abundance in the genomes and their amenability for high-throughput detection formats and platforms. Computational approaches dominate SNP discovery methods due to the ever-increasing sequence information in public databases; however, complex genomes pose special challenges in the identification of informative SNPs warranting alternative strategies in those crops. Many genotyping platforms and chemistries have become available making the use of SNPs even more attractive and efficient. This paper provides a review of historical and current efforts in the development, validation, and application of SNP markers in QTL/gene discovery and plant breeding by discussing key experimental strategies and cases exemplifying their impact. PMID:23316221

  9. Vascular smooth muscle-specific deletion of the leptin receptor attenuates leptin-induced alterations in vascular relaxation.

    PubMed

    Ryan, Michael J; Coleman, T Taylor; Sasser, Jennifer M; Pittman, Katarina M; Hankins, Michael W; Stec, David E

    2016-05-15

    Obesity is a risk factor for cardiovascular disease and is associated with increased plasma levels of the adipose-derived hormone leptin. Vascular smooth muscle cells (VSMC) express leptin receptors (LepR); however, their physiological role is unclear. We hypothesized that leptin, at levels to mimic morbid obesity, impairs vascular relaxation. To test this, we used control and VSM-LepR knockout mice (VSM-LepR KO) created with a tamoxifen-inducible specific Cre recombinase to delete the LepR gene in VSMC. Control (10-12 wk old) and VSM-LepR KO (10-12 wk old) mice were fed a diet containing tamoxifen (50 mg/kg) for 6 wk, after which vascular reactivity was studied in isolated carotid arteries using an organ chamber bath. Vessels were incubated with leptin (100 ng/ml) or vehicle (0.1 mM Tris·HCl) for 30 min. Leptin treatment resulted in significant impairment of vessel relaxation to the endothelial-specific agonist acetylcholine (ACh). When these experiments were repeated in the presence of the superoxide scavenger tempol, relaxation responses to ACh were restored. VSM-LepR deletion resulted in a significant attenuation of leptin-mediated impaired ACh-induced relaxation. These data show that leptin directly impairs vascular relaxation via a VSM-LepR-mediated mechanism, suggesting a potential pathogenic role for leptin to increase cardiovascular risk during obesity. PMID:26936780

  10. SNP-SNP Interaction between TLR4 and MyD88 in Susceptibility to Coronary Artery Disease in the Chinese Han Population

    PubMed Central

    Sun, Dandan; Sun, Liping; Xu, Qian; Gong, Yuehua; Wang, Honghu; Yang, Jun; Yuan, Yuan

    2016-01-01

    The toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-dependent signaling pathway plays a role in the initiation and progression of coronary artery disease (CAD). We investigated SNP–SNP interactions between the TLR4 and MyD88 genes in CAD susceptibility and assessed whether the effects of such interactions were modified by confounding risk factors (hyperglycemia, hyperlipidemia and Helicobacter pylori (H. pylori) infection). Participants with CAD (n = 424) and controls (n = 424) without CAD were enrolled. Polymerase chain restriction-restriction fragment length polymorphism was performed on genomic DNA to detect polymorphisms in TLR4 (rs10116253, rs10983755, and rs11536889) and MyD88 (rs7744). H. pylori infections were evaluated by enzyme-linked immunosorbent assays, and the cardiovascular risk factors for each subject were evaluated clinically. The significant interaction between TLR4 rs11536889 and MyD88 rs7744 was associated with an increased CAD risk (p value for interaction = 0.024). In conditions of hyperglycemia, the interaction effect was strengthened between TLR4 rs11536889 and MyD88 rs7744 (p value for interaction = 0.004). In hyperlipidemic participants, the interaction strength was also enhanced for TLR4 rs11536889 and MyD88 rs7744 (p value for interaction = 0.006). Thus, the novel interaction between TLR4 rs11536889 and MyD88 rs7744 was related with an increased risk of CAD, that could be strengthened by the presence of hyperglycemia or hyperlipidemia. PMID:26959040

  11. FunctSNP: an R package to link SNPs to functional knowledge and dbAutoMaker: a suite of Perl scripts to build SNP databases

    PubMed Central

    2010-01-01

    Background Whole genome association studies using highly dense single nucleotide polymorphisms (SNPs) are a set of methods to identify DNA markers associated with variation in a particular complex trait of interest. One of the main outcomes from these studies is a subset of statistically significant SNPs. Finding the potential biological functions of such SNPs can be an important step towards further use in human and agricultural populations (e.g., for identifying genes related to susceptibility to complex diseases or genes playing key roles in development or performance). The current challenge is that the information holding the clues to SNP functions is distributed across many different databases. Efficient bioinformatics tools are therefore needed to seamlessly integrate up-to-date functional information on SNPs. Many web services have arisen to meet the challenge but most work only within the framework of human medical research. Although we acknowledge the importance of human research, we identify there is a need for SNP annotation tools for other organisms. Description We introduce an R package called FunctSNP, which is the user interface to custom built species-specific databases. The local relational databases contain SNP data together with functional annotations extracted from online resources. FunctSNP provides a unified bioinformatics resource to link SNPs with functional knowledge (e.g., genes, pathways, ontologies). We also introduce dbAutoMaker, a suite of Perl scripts, which can be scheduled to run periodically to automatically create/update the customised SNP databases. We illustrate the use of FunctSNP with a livestock example, but the approach and software tools presented here can be applied also to human and other organisms. Conclusions Finding the potential functional significance of SNPs is important when further using the outcomes from whole genome association studies. FunctSNP is unique in that it is the only R package that links SNPs to

  12. SNP Discovery for mapping alien introgressions in wheat

    PubMed Central

    2014-01-01

    Background Monitoring alien introgressions in crop plants is difficult due to the lack of genetic and molecular mapping information on the wild crop relatives. The tertiary gene pool of wheat is a very important source of genetic variability for wheat improvement against biotic and abiotic stresses. By exploring the 5Mg short arm (5MgS) of Aegilops geniculata, we can apply chromosome genomics for the discovery of SNP markers and their use for monitoring alien introgressions in wheat (Triticum aestivum L). Results The short arm of chromosome 5Mg of Ae. geniculata Roth (syn. Ae. ovata L.; 2n = 4x = 28, UgUgMgMg) was flow-sorted from a wheat line in which it is maintained as a telocentric chromosome. DNA of the sorted arm was amplified and sequenced using an Illumina Hiseq 2000 with ~45x coverage. The sequence data was used for SNP discovery against wheat homoeologous group-5 assemblies. A total of 2,178 unique, 5MgS-specific SNPs were discovered. Randomly selected samples of 59 5MgS-specific SNPs were tested (44 by KASPar assay and 15 by Sanger sequencing) and 84% were validated. Of the selected SNPs, 97% mapped to a chromosome 5Mg addition to wheat (the source of t5MgS), and 94% to 5Mg introgressed from a different accession of Ae. geniculata substituting for chromosome 5D of wheat. The validated SNPs also identified chromosome segments of 5MgS origin in a set of T5D-5Mg translocation lines; eight SNPs (25%) mapped to TA5601 [T5DL · 5DS-5MgS(0.75)] and three (8%) to TA5602 [T5DL · 5DS-5MgS (0.95)]. SNPs (gsnp_5ms83 and gsnp_5ms94), tagging chromosome T5DL · 5DS-5MgS(0.95) with the smallest introgression carrying resistance to leaf rust (Lr57) and stripe rust (Yr40), were validated in two released germplasm lines with Lr57 and Yr40 genes. Conclusion This approach should be widely applicable for the identification of species/genome-specific SNPs. The development of a large number of SNP markers will facilitate the precise introgression and

