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1

A1298C polymorphism in the MTHFR gene predisposes to cardiovascular risk in rheumatoid arthritis  

Microsoft Academic Search

INTRODUCTION: We determined the contribution of the methylene tetrahydrofolate reductase (MTHFR) 677 C>T and 1298 A>C gene polymorphisms to the susceptibility to rheumatoid arthritis (RA). We also assessed whether these two MTHFR gene polymorphisms may be implicated in the development of cardiovascular (CV) events and subclinical atherosclerosis manifested by the presence of endothelial dysfunction, in a series of Spanish patients

Rogelio Palomino-Morales; Carlos Gonzalez-Juanatey; Tomas R Vazquez-Rodriguez; Luis Rodriguez; Jose A Miranda-Filloy; Benjamin Fernandez-Gutierrez; Javier Llorca; Javier Martin; Miguel A Gonzalez-Gay

2010-01-01

2

A1298C polymorphism in the MTHFR gene predisposes to cardiovascular risk in rheumatoid arthritis  

PubMed Central

Introduction We determined the contribution of the methylene tetrahydrofolate reductase (MTHFR) 677 C>T and 1298 A>C gene polymorphisms to the susceptibility to rheumatoid arthritis (RA). We also assessed whether these two MTHFR gene polymorphisms may be implicated in the development of cardiovascular (CV) events and subclinical atherosclerosis manifested by the presence of endothelial dysfunction, in a series of Spanish patients with RA. Methods Six hundred and twelve patients fulfilling the 1987 American College of Rheumatology classification criteria for RA, seen at the rheumatology outpatient clinics of Hospital Xeral-Calde, Lugo and Hospital San Carlos, Madrid, were studied. Patients and controls (n = 865) were genotyped using predesigned TaqMan SNP genotyping assays. Results No significant differences in allele or genotype frequencies for the MTHFR gene polymorphisms between RA patients and controls were found. Also, no association between the MTHFR 677 C>T polymorphism and CV events or endothelial dysfunction was observed. However, the MTHFR 1298 allele C frequency was increased in patients with CV events after 5 years (38.7% versus 30.3%; odds ratio = 1.45; 95% confidence interval = 1.00 to 2.10; P = 0.04) and 10 years (42.2% versus 31.0%; odds ratio = 1.62; 95% confidence interval = 1.08 to 2.43; P = 0.01) follow up. Moreover, patients carrying the MTHFR 1298 AC and CC genotypes had a significantly decreased flow-mediated endothelium-dependent vasodilatation (4.3 ± 3.9%) compared with those carrying the MTHFR 1298 AA genotype (6.5 ± 4.4%) (P = 0.005). Conclusions Our results show that the MTHFR 1298 A>C gene polymorphism confers an increased risk for subclinical atherosclerosis and CV events in patients with RA. PMID:20423475

2010-01-01

3

Severe and mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene, and description of five novel mutations in MTHFR.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, a methyl donor in the conversion of homocysteine to methionine. Patients with severe MTHFR deficiency have hyperhomocysteinemia, hypomethioninemia, and a range of neurological and vascular findings with a variable age at onset. We have previously described nine mutations in patients with severe MTHFR deficiency. A mild form of MTHFR deficiency, associated with a thermolabile enzyme, has been proposed as a genetic risk factor for cardiovascular disease and for neural tube defects. We have shown that a common missense mutation (an alanine-to-valine substitution) encodes this thermolabile variant. We now report an additional five mutations causing severe MTHFR deficiency and an analysis of genotype (alanine/valine status) and enzyme thermolability in 22 patients with this inborn error of metabolism. Six of these patients have four mutations in the MTHFR gene-two rare mutations causing severe deficiency and two mutations for the common alanine-to-valine mutation that results in thermolability. Even in severe MTHFR deficiency, the thermolabile variant is frequently observed, and there is a strong relationship between the presence of this variant and increased enzyme thermolability. PMID:8940272

Goyette, P; Christensen, B; Rosenblatt, D S; Rozen, R

1996-12-01

4

Severe and mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene, and description of five novel mutations in MTHFR.  

PubMed Central

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, a methyl donor in the conversion of homocysteine to methionine. Patients with severe MTHFR deficiency have hyperhomocysteinemia, hypomethioninemia, and a range of neurological and vascular findings with a variable age at onset. We have previously described nine mutations in patients with severe MTHFR deficiency. A mild form of MTHFR deficiency, associated with a thermolabile enzyme, has been proposed as a genetic risk factor for cardiovascular disease and for neural tube defects. We have shown that a common missense mutation (an alanine-to-valine substitution) encodes this thermolabile variant. We now report an additional five mutations causing severe MTHFR deficiency and an analysis of genotype (alanine/valine status) and enzyme thermolability in 22 patients with this inborn error of metabolism. Six of these patients have four mutations in the MTHFR gene-two rare mutations causing severe deficiency and two mutations for the common alanine-to-valine mutation that results in thermolability. Even in severe MTHFR deficiency, the thermolabile variant is frequently observed, and there is a strong relationship between the presence of this variant and increased enzyme thermolability. Images Figure 1 Figure 2 PMID:8940272

Goyette, P.; Christensen, B.; Rosenblatt, D. S.; Rozen, R.

1996-01-01

5

MTHFR Gene C677T Polymorphism in Autism Spectrum Disorders  

PubMed Central

Aim. Autism is a subgroup of autism spectrum disorders, classified as a heterogeneous neurodevelopmental disorder and symptoms occur in the first three years of life. The etiology of autism is largely unknown, but it has been accepted that genetic and environmental factors may both be responsible for the disease. Recent studies have revealed that the genes involved in the folate/homocysteine pathway may be risk factors for autistic children. In particular, C677T polymorphism in the MTHFR gene as a possible risk factor for autism is still controversial. We aimed to investigate the possible effect of C677T polymorphism in a Turkish cohort. Methods. Autism patients were diagnosed by child psychiatrists according to DSM-IV and DSM-V criteria. A total of 98 children diagnosed as autistic and 70 age and sex-matched children who are nonautistic were tested for C677T polymorphism. This polymorphism was studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Results. MTHFR 677T-allele frequency was found to be higher in autistic children compared with nonautistic children (29% versus 24%), but it was not found statistically significant. Conclusions. We conclude that other MTHFR polymorphisms such as A1298C or other folate/homocysteine pathway genes may be studied to show their possible role in autism.

Oztop, Didem Behice; Ozkul, Yusuf

2014-01-01

6

Methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms in chronic myeloid leukemia: an Egyptian study.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) gene plays a pivotal role in folate metabolism. Several genetic variations in MTHFR gene as MTHFR-C677T and MTHFR-A1298C result in decreased MTHFR activity, which could influence efficient DNA methylation and explain susceptibility to different cancers. The etiology of chronic myeloid leukemia (CML) is obscure and little is known about individual's susceptibility to CML. In order to assess the influence of these genetic polymorphisms on the susceptibility to CML and its effect on the course of the disease among Egyptians, we performed an age-gender-ethnic matched case-control study. The study included 97 CML patients and 130 healthy controls. Genotyping of MTHFR-C677T and -A1298C was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The results showed no statistical difference in the distribution of MTHFR-C677T and -A1298C polymorphic genotypes between CML patients and controls. The frequency of MTHFR 677-TT homozygous variant was significantly higher in patients with accelerated/blastic transformation phase when compared to those in the chronic phase of the disease. In conclusion, our study revealed that MTHFR-C677T and -A1298C polymorphisms could not be considered as genetic risk factors for CML in Egyptians. However, MTHFR 677-TT homozygous variant might be considered as a molecular predictor for disease progression. PMID:24338216

Khorshied, Mervat Mamdooh; Shaheen, Iman Abdel Mohsen; Abu Khalil, Reham E; Sheir, Rania Elsayed

2014-01-01

7

Prevalence of MTHFR gene polymorphisms (C677T and A1298C) among Tamilians  

Microsoft Academic Search

We have investigated the incidence of the C677T and A1298C methylene tetrahydrofolate reductase (MTHFR) gene single nucleotide polymorphisms (SNPs) in the South Indian Tamil Nadu population with a total number of 72 individuals. The MTHFR genotyping was performed using the polymerase chain reaction followed by restriction enzyme analysis. Homozygosity for the MTHFR A1298C SNP was detected in 15.3% (11\\/72) of

T. Angeline; Nirmala Jeyaraj; Selena Granito; Gregory J. Tsongalis

2004-01-01

8

Factor V G1691A, Prothrombin G20210A, and Methylenetetrahydrofolate Reductase [MTHFR] C677T Gene Polymorphism in Angiographically Documented Coronary Artery Disease  

Microsoft Academic Search

Background: Single point mutations in the genes coding for factor V [G1691A; Leiden], prothrombin [PRT; G20210A], and methylenetetrahydrofolate reductase [MTHFR, C677T] were shown to be major inherited predisposing factors for venous thromboembolism. However, their contribution in the development of coronary artery disease [CAD] remains controversial. The aim of the study was to examine the association of these mutations in CAD.

Wassim Y. Almawi; Ghada Ameen; Hala Tamim; Ramzi R. Finan; Noha Irani-Hakime

2004-01-01

9

MTHFR C677T Predisposes to POAG but Not to PACG in a North Indian Population: A Case Control Study  

PubMed Central

Hyperhomocysteinemia induced by the C677T genetic variant in MTHFR (methylenetetrahydrofolate reductase) has been implicated in neuronal cell death of retinal ganglion cells (RGC), which is a characteristic feature of glaucoma. However, association of MTHFR C677T with glaucoma has been controversial because of inconsistent results across association studies. Association between MTHFR C677T and glaucoma has not been reported in Indian population. Therefore, with a focus on neurodegenerative death of RGC in glaucoma, the current study aimed to investigate association of MTHFR C677T with Primary Open Angle Glaucoma (POAG) and Primary Angle Closure Glaucoma (PACG) in a North Indian population. A total of 404 participants (231 patients and 173 controls) were included in this study. Genotyping was performed by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism. A few random samples were also tested by direct sequencing. Genotypic and allelic distributions of the POAG and PACG cohorts were compared to that of controls by chi-square test and odds ratios were reported with 95% confidence intervals. Genotypic and allelic distributions between POAG cases and controls were significantly different (p?=?0.03 and p?=?0.01 respectively). Unlike POAG, we did not find significant difference in the genotypic and allelic distributions of C677T between PACG cases and controls (p>0.05). We also observed a higher proportion of TT associated POAG in females than that in males. However, this is a preliminary indication of gender specific risk of C677T that needs to be replicated in a larger cohort of males and females. The present investigation on MTHFR C677T and glaucoma reveals that the TT genotype and T allele of this polymorphism are significant risk factors for POAG but not for PACG in North Indian population. Ours is the first report demonstrating association of MTHFR C677T with POAG but not PACG in individuals from North India. PMID:25054348

Gupta, Shashank; Bhaskar, Pradeep Kumar; Bhardwaj, Ritu; Chandra, Abhishek; Chaudhry, Vidya Nair; Chaudhry, Prashaant; Ali, Akhtar; Mukherjee, Ashim; Mutsuddi, Mousumi

2014-01-01

10

Gene variants predisposing to SIDS: current knowledge  

Microsoft Academic Search

Genetic risk factors play a role in sudden unexpected infant death; either as a cause of death, such as in cases with medium-chain\\u000a acyl-coenzyme A dehydrogenase deficiency and cardiac arrest due to long QT syndrome, or as predisposing factors for sudden\\u000a infant death syndrome (SIDS). Most likely genetic predisposition to SIDS represent a polygenic inheritance pattern leading\\u000a to sudden death

Siri H. OpdalTorleiv; Torleiv O. Rognum

2011-01-01

11

Hyperhomocysteinaemia and MTHFR C677T gene polymorphism in renal transplant recipients  

Microsoft Academic Search

AIMTo study the effect of folate treatment on hyperhomocysteinaemia and the effect of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism on total homocysteine and folate concentrations after renal transplantation.METHODSA total of 30 transplanted children and adolescents were investigated for total homocysteine and folate serum concentrations before and after folate treatment, as well as for the presence of the MTHFR C677T polymorphism.RESULTSThe allele

A J Szabó; T Tulassay; B Melegh; T Szabó; Á Vannay; A Fekete; Z Süveges; G S Reusz

2001-01-01

12

Association between MTHFR gene polymorphism and NTDs in Chinese Han population  

PubMed Central

Objective: This study aims to investigate the single nucleotide polymorphisms (SNPs) of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and neural tube defects (NTDs) in Chinese population. Method: A total of 271 NTDs cases and 192 healthy controls were used in this study. Fifty-two selected single nucleotide polymorphism (SNP) sites in the MTHFR gene were analyzed with next-generation sequencing method. A series of statistical methods were carried out to investigate the correlation between the SNPs and the patient susceptibility to NTDs. Results: Statistical analysis showed a significant correlation between the SNP sites rs1801133 in MTHFR gene and NTDs. The GG genotype, G allele of rs1801133 in MTHFR significantly decreased the incidence of NTDs (OR = 0.449, 95% CI: 0.255-0.789 with genotype, and OR = 0.669, 95% CI: 0.508-0.881 with allele). Conclusions: The gene polymorphism loci rs1801133 in MTHFR gene maybe potential risk factors for NTD in Chinese population.

Yu, Yang; Wang, Fang; Bao, Yihua; Lu, Xiaolin; Quan, Li; Lu, Ping

2014-01-01

13

Effects of MTHFR gene polymorphism on the clinical and electrophysiological characteristics of migraine  

PubMed Central

Background It was previously shown that the MTHFR gene polymorphism correlated with an increased risk of migraine, particularly migraine with aura. The substitution of cytosine for thymine at the position 677 of the MTHFR gene leads to formation of the thermolabile form of the protein and development of hyperhomocysteinemia, which increases the probability of migraine. The purpose of this study was to determine whether the replacement of C677T in the gene MTHFR influenced any particular symptoms of the disease. Methods We have analyzed clinical and electrophysiological characteristics of 83 patients with migraine (migraine with aura (MA), 19 patients, and migraine without aura (MO), 64 patients, according to the ICHD-II (2003)) taking into account their genotypes of C677T variant of MTHFR. Results We have shown that MA was significantly more prevalent among the T-allele carriers (37.2%), as compared to the ?? genotype patients (0%), ? < 0.0001. Patients with TT genotype were not only more likely to have accompanying symptoms (significant differences were found only for photophobia), but also more sensitive to migraine attack triggers. In RP-VEP test results we observed a trend that the T-allele carriers were presented with the decreased N75/P100 amplitudes and a positive habituation index, as compared to the ?? genotype patients. Conclusions Thus, according to our data, the MTHFR genotypes are associated with several clinical and electrophysiological characteristics of migraine. PMID:23915182

2013-01-01

14

[Prevalence of methylenetetrahydrofolate reductase (MTHFR) gene polymorphism (C677T) in the Hungarian population].  

PubMed

MTHFR encodes a critical enzyme in folate and homocysteine metabolism and the C677T allele of the MTHFR gene has some association with an increased risk for neural-tube defects and for adult cardiovascular diseases. As part of an international collaborative study the prevalence of C677T homozygous genotype was 11.1% while the frequency of C677T heterozygous condition was 45.2% in the Hungarian neonate sample. These findings underscore the clinical importance of the C677T variant in the Hungarian population and urge population-based prevention of conditions related to such gene. PMID:11433922

Czeizel, E; Tímár, L; Botto, L

2001-06-10

15

Association of MTHFR gene polymorphism C677T with susceptibility to late-onset alzheimer’s disease  

Microsoft Academic Search

Increased total plasma homocysteine (t-Hcy) levels are found to be associated with Alzheimer’s disease (AD). Because the methylenetetrahydrofolate\\u000a reductase (MTHFR) gene encodes a key enzyme that influences the metabolism of homocysteine, it has been considered as a possible genetic risk\\u000a factor for AD. Although the MTHFR gene C677T polymorphism has a significant impact on reducing enzyme activity and increasing t-Hcy

Binbin Wang; Feng Jin; Rui Kan; Shun Ji; Chuanfang Zhang; Zeping Lu; Chenguang Zheng; Ze Yang; Li Wang

2005-01-01

16

Hyperhomocysteinaemia and MTHFR C677T gene polymorphism in renal transplant recipients  

PubMed Central

AIM—To study the effect of folate treatment on hyperhomocysteinaemia and the effect of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism on total homocysteine and folate concentrations after renal transplantation.?METHODS—A total of 30 transplanted children and adolescents were investigated for total homocysteine and folate serum concentrations before and after folate treatment, as well as for the presence of the MTHFR C677T polymorphism.?RESULTS—The allele frequency of C677T polymorphism in the MTHFR gene in the study population (0.33) was not different to that in controls (0.38). Before folate treatment the homocysteine concentration was raised in all groups; following folate supplementation it was significantly decreased in the CC and CT groups, but not in the TT group. In patients with CC genotype, serum homocysteine correlated with serum creatinine and cholesterol, and time since transplantation before treatment.?CONCLUSION—Folate supplementation appears to be an effective strategy to normalise total homocysteine concentration in renal transplanted children and adolescents.?? PMID:11420199

Szabo, A; Tulassay, T; Melegh, B; Szabo, T; Szabo, A; Vannay, A; Fekete, A; Suveges, Z; Reusz, G

2001-01-01

17

Screening of polymorphisms for MTHFR and DHFR genes in spina bifida children and their mothers  

NASA Astrophysics Data System (ADS)

Mechanism underlying the beneficial effect of folic acid supplementation in reducing the risk of neural tube defect is still not well understood. Current evidences show the involvement of folic acid metabolic gene's polymorphism as contributing factors that regulate this pathway. Therefore, the objective of this research was to determine the presence of C677T polymorphism for methylenetetrahydrofolate reductase (MTHFR) and dihydrofolate reductase (DHFR-19 bp deletion) genes between mother-children pairs of case and control. With the approval of UKMMC ethic committee, genomic DNA was extracted from one hundred and forty consented bloods. Polymerase chain reaction (PCR), PCR-RFLP (Restriction Fragment Length Polymorphism) and sequencing were employed to verify each nucleotide change. Our result shows that mutant MTHFR and DHFR alleles are present in all Malaysian sub-ethnic groups, case and control. Even though mutant MTHFR are found to be slightly higher in the case groups, 75% of the affected child is a non carrier for this allele and 62.5% of the mothers with an affected child are genotypically normal. For DHFR, almost all (87.5-100%) investigated samples are a carrier or having a double DHFR deletion be it a case or control pairs. However, strong maternal inheritance shown by the deleted allele might be due to a cascade effect of lacks of folate consumption or maternal uniparental disomy. In conclusion, the use of MTHFR and DHFR as markers in determining the risk of having spina bifida baby is uninformative and plays a small indirect role as the genetic causes of spina bifida. Therefore, spina bifida remains etiologically unknown polygenic and quantitative developmental trait whereby the searches for positive genetic marker need to be continued.

Husna, M. Z.; Endom, I.; Ibrahim, S.; Selvi, N. Amaramalar; Fakhrurazi, H.; Htwe, R. Ohnmar; Kanehaswari, Y.; Halim, A. R. Abdul; Wong, S. W.; Subashini, K.; Syahira, O. Nur; Aishah, S.

2013-11-01

18

Relationship between methylenetetrahydrofolate reductase (MTHFR) A1298C gene polymorphism and type 2 diabetic nephropathy risk: a meta-analysis.  

PubMed

Relationship between methylenetetrahydrofolate reductase (MTHFR) A1298C gene polymorphism and type 2 diabetic nephropathy (T2DN) risk is still unclear. This study was performed to evaluate if there is an association between the MTHFR A1298C gene polymorphism and T2DN risk using meta-analysis. The relevant reports were searched and identified from PubMed, Cochrane Library on 1 October 2013, and eligible studies were included and synthesized. Eight reports were recruited into this meta-analysis for the association of the MTHFR A1298C gene polymorphism with T2DN risk. The MTHFR A1298C C allele or CC genotype was shown to be not associated with T2DN risk (C allele: OR = 0.76, 95% CI: 0.43-1.34, p = 0.34; CC genotype: OR = 1.18, 95% CI: 0.63-2.22, p = 0.60). Interestingly, AA genotype was associated with the T2DN risk (OR = 0.68, 95% CI: 0.49-0.96, p = 0.03). In the sensitivity analysis according to the Hardy-Weinberg equilibrium (HWE), the results were consistent with those in non-sensitivity analysis. However, in the sensitivity analysis according to the control source from hospital, sample size of case (? 100), sample size of case (<100), the MTHFR A1298C gene polymorphism was not associated with T2DN risk. In conclusion, the MTHFR A1298C gene polymorphism was not associated with T2DN risk. However, additional studies are required to firmly establish a correlation between the MTHFR A1298C gene polymorphism and T2DN risk. PMID:24678913

Zhang, Jie; Xiao, Yan; Zhang, Xian-Wen; Gao, Zhi-Qing; Han, Jing-Hui

2014-07-01

19

Association of Polymorphisms in BDNF, MTHFR, and Genes Involved in the Dopaminergic Pathway with Memory in a Healthy Chinese Population  

ERIC Educational Resources Information Center

The contribution of genetic factors to the memory is widely acknowledged. Research suggests that these factors include genes involved in the dopaminergic pathway, as well as the genes for brain-derived neurotrophic factor (BDNF) and methylenetetrahydrofolate reductase (MTHFR). The activity of the products of these genes is affected by single…

Yeh, Ting-Kuang; Hu, Chung-Yi; Yeh, Ting-Chi; Lin, Pei-Jung; Wu, Chung-Hsin; Lee, Po-Lei; Chang, Chun-Yen

2012-01-01

20

Evaluation of the MTHFR C677T allele and the MTHFR gene locus in a German spina bifida population  

Microsoft Academic Search

A number of recent studies have demonstrated that the occurrence and recurrence risk of neural tube defects (NTD) is reduced\\u000a by folic acid supplementation before and during pregnancy. Epidemiological studies have shown low plasma folate and raised\\u000a plasma homocysteine in women with spina bifida aperta (SB) children suggesting an abnormal folate metabolism. The 5,10-methylenetetrahydrofolate\\u000a reductase (MTHFR) variant C677T, resulting in

M. C. Koch; K. Stegmann; A. Ziegler; B. Schröter; A. Ermert

1998-01-01

21

Folate Levels and Polymorphisms in the Genes MTHFR, MTR, and TS in Colorectal Cancer  

PubMed Central

AIM The aim of the study was to explore and describe the effect of polymorphisms in folate-associated genes regarding the levels of different folate forms and their distribution in tumors and mucosa in patients with colorectal cancer. MATERIALS AND METHODS Tumor and mucosa tissues from 53 patients with colorectal cancer were analyzed. The concentrations of tetrahydrofolate (THF), 5-methylTHF, and 5,10-methyleneTHF were measured by liquid chromatography—mass spectrometry. Genotyping of polymorphisms in the folate-associated genes methylenetetrahydrofolate reductase (MTHFR, C677T), methionine synthase (MTR, A2756G), and thymidylate synthase (TS, 5?-TSER 28 bp tandem repeat and 3?-TSUTR 6 bp deletion/insertion), were done by real-time polymerase chain reaction. Folate levels and distributions were determined in the total patient cohort and after subgrouping by genotypes. RESULTS The total folate level, as well as the THF and 5,10-methyleneTHF levels, were significantly higher in the tumor compared with mucosa tissue (P = 0.030, 0.031, and 0.015, respectively). The individual variation in folate levels in both tumor and mucosa were larger than the variation found when the patients were subgrouped by the gene polymorphisms. No significant differences in the mean concentration of any folate in the mucosa or tumor tissue were found in relation to the analyzed polymorphisms. The percentage level of 5,10-methyleneTHF in tumors was highest in patients with the MTHFR 677 CC genotype, and lowest in patients with the TT genotype (P = 0.033). A significantly lower percentage level of the 5,10-methyleneTHF level was found in tumors of patients with the 5?-TSER 3R/3R genotype (P = 0.0031). CONCLUSION A significant difference was found between the percentage level of 5,10-methyleneTHF in tumor tissues in relation to the MTHFR C677T and 5?-TSER 28 bp repeat polymorphisms. However, no differences were found in the actual tissue folate levels, or in their distribution, in relation to the polymorphisms in the MTHFR, MTR, or TS genes. These findings could be of importance for further research in the field by explaining some of the difficulties of obtaining reproducible and uniform results when using a few selected polymorphisms as predictive markers. PMID:24596472

Taflin, Helena; Wettergren, Yvonne; Odin, Elisabeth; Carlsson, Goran; Derwinger, Kristoffer

2014-01-01

22

Methylenetetrahydrofolate reductase gene polymorphisms are associated with ischemic and hemorrhagic stroke: Dual effect of MTHFR polymorphisms C677T and A1298C  

Microsoft Academic Search

Hyperhomocysteinemia is an independent risk factor for ischemic stroke. The enzyme methylenetetrahydrofolate reductase (MTHFR) plays a critical role in modulating the levels of plasma homocysteine. Two polymorphisms in the MTHFR gene, C677T, A1298C result in reduced enzyme activity. The mechanisms of ischemic and hemorrhagic stroke are not well understood. Although controversial, previous studies have shown evidence of causality of both

Ali Sazci; Emel Ergul; Nese Tuncer; Gurler Akpinar; Ihsan Kara

2006-01-01

23

Methylenetetrahydrofolate reductase (MTHFR) 677C>T gene polymorphism as a possible factor for reducing clinical severity of psoriasis  

PubMed Central

Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in homocysteine/methionine metabolism. It catalysis the formation of 5-methyltetrahydrofolate (5-methyl-THF), which is the methyl donor for synthesis of methionine from homocysteine (Hcy). Decreases in folate consumption due to MTHFR polymorphism may affect production rate of keratinocytes of which had faster reproduction rates with a continuous DNA turnover and this may affect the clinical picture of psoriasis. This study aimed to investigate correlation of C677T polymorphisms in the MTHFR gene with severity of psoriasis and to evaluate the status of plasma Hcy, folate and vitamin B12 levels in patient with chronic plaque psoriasis. The study included 60 patients with chronic plaque psoriasis. The C677T polymorphisms were genotyped using PCR (Qiagen). Psoriasis Area and Severity Index (PASI) score below 7 was defined as mild, between 7 and 12 as moderate, and above 12 as severe disease. There was a significant difference between the severity of disease classification (p<0.05) with respect to the C677T polymorphism in the MTHFR gene. Severe involvement (PASI score >12) was observed in 38.46% of wild type (CC), but only 12.50% of homozygote (TT) and 7.69% of heterozygote (CT) patients. Significant differences between gene polymorphism and Hcy levels were noted in TT and CT genotypes respectively (p=0.025 and p=0.040). Plasma Hcy, folate and vitamin B12 levels were not correlated with the PASI score. Our data indicate a possible correlation of MTHFR polymorphism with severity of psoriasis. PMID:24753765

Karabacak, Ercan; Aydin, Ersin; Ozcan, Omer; Dogan, Bilal; Gultepe, Mustafa; Cosar, Alpaslan; Muftuoglu, Tuba

2014-01-01

24

Role of 677C?T polymorphism a single substitution in methylenetetrahydrofolate reductase (MTHFR) gene in North Indian infertile men.  