  13. Molecular characterization, tissue expression profile and SNP analysis of porcine GLP2R.

    PubMed

    Chai, Y L; Ma, H M; Jiang, J

    2015-01-01

    Glucagon-like peptide-2 receptor (GLP2R), a member of the G-protein-coupled receptor family, plays an important role in intramuscular fat formation. Little is known, however, about porcine GLP2R. In the present study, GLP2R was cloned, and its expression in pig muscle characterized. By rapid amplification of cDNA ends, gene sequence was obtained from Shaziling pigs. Full-length cDNA was 1868 bp, including an open reading frame 1665 bp in length, encoding 554 amino acids, and 203 bp at the 3' end. The GLP2R homology between porcine and other species was performed using bioinformatics techniques to construct a phylogenetic tree. Porcine GLP2R was most closely related to those from Orcinus orca and Ovis aries, and most distantly related to those from Chrysemys picta, Taeniopygia guttata, and Falco peregrinus. Real-time PCR analysis showed expression of porcine GLP2R in 10 different tissues from 25-day-old Yorkshire and Shaziling piglets, with expression levels being highest in the longissimus dorsi muscle and lowest in kidney. For each pig breed, expression level in longissimus dorsi muscle was highest among ten tissues (P < 0.05). Between the two breeds, GLP2R expression levels were significant in pancreas, the crureus and longissimus dorsi muscles (P < 0.05). A single SNP of porcine GLP2R, A343G, was identified, and genotypes were determined by PCR-RFLP. This study provides an insight into the function of GLP2R in swine. PMID:26505446

  14. Identification of SNP barcode biomarkers for genes associated with facial emotion perception using particle swarm optimization algorithm

    PubMed Central

    2014-01-01

    Background Facial emotion perception (FEP) can affect social function. We previously reported that parts of five tested single-nucleotide polymorphisms (SNPs) in the MET and AKT1 genes may individually affect FEP performance. However, the effects of SNP-SNP interactions on FEP performance remain unclear. Methods This study compared patients with high and low FEP performances (n = 89 and 93, respectively). A particle swarm optimization (PSO) algorithm was used to identify the best SNP barcodes (i.e., the SNP combinations and genotypes that revealed the largest differences between the high and low FEP groups). Results The analyses of individual SNPs showed no significant differences between the high and low FEP groups. However, comparisons of multiple SNP-SNP interactions involving different combinations of two to five SNPs showed that the best PSO-generated SNP barcodes were significantly associated with high FEP score. The analyses of the joint effects of the best SNP barcodes for two to five interacting SNPs also showed that the best SNP barcodes had significantly higher odds ratios (2.119 to 3.138; P < 0.05) compared to other SNP barcodes. In conclusion, the proposed PSO algorithm effectively identifies the best SNP barcodes that have the strongest associations with FEP performance. Conclusions This study also proposes a computational methodology for analyzing complex SNP-SNP interactions in social cognition domains such as recognition of facial emotion. PMID:24955105

  15. The development and characterization of a 60K SNP chip for chicken

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In livestock species like the chicken, high throughput SNP genotyping assays are increasingly being used for whole genome association studies and as a tool in breeding (referred to as genomic selection). We describe the design of a moderate density (60K) Illumina SNP BeadChip in chicken consisting o...

  16. A genome-wide SNP panel for genetic diversity, mapping and breeding studies in rice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A genome-wide SNP resource was developed for rice using the GoldenGate assay and used to genotype 400 landrace accessions of O. sativa. SNPs were originally discovered using Perlegen re-sequencing technology in 20 diverse landraces of O. sativa as part of OryzaSNP project (http://irfgc.irri.org). An...

  17. Characterization of the Cattle HapMap Population using the Illumina Bovine-50K SNP Chip

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A Bovine 50K Illumina™ iSelect SNP chip (51,386 polymorphic SNP markers) was designed using a combination of publicly available SNPs along with highly informative novel SNPs discovered using a reduced representation and next-generation sequencing technology strategy. A total of 576 animals (426 mal...

  18. A new SNP panel for evaluating genetic diversity in a composite cattle breed

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A custom 60K SNP panel, extracted from Bovine HD SNP chip was used to evaluate genotypic frequency changes in Braford (BF, a composite breed) when compared to progenitor breeds: Hereford (HF), Brahman (BR), and Nelore (NE). Samples from both the U. S. and Brazil were used. The new panel differentiat...

  19. A Coordinated Approach to Peach SNP Discovery in RosBREED

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In the USDA-funded multi-institutional and trans-disciplinary project, “RosBREED”, crop-specific SNP genome scan platforms are being developed for peach, apple, strawberry, and cherry at a resolution of at least one polymorphic SNP marker every 5 cM in any random cross, for use in Pedigree-Based Ana...

  20. Development and Applications of a Bovine 50,000 SNP Chip

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To develop an Illumina iSelect high density single nucleotide polymorphism (SNP) assay for cattle, the collaborative iBMC (Illumina, USDA ARS Beltsville, University of Missouri, USDA ARS Clay Center) Consortium first performed a de novo SNP discovery project in which genomic reduced representation l...

  1. SNP discovery and allele frequency estimation by deep sequencing of reduced representation libraries

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genome projects routinely produce draft sequences for species from diverse evolutionary clades, but generally do not create single nucleotide polymorphism (SNP) resources. We present an approach for de novo SNP discovery based on short-read sequencing of reduced representation libraries (RRL) to ge...

  2. Strategies to build high-density linkage maps of the porcine 60k SNP chip

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We present here two different strategies to compute high-density linkage maps based on the porcine 60k SNP chip that was genotyped on 4 different pedigrees with a total of 5600 animals. The first strategy uses the draft sequence as a reference order, the SNP being first mapped to it. The second stra...

  3. SNP and haplotype mapping for genetic analysis in the rat.

    PubMed

    Saar, Kathrin; Beck, Alfred; Bihoreau, Marie-Thérèse; Birney, Ewan; Brocklebank, Denise; Chen, Yuan; Cuppen, Edwin; Demonchy, Stephanie; Dopazo, Joaquin; Flicek, Paul; Foglio, Mario; Fujiyama, Asao; Gut, Ivo G; Gauguier, Dominique; Guigo, Roderic; Guryev, Victor; Heinig, Matthias; Hummel, Oliver; Jahn, Niels; Klages, Sven; Kren, Vladimir; Kube, Michael; Kuhl, Heiner; Kuramoto, Takashi; Kuroki, Yoko; Lechner, Doris; Lee, Young-Ae; Lopez-Bigas, Nuria; Lathrop, G Mark; Mashimo, Tomoji; Medina, Ignacio; Mott, Richard; Patone, Giannino; Perrier-Cornet, Jeanne-Antide; Platzer, Matthias; Pravenec, Michal; Reinhardt, Richard; Sakaki, Yoshiyuki; Schilhabel, Markus; Schulz, Herbert; Serikawa, Tadao; Shikhagaie, Medya; Tatsumoto, Shouji; Taudien, Stefan; Toyoda, Atsushi; Voigt, Birger; Zelenika, Diana; Zimdahl, Heike; Hubner, Norbert

    2008-05-01

    The laboratory rat is one of the most extensively studied model organisms. Inbred laboratory rat strains originated from limited Rattus norvegicus founder populations, and the inherited genetic variation provides an excellent resource for the correlation of genotype to phenotype. Here, we report a survey of genetic variation based on almost 3 million newly identified SNPs. We obtained accurate and complete genotypes for a subset of 20,238 SNPs across 167 distinct inbred rat strains, two rat recombinant inbred panels and an F2 intercross. Using 81% of these SNPs, we constructed high-density genetic maps, creating a large dataset of fully characterized SNPs for disease gene mapping. Our data characterize the population structure and illustrate the degree of linkage disequilibrium. We provide a detailed SNP map and demonstrate its utility for mapping of quantitative trait loci. This community resource is openly available and augments the genetic tools for this workhorse of physiological studies. PMID:18443594

  4. SNP-VISTA: An Interactive SNPs Visualization Tool

    SciTech Connect

    Shah, Nameeta; Teplitsky, Michael V.; Pennacchio, Len A.; Hugenholtz, Philip; Hamann, Bernd; Dubchak, Inna L.

    2005-07-05

    Recent advances in sequencing technologies promise better diagnostics for many diseases as well as better understanding of evolution of microbial populations. Single Nucleotide Polymorphisms(SNPs) are established genetic markers that aid in the identification of loci affecting quantitative traits and/or disease in a wide variety of eukaryotic species. With today's technological capabilities, it is possible to re-sequence a large set of appropriate candidate genes in individuals with a given disease and then screen for causative mutations.In addition, SNPs have been used extensively in efforts to study the evolution of microbial populations, and the recent application of random shotgun sequencing to environmental samples makes possible more extensive SNP analysis of co-occurring and co-evolving microbial populations. The program is available at http://genome.lbl.gov/vista/snpvista.

  5. TcSNP: a database of genetic variation in Trypanosoma cruzi

    PubMed Central

    Ackermann, Alejandro A.; Carmona, Santiago J.; Agüero, Fernán

    2009-01-01

    The TcSNP database (http://snps.tcruzi.org) integrates information on genetic variation (polymorphisms and mutations) for different stocks, strains and isolates of Trypanosoma cruzi, the causative agent of Chagas disease. The database incorporates sequences (genes from the T. cruzi reference genome, mRNAs, ESTs and genomic sequences); multiple sequence alignments obtained from these sequences; and single-nucleotide polymorphisms and small indels identified by scanning these multiple sequence alignments. Information in TcSNP can be readily interrogated to arrive at gene sets, or SNP sets of interest based on a number of attributes. Sequence similarity searches using BLAST are also supported. This first release of TcSNP contains nearly 170 000 high-confidence candidate SNPs, derived from the analysis of annotated coding sequences. As new sequence data become available, TcSNP will incorporate these data, mapping new candidate SNPs onto the reference genome sequences. PMID:18974180

  6. Genotyping NAT2 with only two SNPs (rs1041983 and rs1801280) outperforms the tagging SNP rs1495741 and is equivalent to the conventional 7-SNP NAT2 genotype.

    PubMed

    Selinski, Silvia; Blaszkewicz, Meinolf; Lehmann, Marie-Louise; Ovsiannikov, Daniel; Moormann, Oliver; Guballa, Christoph; Kress, Alexander; Truss, Michael C; Gerullis, Holger; Otto, Thomas; Barski, Dimitri; Niegisch, Günter; Albers, Peter; Frees, Sebastian; Brenner, Walburgis; Thüroff, Joachim W; Angeli-Greaves, Miriam; Seidel, Thilo; Roth, Gerhard; Dietrich, Holger; Ebbinghaus, Rainer; Prager, Hans M; Bolt, Hermann M; Falkenstein, Michael; Zimmermann, Anna; Klein, Torsten; Reckwitz, Thomas; Roemer, Hermann C; Löhlein, Dietrich; Weistenhöfer, Wobbeke; Schöps, Wolfgang; Hassan Rizvi, Syed Adibul; Aslam, Muhammad; Bánfi, Gergely; Romics, Imre; Steffens, Michael; Ekici, Arif B; Winterpacht, Andreas; Ickstadt, Katja; Schwender, Holger; Hengstler, Jan G; Golka, Klaus

    2011-10-01

    Genotyping N-acetyltransferase 2 (NAT2) is of high relevance for individualized dosing of antituberculosis drugs and bladder cancer epidemiology. In this study we compared a recently published tagging single nucleotide polymorphism (SNP) (rs1495741) to the conventional 7-SNP genotype (G191A, C282T, T341C, C481T, G590A, A803G and G857A haplotype pairs) and systematically analysed if novel SNP combinations outperform the latter. For this purpose, we studied 3177 individuals by PCR and phenotyped 344 individuals by the caffeine test. Although the tagSNP and the 7-SNP genotype showed a high degree of correlation (R=0.933, P<0.0001) the 7-SNP genotype nevertheless outperformed the tagging SNP with respect to specificity (1.0 vs. 0.9444, P=0.0065). Considering all possible SNP combinations in a receiver operating characteristic analysis we identified a 2-SNP genotype (C282T, T341C) that outperformed the tagging SNP and was equivalent to the 7-SNP genotype. The 2-SNP genotype predicted the correct phenotype with a sensitivity of 0.8643 and a specificity of 1.0. In addition, it predicted the 7-SNP genotype with sensitivity and specificity of 0.9993 and 0.9880, respectively. The prediction of the NAT2 genotype by the 2-SNP genotype performed similar in populations of Caucasian, Venezuelan and Pakistani background. A 2-SNP genotype predicts NAT2 phenotypes with similar sensitivity and specificity as the conventional 7-SNP genotype. This procedure represents a facilitation in individualized dosing of NAT2 substrates without losing sensitivity or specificity. PMID:21750470

  7. Design and Characterization of a 52K SNP Chip for Goats

    PubMed Central

    Tosser-Klopp, Gwenola; Bardou, Philippe; Bouchez, Olivier; Cabau, Cédric; Crooijmans, Richard; Dong, Yang; Donnadieu-Tonon, Cécile; Eggen, André; Heuven, Henri C. M.; Jamli, Saadiah; Jiken, Abdullah Johari; Klopp, Christophe; Lawley, Cynthia T.; McEwan, John; Martin, Patrice; Moreno, Carole R.; Mulsant, Philippe; Nabihoudine, Ibouniyamine; Pailhoux, Eric; Palhière, Isabelle; Rupp, Rachel; Sarry, Julien; Sayre, Brian L.; Tircazes, Aurélie; Jun Wang; Wang, Wen; Zhang, Wenguang

    2014-01-01

    The success of Genome Wide Association Studies in the discovery of sequence variation linked to complex traits in humans has increased interest in high throughput SNP genotyping assays in livestock species. Primary goals are QTL detection and genomic selection. The purpose here was design of a 50–60,000 SNP chip for goats. The success of a moderate density SNP assay depends on reliable bioinformatic SNP detection procedures, the technological success rate of the SNP design, even spacing of SNPs on the genome and selection of Minor Allele Frequencies (MAF) suitable to use in diverse breeds. Through the federation of three SNP discovery projects consolidated as the International Goat Genome Consortium, we have identified approximately twelve million high quality SNP variants in the goat genome stored in a database together with their biological and technical characteristics. These SNPs were identified within and between six breeds (meat, milk and mixed): Alpine, Boer, Creole, Katjang, Saanen and Savanna, comprising a total of 97 animals. Whole genome and Reduced Representation Library sequences were aligned on >10 kb scaffolds of the de novo goat genome assembly. The 60,000 selected SNPs, evenly spaced on the goat genome, were submitted for oligo manufacturing (Illumina, Inc) and published in dbSNP along with flanking sequences and map position on goat assemblies (i.e. scaffolds and pseudo-chromosomes), sheep genome V2 and cattle UMD3.1 assembly. Ten breeds were then used to validate the SNP content and 52,295 loci could be successfully genotyped and used to generate a final cluster file. The combined strategy of using mainly whole genome Next Generation Sequencing and mapping on a contig genome assembly, complemented with Illumina design tools proved to be efficient in producing this GoatSNP50 chip. Advances in use of molecular markers are expected to accelerate goat genomic studies in coming years. PMID:24465974