PubMed

Failure or severe difficulty in conceiving a child is surprisingly common, worldwide problem. Half of these cases are due to male factors with defects in sperm (1 in 15 men) being the single most common cause. Also about 60-75 % of male infertility cases are idiopathic, since the molecular mechanisms underlying the defects remain unknown. DNA methylation is crucial for spermatogenesis and high methylenetetrahydrofolate reductase (MTHFR) activity in adult testis than other organs in mouse, signifies its critical role in spermatogenesis. According to recent findings there is a correlation of epigenetic regulation of several imprinted genes with disturbed spermatogenesis and fertility. Consequently any change in the MTHFR gene sequence can modify the spermatogenesis including transmission of infertility to the carriers. The aim of the study is to analyze the distribution of the single nucleotide polymorphism C677T in the MTHFR gene in 637 North Indian infertile patients and 364 fertile North Indian men as controls by using PCR-RFLP technique and Chi Square test for statistical analysis. The average MTHFR 677CC, 677CT, 677TT genotype frequencies of total infertile men were 70.17, 24.17, 5.65 % in infertile men and 75.27, 21.7, 2.74 % in controls, respectively. The average frequency of the MTHFR 677T allele was 17.73 % in infertile men as compared to 13.59 % in controls. The statistical difference was significant. Disease risk was found 2.27-folds increased in patients who were carrying T allele. We found an association of C677T polymorphism with male infertility and that it may be a genetic risk factor for male infertility in North Indian population. PMID:24366618

Naqvi, Hena; Hussain, Syed Rizwan; Ahmad, Mohammad Kaleem; Mahdi, Farzana; Jaiswar, Shyam Pyari; Shankhwar, Satya Narayain; Mahdi, Abbas Ali

2014-02-01

25

Unilateral Renal Vein Thrombosis and Adrenal Hemorrhage in A Newborn with Homozygous Factor V Leiden and Heterozygous Of MTHFR-677T, MTHFR-1298C Gene Mutations.  

PubMed

Renal vein thrombosis (RVT) occurs as an acute and life-threatening event in neonates. RVT is the most common non-catheter-related thrombosis in infancy and occurs primarily in the newborn period. Non-catheter-related abdominal thrombosis on neonates has a higher incidence of genetic prothrombotic risk factors. RVT and adrenal hemorrhage can both be encountered in the neonatal period and they may occur at the same time (Bokenkamp et al., Eur J Pediatr 159:44-8, 2000; Lau et al. Pediatrics 120:1278-84, 2007). We report a case of unilateral RVT and adrenal hemorrhage in a newborn with homozygous factor V Leiden mutation and heterozygous of the methylene tetrahydrofolate reductase (MTHFR) gene mutations. PMID:25332602

Sandal, Gonca; Ar?kan, Elvan; Kuybulu, Ayça Esra; Ormec?, Ahmet Rifat

2014-09-01

26

Methylenetetrahydrofolate reductase (MTHFR) c677t gene variant modulates the homocysteine folate correlation in a mild folate-deficient population  

Microsoft Academic Search

Background: A large body of evidence links plasma concentrations of homocysteine and cardiovascular disease. Several genetic and environmental variables may modulate such relationship. We investigated the influence of methylenetetrahydrofolate reductase (MTHFR) gene variants C677T, A1298C, and T1317C on homocysteine, folate, and cobalamin concentrations in a sample of individuals from a mild folate deficiency population to better clarify the complex interactions

Alexandre C. Pereira; Isolmar Tadeu Schettert; Antônio Alberto F. Morandini Filho; Elvira Maria Guerra-Shinohara; José E. Krieger

2004-01-01

27

MTHFR C677T and A1298C gene polymorphisms and hyperhomocysteinemia as risk factors of diabetic nephropathy in type 2 diabetes patients  

Microsoft Academic Search

Point mutations in methylenetetrahydrofolate reductase (MTHFR) and hyperhomocysteinemia were implicated in the pathogenesis of diabetic nephropathy (DN) in many ethnic groups. This study addressed the association of C677T and A1298C single nucleotide polymorphisms (SNPs) of MTHFR gene with DN in Tunisian type 2 diabetes (T2DM) patients. Study subjects comprised 93 DN patients, 267 patients with normoalbuminuria, and 400 control subjects.

Nabil Mtiraoui; Intissar Ezzidi; Molka Chaieb; Hela Marmouche; Zied Aouni; Arbi Chaieb; Touhami Mahjoub; Martine Vaxillaire; Wassim Y. Almawi

2007-01-01

28

Effects of the C677T and A1298C polymorphisms of the MTHFR gene on the genetic predisposition for diabetic nephropathy  

Microsoft Academic Search

Background. Methylenetetrahydrofolate reductase (MTHFR) is a regulatory enzyme of homocysteine metabolism. The C677T polymorphism of the MTHFR gene has been reported to be associated with elevated plasma homocysteine in patients with low folic acid intake. A recently reported second common poly- morphism, A1298C, may increase homocysteine, but only in individuals carryingthe T677 allele. This study aimed to investigate the influence

Dariusz Moczulski; Hanna Fojcik; Ewa Zukowska-Szczechowska; Ilona Szydlowska; Wladyslaw Grzeszczak

2003-01-01

29

Association of Methylentetraydrofolate Reductase (MTHFR) 677 C > T gene polymorphism and homocysteine levels in psoriasis vulgaris patients from Malaysia: a case-control study  

PubMed Central

Background The methylenetetrahydrofolate reductase (MTHFR) enzyme catalyzes the reduction of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate and methyl donors. The methyl donors are required for the conversion of homocysteine to methionine. Mutation of MTHFR 677 C > T disrupts its thermostability therefore leads to defective enzyme activities and dysregulation of homocysteine levels. Methods This case-control study (n = 367) was conducted to investigate the correlation of the MTHFR gene polymorphism [NM_005957] and psoriasis vulgaris amongst the Malaysian population. Overnight fasting blood samples were collected from a subgroup of consented psoriasis vulgaris patients and matched controls (n = 84) for the quantification of homocysteine, vitamin B12 and folic acid levels. Results There was no significant increase of the MTHFR 677 C > T mutation in patients with psoriasis vulgaris compared with controls (?2 = 0.733, p = 0.392). No significant association between homocysteine levels and MTHFR gene polymorphism in cases and controls were observed (F = 0.91, df = 3, 80, p = 0.44). However, homocysteine levels in cases were negatively correlated with vitamin B12 (r = -0.173) and folic acid (r = -0.345) levels. Vitamin B12 and folic acid levels in cases were also negatively correlated (r = -0.164). Conclusions Our results indicate that there was no significant association between the MTHFR gene polymorphism and psoriasis vulgaris in the Malaysian population. There was no significant increase of the plasma homocysteine level in the psoriasis patients compared to the controls. PMID:22217364

2012-01-01

30

MTHFR Gene Polymorphism and Age of Onset of Schizophrenia and Bipolar Disorder  

PubMed Central

Objective. Several studies with contradictory results from different cultures about association of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in schizophrenia and bipolar disorders. Little is known about this association in Arab culture and Egypt. So the present study aimed to assess the association of MTHFR C677T polymorphism in bipolar disorder (BD) and schizophrenia in comparison to control group. The association between MTHFR C677T polymorphism and the age at onset in schizophrenia or BD was also studied. Methods. Polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) were used to examine the genotype and allele frequencies of MTHFR C677T polymorphism in 149 healthy subjects and 134 bipolar and 103 schizophrenia patients. Results. In BD and schizophrenia, there was a higher prevalence of MTHFR C677T polymorphism than healthy subjects. Earlier age at onset was found in patients with BD, carrying one copy of the T allele or CT genotypes but not in patients with schizophrenia. Conclusion. The present findings suggest that the MTHFR C677T polymorphisms are likely to be associated with the risk of developing BD and schizophrenia and influence the age at onset of BD but not the age at onset of schizophrenia. PMID:25101272

El-Hadidy, Mohamed A.; Abdeen, Hanaa M.; Abd El-Aziz, Sherin M.

2014-01-01

31

Regional genomic instability predisposes to complex dystrophin gene rearrangements  

Microsoft Academic Search

Mutations in the dystrophin gene (DMD) cause Duchenne and Becker muscular dystrophies and the majority of cases are due to DMD gene rearrangements. Despite the high incidence of these aberrations, little is known about their causative molecular mechanism(s).\\u000a We examined 792 DMD\\/BMD clinical samples by oligonucleotide array-CGH and report on the junction sequence analysis of 15 unique\\u000a deletion cases and

Junko Oshima; Daniel B. Magner; Jennifer A. Lee; Amy M. Breman; Eric S. Schmitt; Lisa D. White; Carol A. Crowe; Michelle Merrill; Parul Jayakar; Aparna Rajadhyaksha; Christine M. Eng; Daniela del Gaudio

2009-01-01

32

Dietary folate intake in combination with MTHFR C677T genotype and promoter methylation of tumor suppressor and DNA repair genes in sporadic colorectal adenomas  

Microsoft Academic Search

Methylation of the promoter region of tumor suppressor genes is increasingly recognized to play a role in cancer development through silencing of gene transcription. We examined the associations between dietary folate intake, MTHFR C677T genotype, and promoter methylation of six tumor suppressor and DNA repair genes. Patients with colorectal adenoma (n = 149) and controls (n = 286) with folate

M. van den Donk; M. van Engeland; E. P. M. Pellis; B. J. M. Witteman; F. J. Kok; J. Keijer; E. Kampman

2007-01-01

33

Associations of variants in MTHFR and MTRR genes with male infertility in the Jordanian population.  

PubMed

Folate pathway is expected to play an important role in spermatogenesis since it is involved in DNA synthesis, repair and methylation. The purpose of this study was to examine the association between male infertility and the MTHFR (C677T and A1298C) and MTRR (A66G) polymorphisms. A group of 300 males was recruited in this study from different Jordanian infertility clinics. Of these, 150 cases of infertile men that included oligozoospermia cases (n=45), severe oligozoospermia (n=71) and azoospermia (n=34) were studied. The other 150 males were age matched fertile controls. Genotyping of MTHFR and MTRR polymorphisms was performed using PCR-RFLP technique. The results showed an association between MTHFR 677TT genotype and male infertility (P<0.05). However, the distribution of MTHFR A1298C and MTRR A66G genotypes were not different between the fertile and infertile groups (P>0.05). In addition, none of the examined polymorphisms was related to any of the semen parameters in the infertile group. In conclusion, this study showed that MTHFR C677T polymorphism is associated with male infertility in Jordanians. PMID:24334125

Mfady, Doaa S; Sadiq, May F; Khabour, Omar F; Fararjeh, Abdulfattah S; Abu-Awad, Aymen; Khader, Yousef

2014-02-15

34

Association of Tagging SNPs in the MTHFR Gene with Risk of Type 2 Diabetes Mellitus and Serum Homocysteine Levels in a Chinese Population  

PubMed Central

Diabetes is a global public health crisis, and the prevalence is increasing rapidly. Folate supplementation is proved to be effective in reducing the risk of diabetes or improving its symptoms. Methylenetetrahydrofolate reductase is an important enzyme involved in folate metabolism. The aim of this study is to examine whether polymorphisms in the MTHFR gene are associated with risk of type 2 diabetes mellitus (T2DM) and fasting total serum homocysteine (tHcy) levels. We genotyped nine tagging SNPs in the MTHFR gene in a case-control study, including 595 T2DM cases and 681 healthy controls in China. We found that C allele of rs9651118 had significant decreased risk of T2DM (adjusted odds ratio (OR) = 0.69, 95% confidence interval (CI): 0.55–0.87, P = 0.002) compared with T allele. Haplotype analysis also showed that MTHFR CTCCGA haplotype (rs12121543-rs13306553-rs9651118-rs1801133-rs2274976-rs1801131) had significant reduced risk of T2DM (adjusted OR = 0.71, 95% CI: 0.58–0.87, P = 0.001) compared with CTTTGA haplotype. Besides, the MTHFR rs1801133 was significantly associated with serum levels of tHcy in healthy controls (P = 0.0002). These associations were still significant after Bonferroni corrections (P < 0.0056). These findings suggest that variants in the MTHFR gene may influence the risk of T2DM and tHcy levels. PMID:25165408

Wang, Han; Wan, Bin

2014-01-01

35

The Genetic Diversity and Structure of Linkage Disequilibrium of the MTHFR Gene in Populations of Northern Eurasia  

PubMed Central

The structure of the haplotypes and linkage disequilibrium (LD) of the methylenetetrahydrofolate reductase gene (MTHFR) in 9 population groups from Northern Eurasia and populations of the international HapMap project was investigated in the present study. The data suggest that the architecture of LD in the human genome is largely determined by the evolutionary history of populations; however, the results of phylogenetic and haplotype analyses seems to suggest that in fact there may be a common “old” mechanism for the formation of certain patterns of LD. Variability in the structure of LD and the level of diversity of MTHFRhaplotypes cause a certain set of tagSNPs with an established prognostic significance for each population. In our opinion, the results obtained in the present study are of considerable interest for understanding multiple genetic phenomena: namely, the association of interpopulation differences in the patterns of LD with structures possessing a genetic susceptibility to complex diseases, and the functional significance of the pleiotropicMTHFR gene effect. Summarizing the results of this study, a conclusion can be made that the genetic variability analysis with emphasis on the structure of LD in human populations is a powerful tool that can make a significant contribution to such areas of biomedical science as human evolutionary biology, functional genomics, genetics of complex diseases, and pharmacogenomics. PMID:22708063

Trifonova, E.A.; Eremina, E.R.; Urnov, F.D.; Stepanov, V.A.

2012-01-01

36

Polymorphisms C677T and A1298C in the MTHFR gene in Mexican patients with rheumatoid arthritis treated with methotrexate: implication with elevation of transaminases  

Microsoft Academic Search

Rheumatoid arthritis (RA) is the prototype of the rheumatic diseases worldwide. Methotrexate (MTX) is the drug of first choice in the treatment of this disease due to its immunosuppressant effect. However, side events are present in 30% of the patients. The C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene are involved in the metabolism of MTX. Earlier studies

J P Mena; M Salazar-Páramo; L González-López; J I Gámez-Nava; L Sandoval-Ramirez; J D Sánchez; L E Figuera; F J Muñoz-Valle; M Vazquez del Mercado; I P Dávalos

2011-01-01

37

Genotypes of the C677T and A1298C polymorphisms of the MTHFR gene as a cause of human spontaneous embryo loss  

Microsoft Academic Search

BACKGROUND: Polymorphisms C677T and A1298C of the MTHFR gene have been implicated in fetal viability. In this study, we determined the allele and genotype frequencies of these polymorphisms in different populations, includ- ing spontaneous abortion (SA) fetal tissues, with the objective of evaluating their impact on fetal viability. METHODS: 342 samples of fetal tissues, selected from SA occurring during the

G. Callejon; A. Mayor-Olea; A. J. Jimenez; M. J. Gaitan; A. R. Palomares; F. Martinez; M. Ruiz; Armando Reyes-Engel

2007-01-01

38

MTHFR gene polymorphism and risk of myeloid leukemia: a meta-analysis.  

PubMed

An increasing body of evidence has shown that the amino acid changes at position 1298 might eliminate methylenetetrahydrofolate reductase (MTHFR) enzyme activity, leading to insufficient folic acid and subsequent human chromosome breakage. Epidemiological studies have linked MTHFR single-nucleotide polymorphism (SNP) rs1801131 to myeloid leukemia risk, with considerable discrepancy in their results. We therefore were prompted to clarify this issue by use of a meta-analysis. The search terms were used to cover the possible reports in the MEDLINE, Web of Knowledge, and China National Knowledge Infrastructure (CNKI) databases. Odds ratios were estimated to assess the association of SNP rs1801131 with myeloid leukemia risk. Statistical heterogeneity was detected using the Q-statistic and I (2) metric. Subgroup analysis was performed by ethnicity, histological subtype, and Hardy-Weinberg equilibrium (HWE). This meta-analysis of eight publications with a total of 1,114 cases and 3,227 controls revealed no global association. Nor did the subgroup analysis according to histological subtype and HWE show any significant associations. However, Asian individuals who harbored the CC genotype were found to have 1.66-fold higher risk of myeloid leukemia (odds ratio, 1.66; 95 % confidence interval, 1.10 to 2.49; P h?=?0.342; I (2)?=?0.114). Our meta-analysis has presented evidence supporting a possible association between the CC genotype of MTHFR SNP rs1801131 and myeloid leukemia in Asian populations. PMID:24894669

Dong, Song; Liu, Yueling; Chen, Jieping

2014-09-01

39

Association of the A1298C polymorphism in MTHFR gene with ischemic stroke.  

PubMed

A meta-analysis was performed to assess the association between the methylenetetrahydrofolate reductase (MTHFR) A1298C genetic polymorphism and ischemic stroke. A comprehensive search was conducted to identify all case-control or cohort studies. The fixed or random effect pooled measure was selected based on the homogeneity between studies, as assessed by I(2). Meta-regression was used to explore the potential sources of between-study heterogeneity. Publication bias was estimated using Egger's linear regression test. Thirteen case-control studies corresponded to the inclusion criteria comprising 2133 patients and 2572 controls which were included in the present meta-analysis. After excluding articles that deviated from Hardy-Weinberg equilibrium in controls and the key contributors to between-study heterogeneity, significant associations between MTHFR A1298C genetic polymorphism and risk of ischemic stroke were observed in dominant (odds ratio [OR] 1.227, 95% confidence interval [CI] 1.062-1.416) and codominant (OR 1.138, 95% CI 1.007-1.286) inheritance models. Moreover, in the subgroup analysis based on region (Asia and Europe), significant associations were observed in most genetic models in Asia but not in Europe. This meta-analysis suggests that MTHFR A1298C genetic polymorphism is associated with increased risk of ischemic stroke, and the C allele may be an important risk factor for ischemic stroke. PMID:24128767

Kang, Shan; Wu, Yili; Liu, Lingling; Zhao, Xinxin; Zhang, Dongfeng

2014-02-01

40

Folate supplementation, MTHFR gene polymorphism and neural tube defects: a community based case control study in North India.  

PubMed

The present study analyses the potential role of MTHFR gene polymorphism, folate supplementation and dietary pattern among the mothers of NTD neonates and controls in heterogeneous populations of North India, with the special focus on their ethnic labels. Results indicated significant increased risk for neural tube defects with respect to low folic acid supplementation and vegetarian diet in univariate and multivariate analyses. There was no significant difference in the genotypic or allelic distribution of MTHFR C677T polymorphism, however, high frequency of CT genotype, as observed, among controls suggests heterozygous advantage probably due to supplementary folate. Among the two communities, Muslim NTD mothers had higher TT genotype showing increased risk for neural tube defects (adjusted OR: 12.9; 95% CI: 1.21-136.8) and lower folic acid supplementation (adjusted OR: 3.5; 95% CI: 1.18-10.22). Whereas, marginal increased risk for NTDs with vegetarian diet was observed among Hindus. Cultural and ethnic variation in the risk factors for neural tube defects is highlighted in the study. PMID:21792640

Deb, Roumi; Arora, Jyoti; Meitei, Sanjenbam Yaiphaba; Gupta, Sangeeta; Verma, Vanita; Saraswathy, Kallur Nava; Saran, Sunil; Kalla, Aloke Kumar

2011-09-01

41

[Neonatal renal vein thrombosis in a heterozygous carrier of both factor V Leiden and the MTHFR gene mutation].  

PubMed

Renal vein thrombosis (RVT) is a rare but potentially serious neonatal disease. Its epidemiology and its clinical and biological expression are currently well known, but its etiological exploration, like that of venous thromboembolism, is increasingly complex. Perinatal risk factors such as prematurity, dehydration, and birth asphyxia have lost their direct accountability at the expense of their interaction with constitutional disorders of hemostasis. We report a case of RVT in a newborn who was a heterozygous carrier of both factor V Leiden and the methylene tetrahydrofolate reductase (MTHFR) gene mutation. We recall the clinical and epidemiological characteristics. A search for inborn blood coagulation disorders should be systematic in the newborn infant with venous thrombosis because of the risk of recurrence, taking into account perinatal factors and maternal thrombophilia (especially if RVT is established during the prenatal period). PMID:22361411

Wannes, S; Soua, H; Ghanmi, S; Braham, H; Hassine, M; Hamza, H A; Ben Hamouda, H; Sfar, M-T

2012-04-01

42

C677T and A1298C Mutations in the MTHFR Gene and Survival in Colorectal Cancer  

Microsoft Academic Search

Background and aims: Our preliminary results laboratory have shown some association between C677T and A1298C MTHFR mutations and factors influencing survival in colorectal cancer. We studied the survival of patients with colorectal cancer depending on the initial Dukes- MAC stage of the disease at the time of diagnosis and the MTHFR mutation present. Methods: We randomly selected 69 patients with

Gelu Osian; Lucia Procopciuc; Liviu Vlad; Cornel Iancu; Teodora Mocan; Lucian Mocan

43

Variation in Telangiectasia Predisposing Genes Is Associated With Overall Radiation Toxicity  

SciTech Connect

Purpose: In patients receiving radiotherapy for breast cancer where the heart is within the radiation field, cutaneous telangiectasiae could be a marker of potential radiation-induced heart disease. We hypothesized that single nucleotide polymorphisms (SNPs) in genes known to cause heritable telangiectasia-associated disorders could predispose to such late, normal tissue vascular damage. Methods and Materials: The relationship between cutaneous telangiectasia as a late normal tissue radiation injury phenotype in 633 breast cancer patients treated with radiotherapy was examined. Patients were clinically assessed for the presence of cutaneous telangiectasia and genotyped at nine SNPs in three candidate genes. Candidate SNPs were within the endoglin (ENG) and activin A receptor, type II-like 1 (ACVRL1) genes, mutations in which cause hereditary hemorrhagic telangiectasia and the ataxia-telangiectasia mutated (ATM) gene associated with ataxia-telangiectasia. Results: A total of 121 (19.1%) patients exhibited a degree of cutaneous telangiectasiae on clinical examination. Regression was used to examine the associations between the presence of telangiectasiae in patients who underwent breast-conserving surgery, controlling for the effects of boost and known brassiere size (n=388), and individual geno- or haplotypes. Inheritance of ACVRL1 SNPs marginally contributed to the risk of cutaneous telangiectasiae. Haplotypic analysis revealed a stronger association between inheritance of a ATM haplotype and the presence of cutaneous telangiectasiae, fibrosis and overall toxicity. No significant association was observed between telangiectasiae and the coinheritance of the candidate ENG SNPs. Conclusions: Genetic variation in the ATM gene influences reaction to radiotherapy through both vascular damage and increased fibrosis. The predisposing variation in the ATM gene will need to be better defined to optimize it as a predictive marker for assessing radiotherapy late effects.

Tanteles, George A. [Department of Genetics, University of Leicester, Leicester (United Kingdom) [Department of Genetics, University of Leicester, Leicester (United Kingdom); Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester (United Kingdom); Murray, Robert J.S. [Department of Genetics, University of Leicester, Leicester (United Kingdom)] [Department of Genetics, University of Leicester, Leicester (United Kingdom); Mills, Jamie [Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester (United Kingdom)] [Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester (United Kingdom); Barwell, Julian [Department of Genetics, University of Leicester, Leicester (United Kingdom) [Department of Genetics, University of Leicester, Leicester (United Kingdom); Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester (United Kingdom); Chakraborti, Prabir [Department of Clinical Oncology, Derby Hospitals NHS Foundation Trust, Derby (United Kingdom)] [Department of Clinical Oncology, Derby Hospitals NHS Foundation Trust, Derby (United Kingdom); Chan, Steve [Department of Clinical Oncology, Nottingham University Hospitals NHS Trust, Nottingham (United Kingdom)] [Department of Clinical Oncology, Nottingham University Hospitals NHS Trust, Nottingham (United Kingdom); Cheung, Kwok-Leung [Division of Breast Surgery, University of Nottingham, Nottingham (United Kingdom)] [Division of Breast Surgery, University of Nottingham, Nottingham (United Kingdom); Ennis, Dawn [Department of Clinical Oncology, Derby Hospitals NHS Foundation Trust, Derby (United Kingdom)] [Department of Clinical Oncology, Derby Hospitals NHS Foundation Trust, Derby (United Kingdom); Khurshid, Nazish [Department of Genetics, University of Leicester, Leicester (United Kingdom)] [Department of Genetics, University of Leicester, Leicester (United Kingdom); Lambert, Kelly [Department of Breast Surgery, University Hospitals of Leicester, Glenfield Hospital, Leicester (United Kingdom)] [Department of Breast Surgery, University Hospitals of Leicester, Glenfield Hospital, Leicester (United Kingdom); Machhar, Rohan; Meisuria, Mitul [Department of Genetics, University of Leicester, Leicester (United Kingdom)] [Department of Genetics, University of Leicester, Leicester (United Kingdom); Osman, Ahmed; Peat, Irene [Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester (United Kingdom)] [Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester (United Kingdom); Sahota, Harjinder [Department of Genetics, University of Leicester, Leicester (United Kingdom)] [Department of Genetics, University of Leicester, Leicester (United Kingdom); Woodings, Pamela [Department of Clinical Oncology, Derby Hospitals NHS Foundation Trust, Derby (United Kingdom)] [Department of Clinical Oncology, Derby Hospitals NHS Foundation Trust, Derby (United Kingdom); Talbot, Christopher J., E-mail: cjt14@le.ac.uk [Department of Genetics, University of Leicester, Leicester (United Kingdom); and others

2012-11-15

44

Factor V gene G1691A mutation, prothrombin gene G20210A mutation, and MTHFR gene C677T mutation are not risk factors for pulmonary thromboembolism in Chinese population  

Microsoft Academic Search

A mutation in coagulant factor V gene, a substitution in the 3? untranslated region of prothrombin gene, and a variant in 5,10-methylenetetrahydrofolate reductase (MTHFR) gene have been reported to be related to venous thromboembolism in Caucasians, but this relationship remains in debate in other populations. In this case–control study, we aimed to determine the prevalence of these three mutations in

Yanhui Lu; Yanfen Zhao; Guozhang Liu; Xiaoling Wang; Zhihong Liu; Baiping Chen; Rutai Hui

2002-01-01

45

Folate intake, alcohol consumption, and the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism: influence on prostate cancer risk and interactions  

PubMed Central

Purpose: Folate is essential to DNA methylation and synthesis and may have a complex dualistic role in prostate cancer. Alcohol use may increase risk and epigenetic factors may interact with lifestyle exposures. We aimed to characterize the independent and joint effects of folate intake, alcohol consumption, and the MTHFR C677T gene polymorphism on prostate cancer risk, while accounting for intakes of vitamins B2, B6, B12, methionine, total energy, and confounders. Methods: A case-control study was conducted at Kingston General Hospital of 80 incident primary prostate cancer cases and 334 urology clinic controls, all with normal age-specific PSA levels (to exclude latent prostate cancers). Participants completed a questionnaire on folate and alcohol intakes and potential confounders prior to knowledge of diagnosis, eliminating recall bias, and blood was drawn for MTHFR genotyping. Joint effects of exposures were assessed using unconditional logistic regression and significance of multiplicative and additive interactions using general linear models. Results: Folate, vitamins B2, B6, B12, methionine, and the CT and TT genotypes were not associated with prostate cancer risk. The highest tertile of lifetime alcohol consumption was associated with increased risk (OR = 2.08; 95% CI: 1.12–3.86). Consumption of >5 alcoholic drinks per week was associated with increased prostate cancer risk among men with low folate intake (OR = 2.38; 95% CI: 1.01–5.57), and higher risk among those with the CC MTHFR genotype (OR = 4.43; 95% CI: 1.15–17.05). Increased risk was also apparent for average weekly alcohol consumption when accounting for the multiplicative interaction between folate intake and MTHFR C677T genotype (OR = 3.22; 95% CI: 1.36–7.59). Conclusion: Alcohol consumption is associated with increased prostate cancer risk, and this association is stronger among men with low folate intake, with the CC MTHFR genotype, and when accounting for the joint effect of folate intake and MTHFR C677T genotype. PMID:22912935

Kobayashi, Lindsay C.; Limburg, Heather; Miao, Qun; Woolcott, Christy; Bedard, Leanne L.; Massey, Thomas E.; Aronson, Kristan J.