  8. Relationship Between Leptin G2548A and Leptin Receptor Q223R Gene Polymorphisms and Obesity and Metabolic Syndrome Risk in Tunisian Volunteers

    PubMed Central

    Boumaiza, Imen; Omezzine, Asma; Rejeb, Jihène; Rebhi, Lamia; Ouedrani, Amani; Ben Rejeb, Nabila; Nabli, Naoufel; Ben Abdelaziz, Ahmed

    2012-01-01

    Leptin is a key hormone of weight regulation that modulates food intake. Since the elaboration of the leptin action mechanism, several studies tried to establish the relationship between obesity and the common polymorphisms of leptin (LEP) and leptin receptor (LEPR) genes, but results were controversial. We studied the association of G2548A of the LEP gene and Q223R of LEPR gene polymorphisms with obesity and metabolic syndrome (MetS). We recruited 169 nonobese volunteers (body mass index [BMI] <30 kg/m2) and 160 obese ones (BMI ≥30 kg/m2). Glucose, insulin, and lipids were measured. BMI, homeostasis model assessment-insulin resistance (HOMA-IR), and daily energy intake were calculated. After adjustment to confounders parameters, 2548AA was found to increase the MetS (p=0.043) and obesity risk (p=0.019) in the studied population. After stratification according to the degree of obesity, the odds ratio [OR] of 2548AA was associated with moderate obesity (p=0.048) and morbid obesity (p=0.048). The LEPR 223RR genotype was associated with obesity in the studied population (OR=1.74, p=0.037) and only in the overweight (OR=1.8, p=0.049). Subjects with 2548AA had significantly higher BMI, daily energy intake, total cholesterol (TC), waist circumference (WC), insulinemia, and low high-density lipoprotein-cholesterol (HDL-C) levels. With regard to 223RR, we noted a significantly higher daily energy intake, BMI, TC, glycemia, insulinemia, HOMA-IR index, and low HDL-C levels. Haplotype model AR (2548A+223R) and AQ (2548A+223Q) increased the risk of obesity (OR=3.36, p<0.001; OR=2.56, p=0.010, respectively). When we added daily energy intake in adjustment, these significant associations disappeared. In addition, the AR and AQ increased the MetS risk. This significant association persisted after we had added daily energy intake in adjustment. This study showed that LEP G2548A and LEPR Q223R polymorphisms and haplotype combination were associated with MetS and obesity risk

  9. A Customized Pigmentation SNP Array Identifies a Novel SNP Associated with Melanoma Predisposition in the SLC45A2 Gene

    PubMed Central

    Alonso, Santos; Boyano, M. Dolores; Peña-Chilet, Maria; Pita, Guillermo; Aviles, Jose A.; Mayor, Matias; Gomez-Fernandez, Cristina; Casado, Beatriz; Martin-Gonzalez, Manuel; Izagirre, Neskuts; De la Rua, Concepcion; Asumendi, Aintzane; Perez-Yarza, Gorka; Arroyo-Berdugo, Yoana; Boldo, Enrique; Lozoya, Rafael; Torrijos-Aguilar, Arantxa; Pitarch, Ana; Pitarch, Gerard; Sanchez-Motilla, Jose M.; Valcuende-Cavero, Francisca; Tomas-Cabedo, Gloria; Perez-Pastor, Gemma; Diaz-Perez, Jose L.; Gardeazabal, Jesus; de Lizarduy, Iñigo Martinez; Sanchez-Diez, Ana; Valdes, Carlos; Pizarro, Angel; Casado, Mariano; Carretero, Gregorio; Botella-Estrada, Rafael; Nagore, Eduardo; Lazaro, Pablo; Lluch, Ana; Benitez, Javier; Martinez-Cadenas, Conrado; Ribas, Gloria

    2011-01-01

    As the incidence of Malignant Melanoma (MM) reflects an interaction between skin colour and UV exposure, variations in genes implicated in pigmentation and tanning response to UV may be associated with susceptibility to MM. In this study, 363 SNPs in 65 gene regions belonging to the pigmentation pathway have been successfully genotyped using a SNP array. Five hundred and ninety MM cases and 507 controls were analyzed in a discovery phase I. Ten candidate SNPs based on a p-value threshold of 0.01 were identified. Two of them, rs35414 (SLC45A2) and rs2069398 (SILV/CKD2), were statistically significant after conservative Bonferroni correction. The best six SNPs were further tested in an independent Spanish series (624 MM cases and 789 controls). A novel SNP located on the SLC45A2 gene (rs35414) was found to be significantly associated with melanoma in both phase I and phase II (P<0.0001). None of the other five SNPs were replicated in this second phase of the study. However, three SNPs in TYR, SILV/CDK2 and ADAMTS20 genes (rs17793678, rs2069398 and rs1510521 respectively) had an overall p-value<0.05 when considering the whole DNA collection (1214 MM cases and 1296 controls). Both the SLC45A2 and the SILV/CDK2 variants behave as protective alleles, while the TYR and ADAMTS20 variants seem to function as risk alleles. Cumulative effects were detected when these four variants were considered together. Furthermore, individuals carrying two or more mutations in MC1R, a well-known low penetrance melanoma-predisposing gene, had a decreased MM risk if concurrently bearing the SLC45A2 protective variant. To our knowledge, this is the largest study on Spanish sporadic MM cases to date. PMID:21559390

  10. Identification, validation and survey of a single nucleotide polymorphism (SNP) associated with pungency in Capsicum spp.

    PubMed

    Garcés-Claver, Ana; Fellman, Shanna Moore; Gil-Ortega, Ramiro; Jahn, Molly; Arnedo-Andrés, María S

    2007-11-01

    A single nucleotide polymorphism (SNP) associated with pungency was detected within an expressed sequence tag (EST) of 307 bp. This fragment was identified after expression analysis of the EST clone SB2-66 in placenta tissue of Capsicum fruits. Sequence alignments corresponding to this new fragment allowed us to identify an SNP between pungent and non-pungent accessions. Two methods were chosen for the development of the SNP marker linked to pungency: tetra-primer amplification refractory mutation system-PCR (tetra-primer ARMS-PCR) and cleaved amplified polymorphic sequence. Results showed that both methods were successful in distinguishing genotypes. Nevertheless, tetra-primer ARMS-PCR was chosen for SNP genotyping because it was more rapid, reliable and less cost-effective. The utility of this SNP marker for pungency was demonstrated by the ability to distinguish between 29 pungent and non-pungent cultivars of Capsicum annuum. In addition, the SNP was also associated with phenotypic pungent character in the tested genotypes of C. chinense, C. baccatum, C. frutescens, C. galapagoense, C. eximium, C. tovarii and C. cardenasi. This SNP marker is a faster, cheaper and more reproducible method for identifying pungent peppers than other techniques such as panel tasting, and allows rapid screening of the trait in early growth stages. PMID:17882396

  11. Nuclear receptor coregulator SNP discovery and impact on breast cancer risk

    PubMed Central

    2009-01-01

    Background Coregulator proteins are "master regulators", directing transcriptional and posttranscriptional regulation of many target genes, and are critical in many normal physiological processes, but also in hormone driven diseases, such as breast cancer. Little is known on how genetic changes in these genes impact disease development and progression. Thus, we set out to identify novel single nucleotide polymorphisms (SNPs) within SRC-1 (NCoA1), SRC-3 (NCoA3, AIB1), NCoR (NCoR1), and SMRT (NCoR2), and test the most promising SNPs for associations with breast cancer risk. Methods The identification of novel SNPs was accomplished by sequencing the coding regions of these genes in 96 apparently normal individuals (48 Caucasian Americans, 48 African Americans). To assess their association with breast cancer risk, five SNPs were genotyped in 1218 familial BRCA1/2-mutation negative breast cancer cases and 1509 controls (rs1804645, rs6094752, rs2230782, rs2076546, rs2229840). Results Through our resequencing effort, we identified 74 novel SNPs (30 in NCoR, 32 in SMRT, 10 in SRC-3, and 2 in SRC-1). Of these, 8 were found with minor allele frequency (MAF) >5% illustrating the large amount of genetic diversity yet to be discovered. The previously shown protective effect of rs2230782 in SRC-3 was strengthened (OR = 0.45 [0.21-0.98], p = 0.04). No significant associations were found with the other SNPs genotyped. Conclusions This data illustrates the importance of coregulators, especially SRC-3, in breast cancer development and suggests that more focused studies, including functional analyses, should be conducted. PMID:20003447

  12. A system for exact and approximate genetic linkage analysis of SNP data in large pedigrees

    PubMed Central

    Silberstein, Mark; Weissbrod, Omer; Otten, Lars; Tzemach, Anna; Anisenia, Andrei; Shtark, Oren; Tuberg, Dvir; Galfrin, Eddie; Gannon, Irena; Shalata, Adel; Borochowitz, Zvi U.; Dechter, Rina; Thompson, Elizabeth; Geiger, Dan

    2013-01-01

    Motivation: The use of dense single nucleotide polymorphism (SNP) data in genetic linkage analysis of large pedigrees is impeded by significant technical, methodological and computational challenges. Here we describe Superlink-Online SNP, a new powerful online system that streamlines the linkage analysis of SNP data. It features a fully integrated flexible processing workflow comprising both well-known and novel data analysis tools, including SNP clustering, erroneous data filtering, exact and approximate LOD calculations and maximum-likelihood haplotyping. The system draws its power from thousands of CPUs, performing data analysis tasks orders of magnitude faster than a single computer. By providing an intuitive interface to sophisticated state-of-the-art analysis tools coupled with high computing capacity, Superlink-Online SNP helps geneticists unleash the potential of SNP data for detecting disease genes. Results: Computations performed by Superlink-Online SNP are automatically parallelized using novel paradigms, and executed on unlimited number of private or public CPUs. One novel service is large-scale approximate Markov Chain–Monte Carlo (MCMC) analysis. The accuracy of the results is reliably estimated by running the same computation on multiple CPUs and evaluating the Gelman–Rubin Score to set aside unreliable results. Another service within the workflow is a novel parallelized exact algorithm for inferring maximum-likelihood haplotyping. The reported system enables genetic analyses that were previously infeasible. We demonstrate the system capabilities through a study of a large complex pedigree affected with metabolic syndrome. Availability: Superlink-Online SNP is freely available for researchers at http://cbl-hap.cs.technion.ac.il/superlink-snp. The system source code can also be downloaded from the system website. Contact: omerw@cs.technion.ac.il Supplementary information: Supplementary data are available at Bioinformatics online. PMID:23162081

  13. Drug-SNPing: an integrated drug-based, protein interaction-based tagSNP-based pharmacogenomics platform for SNP genotyping.

    PubMed

    Yang, Cheng-Hong; Cheng, Yu-Huei; Chuang, Li-Yeh; Chang, Hsueh-Wei

    2013-03-15

    Many drug or single nucleotide polymorphism (SNP)-related resources and tools have been developed, but connecting and integrating them is still a challenge. Here, we describe a user-friendly web-based software package, named Drug-SNPing, which provides a platform for the integration of drug information (DrugBank and PharmGKB), protein-protein interactions (STRING), tagSNP selection (HapMap) and genotyping information (dbSNP, REBASE and SNP500Cancer). DrugBank-based inputs include the following: (i) common name of the drug, (ii) synonym or drug brand name, (iii) gene name (HUGO) and (iv) keywords. PharmGKB-based inputs include the following: (i) gene name (HUGO), (ii) drug name and (iii) disease-related keywords. The output provides drug-related information, metabolizing enzymes and drug targets, as well as protein-protein interaction data. Importantly, tagSNPs of the selected genes are retrieved for genotyping analyses. All drug-based and protein-protein interaction-based SNP genotyping information are provided with PCR-RFLP (PCR-restriction enzyme length polymorphism) and TaqMan probes. Thus, users can enter any drug keywords/brand names to obtain immediate information that is highly relevant to genotyping for pharmacogenomics research. PMID:23418190

  14. Conditional knockout of the leptin receptor in the colonic epithelium revealed the local effects of leptin receptor signaling in the progression of colonic tumors in mice.

    PubMed

    Higurashi, Takuma; Endo, Hiroki; Uchiyama, Takashi; Uchiyama, Shiori; Yamada, Eiji; Ohkubo, Hidenori; Sakai, Eiji; Takahashi, Hirokazu; Maeda, Shin; Wada, Koichiro; Natsumeda, Yutaka; Hippo, Yoshitaka; Nakajima, Atsushi; Nakagama, Hitoshi

    2014-09-01

    Leptin, secreted by the adipose tissue and known to be related to obesity, is considered to be involved in the onset and progression of colorectal cancer. However, the exact role of leptin in colorectal carcinogenesis is still unclear, as several controversial reports have been published on the various systemic effects of leptin. The aim of this study was to clarify the local and precise roles of leptin receptor (LEPR)-mediated signaling in colonic carcinogenesis using intestinal epithelium-specific LEPRb conditional knockout (cKO) mice. We produced and used colonic epithelium-specific LEPRb cKO mice to investigate the carcinogen-induced formation of aberrant crypt foci (ACF) and tumors in the colon, using their littermates as control. There were no differences in the body weight or systemic condition between the control and cKO mice. The tumor sizes and number of large-sized tumors were significantly lower in the cKO mice as compared with those in the control mice. On the other hand, there was no significant difference in the proliferative activity of the normal colonic epithelial cells or ACF formation between the control and cKO mice. In the control mice, marked increase of the LEPRb expression level was observed in the colonic tumors as compared with that in the normal epithelium; furthermore, signal transducer and activator of transcription (STAT3) was activated in the tumor cells. These findings suggest that STAT3 is one of the important molecules downstream of LEPRb, and LEPRb/STAT3 signaling controls tumor cell proliferation. We demonstrated the importance of local/regional LEPR-mediated signaling in colorectal carcinogenesis. PMID:24958593

  15. Porcine colonization of the Americas: a 60k SNP story

    PubMed Central

    Burgos-Paz, W; Souza, C A; Megens, H J; Ramayo-Caldas, Y; Melo, M; Lemús-Flores, C; Caal, E; Soto, H W; Martínez, R; Álvarez, L A; Aguirre, L; Iñiguez, V; Revidatti, M A; Martínez-López, O R; Llambi, S; Esteve-Codina, A; Rodríguez, M C; Crooijmans, R P M A; Paiva, S R; Schook, L B; Groenen, M A M; Pérez-Enciso, M