2012-01-01

46

C677T polymorphism of the MTHFR gene and variant hemoglobins: a study in newborns from Salvador, Bahia, Brazil.  

PubMed

The C677T polymorphism in the methylenetetrahydrofolate reductase gene (MTHFR) is associated with an increase in total homocysteine serum levels (tHcy), described as a risk factor for cardiovascular disease. Eight hundred forty-three neonates from two different maternity hospitals, one public and another private, in Salvador, Bahia, Brazil were screened for this polymorphism by PCR and RFLP. The T-allele frequency in the total sample was 0.23, and the prevalence rates of heterozygous and homozygous carriers were 36.2% and 5.3%, respectively. The T-allele frequency differed and the T/T genotype was more prevalent at the private maternity hospital. The hemoglobin (Hb) profile was investigated by HPLC in 763 newborns. The frequency of variant Hb was higher at the public than at the private maternity hospital. The association of the C677T polymorphism and the Hb profile was investigated in 683 newborns, showing a relatively high frequency of variant Hbs and the T allele. These data could provide an important basis for further studies focusing on potential risks of vaso-occlusive events in these individuals. PMID:15073633

Couto, Fábio David; Adorno, Elisângela Vitória; Menezes, Joelma Figueiredo; Moura Neto, José Pereira; Rêgo, Marco Antônio Vasconcelos; Reis, Mitermayer Galvão dos; Gonçalves, Marilda Souza

2004-01-01

47

MTHFR C677T and A1298C variant genotypes and the risk of microsatellite instability among Iranian colorectal cancer patients  

Microsoft Academic Search

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the folate metabolic pathway. We aimed to test the hypothesis that C677T and A1298C variants of MTHFR predispose to microsatellite instable (MSI) colorectal cancer. We determined MTHFR genotypes in 175 sporadic colorectal cancer patients and a total of 231 normal controls in Shiraz, Southern Iran. Among the genotypes found in our samples,

Fakhraddin Naghibalhossaini; Pooneh Mokarram; Islam Khalili; Mohammad Vasei; Seyed Vahid Hosseini; Hassan Ashktorab; Mozhgan Rasti; Kourosh Abdollahi

2010-01-01

48

Mutation in Phex Gene Predisposes BALB/c-PhexHyp-Duk/Y Mice to Otitis Media  

PubMed Central

Genetic susceptibility underlying otitis media (OM) remains to be understood. We show in this study that mutation in Phex gene predisposes the BALB/c-PhexHyp-Duk/Y (abbreviated Hyp-Duk/Y) mice to OM, which occurs at post-natal day 21 (P21) with an average penetrance of 73%. The OM was identified by effusion in the middle ear cavity and/or thickening of middle ear mucosae, and was characterised by increase in goblet cells, deformity of epithelial cilia and higher expression of proliferating cell nuclear antigen (PCNA) in cells of the middle ear mucosae. Moreover, the transcription levels of Tlr2, Tlr4, Nfkb1, Ccl4, Il1b and Tnf? in the ears of the Hyp-Duk/Y mice at P35 were significantly upregulated, compared to those of the controls. Higher expression levels of TLR2, TLR4, NF-?B and TNF-? in the middle ears were demonstrated by immunohistochemistry (IHC). However, the OM in the mice was not prevented by azithromycin administration from gestational day 18 to P35. Further study showed that, in contrast to the low mRNA levels of Phex gene in the ears of the Hyp-Duk/Y mice, the mRNA level of Fgf23 was significantly elevated at P9, P14, P21 and P35. Meanwhile, mRNA levels of EP2 (PGE2 receptor), which expressed in the middle ear epithelia as demonstrated by IHC, were already increased at P14 even before the occurrence of OM, indicating that PGE2, an inflammatory mediator, is involved in the OM development in the mutants. Taking together, Phex mutation primarily up-regulates gene expression levels in FGF23 mediated pathways in the middle ears, resulting in cell proliferation and defence impairment at the mucosae and subsequently bacterial infection. The Hyp-Duk/Y mouse is a new genetic mouse model of OM. PMID:23028440

Han, Fengchan; Yu, Heping; Li, Ping; Zhang, Jiangping; Tian, Cong; Li, Hongbo; Zheng, Qing Yin

2012-01-01

49

Phosphoinositide 3-kinase ? gene mutation predisposes to respiratory infection and airway damage  

PubMed Central

Genetic mutations cause primary immunodeficiencies (PIDs), which predispose to infections. Here we describe Activated PI3K-? Syndrome (APDS), a PID associated with a dominant gain-of-function mutation E1021K in the p110? protein, the catalytic subunit of phosphoinositide 3-kinase ? (PI3K?), encoded by the PIK3CD gene. We found E1021K in 17 patients from seven unrelated families, but not among 3,346 healthy subjects. APDS was characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased IgM and reduced IgG2 levels in serum and impaired vaccine responses. The E1021K mutation enhanced membrane association and kinase activity of p110?. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein and were prone to activation-induced cell death. Selective p110? inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, suggesting a therapeutic approach for patients with APDS. PMID:24136356

Angulo, Ivan; Vadas, Oscar; Garcon, Fabien; Banham-Hall, Edward; Plagnol, Vincent; Leahy, Timothy R.; Baxendale, Helen; Coulter, Tanya; Curtis, James; Wu, Changxin; Blake-Palmer, Katherine; Perisic, Olga; Smyth, Deborah; Maes, Mailis; Fiddler, Christine; Juss, Jatinder; Cilliers, Deirdre; Markelj, Gasper; Chandra, Anita; Farmer, George; Kielkowska, Anna; Clark, Jonathan; Kracker, Sven; Debre, Marianne; Picard, Capucine; Pellier, Isabelle; Jabado, Nada; Morris, James A.; Barcenas-Morales, Gabriela; Fischer, Alain; Stephens, Len; Hawkins, Phillip; Barrett, Jeffrey C.; Abinun, Mario; Clatworthy, Menna; Durandy, Anne; Doffinger, Rainer; Chilvers, Edwin; Cant, Andrew J.; Kumararatne, Dinakantha; Okkenhaug, Klaus; Williams, Roger L.; Condliffe, Alison; Nejentsev, Sergey

2014-01-01

50

Association of Corticosteroids and Factor V, Prothrombin, and MTHFR Gene Mutations With Avascular Osteonecrosis in Renal Allograft Recipients  

Microsoft Academic Search

The mechanism of posttransplantation avascular osteonecrosis (AVN) is controversial. Besides an increased bone marrow pressure due to reduced blood supply, enhanced coagulation has been considered. We investigated the associations of factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations as well as cumulative corticosteroid doses with AVN in renal allograft recipients. The records of 39 volunteer patients and 11 patients

A. Celik; D. Tekis; F. Saglam; S. Tunali; N. Kabakci; D. Ozaksoy; M. Manisali; M. A. Ozcan; M. Meral; H. Gülay; T. Camsari

2006-01-01

51

MTHFR A1298C and C677T gene polymorphisms and susceptibility to chronic myeloid leukemia in Egypt  

PubMed Central

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating the intracellular folate metabolism which plays an important role in carcinogenesis through DNA methylation. We aimed to evaluate the association between MTHFR A1298C and C677T polymorphisms and the risks of chronic myeloid leukemia (CML). Eighty-five patients with CML and a control group containing 100 healthy, age and sex matched individuals were examined for MTHFR C677T and A1298C polymorphisms using polymerase chain reaction-restriction fragment-length (PCR-RFLP) method. The frequency of 677TT genotype in patients with CML was significantly higher compared to controls (OR = 2.513, 95% CI: 0.722-4.086, P = 0.025). No such association was shown for heterozygous 677CT (OR = 1.010, 95% CI: 0.460-2.218, P = 0.981). Moreover, for A1298C genotype, a statistically significant higher frequency of 1298CC was also detected in CML patients compared to control group (OR = 1.1816, 95% CI: 0.952-3.573, P = 0.036), 0.036). No such statistical significance was demonstrable for heterozygote 1298AC (OR = 1.046, 95% CI: 0.740-1.759, P = 0.092). In addition, patients with joint 677CT/1298AC or 677TT/1298CC genotypes showed an association with increased risk of CML (OR = 1.849, 95% CI: 0.935-2.540, P = 0.024; OR = 1.915, 95% CI: 1.202-3.845, P = 0.020 respectively). .A statistically significant increased risk of resistant to therapy was observed with 677CT and 1298AC genotypes (P = 0.001, P = 0.002 respectively). We conclude that both MTHFR 677TT and 1298CC polymorphisms have been associated with risk of CML and both 677CT and 1298AC genotypes are associated with higher risk of resistant to therapy. PMID:24966971

Aly, Rabab M; Taalab, Mona M; Ghazy, Hayam F

2014-01-01

52

The MTHFR C677T polymorphism modifies age at onset in Parkinson's disease.  

PubMed

Hyperhomocysteinemia is a risk factor for Parkinson's disease (PD) and may result from genetic mutations or/and environmental factors. 5,10-methylenetetrahydrofolate reductase (MTHFR) is a folate-dependent enzyme that catalyzed remethylation of homocysteine (Hcy) and the MTHFR C677T polymorphism makes the MTHFR enzyme thermolabile causing hyperhomocysteinemia. In this study we analyzed whether two functional polymorphisms of MTHFR gene, A1298C and C677T, affect age of onset in PD. We enrolled 120 patients with sporadic PD. Patients were divided into three groups based on MTHFR C677T polymorphisms: (a) homozygotes wild type (CC) (b) heterozygotes (CT) and (c) homozygotes carriers of mutation (TT). MTHFR SNPs were analyzed using High-Resolution Melt analysis and ANOVA was performed to assess whether polymorphisms of MTHFR gene could influence age of onset. The MTHFR A1298C polymorphism had no effect on PD age at onset (p = 1.0) while there was a significant association with MTHFR C677T (p = 0.019 Bonferroni-adjusted post hoc) showing an earlier onset in CC as compared with TT. (p = 0.024). No differences were found for vascular load assessed with magnetic resonance imaging, pharmacological therapy and cognitive state for two MTHFR SNPs. Our results suggest a possible association of MTHFR C677T with age at onset of PD and may have important implications regarding the role of MTHFR. PMID:24052451

Vallelunga, Annamaria; Pegoraro, Valentina; Pilleri, Manuela; Biundo, Roberta; De Iuliis, Angela; Marchetti, Mauro; Facchini, Silvia; Formento Dojot, Patrizia; Antonini, Angelo

2014-01-01

53

Metabolic effects of C677T and A1298C mutations at the MTHFR gene in Brazilian children with neural tube defects  

Microsoft Academic Search

Background: Methylenetetrahydrofolate reductase (MTHFR) deficiency leads to impairment in folate metabolism and is implicated as a risk factor for neural tube defects (NTDs). Both C677T and A1298C MTHFR mutations are associated with NTDs, in some populations. Methods: The frequencies of the C677T and A1298C MTHFR mutations were determined in 25 children with NTDs, case mothers and 75 healthy individuals from

Andrea L. A Cunha; Mario H Hirata; Chong A Kim; Elvira M Guerra-Shinohara; Kymio Nonoyama; Rosario D. C Hirata

2002-01-01

54

Prospective study of homocysteine and MTHFR 677TT genotype and risk for venous thrombosis in a general population--results from the HUNT 2 study.  

PubMed

This case-cohort designed study prospectively investigated whether elevated homocysteine levels measured in blood samples drawn before the event and methylenetetrahydrofolate reductase (MTHFR) gene polymorphism (MTHFR C677T) were associated with subsequent first venous thrombosis (VT) in a general population. Between August 1995 and June 1997, blood was collected from 66 140 people in the second Norwegian Health Study of Nord-Trøndelag (HUNT2). During a seven-year follow-up, 505 VT cases were identified. 1458 age- and sex-matched controls were selected from the original cohort. Serum total homocysteine (tHcy) and MTHFR genotype were measured in stored samples that were drawn a median of 33 months before the events. The overall odds ratio (OR) was 1.50 [95% confidence interval (CI) 0.97-2.30] for homocysteine levels above versus below the 95th percentile. There was no graded association with VT over quintiles of homocysteine. In men the OR was 2.17 (95% CI 1.20-3.91) for levels above versus below the 95th percentile, but no association was found in women (OR 1.00). Stratification by age, predisposing risk factors or time to event did not change these results. The MTHFR 677TT genotype was not related to risk for VT. In conclusion, elevated homocysteine levels in the general population predicted subsequent first VT in men but not in women. PMID:18318759

Naess, Inger Anne; Christiansen, Sverre C; Romundstad, Pål R; Cannegieter, Suzanne C; Blom, Henk J; Rosendaal, Frits R; Hammerstrøm, Jens

2008-05-01

55

SYN2 is an autism predisposing gene: loss-of-function mutations alter synaptic vesicle cycling and axon outgrowth.  

PubMed

An increasing number of genes predisposing to autism spectrum disorders (ASDs) has been identified, many of which are implicated in synaptic function. This 'synaptic autism pathway' notably includes disruption of SYN1 that is associated with epilepsy, autism and abnormal behavior in both human and mice models. Synapsins constitute a multigene family of neuron-specific phosphoproteins (SYN1-3) present in the majority of synapses where they are implicated in the regulation of neurotransmitter release and synaptogenesis. Synapsins I and II, the major Syn isoforms in the adult brain, display partially overlapping functions and defects in both isoforms are associated with epilepsy and autistic-like behavior in mice. In this study, we show that nonsense (A94fs199X) and missense (Y236S and G464R) mutations in SYN2 are associated with ASD in humans. The phenotype is apparent in males. Female carriers of SYN2 mutations are unaffected, suggesting that SYN2 is another example of autosomal sex-limited expression in ASD. When expressed in SYN2 ?knockout neurons, wild-type human Syn II fully rescues the SYN2 knockout phenotype, whereas the nonsense mutant is not expressed and the missense mutants are virtually unable to modify the SYN2 knockout phenotype. These results identify for the first time SYN2 ?as a novel predisposing gene for ASD and strengthen the hypothesis that a disturbance of synaptic homeostasis underlies ASD. PMID:23956174

Corradi, Anna; Fadda, Manuela; Piton, Amélie; Patry, Lysanne; Marte, Antonella; Rossi, Pia; Cadieux-Dion, Maxime; Gauthier, Julie; Lapointe, Line; Mottron, Laurent; Valtorta, Flavia; Rouleau, Guy A; Fassio, Anna; Benfenati, Fabio; Cossette, Patrick

2014-01-01

56

SYN2 is an autism predisposing gene: loss-of-function mutations alter synaptic vesicle cycling and axon outgrowth  

PubMed Central

An increasing number of genes predisposing to autism spectrum disorders (ASDs) has been identified, many of which are implicated in synaptic function. This ‘synaptic autism pathway’ notably includes disruption of SYN1 that is associated with epilepsy, autism and abnormal behavior in both human and mice models. Synapsins constitute a multigene family of neuron-specific phosphoproteins (SYN1-3) present in the majority of synapses where they are implicated in the regulation of neurotransmitter release and synaptogenesis. Synapsins I and II, the major Syn isoforms in the adult brain, display partially overlapping functions and defects in both isoforms are associated with epilepsy and autistic-like behavior in mice. In this study, we show that nonsense (A94fs199X) and missense (Y236S and G464R) mutations in SYN2 are associated with ASD in humans. The phenotype is apparent in males. Female carriers of SYN2 mutations are unaffected, suggesting that SYN2 is another example of autosomal sex-limited expression in ASD. When expressed in SYN2 ?knockout neurons, wild-type human Syn II fully rescues the SYN2 knockout phenotype, whereas the nonsense mutant is not expressed and the missense mutants are virtually unable to modify the SYN2 knockout phenotype. These results identify for the first time SYN2 ?as a novel predisposing gene for ASD and strengthen the hypothesis that a disturbance of synaptic homeostasis underlies ASD. PMID:23956174

Corradi, Anna; Fadda, Manuela; Piton, Amelie; Patry, Lysanne; Marte, Antonella; Rossi, Pia; Cadieux-Dion, Maxime; Gauthier, Julie; Lapointe, Line; Mottron, Laurent; Valtorta, Flavia; Rouleau, Guy A.; Fassio, Anna; Benfenati, Fabio; Cossette, Patrick

2014-01-01

57

Germline variants in the SEMA4A gene predispose to familial colorectal cancer type X  

PubMed Central

Familial colorectal cancer type X (FCCTX) is characterized by clinical features of hereditary non-polyposis colorectal cancer with a yet undefined genetic background. Here we identify the SEMA4A p.Val78Met germline mutation in an Austrian kindred with FCCTX, using an integrative genomics strategy. Compared with wild-type protein, SEMA4AV78M demonstrates significantly increased MAPK/Erk and PI3K/Akt signalling as well as cell cycle progression of SEMA4A-deficient HCT-116 colorectal cancer cells. In a cohort of 53 patients with FCCTX, we depict two further SEMA4A mutations, p.Gly484Ala and p.Ser326Phe and the single-nucleotide polymorphism (SNP) p.Pro682Ser. This SNP is highly associated with the FCCTX phenotype exhibiting increased risk for colorectal cancer (OR 6.79, 95% CI 2.63 to 17.52). Our study shows previously unidentified germline variants in SEMA4A predisposing to FCCTX, which has implications for surveillance strategies of patients and their families. PMID:25307848

Schulz, Eduard; Klampfl, Petra; Holzapfel, Stefanie; Janecke, Andreas R.; Ulz, Peter; Renner, Wilfried; Kashofer, Karl; Nojima, Satoshi; Leitner, Anita; Zebisch, Armin; Wolfler, Albert; Hofer, Sybille; Gerger, Armin; Lax, Sigurd; Beham-Schmid, Christine; Steinke, Verena; Heitzer, Ellen; Geigl, Jochen B.; Windpassinger, Christian; Hoefler, Gerald; Speicher, Michael R.; Richard Boland, C.; Kumanogoh, Atsushi; Sill, Heinz

2014-01-01

58

Association of 677 C>T (rs1801133) and 1298 A>C (rs1801131) Polymorphisms in the MTHFR Gene and Breast Cancer Susceptibility: A Meta-Analysis Based on 57 Individual Studies  

PubMed Central

Objective The 677 C>T and 1298 A>C polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene have been widely reported and considered to have a significant effect on breast cancer risk, but the results are inconsistent. A meta-analysis based on 57 eligible studies was carried out to clarify the role of MTHFR gene polymorphisms in breast cancer. Methods and Results Eligible articles were identified by searching databases including PubMed, Web of Science, EMBASE, CNKI and CBM for the period up to August 2012. Finally, a total of 57 studies were included in this meta-analysis. Crude ORs with 95% CIs were used to assess the association between the MTHFR polymorphisms and breast cancer risk. The pooled ORs were performed with additive model, dominant model and recessive model, respectively. Subgroup analysis was also performed by ethnicity. The statistical heterogeneity across studies was examined with ?2-based Q-test. A meta-analysis was performed using the Stata 12.0 software. Overall, the 677 C allele was significantly associated with breast cancer risk (OR?=?0.942, 95%CI?=?0.898 to 0.988) when compared with the 677 T allele in the additive model, and the same results were also revealed under other genetic models. Simultaneously, the 1298 A allele was not associated with the breast cancer susceptibility when compared with the 1298 C allele (OR?=?0.993, 95%CI?=?0.978 to 1.009). Furthermore, analyses under the dominant, recessive and the allele contrast model yielded similar results. Conclusions The results of this meta-analysis suggest that 677 C>T polymorphism in the MTHFR gene may contribute to breast cancer development. However, the 1298 A>C polymorphism is not significantly associated with increased risks of breast cancer. PMID:24945727

Li, Kai; Li, Wusheng; Dong, Xi

2014-01-01

59

[Search for frequently encountered mutations in genes predisposing to breast cancer].  

PubMed

DNA of oncological patients, including Ashkenazi Jews and Slavs, living in St. Petersburg was collected, and the resultant collection was screened for three common mutations of genes BRCA1 and BRCA2 by means of heteroduplex analysis. The mutation 5382insC in exon 20 of the BRCA1 gene was found in four unrelated patients, including three Slavs and one Ashkenazi Jew, with a positive family history of breast cancer. The mutations 185delAG and 6174delT in the BRCA1 and BRCA2 genes, respectively, which are typical of Ashkenazi Jewish patients with breast cancer, were not found in the patients of either ethnicity living in St. Petersburg, although the 6174delT mutation was found in the control group of Ashkenazi Jews. A new 12-nucleotide duplication g.71741ins12nt found in intron 20 of the BRCA1 gene was described. The high frequency of the 5382insC mutation in the BRCA1 gene in patients with familial breast cancer in both St. Petersburg and Moscow indicates that Russian families with the history of breast cancer should be primarily tested for this mutation. PMID:11785296

Mandel'shtam, M Iu; Golubkov, V I; Lamber, E P; Shapiro, I M; Brezhneva, T V; Semiglazov, V F; Lipovetski?, B M; Hanson, K P; Ga?tskhoki, V S

2001-12-01

60

Influence of maternal MTHFR A1298C polymorphism on the risk in offspring of schizophrenia  

Microsoft Academic Search

Several lines of evidence have suggested that two functional methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms, C677T and A1298C, may be implicated in the etiology of schizophrenia. We examined these MTHFR polymorphisms in 111 families, composed of a patient and their parents, as well as 143 mothers of patients with schizophrenia and 235 age-matched mothers who had healthy children. The maternal MTHFR

Chen Zhang; Bin Xie; Yiru Fang; Wenhong Cheng; Yasong Du; Dongxiang Wang; Shunying Yu

2010-01-01

61

Gene Expression Profiling of Histiocytic Sarcomas in a Canine Model: The Predisposed Flatcoated Retriever Dog  

PubMed Central

Background The determination of altered expression of genes in specific tumor types and their effect upon cellular processes may create insight in tumorigenesis and help to design better treatments. The Flatcoated retriever is a dog breed with an exceptionally high incidence of histiocytic sarcomas. The breed develops two distinct entities of histiocytic neoplasia, a soft tissue form and a visceral form. Gene expression studies of these tumors have value for comparable human diseases such as histiocytic/dendritic cell sarcoma for which knowledge is difficult to accrue due to their rare occurrence. In addition, such studies may help in the search for genetic aberrations underlying the genetic predisposition in this dog breed. Methods Microarray analysis and pathway analyses were performed on fresh-frozen tissues obtained from Flatcoated retrievers with localized, soft tissue histiocytic sarcomas (STHS) and disseminated, visceral histiocytic sarcomas (VHS) and on normal canine spleens from various breeds. Expression differences of nine genes were validated with quantitative real-time PCR (qPCR) analyses. Results QPCR analyses identified the significantly altered expression of nine genes; PPBP, SpiC, VCAM1, ENPEP, ITGAD (down-regulated), and GTSF1, Col3a1, CD90 and LUM (up-regulated) in the comparison of both the soft tissue and the visceral form with healthy spleen. DAVID pathway analyses revealed 24 pathways that were significantly involved in the development of HS in general, most of which were involved in the DNA repair and replication process. Conclusions This study identified altered expression of nine genes not yet implicated in histiocytic sarcoma manifestations in the dog nor in comparable human histiocytic/dendritic sarcomas. Exploration of the downside effect of canine inbreeding strategies for the study of similar sarcomas in humans might also lead to the identification of genes related to these rare malignancies in the human. PMID:23936488

Boerkamp, Kim M.; van Wolferen, Monique E.; Groot Koerkamp, Marian J. A.; van Leenen, Dik; Grinwis, Guy C. M.; Penning, Louis C.; Wiemer, Erik A. C.; Rutteman, Gerard R.

2013-01-01

62

derived growth factor ? -receptor gene predispose to human neural tube defects  

Microsoft Academic Search

Neural tube defects (NTDs), including anencephaly and spina bifida, are multifactorial diseases that occur with an incidence of 1 in 300 births in the United Kingdom 1 . Mouse models have indicated that deregulated expression of the gene encoding the platelet-derived growth factor ? -receptor (Pdgfra) causes congenital NTDs (refs. 2-4), whereas mutant forms of Pax-1 that have been associated

Paul H. L. J. Joosten; Mascha Toepoel; Edwin C. M. Mariman; J. J. Van Zoelen

63

MAPT as a predisposing gene for sporadic amyotrophic lateral sclerosis in the Chinese Han population  

PubMed Central

A previous study of European Caucasian patients with sporadic amyotrophic lateral sclerosis demonstrated that a polymorphism in the microtubule-associated protein Tau (MAPT) gene was significantly associated with sporadic amyotrophic lateral sclerosis pathogenesis. Here, we tested this association in 107 sporadic amyotrophic lateral sclerosis patients and 100 healthy controls from the Chinese Han population. We screened the mutation-susceptible regions of MAPT – the 3' and 5' untranslated regions as well as introns 9, 10, 11, and 12 – by direct sequencing, and identified 33 genetic variations. Two of these, 105788 A > G in intron 9 and 123972 T > A in intron 11, were not present in the control group. The age of onset in patients with the 105788 A > G and/or the 123972 T > A variant was younger than that in patients without either genetic variation. Moreover, the pa-tients with a genetic variation were more prone to bulbar palsy and breathing difficulties than those with the wild-type genotype. This led to a shorter survival period in patients with a MAPT genetic variant. Our study suggests that the MAPT gene is a potential risk gene for sporadic amyotrophic lateral sclerosis in the Chinese Han population.

Fang, Pu; Xu, Wenyuan; Wu, Chengsi; Zhu, Min; Li, Xiaobing; Hong, Daojun

2013-01-01

64

Homocysteine Level and Mechanisms of Injury in Parkinson's Disease as Related to MTHFR, MTR, and MTHFD1 Genes Polymorphisms and L-Dopa Treatment.  

PubMed

An elevated concentration of total homocysteine (tHcy) in plasma and cerebrospinal fluid is considered to be a risk factor for Alzheimer's disease (AD) and Parkinson's disease (PD). Homocysteine (Hcy) levels are influenced by folate concentrations and numerous genetic factors through the folate cycle, however, their role in the pathogenesis of PD remains controversial. Hcy exerts a neurotoxic action and may participate in the mechanisms of neurodegeneration, such as excitotoxicity, oxidative stress, calcium accumulation, and apoptosis. Elevated Hcy levels can lead to prooxidative activity, most probably through direct interaction with N-methyl-D-aspartate (NMDA) receptors and sensitization of dopaminergic neurons to age-related dysfunction and death. Several studies have shown that higher concentration of Hcy in PD is related to long-term administration of levodopa (L-dopa). An elevation of plasma tHcy levels can also reflect deficiencies of cofactors in remethylation of Hcy to methionine (Met) (folates and vitamin B12) and in its transsulfuration to cysteine (Cys) (vitamin B6). It is believed that the increase in the concentration of Hcy in PD can affect genetic polymorphisms of the folate metabolic pathway genes, such as MTHFR (C677T, A1298C and G1793A), MTR (A2756G), and MTHFD1 (G1958A), whose frequencies tend to increase in PD patients, as well as the reduced concentration of B vitamins. In PD, increased levels of Hcy may lead to dementia, depression and progression of the disease. PMID:24532985

Rozycka, Agata; Jagodzinski, Pawel P; Kozubski, Wojciech; Lianeri, Margarita; Dorszewska, Jolanta

2013-12-01

65

Homocysteine Level and Mechanisms of Injury in Parkinson's Disease as Related to MTHFR, MTR, and MTHFD1 Genes Polymorphisms and L-Dopa Treatment  

PubMed Central

An elevated concentration of total homocysteine (tHcy) in plasma and cerebrospinal fluid is considered to be a risk factor for Alzheimer's disease (AD) and Parkinson's disease (PD). Homocysteine (Hcy) levels are influenced by folate concentrations and numerous genetic factors through the folate cycle, however, their role in the pathogenesis of PD remains controversial. Hcy exerts a neurotoxic action and may participate in the mechanisms of neurodegeneration, such as excitotoxicity, oxidative stress, calcium accumulation, and apoptosis. Elevated Hcy levels can lead to prooxidative activity, most probably through direct interaction with N-methyl-D-aspartate (NMDA) receptors and sensitization of dopaminergic neurons to age-related dysfunction and death. Several studies have shown that higher concentration of Hcy in PD is related to long-term administration of levodopa (L-dopa). An elevation of plasma tHcy levels can also reflect deficiencies of cofactors in remethylation of Hcy to methionine (Met) (folates and vitamin B12) and in its transsulfuration to cysteine (Cys) (vitamin B6). It is believed that the increase in the concentration of Hcy in PD can affect genetic polymorphisms of the folate metabolic pathway genes, such as MTHFR (C677T, A1298C and G1793A), MTR (A2756G), and MTHFD1 (G1958A), whose frequencies tend to increase in PD patients, as well as the reduced concentration of B vitamins. In PD, increased levels of Hcy may lead to dementia, depression and progression of the disease. PMID:24532985

Rozycka, Agata; Jagodzinski, Pawel P.; Kozubski, Wojciech; Lianeri, Margarita; Dorszewska, Jolanta

2013-01-01

66

Association between C677T and A1298C MTHFR gene polymorphism and nonsyndromic orofacial clefts in the Turkish population: a case-parent study.  

PubMed

Two common MTHFR gene polymorphisms (C677T and A1298C) have been implicated in the etiology of nonsyndromic cleft lip/palate (nsCL/P). To investigate the genotype association among nsCL/P in the Turkish population, 56 case-parent trios were recruited into the study. Genotype frequencies were compared to two groups of controls from the same population. A total of 46 case-parent trios were included in transmission disequilibrium test (TDT) analysis. The mothers of the study group had a higher frequency of 677TT genotype, with a three-fold increased risk of having nsCL/P offspring (odds ratio [OR]: 3.14, p=0.03). The combined 677CT/1298AC genotype was also common among these mothers (28%), but it did not reach statistical significance (OR: 2.27, p=0.07). TDT analysis for (C677T) T allele transmission did not reveal a significant association. In conclusion, mothers carrying 677TT genotype or with 677CT/1298AC combined genotype have increased risk of having nsCL/P offspring; therefore, higher periconceptional folic acid supplementation should be advised for decreasing the recurrence risk. PMID:23692788

Semiç-Jusufagiç, Aida; Bircan, R?fat; Çelebiler, Özhan; Erdim, Melike; Akarsu, Nurten; Elçio?lu, Nursel H

2012-01-01

67

High Glucose Predisposes Gene Expression and ERK Phosphorylation to Apoptosis and Impaired Glucose-Stimulated Insulin Secretion via the Cytoskeleton  

PubMed Central

Chronic high glucose (HG) inflicts glucotoxicity on vulnerable cell types such as pancreatic ? cells and contributes to insulin resistance and impaired insulin secretion in diabetic patients. To identify HG-induced cellular aberrations that are candidate mediators of glucotoxicity in pancreatic ? cells, we analyzed gene expression in ERoSHK6, a mouse insulin-secreting cell line after chronic HG exposure (six-day exposure to 33.3 mM glucose). Chronic HG exposure which reduced glucose-stimulated insulin secretion (GSIS) increased transcript levels of 185 genes that clustered primarily in 5 processes namely cellular growth and proliferation; cell death; cellular assembly and organization; cell morphology; and cell-to-cell signaling and interaction. The former two were validated by increased apoptosis of ERoSHK6 cells after chronic HG exposure and reaffirmed the vulnerability of ? cells to glucotoxicity. The three remaining processes were partially substantiated by changes in cellular morphology and structure, and instigated an investigation of the cytoskeleton and cell-cell adhesion. These studies revealed a depolymerized actin cytoskeleton that lacked actin stress fibers anchored at vinculin-containing focal adhesion sites as well as loss of E-cadherin-mediated cell-cell adherence after exposure to chronic HG, and were concomitant with constitutive ERK1/2 phosphorylation that was refractory to serum and glucose deprivation. Although inhibition of ERK phosphorylation by PD98059 promoted actin polymerization, it increased apoptosis and GSIS impairment. These findings suggest that ERK phosphorylation is a proximate regulator of cellular processes targeted by chronic HG-induced gene expression and that dynamic actin polymerization and depolymerization is important in ? cell survival and function. Therefore, chronic HG alters gene expression and signal transduction to predispose the cytoskeleton towards apoptosis and GSIS impairment. PMID:23024780

Yeo, Ronne Wee Yeh; Yang, Kaiyuan; Li, GuoDong; Lim, Sai Kiang

2012-01-01

68

Low-copy repeats at the human VIPR2 gene predispose to recurrent and nonrecurrent rearrangements  

PubMed Central

Submicroscopic structural variations, including deletions, duplications, inversions and more complex rearrangements, are widespread in normal human genomes. Inverted segmental duplications or highly identical low-copy repeat (LCR) sequences can mediate the formation of inversions and more complex structural rearrangements through non-allelic homologous recombination. In a patient with 7q36 inverted duplication/terminal deletion, we demonstrated the central role of a pair of short inverted LCRs in the vasoactive intestinal peptide receptor gene (VIPR2)-LCRs in generating the rearrangement. We also revealed a relatively common VIPR2-LCR-associated inversion polymorphism disrupting the gene in almost 1% of healthy subjects, and a small number of complex duplications/triplications. In genome-wide studies of several thousand patients, a significant association of rare microduplications with variable size, all involving VIPR2, with schizophrenia was recently described, suggesting that altered vasoactive intestinal peptide signaling is likely implicated in the pathogenesis of schizophrenia. Genetic testing for VIPR2-LCR-associated inversions should be performed on available cohorts of psychiatric patients to evaluate their potential pathogenic role. PMID:23073313

Beri, Silvana; Bonaglia, Maria Clara; Giorda, Roberto

2013-01-01

69

Normal Weight Obese syndrome: role of single nucleotide polymorphism of IL-1 5Ralpha and MTHFR 677C-->T genes in the relationship between body composition and resting metabolic rate.  

PubMed

We have identified a subset of metabolically obese, but normal weight individuals, with potentially increased risks of developing the metabolic syndrome, despite their normal body mass index. We determined the relationship among body fat distribution, resting metabolic rate (RMR), total body water amount (%TBW), selected gene polymorphism on interleukin-15 receptor-alpha (IL-15Ralpha) and methylenetetrahydrofolate reductase 677C-->T (MTHFR 677C-->T), to distinguish normal weight obese (NWO) from nonobese with a normal metabolic profile and obese individuals. We analysed anthropometric variables, body composition by Dual energy X-ray Absorptiometry (DXA), RMR by indirect calorimetry, %TBW by bioimpedence analysis (BIA), MTHFR 677C-->T and IL-15Ralpha genotypes of 128 clinically healthy Caucasian individuals. We compared a group of female, defined as NWO and characterised by a BMI < or = 25 kg/m(2) and FM > or = 30% with groups of others female, and males, represented by nonobese with a BMI < or = 25 kg/m(2) and FM < or = 30%, and preobese-obese individuals with BMI > or = 25 kg/m(2) and %FM > or = 30%; none of the males was classified as NWO. Significant correlations were found among body fat mass distribution, metabolic variables, percentage of total body water distribution and selected genetic variations. The variables that contributed significantly to the separation of classes were body tissue (Tissue), %TBW, RMR, the volumes of both oxygen (VO2) and carbon dioxide (VCO2). The distribution of MTHFR 677C-->T and IL-15 genotypes was significantly different between classes. Our data highlight that NWO individuals showed a significant relationship between the decrease in the basal metabolism (RMR), body fat mass increasing and total water amount. Possession of wild type homozygotes genotypes regarding IL-15Ralpha cytokine and 677C-->T MTHFR enzyme characterised NWO individuals. PMID:17121316

Di Renzo, L; Bigioni, M; Bottini, F G; Del Gobbo, V; Premrov, M G; Cianci, R; De Lorenzo, A

2006-01-01

70

Identification of germline mutations in the cancer predisposing gene CDH1 in patients with orofacial clefts.  

PubMed

Orofacial clefts (OFC) are among the most common birth defects worldwide. The etiology of non-syndromic OFC is still largely unknown. During embryonic development, the cell adhesion molecule E-cadherin, encoded by CDH1, is highly expressed in the median edge epithelium of the palate. Furthermore, in multiple families with CDH1 mutations, OFC cases are observed. To determine whether CDH1 is a causative gene for non-syndromic OFC and to assess whether CDH1 mutation screening in non-syndromic OFC patients enables identification of families at risk of cancer, direct sequencing of the full coding sequence of CDH1 was performed in a cohort of 81 children with non-syndromic OFC. Eleven children had heterozygous CDH1 sequence variants, 5 cases with 4 distinct missense mutations and 8 cases with 4 intronic variants. Using a combination of in silico predictions and in vitro functional assays, three missense mutations in four non-syndromic OFC patients were predicted to be damaging to E-cadherin protein function. The intronic variants including one tested in an in vitro assay appeared to be benign, showing no influence on splicing. Functionally relevant heterozygous CDH1 missense mutations were found in 4 out of 81 (5%) patients with non-syndromic OFC. This finding opens a new pathway to reveal the molecular basis of non-syndromic OFC. Cancer risk among carriers of these mutations needs to be defined. PMID:23197654

Vogelaar, Ingrid P; Figueiredo, Joana; van Rooij, Iris A L M; Simões-Correia, Joana; van der Post, Rachel S; Melo, Soraia; Seruca, Raquel; Carels, Carine E L; Ligtenberg, Marjolijn J L; Hoogerbrugge, Nicoline

2013-03-01

71

Association between Hcy levels and the CBS844ins68 and MTHFR C677T polymorphisms with essential hypertension  

PubMed Central

The aim of the present study was to investigate the association between the homocysteine (Hcy) levels and polymorphisms of the CBS844ins68 and MTHFR C677T genes in essential hypertension (EH). The effects of the MTHFR C677T and CBS844ins68 haploid genotypes and the combined genotypes on EH and levels of Hcy were further explored. The polymorphisms of CBS844ins68 and MTHFR C677T genes in 200 EH and 200 normal tensive (NT) patients were detected using polymerase chain reaction-restriction fragment length polymorphism and analysis of the distribution of genotypes. An automated biochemical analyzer was used to measure the plasma Hcy levels and the clinical biochemistry data. The plasma Hcy levels in EH were significantly higher than those of the NT group (P<0.05). There were no significant differences (P>0.05) between males and females. Two genotypes, deletion/deletion (DD) and deletion/insertion (DI), of the CBS844ins68 polymorphism were found in two groups with no clear differences in two genotypes and allele frequency distribution (P>0.05). There were significant differences in the three genotype frequencies (?2=6.658, ?2=4.410, P<0.05) for MTHFR C677T locus genotypes CC, CT and TT. The Hcy levels in genotypes DD and DI had no significant differences (P>0.05) and the CT and TT types were significantly higher compared to the CC genotype (P<0.05). The CC/DD combined genotype in the two groups was significantly different (P<0.05), and the odds ratio (OR), 0.569 showed that the CC/DD genotype may be a protective factor of hypertension. In the two groups, the Hcy levels for combined genotypes CC/DD, CT/DD, TT/DD and TT/DI were significantly different (P<0.05). The SHEsis software analysis linkage disequilibrium coefficient=0.216, indicates that there is probably a weak linkage for MTHFR C677T and CBS844ins68. Haplotype analysis suggested that the C-D haplotype was negatively correlated with EH (OR, 0.727) and that there was a positive correlation between T-D haplotype and EH (OR, 1.376). MTHFR C677T and CBS844ins68 polymorphisms were present in the populations studied and the CBS844ins68 homozygous mutation was not present. Therefore, there is a correlation between the polymorphisms of the MTHFR C677T gene and EH, and allele T may be one of the predisposing factors. MTHFR C677T and CBS844ins68 may exist with a certain linkage and the T-D haplotype may be a risk factor for EH. PMID:25279160

CAI, WEIJUAN; YIN, LIANG; YANG, FANG; ZHANG, LEI; CHENG, JIANG

2014-01-01

72

Stability of DNA methylation patterns in mouse spermatogonia under conditions of MTHFR deficiency and methionine supplementation.  

PubMed

Little is known about the conditions contributing to the stability of DNA methylation patterns in male germ cells. Altered folate pathway enzyme activity and methyl donor supply are two clinically significant factors that can affect the methylation of DNA. 5,10-Methylenetetrahydrofolate reductase (MTHFR) is a key folate pathway enzyme involved in providing methyl groups from dietary folate for DNA methylation. Mice heterozygous for a targeted mutation in the Mthfr gene (Mthfr(+/-)) are a good model for humans homozygous for the MTHFR 677C>T polymorphism, which is found in 10% of the population and is associated with decreased MTHFR activity and infertility. High-dose folic acid is administered as an empirical treatment for male infertility. Here, we examined MTHFR expression in developing male germ cells and evaluated DNA methylation patterns and effects of a range of methionine concentrations in spermatogonia from Mthfr(+/-) as compared to wild-type, Mthfr(+/+) mice. MTHFR was expressed in prospermatogonia and spermatogonia at times of DNA methylation acquisition in the male germline; its expression was also found in early spermatocytes and Sertoli cells. DNA methylation patterns were similar at imprinted genes and intergenic sites across chromosome 9 in neonatal Mthfr(+/+) and Mthfr(+/-) spermatogonia. Using spermatogonia from Mthfr(+/+) and Mthfr(+/-) mice in the spermatogonial stem cell (SSC) culture system, we examined the stability of DNA methylation patterns and determined effects of low or high methionine concentrations. No differences were detected between early and late passages, suggesting that DNA methylation patterns are generally stable in culture. Twenty-fold normal concentrations of methionine resulted in an overall increase in the levels of DNA methylation across chromosome 9, suggesting that DNA methylation can be perturbed in culture. Mthfr(+/-) cells showed a significantly increased variance of DNA methylation at multiple loci across chromosome 9 compared to Mthfr(+/+) cells when cultured with 0.25- to 2-fold normal methionine concentrations. Taken together, our results indicate that DNA methylation patterns in undifferentiated spermatogonia, including SSCs, are relatively stable in culture over time under conditions of altered methionine and MTHFR levels. PMID:24048573

Garner, Justine L; Niles, Kirsten M; McGraw, Serge; Yeh, Jonathan R; Cushnie, Duncan W; Hermo, Louis; Nagano, Makoto C; Trasler, Jacquetta M

2013-11-01

73

MTHFR A1298C polymorphism is associated with cardiovascular risk in end stage renal disease in North Indians  

Microsoft Academic Search

The methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism has been shown to be associated with cardiovascular\\u000a disease and in patients with end-stage renal disease (ESRD). However, the relationship between MTHFR polymorphisms and cardiovascular\\u000a disease (CVD) in patients on hemodialysis has not been examined. The aim of this study was to assess the association of polymorphisms\\u000a of MTHFR gene with homocysteine (Hcy)

Aruna Poduri; Debabrata Mukherjee; Kamal Sud; Harbir Singh Kohli; Vinay Sakhuja; Madhu Khullar

2008-01-01

74

A Second Genetic Polymorphism in Methylenetetrahydrofolate Reductase (MTHFR) Associated with Decreased Enzyme Activity  

Microsoft Academic Search

A common mutation in methylenetetrahydrofolate reductase (MTHFR), C677T, results in a thermolabile variant with reduced activity. Homozygous mutant individuals (approximately 10% of North Americans) are predisposed to mild hyperhomocysteinemia, when their folate status is low. This genetic–nutrient interactive effect is believed to increase the risk for neural tube defects and vascular disease. In this communication, we characterize a second common

Ilan Weisberg; Pamela Tran; Benedicte Christensen; Sahar Sibani; Rima Rozen

1998-01-01

75

Ethnic variation of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate-reductase (MTHFR) gene in southwestern Mexico.  

PubMed

In this study, we examined the distribution of genotype and allele frequencies of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate-reductase gene (MTHFR) in two ethnic groups in the State of Guerrero, Mexico, which were compared with those of the Mestizo population of the region. A comparative study was conducted on 455 women from two ethnic groups and a group of Mestizo women of the State of Guerrero, Mexico: 135 Nahuas, 124 Mixtecas, and 196 Mestizas. Genotyping of both polymorphisms were performed by using polymerase chain reaction-restriction fragment length polymorphism methods. We found that the 677TT genotype was more frequent in Nahua and Mixteca women compared to Mestiza women (P = 0.008), and the most prevalent genotype in both ethnic groups was the 1298AA genotype (P < 0.001). We also compared the 677T allele frequency obtained from the groups studied with the frequencies reported in other ethnic groups of Mexico (Huichol, Tarahumara, and Purepecha). There were significant differences between the three ethnic groups compared to Nahuas (Huicholes, P = 0.004; Tarahumaras, P < 0.001; Purepechas, P = 0.042). Our results indicated significant differences in the frequencies of the C677T and A1298C polymorphisms between the two ethnic groups and the Mestizo population of the State of Guerrero. In addition, we found strong differences with other ethnic groups in Mexico. These results could be useful for future studies investigating diseases related to folate metabolism, and could help the government to design specific nutrition programs for different ethnic groups. PMID:25299110

Antonio-Véjar, V; Del Moral-Hernández, O; Alarcón-Romero, L C; Flores-Alfaro, E; Leyva-Vázquez, M A; Hernández-Sotelo, D; Illades-Aguiar, B

2014-01-01

76

The role of point mutations in the genes, predisposing inherited thrombophilia in the pathogeneses of proximal and distal deep vein thrombosis in Georgian population.  

PubMed

Duration of treatment of venous thromboembolism (VTE) and prevention of its recurrence represent significant problems of contemporary medicine, as the basic method of treatment - anticoagulation is frequently complicated by hemorrhage. Therefore, its duration is strictly defined and depends on existence of risk factors related to recurrence of thrombosis. Purpose of the conducted study was to establish the role of point mutations of prothrombin (PHG) - 20210G/A; Factor V Leiden (FVL) - 1691G/A and methylenetetrahydrofolate reductase (MTHFR) - 677C/T genes, i.e. inherited thrombophilia in the pathogenesis of proximal and distal lower extremity deep vein thrombosis in patients of the Georgian population, as in case of proximal thrombosis there is a higher risk of recurrent thrombosis. The above mutations were detected by PCR and single nucleotide primer extension reaction, followed by Enzyme Linked Immuno-Sorbent Assay (ELISA) in 61 patients with venous thromboembolism of various localizations, out of which: 49 patients were diagnosed with unprovoked proximal thromboembolism confirmed by objective studies and 12 patients were diagnosed with distal thromboembolism. The difference between the groups was evaluated by F (Fisher) precise criterion. According to statistical analysis of the results, incidence of FVL mutation in the group of patients with proximal thrombosis was significantly higher compared to patients with distal thrombosis 0.43 and 0.08 (p=0.0256), respectively. Similar tendencies were observed in case of carriage of prothrombin gene and MTHFR gene mutations, as their presence was higher in the group of patients having proximal thrombosis than in patients with distal thrombosis, however, this difference was not found to be statistically significant. It should be particularly mentioned that double or triple heterozygous or homozygous carriage of studied mutations with various options was confirmed in 15 of 61 patients and the above genotypes were observed only in the group of patients having proximal thrombosis. According to the results obtained from this investigation, it is possible to consider inherited thrombophilia, especially Leiden mutation and double or triple heterozygous and homozygous carriage of studied mutations in the Georgian population as an independent risk factor of development of proximal thrombosis, which on its part, represents one of the risk factors of development of recurrent thrombosis and conduct proper long-standing anticoagulation therapy and take secondary preventive measures in patients of similar genotype to reduce the risk of recurrent thrombosis. PMID:24632657

Pirtskhelani, N; Kochiashvili, N; Makhaldiani, L; Pargalava, N; Gaprindashvili, E; Kartvelishvili, K

2014-02-01

77

Genome-wide association analysis and fine mapping of NT-proBNP level provide novel insight into the role of the MTHFR-CLCN6-NPPA-NPPB gene cluster  

PubMed Central

High blood concentration of the N-terminal cleavage product of the B-type natriuretic peptide (NT-proBNP) is strongly associated with cardiac dysfunction and is increasingly used for heart failure diagnosis. To identify genetic variants associated with NT-proBNP level, we performed a genome-wide association analysis in 1325 individuals from South Tyrol, Italy, and followed up the most significant results in 1746 individuals from two German population-based studies. A genome-wide significant signal in the MTHFR-CLCN6-NPPA-NPPB gene cluster was replicated, after correction for multiple testing (replication one-sided P-value = 8.4 × 10?10). A conditional regression analysis of 128 single-nucleotide polymorphisms in the region of interest identified novel variants in the CLCN6 gene as independently associated with NT-proBNP. In this locus, four haplotypes were associated with increased NT-proBNP levels (haplotype-specific combined P-values from 8.3 × 10?03 to 9.3 × 10?11). The observed increase in the NT-proBNP level was proportional to the number of haplotype copies present (i.e. dosage effect), with an increase associated with two copies that varied between 20 and 100 pg/ml across populations. The identification of novel variants in the MTHFR-CLCN6-NPPA-NPPB cluster provides new insights into the biological mechanisms of cardiac dysfunction. PMID:21273288

Del Greco M., Fabiola; Pattaro, Cristian; Luchner, Andreas; Pichler, Irene; Winkler, Thomas; Hicks, Andrew A.; Fuchsberger, Christian; Franke, Andre; Melville, Scott A.; Peters, Annette; Wichmann, H. Erich; Schreiber, Stefan; Heid, Iris M.; Krawczak, Michael; Minelli, Cosetta; Wiedermann, Christian J.; Pramstaller, Peter P.

2011-01-01

78

MTHFR gene C677T and A1298C polymorphisms and homocysteine levels in primary open angle and primary closed angle glaucoma  

Microsoft Academic Search

PURPOSE: To investigate the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C genotypes and plasma concentrations of total homocysteine (tHcy) in Pakistani patients with primary open angle glaucoma (POAG) and primary closed angle glaucoma (PCAG). METHODS: This was a prospective case-control study. A total of 295 patients (173 POAG, 122 PCAG) and 143 age- and sex-matched controls were subdivided into two ethnic

Shazia Micheal; Raheel Qamar; Farah Akhtar; Muhammad Imran Khan; Wajid Ali Khan; Asifa Ahmed

2009-01-01

79

Univariate and multiple linear regression analyses for 23 single nucleotide polymorphisms in 14 genes predisposing to chronic glomerular diseases and IgA nephropathy in Han Chinese.  

PubMed

Immunoglobulin A nephropathy (IgAN) is a complex trait regulated by the interaction among multiple physiologic regulatory systems and probably involving numerous genes, which leads to inconsistent findings in genetic studies. One possibility of failure to replicate some single-locus results is that the underlying genetics of IgAN nephropathy is based on multiple genes with minor effects. To learn the association between 23 single nucleotide polymorphisms (SNPs) in 14 genes predisposing to chronic glomerular diseases and IgAN in Han males, the 23 SNPs genotypes of 21 Han males were detected and analyzed with a BaiO gene chip, and their associations were analyzed with univariate analysis and multiple linear regression analysis. Analysis showed that CTLA4 rs231726 and CR2 rs1048971 revealed a significant association with IgAN. These findings support the multi-gene nature of the etiology of IgAN and propose a potential gene-gene interactive model for future studies. PMID:25193896

Wang, Hui; Sui, Weiguo; Xue, Wen; Wu, Junyong; Chen, Jiejing; Dai, Yong

2014-09-01

80

MTHFR homozygous mutation and additional risk factors for cerebral infarction in a large Italian family.  