    2013-01-01

    The pig, Sus scrofa, is a foreign species to the American continent. Although pigs originally introduced in the Americas should be related to those from the Iberian Peninsula and Canary islands, the phylogeny of current creole pigs that now populate the continent is likely to be very complex. Because of the extreme climates that America harbors, these populations also provide a unique example of a fast evolutionary phenomenon of adaptation. Here, we provide a genome wide study of these issues by genotyping, with a 60k SNP chip, 206 village pigs sampled across 14 countries and 183 pigs from outgroup breeds that are potential founders of the American populations, including wild boar, Iberian, international and Chinese breeds. Results show that American village pigs are primarily of European ancestry, although the observed genetic landscape is that of a complex conglomerate. There was no correlation between genetic and geographical distances, neither continent wide nor when analyzing specific areas. Most populations showed a clear admixed structure where the Iberian pig was not necessarily the main component, illustrating how international breeds, but also Chinese pigs, have contributed to extant genetic composition of American village pigs. We also observe that many genes related to the cardiovascular system show an increased differentiation between altiplano and genetically related pigs living near sea level. PMID:23250008

  16. Sturgeon conservation genomics: SNP discovery and validation using RAD sequencing.

    PubMed

    Ogden, R; Gharbi, K; Mugue, N; Martinsohn, J; Senn, H; Davey, J W; Pourkazemi, M; McEwing, R; Eland, C; Vidotto, M; Sergeev, A; Congiu, L

    2013-06-01

    Caviar-producing sturgeons belonging to the genus Acipenser are considered to be one of the most endangered species groups in the world. Continued overfishing in spite of increasing legislation, zero catch quotas and extensive aquaculture production have led to the collapse of wild stocks across Europe and Asia. The evolutionary relationships among Adriatic, Russian, Persian and Siberian sturgeons are complex because of past introgression events and remain poorly understood. Conservation management, traceability and enforcement suffer a lack of appropriate DNA markers for the genetic identification of sturgeon at the species, population and individual level. This study employed RAD sequencing to discover and characterize single nucleotide polymorphism (SNP) DNA markers for use in sturgeon conservation in these four tetraploid species over three biological levels, using a single sequencing lane. Four population meta-samples and eight individual samples from one family were barcoded separately before sequencing. Analysis of 14.4 Gb of paired-end RAD data focused on the identification of SNPs in the paired-end contig, with subsequent in silico and empirical validation of candidate markers. Thousands of putatively informative markers were identified including, for the first time, SNPs that show population-wide differentiation between Russian and Persian sturgeons, representing an important advance in our ability to manage these cryptic species. The results highlight the challenges of genotyping-by-sequencing in polyploid taxa, while establishing the potential genetic resources for developing a new range of caviar traceability and enforcement tools. PMID:23473098

  17. SNP Markers as Additional Information to Resolve Complex Kinship Cases

    PubMed Central

    Pontes, M. Lurdes; Fondevila, Manuel; Laréu, Maria Victoria; Medeiros, Rui

    2015-01-01

    Summary Background DNA profiling with sets of highly polymorphic autosomal short tandem repeat (STR) markers has been applied in various aspects of human identification in forensic casework for nearly 20 years. However, in some cases of complex kinship investigation, the information provided by the conventionally used STR markers is not enough, often resulting in low likelihood ratio (LR) calculations. In these cases, it becomes necessary to increment the number of loci under analysis to reach adequate LRs. Recently, it has been proposed that single nucleotide polymorphisms (SNPs) could be used as a supportive tool to STR typing, eventually even replacing the methods/markers now employed. Methods In this work, we describe the results obtained in 7 revised complex paternity cases when applying a battery of STRs, as well as 52 human identification SNPs (SNPforID 52plex identification panel) using a SNaPshot methodology followed by capillary electrophoresis. Results Our results show that the analysis of SNPs, as complement to STR typing in forensic casework applications, would at least increase by a factor of 4 total PI values and correspondent Essen-Möller's W value. Conclusions We demonstrated that SNP genotyping could be a key complement to STR information in challenging casework of disputed paternity, such as close relative individualization or complex pedigrees subject to endogamous relations. PMID:26733770

  18. Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function

    PubMed Central

    Imboden, Medea; Koch, Beate; McArdle, Wendy L.; Smith, Albert V.; Smolonska, Joanna; Sood, Akshay; Tang, Wenbo; Wilk, Jemma B.; Zhai, Guangju; Zhao, Jing Hua; Aschard, Hugues; Burkart, Kristin M.; Curjuric, Ivan; Eijgelsheim, Mark; Elliott, Paul; Gu, Xiangjun; Harris, Tamara B.; Janson, Christer; Homuth, Georg; Hysi, Pirro G.; Liu, Jason Z.; Loehr, Laura R.; Lohman, Kurt; Loos, Ruth J. F.; Manning, Alisa K.; Marciante, Kristin D.; Obeidat, Ma'en; Postma, Dirkje S.; Aldrich, Melinda C.; Brusselle, Guy G.; Chen, Ting-hsu; Eiriksdottir, Gudny; Franceschini, Nora; Heinrich, Joachim; Rotter, Jerome I.; Wijmenga, Cisca; Williams, O. Dale; Bentley, Amy R.; Hofman, Albert; Laurie, Cathy C.; Lumley, Thomas; Morrison, Alanna C.; Joubert, Bonnie R.; Rivadeneira, Fernando; Couper, David J.; Kritchevsky, Stephen B.; Liu, Yongmei; Wjst, Matthias; Wain, Louise V.; Vonk, Judith M.; Uitterlinden, André G.; Rochat, Thierry; Rich, Stephen S.; Psaty, Bruce M.; O'Connor, George T.; North, Kari E.; Mirel, Daniel B.; Meibohm, Bernd; Launer, Lenore J.; Khaw, Kay-Tee; Hartikainen, Anna-Liisa; Hammond, Christopher J.; Gläser, Sven; Marchini, Jonathan; Kraft, Peter; Wareham, Nicholas J.; Völzke, Henry; Stricker, Bruno H. C.; Spector, Timothy D.; Probst-Hensch, Nicole M.; Jarvis, Deborah; Jarvelin, Marjo-Riitta; Heckbert, Susan R.; Gudnason, Vilmundur; Boezen, H. Marike; Barr, R. Graham; Cassano, Patricia A.; Strachan, David P.; Fornage, Myriam; Hall, Ian P.; Dupuis, Josée; Tobin, Martin D.; London, Stephanie J.

    2012-01-01

    Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest PJMA = 5.00×10−11), HLA-DQB1 and HLA-DQA2 (smallest PJMA = 4.35×10−9), and KCNJ2 and SOX9 (smallest PJMA = 1.28×10−8) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects. PMID:23284291

  19. Fish scales and SNP chips: SNP genotyping and allele frequency estimation in individual and pooled DNA from historical samples of Atlantic salmon (Salmo salar)

    PubMed Central

    2013-01-01

    Background DNA extracted from historical samples is an important resource for understanding genetic consequences of anthropogenic influences and long-term environmental change. However, such samples generally yield DNA of a lower amount and quality, and the extent to which DNA degradation affects SNP genotyping success and allele frequency estimation is not well understood. We conducted high density SNP genotyping and allele frequency estimation in both individual DNA samples and pooled DNA samples extracted from dried Atlantic salmon (Salmo salar) scales stored at room temperature for up to 35 years, and assessed genotyping success, repeatability and accuracy of allele frequency estimation using a high density SNP genotyping array. Results In individual DNA samples, genotyping success and repeatability was very high (> 0.973 and > 0.998, respectively) in samples stored for up to 35 years; both increased with the proportion of DNA of fragment size > 1000 bp. In pooled DNA samples, allele frequency estimation was highly repeatable (Repeatability = 0.986) and highly correlated with empirical allele frequency measures (Mean Adjusted R2 = 0.991); allele frequency could be accurately estimated in > 95% of pooled DNA samples with a reference group of at least 30 individuals. SNPs located in polyploid regions of the genome were more sensitive to DNA degradation: older samples had lower genotyping success at these loci, and a larger reference panel of individuals was required to accurately estimate allele frequencies. Conclusions SNP genotyping was highly successful in degraded DNA samples, paving the way for the use of degraded samples in SNP genotyping projects. DNA pooling provides the potential for large scale population genetic studies with fewer assays, provided enough reference individuals are also genotyped and DNA quality is properly assessed beforehand. We provide recommendations for future studies intending to conduct high-throughput SNP