PubMed

Several cases with cerebral infarctions associated with the C677T mutation in the methylenetetrahydrofolate reductase gene (MTHFR) have been reported. Given the large number of asymptomatic individuals with the MTHFR mutation, additional risk factors for cerebral infarction should be considered. This study describes a large family with the MTHFR mutation and a combination of heterozygous factor V Leiden mutations and different additional exogenous and endogenous thrombogenic risk factors. Psychomotor retardation and a left fronto-insular infarct associated with the MTHFR mutation together with diminished factor VII and low level of protein C was documented in the first patient. In the second patient, generalized epilepsy and a malacic area in the right nucleus lenticularis was associated with the MTHFR mutation and a low level of protein C. In the third patient, right hemiparesis and a left fronto-temporal porencephalic cyst were documented, together with the MTHFR mutation and hyperhomocysteinemia. An extensive search of additional circumstantial and genetic thrombogenic risk factors should be useful for prophylaxis and prognosis of infants with cerebral infarctions associated with the MTHFR mutation and of their related family members. PMID:19068258

Del Balzo, Francesca; Spalice, Alberto; Perla, Massimo; Properzi, Enrico; Iannetti, Paola

2009-01-01

81

Effect of MTHFR 677C>T on plasma total homocysteine levels in renal graft recipients  

Microsoft Academic Search

Effect of MTHFR 677C>T on plasma total homocysteine levels in renal graft recipients.BackgroundHyperhomocysteinemia is an established, independent risk factor for vascular disease morbidity and mortality. The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism C677T has been shown to result in increased total homocysteine concentrations on the basis of low folate levels caused by a decreased enzyme activity. The effect of this polymorphism

MANUELA FÖDINGER; GABRIELE WÖLFL; GOTTFRIED FISCHER; SUSANNE RASOUL-ROCKENSCHAUB; RAINER SCHMID; WALTER H. HORL; GERE SUNDER-PLASSMANN

1999-01-01

82

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to pediatric acute lymphoblastic leukemia in a German study population  

PubMed Central

Background Methylenetetrahydrofolate reductase (MTHFR) has a major impact on the regulation of the folic acid pathway due to conversion of 5,10-methylenetetrahydrofolate (methylene-THF) to 5-methyl-THF. Two common polymorphisms (677C>T and 1298A>C) in the gene coding for MTHFR have been shown to reduce MTHFR enzyme activity and were associated with the susceptibility to different disorders, including vascular disease, neural tube defects and lymphoid malignancies. Studies on the role of these polymorphisms in the susceptibility to acute lymphoblastic leukemia (ALL) led to discrepant results. Methods We retrospectively evaluated the association of the MTHFR 677C>T and 1298A>C polymorphisms with pediatric ALL by genotyping a study sample of 443 ALL patients consecutively enrolled onto the German multicenter trial ALL-BFM 2000 and 379 healthy controls. We calculated odds ratios of MTHFR genotypes based on the MTHFR 677C>T and 1298A>C polymorphisms to examine if one or both of these polymorphisms are associated with pediatric ALL. Results No significant associations between specific MTHFR variants or combinations of variants and risk of ALL were observed neither in the total patient group nor in analyses stratified by gender, age at diagnosis, DNA index, immunophenotype, or TEL/AML1 rearrangement. Conclusion Our findings suggest that the MTHFR 677C>T and 1298A>C gene variants do not have a major influence on the susceptibility to pediatric ALL in the German population. PMID:15921520

Schnakenberg, Eckart; Mehles, Andrea; Cario, Gunnar; Rehe, Klaus; Seidemann, Kathrin; Schlegelberger, Brigitte; Elsner, Holger A; Welte, Karl H; Schrappe, Martin; Stanulla, Martin

2005-01-01

83

Factors Predisposing Drug Abuse.  

ERIC Educational Resources Information Center

The exact nature of the events which may predispose a person to substance abuse is not known. This paper provides a theoretical discussion and review which emphasizes three contexts which have been shown to predispose on individual to drug abuse: (1) prenatal exposure to a given substance; (2) environmental conditions present upon first exposure…

Cheney, Carl D.; Phelps, Brady J.

84

MTHFR ( C677T and A1298C ) Polymorphisms and Risk of Sporadic Distal Colorectal Adenoma in the UK Flexible Sigmoidoscopy Screening Trial (United Kingdom)  

Microsoft Academic Search

Objective  The purpose of this study was to further evaluate the role of low activity MTHFR variants as well as to explore interactive effects between alcoholic drink consumption and MTHFR variants and risk of distal colorectal adenomatous polyps.\\u000a \\u000a \\u000a \\u000a Methods  We examined the relationship between MTHFR C677T and A1298C gene polymorphisms and risk of distal adenomas in one of the largest case control

Panagiota N. Mitrou; Mark A. Watson; Alexandre S. Loktionov; Christopher Cardwell; Marc J. Gunter; Wendy S. Atkin; Christopher P. Macklin; Tom Cecil; Timothy D. Bishop; John Primrose; Sheila A. Bingham

2006-01-01

85

Sensitized phenotypic screening identifies gene dosage sensitive region on chromosome 11 that predisposes to disease in mice  

PubMed Central

The identification of susceptibility genes for human disease is a major goal of current biomedical research. Both sequence and structural variation have emerged as major genetic sources of phenotypic variability and growing evidence points to copy number variation as a particularly important source of susceptibility for disease. Here we propose and validate a strategy to identify genes in which changes in dosage alter susceptibility to disease-relevant phenotypes in the mouse. Our approach relies on sensitized phenotypic screening of megabase-sized chromosomal deletion and deficiency lines carrying altered copy numbers of ?30 linked genes. This approach offers several advantages as a method to systematically identify genes involved in disease susceptibility. To examine the feasibility of such a screen, we performed sensitized phenotyping in five therapeutic areas (metabolic syndrome, immune dysfunction, atherosclerosis, cancer and behaviour) of a 0.8 Mb reciprocal chromosomal duplication and deficiency on chromosome 11 containing 27 genes. Gene dosage in the region significantly affected risk for high-fat diet-induced metabolic syndrome, antigen-induced immune hypersensitivity, ApoE-induced atherosclerosis, and home cage activity. Follow up studies on individual gene knockouts for two candidates in the region showed that copy number variation in Stat5 was responsible for the phenotypic variation in antigen-induced immune hypersensitivity and metabolic syndrome. These data demonstrate the power of sensitized phenotypic screening of segmental aneuploidy lines to identify disease susceptibility genes. PMID:21204268

Ermakova, Olga; Piszczek, Lukasz; Luciani, Luisa; Cavalli, Florence M G; Ferreira, Tiago; Farley, Dominika; Rizzo, Stefania; Paolicelli, Rosa Chiara; Al-Banchaabouchi, Mumna; Nerlov, Claus; Moriggl, Richard; Luscombe, Nicholas M; Gross, Cornelius

2011-01-01

86

Sensitized phenotypic screening identifies gene dosage sensitive region on chromosome 11 that predisposes to disease in mice.  

PubMed

The identification of susceptibility genes for human disease is a major goal of current biomedical research. Both sequence and structural variation have emerged as major genetic sources of phenotypic variability and growing evidence points to copy number variation as a particularly important source of susceptibility for disease. Here we propose and validate a strategy to identify genes in which changes in dosage alter susceptibility to disease-relevant phenotypes in the mouse. Our approach relies on sensitized phenotypic screening of megabase-sized chromosomal deletion and deficiency lines carrying altered copy numbers of ?30 linked genes. This approach offers several advantages as a method to systematically identify genes involved in disease susceptibility. To examine the feasibility of such a screen, we performed sensitized phenotyping in five therapeutic areas (metabolic syndrome, immune dysfunction, atherosclerosis, cancer and behaviour) of a 0.8?Mb reciprocal chromosomal duplication and deficiency on chromosome 11 containing 27 genes. Gene dosage in the region significantly affected risk for high-fat diet-induced metabolic syndrome, antigen-induced immune hypersensitivity, ApoE-induced atherosclerosis, and home cage activity. Follow up studies on individual gene knockouts for two candidates in the region showed that copy number variation in Stat5 was responsible for the phenotypic variation in antigen-induced immune hypersensitivity and metabolic syndrome. These data demonstrate the power of sensitized phenotypic screening of segmental aneuploidy lines to identify disease susceptibility genes. PMID:21204268

Ermakova, Olga; Piszczek, Lukasz; Luciani, Luisa; Cavalli, Florence M G; Ferreira, Tiago; Farley, Dominika; Rizzo, Stefania; Paolicelli, Rosa Chiara; Al-Banchaabouchi, Mumna; Nerlov, Claus; Moriggl, Richard; Luscombe, Nicholas M; Gross, Cornelius

2011-01-01

87

Presence of Potent Transcriptional Activation Domains in the Predisposing Tuberous Sclerosis (Tsc2) Gene Product of the Eker Rat Model  

Microsoft Academic Search

The Eker rat hereditaryrenal carcinomais an excellent exampleof a Mendeliandominantpredispositionto a specific cancer in an experimen tal animal. We recently reported that a germline insertion in the rat homologue of the human tuberous sclerosis gene (TSC2) gives rise to dominantlyinherited cancer in the Eker rat model, as well as a tumor suppressor nature for the Tsc2 gene function. We also

Haruo Tsuchiya; Kenji Orimoto; Toshiyuki Kobayashi; Okio Hino

88

Effect of GDNF on depressive-like behavior, spatial learning and key genes of the brain dopamine system in genetically predisposed to behavioral disorders mouse strains.  

PubMed

The effect of glial cell line-derived neurotrophic factor (GDNF) on behavior and brain dopamine system in predisposed to depressive-like behavior ASC (Antidepressant Sensitive Cataleptics) mice in comparison with the parental "nondepressive" CBA mice was studied. In 7days after administration (800ng, i.c.v.) GDNF decreased escape latency time and the path traveled to reach hidden platform in Morris water maze in ASC mice. GDNF enhanced depressive-like behavioral traits in both "nondepressive" CBA and "depressive" ASC mice. In CBA mice, GDNF decreased functional response to agonists of D1 (chloro-APB hydrobromide) and D2 (sumanirole maleate) receptors in tail suspension test, reduced D2 receptor gene expression in the substantia nigra and increased monoamine oxydase A (MAO A) gene expression in the striatum. GDNF increased D1 and D2 receptor genes expression in the nucleus accumbens of ASC mice but failed to alter expression of catechol-O-methyltransferase, dopamine transporter, MAO B and tyrosine hydroxylase genes in both investigated mouse strains. Thus, GDNF produced long-term genotype-dependent effect on behavior and the brain dopamine system. GDNF pretreatment (1) reduced D1 and D2 receptors functional responses and D2 receptor gene expression in s. nigra of CBA mice; (2) increased D1 and D2 receptor genes expression in n. accumbens of ASC mice and (3) improved spatial learning in ASC mice. GDNF enhanced depressive-like behavior both in CBA and ASC mice. The data suggest that genetically defined variance in the cross-talk between GDNF and brain dopamine system contributes to the variability of GDNF-induced responses and might be responsible for controversial GDNF effects. PMID:25101543

Naumenko, Vladimir S; Kondaurova, Elena M; Bazovkina, Daria V; Tsybko, Anton S; Ilchibaeva, Tatyana V; Khotskin, Nikita V; Semenova, Alina A; Popova, Nina K

2014-11-01

89

DNA repair gene deficiency does not predispose human bronchial epithelial cells to benzo(a)pyrene-induced cell transformation.  

PubMed

The development of cost and time-efficient in vitro assays to predict carcinogenicity of chemicals has become a very important direction for toxicological research. In this study, we generated a series of human bronchial epithelial (HBE) cells defect in DNA repair gene excision repair cross-completion 1 (ERCC1), excision repair cross-completion 2 (ERCC2), ataxia-telangiectasia mutated (ATM) and mutS homolog 2 (MSH2), respectively. The inhibition of gene expression was verified by detection of mRNA and protein levels of respective genes. The suppression of these DNA repair genes has no impact on cell proliferation or cell transformation. Although we found that the transgenic HBE cells were more sensitive in benzo(a)pyrene (BaP)-induced DNA damages measured by cytokinesis-block micronucleus (CBMN) assay and comet assay, we failed to observe enhanced effects on induction of cell transformation. HBE cells defect in DNA repair pathways did not exhibit malignantly transformed phenotype up to 20 weeks of BaP treatment, indicating that the deficiency of ERCC1, ERCC2, ATM, or MSH2 alone did not shorten the latency of cell transformation. In contrast, we found that HBE cells expressing H-Ras or c-Myc were transformed 8 or 12 weeks after BaP treatment. These findings demonstrate that silencing of a single DNA repair gene does not confer cells susceptible to chemical-induced cell transformation. PMID:22382310

Xing, Xiumei; Liu, Caixia; Tang, Shifu; Li, Daochuan; Chen, Liping; Pang, Yaqin; Wang, Qing; Zhang, Bo; Zeng, Xiaowen; Chen, Wen; Xiao, Yongmei

2012-06-01

90

MTHFR gene C677T and A1298C polymorphisms and homocysteine levels in primary open angle and primary closed angle glaucoma  

PubMed Central

Purpose To investigate the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C genotypes and plasma concentrations of total homocysteine (tHcy) in Pakistani patients with primary open angle glaucoma (POAG) and primary closed angle glaucoma (PCAG). Methods This was a prospective case-control study. A total of 295 patients (173 POAG, 122 PCAG) and 143 age- and sex-matched controls were subdivided into two ethnic groups, Punjabis (Punjab province, central Pakistan) and Pathans (North-West Frontier Province, northern Pakistan). Genotypes of the MTHFR C677T and A1298C polymorphisms were detected by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). An enzyme-linked immunosorbent assay was used to determine the total serum homocysteine (tHcy) levels. Associations were determined by logistic regression analysis. Results Frequency distributions of genotypes and combined genotypes as well as homocysteine levels were obtained. The overall distribution of the C677T genotype was found to be significantly associated with PCAG (CC 69%, CT 21%, TT 10%; p=0.001, ?2=12.6), but not with POAG (CC 71%, CT 28%, TT 1%; p=0.98, ?2=0.02) as compared to the controls (CC 71%, CT 29%, TT 1%). The Pathan cohorts revealed no association with the disease; however, the Punjabis demonstrated a significant association with PCAG (CC 75%, CT 11%, TT 13%; p<0.001, ?2=17.2). PCAG in the Punjabi subjects was also significantly associated with the A1298C polymorphism (AA 43%, AC 54%, CC 3%; p<0.001, ?2=33.9) as compared to the controls. Combined genotype data showed no association with POAG; however, a significant association with all combined genotypes was observed in the overall PCAG subjects (p<0.05, ?2=20.1). This difference was particularly apparent in the TTAA and TTAC combinations that were completely absent in the control groups (p<0.05. ?2=49.6). Mean serum tHcy levels were found to be significantly increased in the POAG (15.2±1.28 µmol/l, p<0.001) and PCAG (20.8±4.8 µmol/l) groups as compared to the controls (10.0±0.97 µmol/l). The tHcy levels in the TT and AC genotype were significantly elevated in the PCAG group (67±12.39 µmol/l, p<0.001; 23±5.94 µmol/l, p=0.027) as compared to the controls. Conclusion The TT and AC genotypes of MTHFR C677T and A1298C polymorphisms and the combined genotype TTAC were associated with PCAG in Punjabi subjects of Pakistani origin and correlated with the high serum tHcy levels seen in these patients. PMID:19936026

Micheal, Shazia; Qamar, Raheel; Akhtar, Farah; Khan, Muhammad Imran; Khan, Wajid Ali

2009-01-01

91

Identification of Fetal and Maternal Single Nucleotide Polymorphisms in Candidate Genes That Predispose to Spontaneous Preterm Labor with Intact Membranes  

PubMed Central

Objective To determine whether maternal/fetal SNPs in candidate genes are associated with spontaneous preterm labor/delivery. Study Design A genetic association study was conducted in 223 mothers and 179 fetuses [preterm labor with intact membranes who delivered <37 weeks (PTB)], and 599 mothers and 628 fetuses (normal pregnancy): 190 candidate genes and 775 SNPs were studied. Single locus/haplotype association analyses were performed; FDR was used to correct for multiple testing (q*=0.15)]. Results 1) The strongest single locus associations with PTB were IL6R (fetus: p=0.000148) and TIMP2 (mother: p=0.000197), remaining significant after correction for multiple comparisons; 2) Global haplotype analysis indicated an association between a fetal DNA variant in IGF2 and maternal COL4A3 (global p=0.004 and 0.007, respectively). Conclusion A SNP involved in controlling fetal inflammation (IL6R) and DNA variants in maternal genes encoding for proteins involved in extracellular matrix biology approximately doubled the risk of PTB. PMID:20452482

Romero, Roberto; Velez, Digna R.; Kusanovic, Juan Pedro; Hassan, Sonia S.; Mazaki-Tovi, Shali; Vaisbuch, Edi; Kim, Chong Jai; Chaiworapongsa, Tinnakorn; Pearce, Brad; Friel, Lara A.; Bartlett, Jacquelaine; Anant, Madan Kumar; Salisbury, Benjamin A.; Vovis, Gerald F.; Lee, Min Seob; Gomez, Ricardo; Behnke, Ernesto; Oyarzun, Enrique; Tromp, Gerard; Williams, Scott M.; Menon, Ramkumar

2013-01-01

92

Can Certain Genotypes Predispose to Poor Asthma Control in Children? A Pharmacogenetic Study of 9 Candidate Genes in Children with Difficult Asthma  

PubMed Central

Objective We tested the hypothesis that patients with difficult asthma have an increased frequency of certain genotypes that predispose them to asthma exacerbations and poor asthma control. Methods A total of 180 Caucasian children with confirmed asthma diagnosis were selected from two phenotypic groups; difficult (n?=?112) versus mild/moderate asthma (n?=?68) groups. All patients were screened for 19 polymorphisms in 9 candidate genes to evaluate their association with difficult asthma. Key Results The results indicated that LTA4H A-9188>G, TNF? G-308>A and IL-4R? A1727>G polymorphisms were significantly associated with the development of difficult asthma in paediatric patients (p<0.001, p?=?0.019 and p?=?0.037, respectively). Haplotype analysis also revealed two haplotypes (ATA haplotype of IL-4R? A1199>C, IL-4R? T1570>C and IL-4R? A1727>G and CA haplotype of TNF? C-863>A and TNF? G-308>A polymorphisms) which were significantly associated with difficult asthma in children (p?=?0.04 and p?=?0.018, respectively). Conclusions and Clinical Relevance The study revealed multiple SNPs and haplotypes in LTA4H, TNF? and IL4-R? genes which constitute risk factors for the development of difficult asthma in children. Of particular interest is the LTA4H A-9188>G polymorphism which has been reported, for the first time, to have strong association with severe asthma in children. Our results suggest that screening for patients with this genetic marker could help characterise the heterogeneity of responses to leukotriene-modifying medications and, hence, facilitate targeting these therapies to the subset of patients who are most likely to gain benefit. PMID:23573270

Almomani, Basima; Hawwa, Ahmed F.; Millership, Jeffrey S.; Heaney, Liam; Douglas, Isabella; McElnay, James C.; Shields, Michael D.

2013-01-01

93

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with osteoporotic vertebral fractures, but is a weak predictor of BMD  

Microsoft Academic Search

Osteoporosis is a common disease with a strong genetic component. Linkage studies have suggested linkage between BMD and loci on chromosome 1. The MTHFR gene is located on chromosome 1. MTHFR catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methylenetetrahydrofolate, which is used for homocysteine methylation to methionine. The rare genotype (TT) of the C677T polymorphism has previously been demonstrated to be

Morten M. Villadsen; Mathias H. Bünger; Mette Carstens; Liselotte Stenkjær; Bente L. Langdahl

2005-01-01

94

Frequency of APOE, MTHFR and ACE polymorphisms in the Zambian population  

PubMed Central

Background Polymorphisms within the apolipoprotein-E (APOE), Methylenetetrahydrofolate reductase (MTHFR) and Angiotensin I-converting enzyme (ACE) genes has been associated with cardiovascular and cerebrovascular disorders, Alzheimer’s disease and other complex diseases in various populations. The aim of the study was to analyze the allelic and genotypic frequencies of APOE, MTHFR C677T and ACE I/D gene polymorphisms in the Zambian population. Results The allele frequencies of APOE polymorphism in the Zambian populations were 13.8%, 59.5% and 26.7% for the ?2, ?3 and ?4 alleles respectively. MTHFR C677T and ACE I/D allele frequencies were 8.6% and 13.8% for the T and D minor alleles respectively. The ?2?2 genotype and TT genotype were absent in the Zambian population. The genetic distances between Zambian and other African and non-African major populations revealed an independent variability of these polymorphisms. Conclusion We found that the APOE ?3 allele and the I allele of the ACE were significantly high in our study population while there were low frequencies observed for the MTHFR 677 T and ACE D alleles. Our analysis of the APOE, MTHFR and ACE polymorphisms may provide valuable insight into the understanding of the disease risk in the Zambian population. PMID:24679048

2014-01-01

95

Investigation of MTHFR in birth defects : pharmacogenetic studies with valproic acid and MTHFR promoter analyses.  

E-print Network

??Valproic acid (VPA) during pregnancy leads to congenital anomalies, possibly by disrupting folate metabolism. Mild deficiency of methylenetetrahydrofolate reductase (MTHFR), an enzyme of folate-dependent homocysteine… (more)

Roy, Marc André, 1981-

2006-01-01

96

Methylation loss at H19 imprinted gene correlates withmethylenetetrahydrofolate reductase gene promoter hypermethylation in semen samples from infertile males  

PubMed Central

Aberrant methylation at the H19 paternal imprinted gene has been identified in different cohorts of infertile males. The causes of H19 methylation errors are poorly understood. In this study, we investigated the methylation status of the H19 gene in semen DNA samples from infertile males affected by MTHFR gene promoter hypermethylation. DNA from normal and abnormal semen samples harbouring MTHFR gene promoter hypermethylated, hmMTHFR-nor and hmMTHFR-abn, and without MTHFR methylation, MTHFR-nor and MTHFR-abn, were investigated for methylation status in the H19 locus using bisulfite-treated DNA PCR, followed by cloning and sequencing. The prevalence of H19 hypomethylated clones was 20% in hmMTHFR-nor and 0% in MTHFR-nor semen samples (p < 0.05), and 28% in hmMTHFR-abn compared with 16% in MTHFR-abn semen samples (p > 0.05). These results underscore the association between H19 methylation defects and hypermethylation of the MTHFR gene promoter in normal semen samples and suggest that aberrant methylation at H19 may occur in the normal sperm of infertile males affected by MTHFR gene dysfunction. These findings provide new insights into the mechanisms causing abnormal methylation in imprinted genes and, in turn, male infertility. PMID:23975186

Rotondo, John C; Selvatici, Rita; Di Domenico, Maura; Marci, Roberto; Vesce, Fortunato; Tognon, Mauro; Martini, Fernanda

2013-01-01

97

The association between first trimester micronutrient intake, MTHFR genotypes, and global DNA methylation in pregnant women  

PubMed Central

Objective Our aim was to evaluate possible associations between consumption of micronutrients involved in one-carbon metabolism, MTHFR genotypes, and global DNA methylation in pregnant women. Methods A semi-quantitative dietary questionnaire was administered to 195 women during their first trimester in Morelos, Mexico. Two functional polymorphisms of the key folate-metabolizing gene, i.e. MTHFR 677 C>T and 1298 A>C, as well as global DNA methylation were assessed in peripheral blood drawn during the interview. Results Independent of maternal age and caloric intake, vitamin B6 deficiency was associated with 1.8 fold increased risk of hypomethylation in women carrying the MTHFR 677 T allele. Conclusions There exists a subpopulation that is more susceptible to B vitamin deficiencies. PMID:21443409

La Merrill, Michele; Torres-Sanchez, Luisa; Ruiz-Ramos, Ruben; Lopez-Carrillo, Lizbeth; Cebrian, Mariano E; Chen, Jia

2012-01-01

98

MTHFR polymorphisms and serum cobalamin affect plasma homocysteine concentrations differentially in females and males.  

PubMed

A total of 523 subjects (297 females and 226 males) from the Canary Islands Nutrition Study (ENCA) were studied in order to examine the effect of the MTHFR 677C>T, 1298A>C and 1793G>A polymorphisms, adjusted for age, serum (S)?folate and S?cobalamin levels, on total plasma homocysteine concentrations (tHcy). Genotyping was performed with Pyrosequencing® technology. The MTHFR 677T?allele was associated with increased tHcy concentrations only in males (P=0.005). The MTHFR 1298C?allele was found to be associated with higher tHcy levels but similarly, only in males (P=0.025). The MTHFR 1793A?allele was associated with decreased tHcy concentrations in the younger males (P=0.042). A haplotype?based approach was marginally superior in explaining the genetic interaction of the MTHFR polymorphisms on tHcy plasma levels (R2 0.352 vs. 0.342 for a simple genotype?based approach). A nutrigenetic interaction between the MTHFR 677C>T genotype and S?cobalamin on tHcy levels was demonstrated in both genders. The increase in tHcy was more pronounced with decreasing S?cobalamin quintiles in 677TT homozygotes (P=0.005 for males and P=0.015 for females) than with decreasing S?folate quintiles (P for trend not significant). It was concluded that gene?nutrient interactions may differ depending on the sex and age of the subjects. The transferability of gene?nutrient interactions from one community to others may therefore be limited not only by different food patterns but also by different ages, genders and genotype distributions. PMID:25176448

Nilsson, Torbjörn K; Böttiger, Anna K; Henríquez, Patricia; Serra Majem, Lluís

2014-11-01

99

Review and pooled analysis of studies on MTHFR C677T polymorphism and esophageal cancer  

Microsoft Academic Search

Esophageal cancer has been associated with tobacco and alcohol consumption, gastric reflux, exposure to nitrosamines from food or other environmental sources, and diets lacking folate. Susceptibility to esophageal cancer may be modified by functional polymorphisms in genes along the folate metabolic pathway, such as methylenetetrahydrofolate reductase (MTHFR). The C677T polymorphism is the most common functional variant, leading to a reduction

S. M. Langevin; D. Lin; K. Matsuo; C. M. Gao; T. Takezaki; R. Z. Stolzenberg-Solomon; M. Vasavi; Q. Hasan; E. Taioli

2009-01-01

100

Maternal MTHFR genotype and haplotype predict deficits in early cognitive development in a lead-exposed birth cohort in Mexico City1234  

PubMed Central

Background: Maternal folate nutritional status and prenatal lead exposure can influence fetal development and subsequent health. The methylenetetrahydrofolate reductase (MTHFR) gene is important for folate metabolism, and 2 common polymorphisms, C677T and A1298C, reduce enzymatic activity; C677T is present at high penetrance in Mexican populations. Objective: The objective of this study was to examine potential links between maternal and child MTHFR polymorphisms and child neurodevelopment in a lead-exposed population. Design: Data regarding MTHFR polymorphisms C677T and A1298C, peri- and postnatal lead measures, and Bayley Mental Development Index at 24 mo of age (MDI-24) scores were available for 255 mother-child pairs who participated in the ELEMENT (Early Life Exposures in Mexico to Environmental Toxicants) study during 1994–1995. Results: In covariate-adjusted regression models, maternal MTHFR 677 genotype predicted MDI-24 scores, in which each copy of the maternal MTHFR 677T variant allele was associated with lower MDI-24 scores (? = ?3.52; 95% CI: ?6.12, ?0.93; P = 0.004). Maternal MTHFR haplotype also predicted MDI-24 scores (mean ± SE: 93.3 ± 1.2 for 677C-1298A compared with 89.9 ± 0.8 for 677T-1298A; P < 0.05). MDI-24 scores were not associated with maternal MTHFR 1298 genotype or child MTHFR genotypes. We did not observe significant MTHFR genotype × lead interactions with respect to any of the subject biomarkers of lead exposure. Conclusions: The maternal MTHFR 677T allele is an independent predictor of poorer child neurodevelopment at 24 mo. These results suggest that maternal genetic variations in folate metabolism during pregnancy may program offspring neurodevelopment trajectories. Further research is warranted to determine the generalizability of these results across other populations. PMID:20504979

Hu, Howard; Wright, Robert O; Kordas, Katarzyna; Ettinger, Adrienne S; Sanchez, Brisa N; Cantonwine, David; Lazarus, Alicia L; Cantoral, Alejandra; Schnaas, Lourdes; Tellez-Rojo, Martha Maria; Hernandez-Avila, Mauricio

2010-01-01

101

Prevalence of MTHFR C677T Polymorphism in North Indian Mothers Having Babies with Trisomy 21 Down Syndrome  

ERIC Educational Resources Information Center

Recent studies have evaluated possible links between polymorphisms in maternal folate metabolism genes and Down syndrome. Some of these studies show a significantly increased prevalence of the C677T polymorphism of the 5,10-methylene tetrahydrofolate reductase (NADPH) gene (MTHFR) among mothers who have had babies with Down syndrome. This study…

Kohli, Utkarsh; Arora, Sadhna; Kabra, Madhulika; Ramakrishnan, Lakshmy; Gulati, Sheffali; Pandey, Ravindra

2008-01-01

102

The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and tumor risk: evidence from 134 case-control studies.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism, which is essential for DNA synthesis and methylation. Genetic variations in the MTHFR gene seem to contribute to a decreased activity of MTHFR, ultimately confer increased susceptibility to cancer. As the most extensively studied polymorphism, MTHFR C677T polymorphism was shown to contribute to cancer susceptibility but the results were inconsistent. The authors performed a meta-analysis including 134 studies (46,207 cases and 69,160 controls) to address the issue. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to assess the association. Overall, a significant elevated risk of cancer was associated with the MTHFR C677T polymorphism in T-allele versus C-allele comparison (OR = 1.06, 95% CI 1.02-1.11, P(heterogeneity) < 0.001), homozygote model (OR = 1.08, 95% CI 1.01-1.17, P(heterogeneity) < 0.001) and dominant model (OR = 1.05, 95% CI 1.00-1.10, P(heterogeneity) < 0.001). In the stratified analyses, significantly increased cancer risks were indicated among Asians in all genetic models except for heterozygote model. Further analysis revealed that C677T was significantly associated with an increased risk of esophageal and stomach cancer. This meta-analysis supports an association between the MTHFR C677T polymorphism and increased risk of esophageal and stomach cancer, especially among Asians. Additionally, more high-quality studies and that the covariates responsible for heterogeneity should be controlled to obtain a more conclusive response about the function of MTHFR C677T in cancer. PMID:24744129

Tang, Min; Wang, Shang-Qian; Liu, Bian-Jiang; Cao, Qiang; Li, Bing-Jie; Li, Peng-Chao; Li, Yong-Fei; Qin, Chao; Zhang, Wei

2014-07-01

103

Enrichment of MTHFR 677?T in a Chinese long-lived cohort and its association with lipid modulation  

PubMed Central

Background Variants in the Methylenetetrahydrofolate reductase (MTHFR) gene may result in a lowered catalytic activity and associate with subsequent elevated serum homocysteine (Hcy) concentration, abnormal DNA synthesis and methylation, cardiovascular risk, and unhealthy aging. Several investigations on the relationship of MTHFR C677T polymorphism with serum lipid profile and longevity have been conducted in some populations, but the findings remain mixed. Herein, we sought to look at the association between MTHFR C677T and lipid profile in a longevous cohort in Bama, a well-known home of longevity in China. Methods Genotyping of MTHFR C677T was undertaken in 516 long-lived inhabitants (aged 90 and older, long-lived group, LG) and 493 healthy controls (aged 60–75, non-long-lived group, non-LG) recruited from Bama area. Correlation between MTHFR genotypes and lipids was then evaluated. Results T allele and TT genotype were significantly more prevalent in LG (P?=?0.001 and 0.002, respectively), especially in females, than in non-LG. No difference in the tested lipid measures among MTHFR C677T genotypes was observed in LG, non-LG and total population (P?>?0.05 for all). However, female but not male T carriers exhibited higher TC and LDL-C levels than did T noncarriers in the total population and in LG after stratification by sex (P?MTHFR 677?T genotypes and its modest unfavorable impact on lipids in Bama long-lived individuals may imply an existence of other protective genotypes which require further determination. PMID:24968810

2014-01-01

104

MTHFR polymorphisms C677T and A1298C and associations with IVF outcomes in Brazilian women.  

PubMed

The aim of this study was to investigate the association between MTHFR gene polymorphisms and IVF outcomes in Brazilian women undergoing assisted reproduction treatment. A prospective study was conducted in the Human Reproduction Department at the ABC University School of Medicine and the Ideia Fertility Institute between December 2010 and April 2012. The patient population was 82 women undergoing assisted reproduction cycles. The MTHFR polymorphisms C677T and A1298C were evaluated and compared with laboratory results and pregnancy rates. The C677T variant was associated with proportions of mature (P=0.006) and immature (P=0.003) oocytes whereas the A1298C variant was associated with number of oocytes retrieved (P=0.044). The polymorphisms, whether alone or in combination, were not associated with normal fertilization, good-quality embryo or clinical pregnancy rates. This study suggests that the number and maturity of oocytes retrieved may be related to the MTHFR polymorphisms C677T and A1298C. It is believed that folate has a crucial function in human reproduction and that folate deficiency can compromise the function of the metabolic pathways it is involved in, leading to an accumulation of homocysteine. The gene MTHFR encodes the 5-MTHFR enzyme, which is involved in folate metabolism, and C677T/A1298C polymorphisms of this gene are related to decreased enzyme activity and consequent changes in homocysteine concentration. Folate deficiency and hyperhomocysteinaemia can also compromise fertility and lead to pregnancy complications by affecting the development of oocytes, preparation of endometrial receptivity, implantation of the embryo and pregnancy. In folliculogenesis, hyperhomocysteinaemia can activate apoptosis, leading to follicular atresia and affecting the maturity of oocytes and the quality of embryos cultured in vitro. This study was performed to investigate the association between MTHFR polymorphisms and IVF outcomes in women undergoing assisted reproduction treatment. PMID:24746944

D'Elia, Priscila Queiroz; dos Santos, Aline Amaro; Bianco, Bianca; Barbosa, Caio Parente; Christofolini, Denise Maria; Aoki, Tsutomu

2014-06-01

105

MTHFR C677T Polymorphism and Risk of Congenital Heart Defects: Evidence from 29 Case-Control and TDT Studies  

PubMed Central

Background Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme for folate metabolism in humans; it is encoded by the MTHFR gene. Several studies have assessed the association between MTHFR C677T polymorphism and the risk of congenital heart defects (CHDs), while the results were inconsistent. Methods and Findings Multiple electronic databases were searched to identify relevant studies published up to July 22, 2012. Data from case-control and TDT studies were integrated in an allelic model using the Catmap and Metafor software. Twenty-nine publications were included in this meta-analysis. The overall meta-analysis showed significant association between MTHFR C677T polymorphism and CHDs risk in children with heterogeneity (Pheterogeneity?=?0.000) and publication bias (Pegger?=?0.039), but it turned into null after the trim-and-fill method was implemented (OR?=?1.12, 95% CI?=?0.95–1.31). Nevertheless, positive results were obtained after stratified by ethnicity and sample size in all subgroups except the mixed population. For mothers, there was significant association between the variant and CHDs without heterogeneity (Pheterogeneity?=?0.150, OR?=?1.16, 95% CI?=?1.05–1.29) and publication bias (Pegger?=?0.981). However, the results varied across each subgroup in the stratified analysis of ethnicity and sample size. Conclusions Both infant and maternal MTHFR C677T polymorphisms may contribute to the risk of CHDs. PMID:23536781

Gong, Fangqi; Zhu, Weihua; Fu, Songling

2013-01-01

106

A retrospective comparative exploratory study on two Methylentetrahydrofolate Reductase (MTHFR) polymorphisms in esophagogastric cancer: the A1298C MTHFR polymorphism is an independent prognostic factor only in neoadjuvantly treated gastric cancer patients  

PubMed Central

Background Methylentetrahydrofolate reductase (MTHFR) plays a major role in folate metabolism and consequently could be an important factor for the efficacy of a treatment with 5-fluorouracil. Our aim was to evaluate the prognostic and predictive value of two well characterized constitutional MTHFR gene polymorphisms for primarily resected and neoadjuvantly treated esophagogastric adenocarcinomas. Methods 569 patients from two centers were analyzed (gastric cancer: 218, carcinoma of the esophagogastric junction (AEG II, III): 208 and esophagus (AEG I): 143). 369 patients received neoadjuvant chemotherapy followed by surgery, 200 patients were resected without preoperative treatment. The MTHFR C677T and A1298C polymorphisms were determined in DNA from peripheral blood lymphozytes. Associations with prognosis, response and clinicopathological factors were analyzed retrospectively within a prospective database (chi-square, log-rank, cox regression). Results Only the MTHFR A1298C polymorphisms had prognostic relevance in neoadjuvantly treated patients but it was not a predictor for response to neoadjuvant chemotherapy. The AC genotype of the MTHFR A1298C polymorphisms was significantly associated with worse outcome (p?=?0.02, HR 1.47 (1.06-2.04). If neoadjuvantly treated patients were analyzed based on their tumor localization, the AC genotype of the MTHFR A1298C polymorphisms was a significant negative prognostic factor in patients with gastric cancer according to UICC 6th edition (gastric cancer including AEG type II, III: HR 2.0, 95% CI 1.3-2.0, p?=?0.001) and 7th edition (gastric cancer without AEG II, III: HR 2.8, 95% CI 1.5-5.7, p?=?0.003), not for AEG I. For both definitions of gastric cancer the AC genotype was confirmed as an independent negative prognostic factor in cox regression analysis. In primarily resected patients neither the MTHFR A1298C nor the MTHFR C677T polymorphisms had prognostic impact. Conclusions The MTHFR A1298C polymorphisms was an independent prognostic factor in patients with neoadjuvantly treated gastric adenocarcinomas (according to both UICC 6th or 7th definitions for gastric cancer) but not in AEG I nor in primarily resected patients, which confirms the impact of this enzyme on chemotherapy associated outcome. PMID:24490800

2014-01-01

107

MTHFR C677T polymorphism: association with lymphoid neoplasm and effect on methotrexate therapy.  

PubMed

The aim of this study was to detect the possible role of methylene tetrahydrofolate reductase gene polymorphism (MTHFR C677T) in the pathogenesis of lymphoid neoplasms and to investigate the influence of this polymorphism on methotrexate toxicity in adult ALL patients treated with methotrexate maintenance therapy. There was a statistically significant increase in the risk of non-Hodgkin lymphoma in patients with CT genotype (OR, 2.9; 95% CI, 1.3-6.3; P = 0.007) and combined CT + TT genotype (OR, 3.2; 95% CI, 1.5-6.6; P = 0.006). While no significant association was found between this polymorphism and ALL risk. The patients with ALL treated with methotrexate during maintenance therapy were observed for signs of toxicity. MTHFR 677C>T polymorphism (CT + TT) was significantly overrepresented among cases with hepatic toxicity (OR = 15.6; 95% CI, 2.6-81.3; P = 0.001). In addition, they were overrepresented among cases with mucositis, anemia, thrombocytopenia, and leukopenia. However, it did not reach statistical significance level. Further studies on larger number of subjects are necessary. Additional studies on the role of MTHFR gene polymorphism with environment (folate intake) interaction are needed to confirm the role of these genetic polymorphisms. PMID:24592886

Ayad, Mona W; El Naggar, Amel A; El Naggar, Mostafa

2014-07-01

108

Capturing the biological impact of CDKN2A and MC1R genes as an early predisposing event in melanoma and non melanoma skin cancer  

PubMed Central

Germline mutations in CDKN2A and/or red hair color variants in MC1R genes are associated with an increased susceptibility to develop cutaneous melanoma or non melanoma skin cancer. We studied the impact of the CDKN2A germinal mutation p.G101W and MC1R variants on gene expression and transcription profiles associated with skin cancer. To this end we set-up primary skin cell co-cultures from siblings of melanoma prone-families that were later analyzed using the expression array approach. As a result, we found that 1535 transcripts were deregulated in CDKN2A mutated cells, with over-expression of immunity-related genes (HLA-DPB1, CLEC2B, IFI44, IFI44L, IFI27, IFIT1, IFIT2, SP110 and IFNK) and down-regulation of genes playing a role in the Notch signaling pathway. 3570 transcripts were deregulated in MC1R variant carriers. In particular, genes related to oxidative stress and DNA damage pathways were up-regulated as well as genes associated with neurodegenerative diseases such as Parkinson’s, Alzheimer and Huntington. Finally, we observed that the expression signatures indentified in phenotypically normal cells carrying CDKN2A mutations or MC1R variants are maintained in skin cancer tumors (melanoma and squamous cell carcinoma). These results indicate that transcriptome deregulation represents an early event critical for skin cancer development. PMID:24742402

Puig-Butille, Joan Anton; Escamez, Maria Jose; Garcia-Garcia, Francisco; Tell-Marti, Gemma; Fabra, Angels; Martinez-Santamaria, Lucia; Badenas, Celia; Aguilera, Paula; Pevida, Marta; Dopazo, Joaquin; del Rio, Marcela; Puig, Susana

2014-01-01

109

The Association between Two Common Mutations C677T and A1298C in Human Methylenetetrahydrofolate Reductase Gene and the Risk for Diabetic Nephropathy in Type II Diabetic Patients1  

Microsoft Academic Search

Mutations of the methylenetetrahydrofolate reductase (MTHFR) gene have been shown to be associated with a predisposition to developing diabetic nephropathy (DN) in specific populations. The frequency of two MTHFR mutations, a recently described mutation in the human MTHFR gene A1298C and C677T, whose association with DN is already known, was determined in an Israeli Jewish population with type 2 diabetes

Vlad Shpichinetsky; Itamar Raz; Yechiel Friedlander; Neta Goldschmidt; Isaiah D. Wexler; Arie Ben-Yehuda; Gideon Friedman

110

Contribution of GSTM1, GSTT1, and MTHFR polymorphisms to end-stage renal disease of unknown etiology in Mexicans  

PubMed Central

Oxidative stress is increased in chronic kidney disease, owing to an imbalance between the oxidative and antioxidant pathways as well as a state of persistent hyperhomocysteinemia. The enzymes glutathione S-transferases (GSTs) and methylenetetrahydrofolate reductase (MTHFR) are implicated in the regulation of these pathways. This study investigates the association between polymorphisms in the Glutathione S-transferase Mu 1 (GSTM1), glutathione S-transferase theta 1 (GSTT1), and MTHFR genes and end-stage renal disease (ESRD) of unknown etiology in patients in Mexico. A Case-control study included 110 ESRD patients and 125 healthy individuals. GSTM1 and GSTT1 genotypes were determined using the multiplex polymerase chain reaction (PCR). The MTHFR C677T polymorphism was studied using a PCR/restriction fragment length polymorphism method. In ESRD patients, GSTM1 and GSTT1 null genotype frequencies were 61% and 7% respectively. GSTM1 genotype frequencies differed significantly between groups, showing that homozygous deletion of the GSTM1 gene was associated with susceptibility to ESRD of unknown etiology (P = 0.007, odds ratios = 2.05, 95% confidence interval 1.21-3.45). The MTHFR C677T polymorphism genotype and allele distributions were similar in both groups (P > 0.05), and the CT genotype was the most common genotype in both groups (45.5% and 46.6%). Our findings suggest that the GSTM1 null polymorphism appears to be associated with the ESRD of unknown etiology in patients in Mexico. PMID:24339523

Gutierrez-Amavizca, B. E.; Orozco-Castellanos, R.; Ortiz-Orozco, R.; Padilla-Gutierrez, J.; Valle, Y.; Gutierrez-Gutierrez, N.; Garcia-Garcia, G.; Gallegos-Arreola, M.; Figuera, L. E.

2013-01-01

111

Association of genetic variants of MTHFR, ENPP1, and ADIPOQ with myocardial infarction in Egyptian patients.  

PubMed

The study aimed to investigate the association between MTHFR C677T, ENPP1 K121Q, and ADIPOQ 45 T/G gene polymorphisms and incidence of myocardial infarction (MI) in Egyptian patients. The study included 60 unrelated patients suffering from their first MI and 60 unrelated controls. Patients were recruited from Kasr-El Eini hospital, Cairo University. The previously mentioned polymorphisms were determined in all participants by PCR-RFLP. There was no significant difference in the distribution of genotypes and alleles of MTHFR C677T between groups. In contrast, significant difference was found in the distributions of genotypes and alleles of ENPP1 K121Q and ADIPOQ 45 T/G between MI patients and controls (P = 0.01, P = 0.004, P = 0.009, P = 0.001, respectively). Univariate analysis revealed that 121Q ENPP1 and 45 G ADIPOQ alleles were associated with the increased risk of MI (OR = 3; 95 % CI = 1.45-6.2; P = 0.004 and OR = 5.8; 95 % CI = 1.92-17.54; P = 0.001, respectively). The mutant homozygous genotypes of MTHFR, ENPP1, and ADIPOQ were more prevalent in diabetic hypertensive MI patients than it was among non-diabetic normotensive MI patients. Regarding the coagulation profile, INR (P = 0.009) and PC % (P = 0.022) were significantly different among the three genotypes of MTHFR C677T. The 677 T, 121 Q, and 45G variants were associated with MI in Egyptian patients; however, more studies are needed to determine the possible protective effect for these polymorphisms in our population. PMID:24242286

Shaker, Olfat Gamil; Ismail, Manal Fouad

2014-06-01

112

Stromelysin-1 5A/6A and eNOS T-786C polymorphisms, MTHFR C677T and A1298C mutations, and cigarette-cannabis smoking: a pilot, hypothesis-generating study of gene-environment pathophysiological associations with Buerger's disease.  

PubMed

Buerger's disease (BD) etiologies are poorly understood. Beyond smoking cessation, medical-surgical treatments have limited success. We hypothesized that mutations associated with arterial vasospasm (stromelysin-1 5A/6A, eNOS T-786C) and C677T-A1298C methylene tetrahydrofolate reductase (MTHFR) interacted with cigarette-cannabis smoking, reducing vasodilatory nitric oxide (NO), promoting arterial spasm-thrombosis. Of 21 smoking BD patients (14 men [2 siblings], 7 women; 20 white, 1 African-American), compared to 21 age-gender-race matched healthy controls, 5A/6A stromelysin- 1 homozygosity was present in 7 of 21 (33%) BD cases versus 5 of 21 (24%) controls (risk ratio 1.4; 95% confidence interval [CI] 0.5-3.7), and eNOS T-786C homozygosity was present in 3 of 21 (14%) BD cases versus 1 of 21 (5%) controls (risk ratio 3.0; 95% CI 0.3-26.6). C677T MTHFR homozygosity or compound C677T-A1298C heterozygosity was present in 7 of 21 cases (33%) versus 11 of 21 controls (52%) (risk ratio 0.6; 95% CI 0.3-1.3). In 18 patients who stopped and 3 who continued smoking, all stromelysin-1 5A/6A and/or eNOS heterozygotes-homozygotes, superficial phlebitis, lower limb gangrenous ulcers, and intractable ischemic rest pain with arterial occlusion progressed despite conventional medical therapy, threatening amputation. In 15 patients, to increase vasodilatory NO via endothelial NO synthase, l-arginine (15 g/day) was given, along with folic acid (5 mg), vitamin B6 (100 mg), and B12 (2000 mg/day) to optimize homocysteine metabolism and reduce asymmetric dimethylarginine, a NO synthase inhibitor. Unexpectedly quickly and strikingly, within 8 weeks to 8 months receiving l-arginine-folic acid, 11 of 15 treated patients improved with uniform pain reduction, ulcer healing, and in 5, full recovery of previously absent peripheral pulses. In smokers homo/heterozygous for stromelysin-1 5A/6A and eNOS T-786C mutations, we speculate that the development and severity of BD are related to a gene-environment vasospastic interaction with reduced NO-mediated vasodilatation. Increasing NO production by l-arginine while optimizing homocysteine metabolism by folic acid-B6-B12 may have therapeutic benefit. Further blinded, placebo-controlled studies are needed to determine whether our observations can be generalized to larger BD cohorts. PMID:17000887

Glueck, Charles J; Haque, Mofiz; Winarska, Magdalena; Dharashivkar, Swapna; Fontaine, Robert N; Zhu, Binghua; Wang, Ping

2006-10-01

113

Study of MTHFR and MS polymorphisms as risk factors for NTD in the Italian population.  

PubMed

Homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase ( MTHFR) gene is a risk factor for neural tube defects (NTDs) in many populations, including Italians. Another common mutation on the MTHFR gene, A1298C, has also been described as a risk mutation. Furthermore, several studies have suggested that a defective methionine synthase ( MS) enzyme could be a critical defect in folate-related NTDs. An A-to-G transition at bp 2756 on the MS gene has also been reported. In this case-control study, we studied the frequencies of these two polymorphisms in 203 Italian probands with non-syndromic NTDs: 98 mothers, 67 fathers, and 210 control individuals. Although the A1298C polymorphism is common in the Italian population (0.25), the allelic frequency was significantly higher among NTD cases and their parents. Heterozygous patients and mothers have an odds ratio (OR) of 1.98 and 2.11, respectively. The risk associated with the 1298CC genotype was higher for cases (OR = 3.67), for fathers (OR = 3.28), and, above all, for mothers (OR = 6.23). The prevalence of the A2756G polymorphism of the MS gene was determined (0.15). No increased prevalence of the mutated G allele was found in NTD families. This study shows that the MTHFRA1298C polymorphism is a genetic determinant for NTD risk in Italy. No association between the MSA2756G and NTD susceptibility was found. PMID:12111380

De Marco, Patrizia; Calevo, Maria Grazia; Moroni, Anna; Arata, Lorenza; Merello, Elisa; Finnell, Richard H; Zhu, Huiping; Andreussi, Luciano; Cama, Armando; Capra, Valeria

2002-01-01

114

MTHFR C677T and A1298C polymorphisms are risk factors for Down’s syndrome in Indian mothers  

Microsoft Academic Search

Downs syndrome (DS), a chromosomal disorder due to trisomy 21, results mostly from nondisjunction in maternal meiosis. The present case-control study examined the association of genetic polymorphisms with predisposition to nondisjunction. Two common polymorphisms (SNPs), C677T and A1298C, in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene involved in folate metabolism, are known to lower the activity of this enzyme. Three hundred and

Amit Kumar Rai; Satya Singh; Stuti Mehta; Ashok Kumar; L. K. Pandey; Rajiva Raman

2006-01-01

115

C677T MTHFR Mutation and Factor V Leiden Mutation in Patients with TIA\\/Minor Stroke  

Microsoft Academic Search

A common C677T mutation in the gene for the enzyme 5,10-methylenetetrahydrofolate reductase (5,10-MTHFR) has been linked to elevated levels of homocysteine and was therefore suspected to be a candidate genetic risk factor for arterial occlusive disease. Another mutation, factor V Leiden, has been established as a common hereditary risk factor for venous thrombosis, but its role in arterial disease remains

Wolfgang Lalouschek; Susanne Aull; Wolfgang Serles; Peter Schnider; Christine Mannhalter; Ingrid Pabinger-Fasching; Lüder Deecke; Karl Zeiler

1999-01-01

116

Combined heterozygosity for methylenetetrahydrofolate reductase (MTHFR) mutations C677T and A1298C is associated with abruptio placentae but not with intrauterine growth restriction  

Microsoft Academic Search

Objective: This study was undertaken to investigate the involvement of MTHFR gene mutations C677T and A1298C implicated in vascular disease, in patients with abruptio placentae and intrauterine growth restriction (IUGR). Study Design: DNA was extracted from blood samples of 54 patients with placental vasculopathy (18 patients with abruptio placentae and 36 with IUGR) and 114 control patients and amplified by

Gabriël S. Gebhardt; Charlotte L. Scholtz; Renate Hillermann; Hein J. Odendaal

2001-01-01

117

Emphysematous pancreatitis predisposed by Olanzapine  

PubMed Central

A 32-year-old male presented to our intensive care unit with severe abdominal pain and was diagnosed as acute pancreatitis after 2 months of olanzapine therapy for bipolar disorder. His serum lipase was 900 u/L, serum triglyceride 560 mg/dL, and blood sugar, fasting and postprandial were 230 and 478 mg/dL, respectively on admission. Contrast enhanced computed tomography (CECT) of abdomen was suggestive of acute pancreatitis. Repeat CECT showed gas inside pancreas and collection in peripancreatic area and patient underwent percutaneous drainage and antibiotics irrigation through the drain into pancreas. We describe the rare case of emphysematous pancreatitis due to development of diabetes, hypertriglyceridemia and immunosuppression predisposed by short duration olanzapine therapy. PMID:25024479

Samanta, Sukhen; Samanta, Sujay; Banik, Krishanu; Baronia, Arvind Kumar

2014-01-01

118

Mannose-binding lectin gene polymorphic variants predispose to the development of bronchopulmonary complications but have no influence on other clinical and laboratory symptoms or signs of common variable immunodeficiency  

PubMed Central

Mannose-binding lectin (MBL), activating protein of the lectin pathway of the complement system, is an important component of the non-specific immune response. MBL2 gene polymorphisms, both in the coding and promoter regions, lead to low or deficient serum MBL levels. Low serum MBL levels were shown to be associated with serious infectious complications, mainly in patients in whom other non-specific immune system barriers were disturbed (granulocytopenia, cystic fibrosis). We have analysed two promoter (?550 and ?221) and three exon (codons 52, 54 and 57) MBL2 polymorphisms in a total of 94 patients with common variable immunodeficiency (CVID) from two immunodeficiency centres. Low-producing genotypes were associated with the presence of bronchiectasis (P = 0·009), lung fibrosis (P = 0·037) and also with respiratory insufficiency (P = 0·029). We could not demonstrate any association of MBL deficiency with age at onset of clinical symptoms, age at diagnosis, the number of pneumonias before diagnosis or serum immunoglobulin (Ig)G, IgA and IgM levels before initiation of Ig treatment. No association with emphysema development was observed, such as with lung function test abnormalities. No effect of MBL2 genotypes on the presence of diarrhoea, granuloma formation, lymphadenopathy, splenomegaly, frequency of respiratory tract infection or the number of antibiotic courses of the patients was observed. Our study suggests that low MBL-producing genotypes predispose to bronchiectasis formation, and also fibrosis and respiratory insufficiency development, but have no effect on other complications in CVID patients. PMID:18637104

Litzman, J; Freiberger, T; Grimbacher, B; Gathmann, B; Salzer, U; Pavlík, T; Vl?ek, J; Postránecká, V; Trávní?ková, Z; Thon, V

2008-01-01

119

MTHFR/p53 polymorphisms as genetic factors for cervical intraepithelial neoplasia and cervical cancer in HPV-infected Mexican women.  