  20. Prevalence of PIK3CA mutations and the SNP rs17849079 in Arab breast cancer patients

    PubMed Central

    Karakas, Bedri; Colak, Dilek; Kaya, Namik; Ghebeh, Hazem; Al-Qasem, Abeer; Hendrayani, Fawziah; Toulimat, Mohamed; Al-Tweigeri, Taher; Park, Ben Ho; Aboussekhra, Abdelilah

    2013-01-01

    Carcinomas initiate and progress due to genetic and epigenetic alterations in epithelial cells. However, recently, these alterations have also been reported in stromal fibroblasts. The gain-of-function mutations in the PI3K p110 catalytic subunit (PIK3CA) have been identified in many cancers with a current global incidence of 26% (18–40%) in breast carcinomas. We analyzed the mutational frequency of PIK3CA of three hotspots (exons 1, 9, and 20) in 81 primary invasive breast cancers (BC) and 25 cultured breast cancer-associated fibroblast (CAF) samples by Sanger sequencing in Arab breast cancer patients. Associations between the incidence of any PIK3CA mutation and several clinicopathologic characteristics were assessed using chi-square tests for categorical or t test for continuous variables. Furthermore, survival curves were estimated using the Kaplan–Meier method with the log rank test to evaluate the significance of their differences. We identified a total of 21 PIK3CA missense mutations with a frequency of 25.9%. The majority of the mutations, 17 out of 21 (81%), were in exon 20 (p.His1047Arg, p.His1047Lys, p.Thr1025Ala, p.Gly1049Arg, p.Asp1056Asn) while the remainder, 4 out of 21 (19%) were in exon 9 (p.Glu545Lys). PIK3CA mutations were significantly associated with lower grade and hormone receptor positivity. Although there was a favorable trend in overall survival for patients whose tumor harbored PIK3CA mutations, the difference was not statistically significant (P = 0.10). However, we did not detect any somatic mutations in CAFs. Furthermore, we have shown a high prevalence (8.2-fold) of a silent variant (SNP, rs17849079) in the Arab breast cancer population compared with disease-free individuals. PMID:23982433

  1. Prevalence of PIK3CA mutations and the SNP rs17849079 in Arab breast cancer patients.

    PubMed

    Karakas, Bedri; Colak, Dilek; Kaya, Namik; Ghebeh, Hazem; Al-Qasem, Abeer; Hendrayani, Fawziah; Toulimat, Mohamed; Al-Tweigeri, Taher; Park, Ben Ho; Aboussekhra, Abdelilah

    2013-10-01

    Carcinomas initiate and progress due to genetic and epigenetic alterations in epithelial cells. However, recently, these alterations have also been reported in stromal fibroblasts. The gain-of-function mutations in the PI3K p110 catalytic subunit (PIK3CA) have been identified in many cancers with a current global incidence of 26% (18-40%) in breast carcinomas. We analyzed the mutational frequency of PIK3CA of three hotspots (exons 1, 9, and 20) in 81 primary invasive breast cancers (BC) and 25 cultured breast cancer-associated fibroblast (CAF) samples by Sanger sequencing in Arab breast cancer patients. Associations between the incidence of any PIK3CA mutation and several clinicopathologic characteristics were assessed using chi-square tests for categorical or t test for continuous variables. Furthermore, survival curves were estimated using the Kaplan-Meier method with the log rank test to evaluate the significance of their differences. We identified a total of 21 PIK3CA missense mutations with a frequency of 25.9%. The majority of the mutations, 17 out of 21 (81%), were in exon 20 (p.His1047Arg, p.His1047Lys, p.Thr1025Ala, p.Gly1049Arg, p.Asp1056Asn) while the remainder, 4 out of 21 (19%) were in exon 9 (p.Glu545Lys). PIK3CA mutations were significantly associated with lower grade and hormone receptor positivity. Although there was a favorable trend in overall survival for patients whose tumor harbored PIK3CA mutations, the difference was not statistically significant (P = 0.10). However, we did not detect any somatic mutations in CAFs. Furthermore, we have shown a high prevalence (8.2-fold) of a silent variant (SNP, rs17849079) in the Arab breast cancer population compared with disease-free individuals. PMID:23982433

  2. SNP discovery through de novo deep sequencing using the next generation of DNA sequencers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The production of high volumes of DNA sequence data using new technologies has permitted more efficient identification of single nucleotide polymorphisms in vertebrate genomes. This chapter presented practical methodology for production and analysis of DNA sequence data for SNP discovery....

  3. Identification of SNP Haplotypes and Prospects of Association Mapping in Watermelon

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Watermelon is the fifth most economically important vegetable crop cultivated world-wide. Implementing Single Nucleotide Polymorphism (SNP) marker technology in watermelon breeding and germplasm evaluation programs holds a key to improve horticulturally important traits. Next-generation sequencing...

  4. SNP analysis of AMY2 and CTSL genes in Litopenaeus vannamei and Penaeus monodon shrimp.

    PubMed

    Glenn, K L; Grapes, L; Suwanasopee, T; Harris, D L; Li, Y; Wilson, K; Rothschild, M F

    2005-06-01

    Genetic studies in shrimp have focused on disease, with production traits such as growth left unexamined. Two shrimp species, Litopenaeus vannamei and Penaeus monodon, which represent the majority of US shrimp imports, were selected for single nucleotide polymorphism (SNP) discovery in alpha-amylase (AMY2) and cathepsin-l (CTSL), both candidate genes for growth. In L. vannamei, four SNPs were found in AMY2 and one SNP was found in CTSL. In P. monodon, one SNP was identified in CTSL. The CTSL gene was mapped to linkage group 28 of P. monodon using the female map developed with the Australian P. monodon mapping population. Association analyses for the AMY2 and CTSL genes with body weight (BW) were performed in two L. vannamei populations. While neither gene was found to be significantly associated with BW in these populations, there was a trend in one population towards higher BW for allele G of CTSL SNP C681G. PMID:15932404

  5. Interim report on updated microarray probes for the LLNL Burkholderia pseudomallei SNP array

    SciTech Connect

    Gardner, S; Jaing, C

    2012-03-27

    The overall goal of this project is to forensically characterize 100 unknown Burkholderia isolates in the US-Australia collaboration. We will identify genome-wide single nucleotide polymorphisms (SNPs) from B. pseudomallei and near neighbor species including B. mallei, B. thailandensis and B. oklahomensis. We will design microarray probes to detect these SNP markers and analyze 100 Burkholderia genomic DNAs extracted from environmental, clinical and near neighbor isolates from Australian collaborators on the Burkholderia SNP microarray. We will analyze the microarray genotyping results to characterize the genetic diversity of these new isolates and triage the samples for whole genome sequencing. In this interim report, we described the SNP analysis and the microarray probe design for the Burkholderia SNP microarray.