PubMed

We performed a case-control association study to evaluate the association between common polymorphisms in MTHFR (C677T and A1298C) and the Arg72Pro polymorphism in the p53 gene and the risk for cervical intraepithelial neoplasia (CIN) or invasive cervical cancer (ICC) in Mexican HPV-infected women. We included 131 women with diagnosis of CIN grade I-II and 78 with CIN III or ICC; as controls we also included 274 women with normal Pap smear and negative HPV test. Genotyping for MTHFR and p53 polymorphisms was performed by PCR-RFPLs. HPV was tested by Hybrid Capture II. Odds ratios and 95% confidence intervals were estimated. Genotype frequencies for the 3 studied polymorphisms were distributed according to the Hardy-Weinberg equilibrium. The A1298C-MTHFR polymorphism showed significant differences for the heterozygous AC genotype and the C allele, whereas the AA genotype and A allele resulted to be genetic risk factors for CIN or ICC (p<0.03). The Arg72Pro-p53 polymorphism showed for the genotypes Arg/Pro and Pro/Pro, and for the Pro allele, a significant association only to the risk for CIN (p<0.03). The MTHFR/p53 interaction showed that the genotype combinations AA/ArgArg and AA/ArgPro were associated, respectively, to the risk of ICC and CIN (p<0.05). This study suggests that the A1298C-MTHFR polymorphism contributes to the genetic risk for both CIN and ICC, whereas the Arg72Pro-p53 polymorphism only contributes to the risk for CIN. The MTHFR/p53 genetic combinations AA/ArgArg and AA/ArgPro are associated genetic risk factors for ICC and CIN in Mexican HPV-infected women. PMID:24474455

González-Herrera, Lizbeth; Rodríguez-Morales, Patricia; Gonza Lez-Losa, María Del Refugio; Pérez-Mendoza, Gerardo; Canul-Canché, Jaqueline; Rosado-López, Iván; Cetina, Thelma Canto de

2014-01-01

120

A Common Mutation A1298C in Human Methylenetetrahydrofolate Reductase Gene: Association with Plasma Total Homocysteine and Folate Concentrations1  

Microsoft Academic Search

Methylenetetrahydrofolate reductase (MTHFR) is one of the main regulatory enzymes of homocys- teine metabolism. Previous studies revealed that a common mutation in MTHFR gene C677T is related to hyperhomocysteinemia and occlusive vascular pathology. In the current study, we determined the prevalence of a newly described mutation in the human MTHFR gene A1298C, and the already known C677T mutation, and related

Gideon Friedman; Netta Goldschmidt; Yechiel Friedlander; Arie Ben-Yehuda; Jacob Selhub; Sharona Babaey; Malka Mendel; Miriam Kidron; Hanoch Bar-On

121

Polymorphisms of MTHFR Associated with Higher Relapse/Death Ratio and Delayed Weekly MTX Administration in Pediatric Lymphoid Malignancies  

PubMed Central

Backgrounds. Outcome of childhood malignancy has been improved mostly due to the advances in diagnostic techniques and treatment strategies. While methotrexate (MTX) related polymorphisms have been under investigation in childhood malignancies, many controversial results have been offered. Objectives. To evaluate associations of polymorphisms related MTX metabolisms and clinical course in childhood lymphoid malignancies. Method. Eighty-two acute lymphoblastic leukemia and 21 non-Hodgkin's lymphoma children were enrolled in this study. Four single nucleotide polymorphisms in 2 genes (MTHFR (rs1801133/c.677C>T/p.Ala222Val and rs1801131/c.1298A>C/p.Glu429Ala) and SLCO1B1 (rs4149056/c.521T>C/p.V174A and rs11045879/c.1865+4846T>C)) were genotyped by Taqman PCR method or direct sequencing. Clinical courses were reviewed retrospectively. Results. No patient who had the AC/CC genotype of rs1801131 (MTHFR) had relapsed or died, in which distribution was statistically different among the AA genotype of rs1801131 (P = 0.004). Polymorphisms of SLCO1B1 (rs11045879 and rs4149056) were not correlated with MTX concentrations, adverse events, or disease outcome. Conclusions. Polymorphisms of MTHFR (rs1801131) could be the plausive candidate for prognostic predictor in childhood lymphoid malignancies. PMID:24386571

Fukushima, Takashi; Sakai, Aiko; Suzuki, Ryoko; Nakajima-Yamaguchi, Ryoko; Kobayashi, Chie; Iwabuchi, Atsushi; Saito, Makoto; Yoshimi, Ai; Nakao, Tomohei; Kato, Keisuke; Tsuchida, Masahiro; Takahashi, Hideto; Koike, Kazutoshi; Kiyokawa, Nobutaka; Noguchi, Emiko; Sumazaki, Ryo

2013-01-01

122

Variable contribution of the MTHFR C677T polymorphism to non-syndromic cleft lip and palate risk in China.  

PubMed

Non-syndromic cleft lip with or without cleft palate (nsCL/P) is one of the most common craniofacial malformations among newborn infants. It has been demonstrated that periconceptional folic acid supplementation may reduce the occurrence of offspring with clefts, particularly in the North China; however, the mechanism remains unknown. Our study of a thermolabile polymorphism (C677T) of methylenetetrahydrofolate reductase (MTHFR) gene in 170 Chinese case-parent triads revealed a moderate association between this MTHFR polymorphism and nsCL/P in a population from North China, but not in a population from South China. Moreover, the study revealed that the heterozygous parents in the North were about twice as likely to transmit the high-risk T allele to affected cases, as that observed in the South (OR = 2.24, 95% CI: 1.08-4.65). Thus, the MTHFR polymorphism is a significant risk factor for nsCL/P in this Northern Chinese population. Our study suggested possible genetic heterogeneity in the development of nsCL/P among Northern and Southern populations in China. PMID:16470725

Zhu, JiangHui; Ren, AiGuo; Hao, Ling; Pei, LiJun; Liu, JianMeng; Zhu, HuiPing; Li, Song; Finnell, Richard H; Li, Zhu

2006-03-15

123

MTHFR polymorphisms in Puerto Rican children with isolated congenital heart disease and their mothers  

PubMed Central

Congenital heart defects (CHD) are among the most common birth defects. There is evidence suggesting that polymorphisms in folate metabolism could alter susceptibility to CHD. The MTHFR 677TT genotype has been associated with the development of structural congenital heart malformations. The objective of this study was to identify common polymorphisms in the MTHFR gene in children with isolated CHD and their mothers. The DNA analysis for the C677T and A1298C mutations was performed. The study group included 27 mothers, 27 children with CHD, and 220 controls. The prevalence of the TT polymorphism was higher in mothers (22%) than in controls (10%). Compound heterozygosity for both polymorphisms was 3.7 times more common in children with CHD than in the newborn controls. Mothers of children with CHD were more likely to be compound heterozygotes. The higher prevalence of C677T polymorphisms in mothers of children with CHD and of compound heterozygosity for both polymorphisms suggests the possible role of folic acid in the prevention of CHD. Due to the relation of this enzyme to folate metabolism, current folate recommendations for women in childbearing age in Puerto Rico to reduce neural tube defects may need to be extended to the prevention of CHD. PMID:20657745

Garcia-Fragoso, Lourdes; Garcia-Garcia, Ines; Leavitt, Gloria; Renta, Jessicca; Ayala, Miguel A.; Cadilla, Carmen L.

2010-01-01

124

Association of the C677T and A1298C polymorphisms in the 5,10 methylenetetrahydrofolate reductase gene in patients with migraine risk  

Microsoft Academic Search

Although controversial, diminished activity of 5,10 methylenetetrahydrofolate reductase (MTHFR), a regulatory enzyme of homocysteine metabolism, may predispose to migraine in Turkish people. In a case-control study, we determined the prevalence of two common MTHFR polymorphisms,C677T and A1298C, in 102 migraine patients (23 migraine with aura, 70 migraine without aura and nine with tension-type headache) and compared it to that of

Ihsan Kara; Ali Sazci; Emel Ergul; Guner Kaya; Gamze Kilic

2003-01-01

125

Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia  

E-print Network

(MTHFR) gene at positions C677T and A1298C were associated with lower risk of adult acute lymphocytic an association between polymorphic variants at positions C677T and A1298C in the folate-metabolizing gene 5,10- methylenetetrahydrofolate reductase (MTHFR), and a decreased risk of adult acute lymphocytic leukemia (ALL).1 Similar

California at Berkeley, University of

126

Polymorphism C776G in the transcobalamin II gene and homocysteine, folate and vitamin B 12 concentrations. Association with MTHFR C677T and A1298C and MTRR A66G polymorphisms in healthy children  

Microsoft Academic Search

One of the etiologies of hyperhomocysteinemia is decreased vitamin B12. Genetic variation in the transcobalamin II gene, the transporter of vitamin B12 to the cells, may produce altered homocysteine levels. We determined transcobalamin II C776G polymorphism, homocysteine, folate and vitamin B12 levels and analyzed the interactive effect with the methylenetetrahydrofolate reductase C677T and A1298C and methionine synthase reductase A66G polymorphisms

Ana C. M. Aléssio; Nelci F. Höehr; Lúcia H. Siqueira; Sérgio P. Bydlowski; Joyce M. Annichino-Bizzacchi

2007-01-01

127

The MTHFR C677T polymorphism is associated with depressive episodes in patients from Northern Ireland  

Microsoft Academic Search

Low plasma folate and its derivatives have been linked with depressive disorders in studies dating back over 30 years. A thermolabile variant (677C>T) of the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with low serum folate. The present study aimed to explore whether the thermolabile variant of MTHFR is associated with a vulnerability to depressive episodes. MTHFR C677T genotype frequencies in

Christopher B. Kelly; Anne P. McDonnell; Timothy G. Johnston; Ciaran Mulholland; Stephen J. Cooper; Dorothy McMaster; Alun Evans; Alexander S. Whitehead

2004-01-01

128

MTHFR C677T has differential influence on risk of MSI and MSS colorectal cancer  

Microsoft Academic Search

The majority of colorectal cancer (CRC) exhibiting the micosatellite instability (MSI) phenotype is due to hypermethylation of the hMLH1 gene promoter. We aimed to test the hypothesis that polymorphisms in genes coding for enzymes involved in folate metabolism play a role in altered promoter-specific hypermethy- lation and thus predispose to MSI CRC. Analysis of MSI was performed in 1685 CRCs,

Richard A. Hubner; Steven Lubbe; Ian Chandler; Richard S. Houlston

2007-01-01

129

The common MTHFR C677T and A1298C variants are not associated with the risk of non-syndromic cleft lip\\/palate in northern Venezuela  

Microsoft Academic Search

Non-syndromic cleft lip with or without cleft palate (nsCL\\/P) is among the most common major birth defects, with complex inheritance involving multiple genes and environmental factors. Numerous studies of MTHFR, encoding methylenetetrahydrofolate reductase, which catalyzes the rate-limiting step of folic acid biosynthesis, have shown inconsistent association of two common hypomorphic allelic variants, C677T and A1298C, in nsCL\\/P patients and, in

Mehmet A. Sözen; Marie M. Tolarova; Richard A. Spritz

2009-01-01

130

Maternal MTHFR polymorphisms and risk of spontaneous abortion  

Microsoft Academic Search

Objective. To asses the association between intake of folate and B vitamins and the incidence of spontaneous abortion (SA) according to the maternal methylenetetrahydrofolate reductase (MTHFR) polymorphisms (677 C>T and 1298 A>C). Material and Methods. We conducted a nested case-control study within a perinatal cohort of women re - cruited in the state of Morelos, Mexico. Twenty-three women with SA

María del Rosario Rodríguez-Guillén; Luisa Torres-Sánchez; Jia Chen; Marcia Galván-Portillo; Julia Blanco-Muñoz; Miriam Aracely Anaya; Irma Silva-Zolezzi; María A Hernández-Valero; Lizbeth López-Carrillo

2009-01-01

131

Low Birthweight (LBW) and Neonatal Hyperbilirubinemia (NNH) in an Indian Cohort: Association of Homocysteine, Its Metabolic Pathway Genes and Micronutrients as Risk Factors  

PubMed Central

Background & Aims Indian subcontinent has the highest child mortality rates along with a very high frequency of low birthweight (LBW). Folate and vitamin B12 (Vit-B12) are necessary during foetal development and their deficiency prevalence in Indians is very high. The objective of the present paper is to assess whether foetal homocysteine (Hcy)/folate metabolic pathway genes, their cofactors and homocysteine level independently (or collectively) predispose children to Low birth weight. Methods Cord blood was collected for the study. Frequency of 5 SNPs in 4-Hcy-pathway genes, and levels of Hcy, Vit-B12 and folate were evaluated. Results Of the 421 newborns recruited for the study, 38% showed low birth weight (<2.5kg) and 16% were preterm babies. 101 neonates developed neonatal hyperbilirubinemia (NNH). High prevalence of Vit-B12 (65%) and folate (27%) deficiency was observed in newborns along with hyperhomocystinemia (hypHcy-25%). Preterm delivery, micronutrient deficiency, hypHcy and MTHFR 677T SNP are associated as risk factor while G allele of TCN2 C776G is protective against LBW. MTHFR 677T allele and folate deficiency are also independent risk factors for NNH. Conclusion We record the highest incidence of Vit-B12, folate deficiency and elevated Hcy levels, of all the studies so far reported on neonates. These together with MTHFR 677T are potential risk factors for LBW. Association of impaired folate/Hcy metabolism with NNH is reported for the first time and the possible way of interaction is discussed. It appears that proper nutritional management during pregnancy would reduce the risk of complex clinical outcomes. PMID:23936521

Sukla, Krishna Kishore; Tiwari, Pankaj Kumar; Kumar, Ashok; Raman, Rajiva

2013-01-01

132

FACTORS PREDISPOSING CALVES FOR E. COLI ENTERITIS  

E-print Network

FACTORS PREDISPOSING CALVES FOR E. COLI ENTERITIS L. PROHÁSZKA Vetevinavy Medical Reseavch outbreaks of E. coli enteritis were studied. It was found that in newborn calves the serum bicarbonate level rose/32-35 meq/l/at 2-5 days of age at the critical time of E. coli infection and normalized again/22

Boyer, Edmond

133

Infant C677T mutation in MTHFR, maternal periconceptional vitamin use, and cleft lip.  

PubMed

Studies have reported an association between homozygosity for a variant form of the methylenetetrahydrofolate reductase (MTHFR) gene and risk for neural tube defects. Because of MTHFR's involvement with folate metabolism and evidence that maternal use of a multivitamin with folic acid in early pregnancy reduces risk for cleft lip with or without cleft palate (CLP), we hypothesized that infants homozygous for the C677T genotype would be at increased risk for CLP because of lower MTHFR enzymatic activity. Data were derived from a large population-based, case-control study of fetuses and liveborn infants among a cohort of 1987 to 1989 California births. The analyses involved 310 infants with isolated CLP whose mothers completed a telephone interview and whose DNA was available from newborn screening blood specimens and involved 383 control infants without a congenital anomaly whose mothers completed a telephone interview and whose DNA was available. Cases and controls were genotyped TT if homozygous for the C677T allele, CT if heterozygous for the C677T allele, and CC if homozygous for the C677 (wild-type) allele. Odds ratios for CLP were 0.89 (0.55 to 1.4) and 0.78 (0.56 to 1.1) for infants with TT versus CC and infants with CT versus CC genotypes, respectively. Compared with the CC genotype, the odds ratios for CLP among infants with the TT genotype were 0.74 (0.39 to 1.4) for those infants whose mothers were users and 1.4 (0.54 to 3.6) for those infants whose mothers were not users of multivitamins containing folic acid periconceptionally. The two estimates were not statistically heterogeneous (P = 0.30). Our results did not indicate increased risks for CLP among infants homozygous for the C677T genotype, nor do they indicate an interaction between infant C677T genotype and maternal multivitamin use on the occurrence of CLP. PMID:9843036

Shaw, G M; Rozen, R; Finnell, R H; Todoroff, K; Lammer, E J

1998-11-16

134

Migraine and MTHFR C677T genotype in a population-based sample  

Microsoft Academic Search

OBJECTIVE: Migraine with aura is associated with increased risk of stroke. The MTHFR C677T genotype has been associated with increased risk of migraine in selected clinical samples and with elevated homocysteine, a risk factor for stroke. We assessed the association of the MTHFR C677T variant with migraine and the mediating effect of cardiovascular risk factors and metabolic markers of genotype

Ann I. Scher; Gisela M. Terwindt; W. M. Monique Verschuren; Mark C. Kruit; Henk J. Blom; Hisanori Kowa; Rune R. Frants; Arn M. J. M. van den Maagdenberg; Mark van Buchem; Michel D. Ferrari; Lenore J. Launer

2006-01-01

135

Biological and clinical implications of the MTHFR C677T polymorphism  

Microsoft Academic Search

The enzyme methylenetetrahydrofolate reductase (MTHFR) directs folate species either to DNA synthesis or to homocysteine (Hcy) remethylation. The common MTHFR C677T polymorphism affects the activity of the enzyme and hence folate distribution. Under conditions of impaired folate status, the homozygous TT genotype has been regarded as harmful because it is associated with a high concentration of plasma total Hcy, increased

Per Magne Ueland; Steinar Hustad; Jørn Schneede; Helga Refsum; Stein Emil Vollset

2001-01-01

136

Effects of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism on executive function in schizophrenia  

Microsoft Academic Search

BackgroundThe methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism has been associated with both overall schizophrenia risk and severity of negative symptoms. This study examined whether schizophrenia patients homozygous for the risk allele (T\\/T) exhibit greater impairment in executive function, and determined the extent to which MTHFR's effects on negative symptoms underlie this relationship.

Joshua L. Roffman; Anthony P. Weiss; Thilo Deckersbach; Oliver Freudenreich; David C. Henderson; Shaun Purcell; Donna H. Wong; Charles H. Halsted; Donald C. Goff

2007-01-01

137

Association of the MTHFR 1298A>C (rs1801131) polymorphism with speed and strength sports in Russian and Polish athletes.  

PubMed

It has been suggested that DNA hypomethylation because of poorer effectiveness of the 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme induces muscular growth. We hypothesised that the common, functional 1298A>C polymorphism in the MTHFR gene is associated with athletic status. To test this hypothesis, we investigated the distribution of the 1298A>C variant in Polish (n = 302) and Russian (n = 842) athletes divided into four groups: endurance, strength-endurance, sprint-strength and strength-endurance, as well as in 1540 control participants. We found different genotypes (the AC heterozygote advantage) and allele distributions among sprint-strength athletes and strength athletes than the groups of sedentary controls for each nationality. In the combined study, the allelic frequencies for the 1298C variant were 35.6% in sprint-strength athletes (OR 1.18 [1.02-1.36], P = 0.024 vs. controls) and 38.6% in strength athletes (OR 1.34 [1.10-1.64], P = 0.003 vs. controls). The results of the initial and repetition studies as well as the combined analysis suggest that the functional 1298A>C polymorphism in the MTHFR gene is associated with athletic status. The presence of the C allele seems to be beneficial in sprint-strength and strength athletes. It needs to be established whether and to what extent this effect is mediated by alteration in DNA methylation status. PMID:24015812

Zarebska, Aleksandra; Ahmetov, Ildus I; Sawczyn, Stanislaw; Weiner, Alexandra S; Kaczmarczyk, Mariusz; Ficek, Krzysztof; Maciejewska-Karlowska, Agnieszka; Sawczuk, Marek; Leonska-Duniec, Agata; Klocek, Tomasz; Voronina, Elena N; Boyarskikh, Uljana A; Filipenko, Maksim L; Cieszczyk, Pawel

2014-01-01

138

Homocysteine and nitrite levels are modulated by MTHFR 677C>T polymorphism in obese women treated with simvastatin.  

PubMed

Higher homocysteine (Hcy) levels are associated with cardiovascular risk. The aim of the present study was to evaluate the effect of simvastatin treatment on circulating Hcy levels in obese women without hypertension, diabetes or dyslipidaemia; and to determine whether the 677C>T polymorphism located in methylenetetrahydrofolate reductase (NAD(P)H) (MTHFR) gene modulates the effects of this treatment on Hcy and nitrite (as a biomarker of nitric oxide (NO) bioavailability). Twenty-five obese women (body mass index ? 30 kg/m(2) ) who had received 20 mg/day simvastatin for 6 weeks were enrolled in the study. Venous blood samples were collected to measure plasma biomarkers and gene polymorphisms. Simvastatin treatment significantly reduced total cholesterol, low-density lipoprotein-cholesterol, thiobarbituric acid-reactive substances, high-sensitivity C-reactive protein and Hcy, whereas nitrite levels were increased. The reduction in Hcy levels in carriers of the T allele was -20.3% compared with -9.4% in patients with the CC genotype. Importantly, before treatment, nitrite levels were significantly higher in patients with the CC genotype compared with T allele carriers, whereas after treatment these levels were similar between groups. Our findings demonstrate that obese women without comorbidities and carrying the T variant of the 677C>T polymorphism of MTHFR exhibit benefits with simvastatin treatment, mainly in terms of increased NO levels. PMID:25115547

Villela, Maria P; Andrade, Vanessa L; Eccard, Bryelle; Jordão, Alceu A; Sertório, Jonas T; Tanus-Santos, Jose E; Silva, Ieda Fo; Silveira, Josianne N; Sandrim, Valéria C

2014-10-01

139

Stromelysin-1 5A\\/6A and eNOS T-786C Polymorphisms, MTHFR C677T and A1298C Mutations, and Cigarette-Cannabis Smoking: A Pilot, Hypothesis-Generating Study of Gene-Environment Pathophysiological Associations With Buerger’s Disease  

Microsoft Academic Search

Buerger’s disease (BD) etiologies are poorly understood. Beyond smoking cessation, medical-surgical treatments have limited success. We hypothesized that mutations associated with arterial vasospasm (stromelysin-1 5A\\/6A, eNOS T-786C) and C677T-A1298C methylene tetrahydrofolate reductase (MTHFR) interacted with cigarette-cannabis smoking, reducing vasodilatory nitric oxide (NO), promoting arterial spasm-thrombosis. Of 21 smoking BD patients (14 men [2 siblings], 7 women; 20 white, 1 African-American),

Charles J. Glueck; Mofiz Haque; Magdalena Winarska; Swapna Dharashivkar; Robert N. Fontaine; Binghua Zhu; Ping Wang

2006-01-01

140

MTHFR 677C>T effects on anterior cingulate structure and function during response monitoring in schizophrenia: a preliminary study  

PubMed Central

Patients with schizophrenia exhibit deficient response monitoring as indexed by blunted activation of the dorsal anterior cingulate cortex (dACC) and functionally related regions during error commission. This pattern may reflect heritable alterations of dACC function. We examined whether the hypofunctional 677C>T variant in MTHFR, a candidate schizophrenia risk gene, contributed to our previous findings of blunted error-related dACC activation and reduced microstructural integrity of dACC white matter. Eighteen medicated outpatients with schizophrenia underwent diffusion tensor imaging and performed an antisaccade paradigm during functional magnetic resonance imaging (fMRI). T allele carriers exhibited significantly less error-related activation than C/C patients in bilateral dACC and substantia nigra, regions that are thought to mediate dopamine-dependent error-based reinforcement learning. T carrier patients also showed significantly lower fractional anisotropy in bilateral dACC. These findings suggest that the MTHFR 677T allele blunts response monitoring in schizophrenia, presumably via effects on dopamine signaling and dACC white matter microstructural integrity. PMID:21190096

Brohawn, David G.; Friedman, Jesse S.; Dyckman, Kara A.; Thakkar, Katharine N.; Agam, Yigal; Vangel, Mark G.; Goff, Donald C.; Manoach, Dara S.

2014-01-01

141

Association of MTHFR C677T and SHMT 1 C1420T with susceptibility to ESCC and GCA in a high incident region of Northern China  

Microsoft Academic Search

Objective  To assess the association between the C to T transition in the methylenetetrahydro folate reductase gene (MTHFR C677T) and the C to T transition in the serine hydroxymethyltransferase\\u000a \\u000a 1\\u000a gene (SHMT\\u000a \\u000a 1\\u000a C1420T) and the increased risk of carcinogenesis of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma\\u000a (GCA) in a population of high incident region of Northern China.

Yimin Wang; Wei Guo; Yutong He; Zhifeng Chen; Denggui Wen; Xiufeng Zhang; Na Wang; Yan Li; Hui Ge; Jianhui Zhang

2007-01-01

142

Methylenetetrahydrofolate reductase polymorphism (MTHFR C677T) and bone mineral density in Chinese men and women  

Microsoft Academic Search

The relationship between MTHFR (C677T) genotypes of the methylenetetrahydrofolate reductase, bone mineral density (BMD), and vertebral fracture was studied in 657 Chinese men and women. No association between MTHFR (C677T) and BMD was found in postmenopausal women (aged 55–59 years, n = 178), elderly women (aged 70–79 years, n = 247), or elderly men (aged 70–79 years, n = 232)

M. Li; E. M. C. Lau; J. Woo

2004-01-01

143

Quantitative assessment of the association between MTHFR rs1801131 polymorphism and risk of liver cancer.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) is one of the most important enzymes for folate metabolism which plays a key role in cell metabolism. MTHFR rs1801131 (A1298C) polymorphism can decrease in vitro MTHFR enzyme activity and has been hypothesized to be associated with liver cancer risk. This study aimed to quantify the strength of the association between MTHFR rs1801131 polymorphism and liver cancer risk by performing a meta-analysis. We searched the PubMed and Wanfang databases for studies relating on the association between MTHFR rs1801131 polymorphism and risk of liver cancer. Seven studies with 2,030 cases of liver cancer and 3,096 controls were finally included into the meta-analysis. Meta-analysis of a total of seven studies showed that the homozygote genotype CC of MTHFR rs1801131 polymorphism was significantly associated with decreased risk of liver cancer (for CC versus AA: odds ratio (OR)?=?0.65, 95% confidence interval (CI) 0.47-0.89, P?=?0.007; for CC versus AA?+?AC: OR?=?0.65, 95% CI 0.48-0.89, P?=?0.006). Subgroup by race showed that the homozygote genotype CC of MTHFR rs1801131 polymorphism was significantly associated with decreased risk of liver cancer in Asians (CC versus AA: OR?=?0.64, 95% CI 0.46-0.90, P?=?0.010; for CC versus AA?+ AC: OR?=?0.63, 95% CI 0.45-0.88, P?=?0.007). However, the association in Caucasians was still unclear owing to the limited data available now. Thus, Asian individuals with the homozygote genotype CC of MTHFR rs1801131 polymorphism are significantly associated with decreased risk of liver cancer. The association in Caucasians needs further studies. PMID:24014085

Liang, Tie-Jun; Liu, Hui; Zhao, Xiao-Qian; Tan, Yan-Rong; Jing, Kai; Qin, Cheng-Yong

2014-01-01

144

Birth trauma: incidence and predisposing factors.  