  6. Evaluation of approaches for identifying population informative markers from high density SNP Chips

    PubMed Central

    2011-01-01

    Background Genetic markers can be used to identify and verify the origin of individuals. Motivation for the inference of ancestry ranges from conservation genetics to forensic analysis. High density assays featuring Single Nucleotide Polymorphism (SNP) markers can be exploited to create a reduced panel containing the most informative markers for these purposes. The objectives of this study were to evaluate methods of marker selection and determine the minimum number of markers from the BovineSNP50 BeadChip required to verify the origin of individuals in European cattle breeds. Delta, Wright's FST, Weir & Cockerham's FST and PCA methods for population differentiation were compared. The level of informativeness of each SNP was estimated from the breed specific allele frequencies. Individual assignment analysis was performed using the ranked informative markers. Stringency levels were applied by log-likelihood ratio to assess the confidence of the assignment test. Results A 95% assignment success rate for the 384 individually genotyped animals was achieved with < 80, < 100, < 140 and < 200 SNP markers (with increasing stringency threshold levels) across all the examined methods for marker selection. No further gain in power of assignment was achieved by sampling in excess of 200 SNP markers. The marker selection method that required the lowest number of SNP markers to verify the animal's breed origin was Wright's FST (60 to 140 SNPs depending on the chosen degree of confidence). Certain breeds required fewer markers (< 100) to achieve 100% assignment success. In contrast, closely related breeds require more markers (~200) to achieve > 95% assignment success. The power of assignment success, and therefore the number of SNP markers required, is dependent on the levels of genetic heterogeneity and pool of samples considered. Conclusions While all SNP selection methods produced marker panels capable of breed identification, the power of assignment varied markedly among

  7. Association of the SNP rs2623047 in the HSPG modification enzyme SULF1 with an Australian Caucasian breast cancer cohort.

    PubMed

    Okolicsanyi, Rachel K; Faure, Marion; Jacinto, Jose M E; Chacon-Cortes, Diego; Chambers, Suzanne; Youl, Philippa H; Haupt, Larisa M; Griffiths, Lyn R

    2014-08-15

    Breast cancer is the second most common cancer worldwide and the most common cancer reported in women. This malignant tumour is characterised by a number of specific features including uncontrolled cell proliferation. It ranks fifth in the world as a cause of cancer death overall in developed countries and is the second most frequent cause of cancer death in women. Early diagnosis increases 5-year survival rates up to 95%. Heparan sulfate proteoglycans (HSPGs) are complex proteins composed of a core protein to which a number of highly sulfated side chains attach, ubiquitous to the cell surface and within the extracellular matrix. HSPG side chains are synthesised by a highly co-ordinated process resulting in distinct sulfation patterns, which determine specific interactions with cell-signalling partners including growth factors, their receptors, ligands and morphogens. The enzymes responsible for chain initiation, elongation and sulfation are critical for creating HS chain variability conferring biological functionality. This study investigated a single nucleotide polymorphism in SULF1, the enzyme responsible for the 6-O desulfation of heparan sulfate side chains. We investigated this SNP in an Australian Caucasian case-control breast cancer population and found a significant association between SULF1 and breast cancer at both the allelic and genotypic levels (allele, p=0.016; genotype, p=0.032). Our results suggest that the rs2623047 SNP in SULF1 may impact breast cancer susceptibility. Specifically, the T allele of rs2623047 in SULF1 is associated with an increased risk of developing breast cancer in our cohort. The identification of markers including SULF1 may improve detection of this disease at its earliest stages improving patient treatment and prognosis. PMID:24911625

  8. Hybridization modeling of oligonucleotide SNP arrays for accurate DNA copy number estimation

    PubMed Central

    Wan, Lin; Sun, Kelian; Ding, Qi; Cui, Yuehua; Li, Ming; Wen, Yalu; Elston, Robert C.; Qian, Minping; Fu, Wenjiang J

    2009-01-01

    Affymetrix SNP arrays have been widely used for single-nucleotide polymorphism (SNP) genotype calling and DNA copy number variation inference. Although numerous methods have achieved high accuracy in these fields, most studies have paid little attention to the modeling of hybridization of probes to off-target allele sequences, which can affect the accuracy greatly. In this study, we address this issue and demonstrate that hybridization with mismatch nucleotides (HWMMN) occurs in all SNP probe-sets and has a critical effect on the estimation of allelic concentrations (ACs). We study sequence binding through binding free energy and then binding affinity, and develop a probe intensity composite representation (PICR) model. The PICR model allows the estimation of ACs at a given SNP through statistical regression. Furthermore, we demonstrate with cell-line data of known true copy numbers that the PICR model can achieve reasonable accuracy in copy number estimation at a single SNP locus, by using the ratio of the estimated AC of each sample to that of the reference sample, and can reveal subtle genotype structure of SNPs at abnormal loci. We also demonstrate with HapMap data that the PICR model yields accurate SNP genotype calls consistently across samples, laboratories and even across array platforms. PMID:19586935

  9. SNP Microarray in FISH Negative Clinically Suspected 22q11.2 Microdeletion Syndrome

    PubMed Central

    Jain, Manish; Kalsi, Amanpreet Kaur

    2016-01-01

    The present study evaluated the role of SNP microarray in 101 cases of clinically suspected FISH negative (noninformative/normal) 22q11.2 microdeletion syndrome. SNP microarray was carried out using 300 K HumanCytoSNP-12 BeadChip array or CytoScan 750 K array. SNP microarray identified 8 cases of 22q11.2 microdeletions and/or microduplications in addition to cases of chromosomal abnormalities and other pathogenic/likely pathogenic CNVs. Clinically suspected specific deletions (22q11.2) were detectable in approximately 8% of cases by SNP microarray, mostly from FISH noninformative cases. This study also identified several LOH/AOH loci with known and well-defined UPD (uniparental disomy) disorders. In conclusion, this study suggests more strict clinical criteria for FISH analysis. However, if clinical criteria are few or doubtful, in particular newborn/neonate in intensive care, SNP microarray should be the first screening test to be ordered. FISH is ideal test for detecting mosaicism, screening family members, and prenatal diagnosis in proven families. PMID:27051557

  10. High-resolution SNP arrays in mental retardation diagnostics: how much do we gain?

    PubMed Central

    Bernardini, Laura; Alesi, Viola; Loddo, Sara; Novelli, Antonio; Bottillo, Irene; Battaglia, Agatino; Digilio, Maria Cristina; Zampino, Giuseppe; Ertel, Adam; Fortina, Paolo; Surrey, Saul; Dallapiccola, Bruno

    2010-01-01

    We used Affymetrix 6.0 GeneChip SNP arrays to characterize copy number variations (CNVs) in a cohort of 70 patients previously characterized on lower-density oligonucleotide arrays affected by idiopathic mental retardation and dysmorphic features. The SNP array platform includes ∼900 000 SNP probes and 900 000 non-SNP oligonucleotide probes at an average distance of 0.7 Kb, which facilitates coverage of the whole genome, including coding and noncoding regions. The high density of probes is critical for detecting small CNVs, but it can lead to data interpretation problems. To reduce the number of false positives, parameters were set to consider only imbalances >75 Kb encompassing at least 80 probe sets. The higher resolution of the SNP array platform confirmed the increased ability to detect small CNVs, although more than 80% of these CNVs overlapped to copy number ‘neutral' polymorphism regions and 4.4% of them did not contain known genes. In our cohort of 70 patients, of the 51 previously evaluated as ‘normal' on the Agilent 44K array, the SNP array platform disclosed six additional CNV changes, including three in three patients, which may be pathogenic. This suggests that about 6% of individuals classified as ‘normal' using the lower-density oligonucleotide array could be found to be affected by a genomic disorder when evaluated with the higher-density microarray platforms. PMID:19809473