PubMed

The authors retrospectively studied 13,870 singleton full-term consecutive live births at a major teaching hospital and assessed the frequency of brachial plexus injury, clavicular fracture, and facial nerve injury in newborns delivered from January 1974 through December 1977 and from January 1979 through September 1981. Predisposing factors relating to mechanical birth trauma were defined, and a risk assessment profile was developed to identify the fetus at risk. Mechanical injuries were identified according to the International Classification of Diseases codes 761. The incidence of selected birth injuries in the study group were: brachial plexus injury, 2.6 per 1000 or 1 in 385 single full-term live births; fractured clavicle, 2.0 per 1000 or 1 in 495 single full-term live births; and facial nerve injury, 7.5 per 1000 or 1 in 133 single full-term live births. There were 162 full-term infants born with 168 injuries relevant to this study. Of the six infants who incurred more than one injury, three had a combined fractured clavicle-brachial plexus injury, and three had facial nerve-branchial plexus injuries. Logistic regression analysis of fetal, maternal, and intrapartum complications in labor and delivery revealed that midforceps , shoulder dystocia, low forceps, infants greater than 3500 g, and second stage labor exceeding 60 minutes were the predominant events associated with fetal injury. The authors then applied a risk assessment profile to successfully identify over 50% of the injured and 84% of the uninjured groups. From their results, the authors suggest that obstetricians should alert the pediatricians when these predisposing factors exist to aid in the recognition and early treatment of these birth injuries. PMID:6728359

Levine, M G; Holroyde, J; Woods, J R; Siddiqi, T A; Scott, M; Miodovnik, M

1984-06-01

145

Association of a Common Allelic Polymorphism (C677T) in the Methylene Tetrahydrofolate Reductase Gene with a Reduced Risk of Osteoporotic Fractures. A Case Control Study in Danish Postmenopausal Women  

Microsoft Academic Search

Twin studies indicate a substantial genetic component in the development of osteoporosis. One of the latest studied candidate genes is the one coding for methylene tetrahydrofolate reductase (MTHFR) (C677T) in which a point mutation gives rise to a thermolabile variant of MTHFR. The aim of this study was to investigate the influence of this mutation on peripheral measures of bone

H. L. Jørgensen; J. S. Madsen; B. Madsen; M. M. A. Saleh; B. Abrahamsen; M. Fenger; J. B. Lauritzen

2002-01-01

146

MTHFR 677 (C?T) polymorphism is not relevant for prognosis or therapy-associated toxicity in pediatric NHL: results from 484 patients of multicenter trial NHL-BFM 95  

Microsoft Academic Search

We analyzed the relationship of genetic variation within the methylenetetrahydrofolate reductase gene (MTHFR 677 C?T) with clinical characteristics, outcome, and therapy-related toxicity in pediatric non-Hodgkin’s lymphoma (NHL) in our\\u000a multicenter trial NHL-BFM 95. In this trial, high-dose methotrexate (MTX) infusion regimens were randomized (4- vs 24-h infusion)\\u000a in patients with B-cell lymphoma; MTX was applied as 24-h infusion in all

Kathrin Seidemann; Martin Zimmermann; Ulrike Meyer; Karl Welte; Martin Stanulla; Alfred Reiter

2006-01-01

147

Association of MTHFR C677T polymorphism and risk of cerebrovascular disease in Chinese population: an updated meta-analysis.  

PubMed

A variety of epidemiological studies have evaluated the association between methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism and cerebrovascular disease, but the results were inconsistent. The present meta-analysis was therefore performed to investigate the relationship between C677T polymorphism and cerebrovascular disease in Chinese population. Systematically searching for related studies from PubMed, Embase, Web of Science, CBMdisc and CNKI databases up to 20 September 2013 and manual searching of the reference lists of identified articles was performed. Information was extracted to calculate for the additive, dominant, and recessive models using the pooled odds ratios (ORs) along with 95 % confidence intervals (CIs), using Review Manager 5.0, STATA 11.0 and SPSS 17. Logistic regression, fixed or random effects model, subgroup analysis, sensitivity analysis, meta-regression analysis and publication bias were conducted to improve the comprehensive analysis. A total of 68 case-control studies containing 7,990 cases and 6,941 controls were included in the final meta-analysis. Evidence of significant association between C677T polymorphism and risk of cerebrovascular disease was found in all three genetic models (additive model OR 1.472, 95 % CI 1.368-1.585, P L < 0.001 (CT vs. CC); OR 1.819, 95 % CI 1.666-1.985, P L < 0.001 (TT vs. CC); dominant model OR 1.77, 95 % CI 1.57-1.98, p < 0.00001; and recessive model OR 1.54, 95 % CI 1.39-1.71, p < 0.00001, respectively) based on the overall population. In addition, the results were verified by the subgroup analysis and sensitivity analysis. The present meta-analysis suggests that MTHFR gene C677T polymorphism is significantly associated with increased risk of cerebrovascular disease. TT genotype may act as an independent risk factor for cerebrovascular disease in Chinese population. PMID:24603976

Zhang, Ming-Jie; Li, Jing-Cheng; Yin, Yan-Wei; Li, Bing-Hu; Liu, Yun; Liao, Shao-Qiong; Gao, Chang-Yue; Zhang, Li-Li

2014-05-01

148

Inverse Association between Obesity Predisposing FTO Genotype and Completed Suicide  

PubMed Central

The A allele of rs9939609 in the FTO gene predisposes to increased body mass index (BMI) and obesity. Recently we showed an inverse association between the obesity related A allele of rs9939609 and alcohol dependence which was replicated by others. Since this finding raises a possibility that FTO may be associated with other psychiatric phenotypes, we aimed to examine association of rs9939609 with completed suicide. We genotyped rs9939609 in 912 suicide victims and 733 controls using TaqMan approach. We observed an inverse association between suicide and the rs9939609 A allele (OR?=?0.80, P?=?0.002, Pcor?=?0.006) with genotype distribution suggesting a co-dominant effect. Given the link between alcoholism and suicide under influence of alcohol reported in Polish population, confounding by alcohol addiction was unlikely due to apparently similar effect size among cases who were under influence of ethanol at the time of death (OR?=?0.76, P?=?0.003, N?=?361) and those who were not (OR?=?0.80, P?=?0.007, N?=?469). The search for genotype-phenotype correlations did not show significant results. In conclusion, our study proves that there is an inverse association between rs9939609 polymorphism in FTO gene and completed suicide which is independent from association between FTO and alcohol addiction. PMID:25265168

Chojnicka, Izabela; Fudalej, Sylwia; Walczak, Anna; Wasilewska, Krystyna; Fudalej, Marcin; Stawinski, Piotr; Strawa, Katarzyna; Pawlak, Aleksandra; Wojnar, Marcin; Krajewski, Pawel; Ploski, Rafal

2014-01-01

149

Radiographic predisposing factors for degenerative spondylolisthesis.  

PubMed

This study was a retrospective radiographic study involving analysis of computed tomography scans obtained for patients with degenerative spondylolisthesis of the L4-L5 segment and a control group. The purpose of the study was to identify radiological predisposing factors for degenerative spondylolisthesis of the L4-L5 segment. The authors reviewed all computed tomography scans (N=3370) performed at their institution between January 2005 and December 2008. Eighty-four patients with degenerative spondylolisthesis were identified and compared with a control group regarding facet joint orientation, the presence of sacralization of the L5 vertebra, the presence of major degenerative changes in the L5-S1 disk space, and the location of the intercrestal line. There was a statistically significant difference between the 2 groups regarding facet joint orientation, with more sagittal facet joints in the degenerative spondylolisthesis group (56° and 54° in the right and left facets, respectively, in the study group, and 46° and 42° in the right and left facets, respectively, in the control group) (P<.001). There was no statistically significant difference between the 2 groups regarding the presence of sacralization of the L5 vertebra, the presence of major degenerative changes in the L5-S1 disk space, and the location of the intercrestal line relative to the lumbar spine. There is an association between sagittal orientation of the facet joints at the L4-L5 segment and degenerative spondylolisthesis at the same level. PMID:24762153

Smorgick, Yossi; Mirovsky, Yigal; Fischgrund, Jeffrey S; Baker, Kevin C; Gelfer, Yael; Anekstein, Yoram

2014-03-01

150

Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer  

Microsoft Academic Search

About 1.4% of the general population are heterozygous carriers of the gene for ataxia-telangiectasia (A-T), an autosomal recessive progressive neurologic syndrome in which cancer incidence of homozygotes is approximately 100 fold greater than the general population's rates. The hypothesis that A-T heterozygotes are predisposed to breast cancer was tested by the unbiased statistically powerful index-test method based on molecular genotyping.

Prasanna Athma; Rebecca Rappaport; Michael Swift

1996-01-01

151

Association of dietary intake of folate and MTHFR genotype with breast cancer risk.  

PubMed

We conducted a hospital-based case-control study to investigate the associations of dietary intake of folate and MTHFR C677T and A1298C polymorphisms with breast cancer in a Chinese population. A 1:1-matched case-control study was conducted. Two hundred and thirty patients who were newly diagnosed and histologically confirmed breast cancer and 230 controls were enrolled from Xinxiang Central Hospital. Folate intake was calculated by standard portion size and relative size for each food item in the questionnaire. Genotyping of MTHFR C677T and A1298C was performed by PCR-RFLP. MTHFR 677TT (OR = 2.26, 95%CI = 1.09-4.87, P = 0.02) and T allele (OR = 1.40, 95%CI = 1.03-1.90, P = 0.03) had an increased risk of laryngeal cancer when compared with the CC genotype. We found any interaction between MTHFR C677T and folate intake (P for interaction = 0.02). In conclusion, our study demonstrated that MTHFR C677T polymorphism and folate are associated with risk of breast cancer. PMID:25078601

Wang, Z G; Cui, W; Yang, L F; Zhu, Y Q; Wei, W H

2014-01-01

152

Positive association between MTHFR C677T polymorphism and oral cancer risk: a meta-analysis.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) is a central enzyme involved in regulating the metabolic function of folate, which plays a pivotal role in DNA synthesis, repair, and methylation. The role of MTHFR C677T polymorphism in oral cancer risk has been reported with conflicting evidence. We conducted this study to appropriately estimate the effect size. We searched eligible studies in medicine-specific databases (PubMed, EMBASE, and Web of Knowledge) using (polymorphism) OR (polymorphisms) AND (methylenetetrahydrofolate reductase) OR (MTHFR) AND (oral cancer). A total of seven studies were summarized. This meta-analysis of the combined data showed a marginal association of MTHFR C677T polymorphism with oral cancer risk [odds ratio (OR)?=?0.86, 95% confidence interval (CI)?=?0.73-1.00 for CT vs. CC]. We also found decreased oral cancer risk in Asian population and hospital-based studies. Moreover, heavy drinkers were found to have a significantly higher risk of developing such cancer as compared to the non-heavy drinkers. These results suggest that MTHFR C677T polymorphism may play a role in oral cancer carcinogenesis in Asian population and heavy drinkers. PMID:24488626

Jia, Juan; Ma, Zheng; Wu, Shuangjiang

2014-05-01

153

MTHFR C677T polymorphism and osteoporotic fracture in postmenopausal women: a meta-analysis.  

PubMed

Numerous studies have evaluated the association between MTHFR C677T polymorphism and osteoporotic fracture risk in postmenopausal women. However, the results have been inconsistent. We performed a meta-analysis of the association between MTHFR C677T polymorphism and osteoporotic fracture risk in postmenopausal women. Only seven case-control studies were retrieved, with a total of 4258 patients and 3454 healthy controls. Meta-analysis results showed no significant association between MTHFR C677T polymorphism and osteoporotic fracture risk in postmenopausal women for all genetic models (for TT vs CC: OR=0.99, 95%CI=0.72-1.39; for TT vs TC: OR=1.02, 95%CI=0.87-1.20; for CC+TC vs TT: OR=0.96, 95%CI=0.71-1.28; for TT+TC vs CC: OR=0.93, 95%CI=0.84-1.03). In the subgroup analysis by ethnicity, the results also showed no significant association between MTHFR C677T polymorphism and susceptibility to osteoporotic fracture in postmenopausal women in both Caucasian and Asian populations. In conclusion, this meta-analysis suggests that MTHFR C677T polymorphism may not be associated with susceptibility to osteoporotic fracture in postmenopausal women. PMID:25222234

Guan, J Z; Wu, M; Xiao, Y Z; Zhou, J S; Wang, Z D

2014-01-01

154

An association between the methylenetetrahydrofolate reductase (MTHFR) C677T mutation and inflammation markers related to cardiovascular disease  

Microsoft Academic Search

BackgroundProspective studies have identified many markers of systemic inflammation that are powerful predictors of future cardiovascular events. The methylenetetrahydrofolate reductase (MTHFR) C677T genotype, a common polymorphism that induces hyperhomocysteinaemia, has been proposed as a genetic risk factor for cardiovascular disease. In this work, we evaluated the relationship between the levels of inflammation markers and MTHFR genotype among cardiovascular disease free

George V. Z. Dedoussis; Demosthenes B. Panagiotakos; Christos Pitsavos; Christina Chrysohoou; John Skoumas; Despoina Choumerianou; Christodoulos Stefanadis

2005-01-01

155

[Predisposing factors of pregnancy in adolescents].  

PubMed

Results of a study of social characteristics and sexual development of 107 pregnant and 228 nonpregnant adolescents aged 14-19 are presented and compared to earlier findings. The pregnant girls were interviewed after applying for abortions. Fathers of the pregnant girls were found to have had significnatly less education. The pregnant girls had an average of 2.4 siblings compared to 1.7 in the control group, and 32.6% came from families with 3 or more children compared to 20.4% in the control group. 24.2% of the pregnant adolescents lived in incomplete homes compared to 11.8% of controls. 82.2% of pregnant and 88.6% of control subjects reported their family life to be good or very good. A significantly higher proportion in the control group had good or very good school performance and behavior. No significant difference was noted in age at menarche or 1st heterosexual contact. The pregnant girls engaged in genital stimulation and intercourse at significantly earlier ages than the controls, had less knowledge and use of contraceptives, and had fewer female friends. Results of the study are summarized and compared with previous work in the broad areas of social situation and sexual development. 2 concepts of predisposing factors to adolescent pregnancy, 1 using physical precocity as a starting point and the other, environmental risks such as disturbed family life, early sexual contact and frequent changes of partners, are contrasted and questioned. Adequate sex education and better instruction on contraception and contraceptive behavior, particularly for male adolescents, are seen as the best strategies for reducing unwanted pregnancies in adolescents. PMID:7148012

Wagner, K D; Nagel, H; Eggers, H; Göretzlehner, G; Voigt, M

1982-08-15

156

Homocysteine and Coronary Heart Disease: Meta-analysis of MTHFR Case-Control Studies, Avoiding Publication Bias  

PubMed Central

Background Moderately elevated blood levels of homocysteine are weakly correlated with coronary heart disease (CHD) risk, but causality remains uncertain. When folate levels are low, the TT genotype of the common C677T polymorphism (rs1801133) of the methylene tetrahydrofolate reductase gene (MTHFR) appreciably increases homocysteine levels, so “Mendelian randomization” studies using this variant as an instrumental variable could help test causality. Methods and Findings Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T. These datasets did not include measurements of blood homocysteine, but homocysteine levels would be expected to be about 20% higher with TT than with CC genotype in the populations studied. In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98–1.07; p?=?0.28) overall, and 1.01 (0.95–1.07) in unsupplemented low-folate populations. By contrast, in a slightly updated meta-analysis of the 86 published studies (28,617 CHD cases and 41,857 controls), the OR was 1.15 (1.09–1.21), significantly discrepant (p?=?0.001) with the OR in the unpublished datasets. Within the meta-analysis of published studies, the OR was 1.12 (1.04–1.21) in the 14 larger studies (those with variance of log OR<0.05; total 13,119 cases) and 1.18 (1.09–1.28) in the 72 smaller ones (total 15,498 cases). Conclusions The CI for the overall result from large unpublished datasets shows lifelong moderate homocysteine elevation has little or no effect on CHD. The discrepant overall result from previously published studies reflects publication bias or methodological problems. Please see later in the article for the Editors' Summary PMID:22363213

Verhoef, Petra; Dotsch-Klerk, Mariska; Lathrop, Mark; Xu, Peng; Nordestgaard, B?rge G.; Holm, Hilma; Hopewell, Jemma C.; Saleheen, Danish; Tanaka, Toshihiro; Anand, Sonia S.; Chambers, John C.; Kleber, Marcus E.; Ouwehand, Willem H.; Yamada, Yoshiji; Elbers, Clara; Peters, Bas; Stewart, Alexandre F. R.; Reilly, Muredach M.; Thorand, Barbara; Yusuf, Salim; Engert, James C.; Assimes, Themistocles L.; Kooner, Jaspal; Danesh, John; Watkins, Hugh; Samani, Nilesh J.

2012-01-01

157

Mutations in LRRC50 Predispose Zebrafish and Humans to Seminomas  

PubMed Central

Seminoma is a subclass of human testicular germ cell tumors (TGCT), the most frequently observed cancer in young men with a rising incidence. Here we describe the identification of a novel gene predisposing specifically to seminoma formation in a vertebrate model organism. Zebrafish carrying a heterozygous nonsense mutation in Leucine-Rich Repeat Containing protein 50 (lrrc50 also called dnaaf1), associated previously with ciliary function, are found to be highly susceptible to the formation of seminomas. Genotyping of these zebrafish tumors shows loss of heterozygosity (LOH) of the wild-type lrrc50 allele in 44.4% of tumor samples, correlating with tumor progression. In humans we identified heterozygous germline LRRC50 mutations in two different pedigrees with a family history of seminomas, resulting in a nonsense Arg488* change and a missense Thr590Met change, which show reduced expression of the wild-type allele in seminomas. Zebrafish in vivo complementation studies indicate the Thr590Met to be a loss-of-function mutation. Moreover, we show that a pathogenic Gln307Glu change is significantly enriched in individuals with seminoma tumors (13% of our cohort). Together, our study introduces an animal model for seminoma and suggests LRRC50 to be a novel tumor suppressor implicated in human seminoma pathogenesis. PMID:23599692

Basten, Sander G.; van Rooijen, Ellen; Stoop, Hans; Babala, Nikolina; Logister, Ive; Heath, Zachary G.; Jonges, Trudy N.; Katsanis, Nicholas; Voest, Emile E.; van Eeden, Freek J.; Medema, Rene H.; Ketting, Rene F.; Schulte-Merker, Stefan; Looijenga, Leendert H. J.; Giles, Rachel H.

2013-01-01

158

Association between dietary intake of folate and MTHFR and MTR genotype with risk of breast cancer.  

PubMed

We investigated the association between dietary intake of folate, vitamin B6, and the 5,10-methylenetetrahydrofolate reductase (MTHFR) genotype with breast cancer. A matched case-control study was conducted, and 413 patients with newly diagnosed and histologically confirmed breast cancer and 436 controls were recruited. Folate intake, vitamin B6, and vitamin B12 levels were calculated, and the MTHFR C677T and A1298C and MTR A2756G polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism. Breast cancer cases were generally older, older at first live birth, and younger at menarche, had a higher body mass index, were smokers, had higher energy intake, and more first-degree relatives with breast cancer as well as more live births compared to controls. With respect to energy intake, we found that higher energy intake were more likely to increase the risk of breast cancer. The MTHFR 667TT genotype was associated with a moderately increased risk of breast cancer when compared with the CC genotype, and a significant odds ratio (OR; 95% confidence interval, CI) was found (OR = 1.70, 95%CI = 1.06-2.73). Individuals carrying T allele were associated with higher risk of breast cancer when compared with C allele (OR = 1.34, 95%CI = 1.06-1.70). We did not find a significant effect of the MTHFR A1298C and MTR A2756G on the risk of breast cancer. We did not find any association between folate intake and MTHFR C677T polymorphisms. In conclusion, we found that the MTHFR C667T polymorphism is associated with the risk of breast cancer, indicating that this genotype plays a role in breast cancer development. PMID:25366783

He, J M; Pu, Y D; Wu, Y J; Qin, R; Zhang, Q J; Sun, Y S; Zheng, W W; Chen, L P

2014-01-01

159

Interaction between the MTHFR C677T polymorphism and traumatic childhood events predicts depression  

PubMed Central

Childhood trauma is associated with the onset and recurrence of major depressive disorder (MDD). The thermolabile T variant of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) is associated with a limited (oxidative) stress defense. Therefore, C677T MTHFR could be a potential predictor for depressive symptomatology and MDD recurrence in the context of traumatic stress during early life. We investigated the interaction between the C677T MTHFR variant and exposure to traumatic childhood events (TCEs) on MDD recurrence during a 5.5-year follow-up in a discovery sample of 124 patients with recurrent MDD and, in an independent replication sample, on depressive symptomatology in 665 healthy individuals from the general population. In the discovery sample, Cox regression analysis revealed a significant interaction between MTHFR genotype and TCEs on MDD recurrence (P=0.017). Over the 5.5-year follow-up period, median time to recurrence was 191 days for T-allele carrying patients who experienced TCEs (T+ and TCE+); 461 days for T? and TCE+ patients; 773 days for T+ and TCE? patients and 866 days for T? and TCE? patients. In the replication sample, a significant interaction was present between the MTHFR genotype and TCEs on depressive symptomatology (P=0.002). Our results show that the effects of TCEs on the prospectively assessed recurrence of MDD and self-reported depressive symptoms in the general population depend on the MTHFR genotype. In conclusion, T-allele carriers may be at an increased risk for depressive symptoms or MDD recurrence after exposure to childhood trauma. PMID:23900311

Lok, A; Bockting, C L H; Koeter, M W J; Snieder, H; Assies, J; Mocking, R J T; Vinkers, C H; Kahn, R S; Boks, M P; Schene, A H

2013-01-01

160

Gene-gene interaction in folate-related genes and risk of neural tube defects in a UK population  

PubMed Central

Objective: To investigate the contribution of polymorphic variation in genes involved in the folate-dependent homocysteine pathway in the aetiology of neural tube defects (NTD). Design: Case-control association study. Subjects: A total of 530 individuals from families affected by NTD, 645 maternal controls, and 602 healthy newborn controls from the northern UK. Main outcome measures: Seven polymorphisms in six genes coding for proteins in the folate-dependent homocysteine pathway (MTHFR 677C?T, MTHFR 1298A?C, MTRR 66A?G, SHMT 1420C?T, CßS 844ins68, GCPII 1561C?T, RFC-1 80G?A). The impact of each polymorphism and the effect of gene–gene interactions (epistasis) upon risk of NTD were assessed using logistic regression analysis. Results: The MTHFR 677C?T polymorphism was shown to represent a risk factor in NTD cases (CC v CT+TT odds ratio (OR) 2.03 [95% confidence interval (CI) 1.09, 3.79] p = 0.025) and the MTRR 66A?G polymorphism was shown to exert a protective effect in NTD cases (AA v AG+GG OR 0.31 [95% CI 0.10, 0.94] p = 0.04). When statistical tests for interaction were conducted, three genotype combinations in cases (MTRR/GCPII; MTHFR 677/CßS; MTHFR 677/MTRR) and one combination in case mothers (CßS/RFC-1) were shown to elevate NTD risk. Maternal–fetal interaction was also detected when offspring carried the MTHFR 677C?T variant and mothers carried the MTRR 66A?G variant, resulting in a significantly elevated risk of NTD. Conclusion: Both independent genetic effects and gene–gene interaction were observed in relation to NTD risk. Multi-locus rather than single locus analysis might be preferable to gain an accurate assessment of genetic susceptibility to NTD. PMID:15060097

Relton, C; Wilding, C; Pearce, M; Laffling, A; Jonas, P; Lynch, S; Tawn, E; Burn, J

2004-01-01

161

Evaluating for suspected child abuse: conditions that predispose to bleeding.  

PubMed

Child abuse might be suspected when children present with cutaneous bruising, intracranial hemorrhage, or other manifestations of bleeding. In these cases, it is necessary to consider medical conditions that predispose to easy bleeding/bruising. When evaluating for the possibility of bleeding disorders and other conditions that predispose to hemorrhage, the pediatrician must consider the child's presenting history, medical history, and physical examination findings before initiating a laboratory investigation. Many medical conditions can predispose to easy bleeding. Before ordering laboratory tests for a disease, it is useful to understand the biochemical basis and clinical presentation of the disorder, condition prevalence, and test characteristics. This technical report reviews the major medical conditions that predispose to bruising/bleeding and should be considered when evaluating for abusive injury. PMID:23530171

Carpenter, Shannon L; Abshire, Thomas C; Anderst, James D

2013-04-01

162

Correlations of MTHFR 677C>T Polymorphism with Cardiovascular Disease in Patients with End-Stage Renal Disease: A Meta-Analysis  

PubMed Central

Objective This meta-analysis was conducted to evaluate the correlations of a common polymorphism (677C>T) in the methylenetetrahydrofolate reductase (MTHFR) gene with risk of cardiovascular disease (CVD) in patients with end-stage renal disease (ESRD). Method The following electronic databases were searched without language restrictions: Web of Science (1945?2013), the Cochrane Library Database (Issue 12, 2013), MEDLINE (1966?2013), EMBASE (1980?2013), CINAHL (1982?2013) and the Chinese Biomedical Database (CBM) (1982?2013). Meta-analysis was performed using STATA statistical software. Odds ratios (ORs) with their 95% confidence intervals (95%CIs) were calculated. Results Eight cohort studies met all inclusion criteria and were included in this meta-analysis. A total of 2,292 ESRD patients with CVD were involved in this meta-analysis. Our meta-analysis results revealed that the MTHFR 677C>T polymorphism might increase the risk of CVD in ESRD patients (TT vs. CC: OR?=?2.75, 95%CI?=?1.35?5.59, P?=?0.005; CT+TT vs. CC: OR?=?1.39, 95%CI?=?1.09?1.78, P?=?0.008; TT vs. CC+CT: OR?=?2.52, 95%CI?=?1.25?5.09, P?=?0.010; respectively). Further subgroup analysis by ethnicity suggested that the MTHFR 677C>T polymorphism was associated with an elevated risk for CVD in ESRD patients among Asians (TT vs. CC: OR?=?3.38, 95%CI?=?1.11?10.28, P?=?0.032; CT+TT vs. CC: OR?=?1.44, 95%CI?=?1.05?1.97, P?=?0.022; TT vs. CC+CT: OR?=?3.15, 95%CI?=?1.02?9.72, P?=?0.046; respectively), but not among Africans or Caucasians (all P>0.05). Conclusion Our findings indicate that the MTHFR 677C>T polymorphism may be associated with an elevated risk for CVD in ESRD patients, especially among Asians. PMID:25050994

Gao, Xian-Hui; Zhang, Guo-Yi; Wang, Ying; Zhang, Hui-Ying

2014-01-01

163

A Novel Germline Mutation in BAP1 Predisposes to Familial Clear-Cell Renal Cell Carcinoma  

PubMed Central

Renal cell carcinoma (RCC) clusters in some families. Familial RCC arises from mutations in several genes, including VHL, which is also mutated in sporadic RCC. However, a significant percentage of familial RCC remains unexplained. Recently, we discovered that the BAP1 gene is mutated in sporadic RCC. BAP1, which encodes a nuclear deubiquitinase, is a two-hit tumor suppressor gene. Somatic BAP1 mutations are associated with high-grade ccRCC and poor patient outcomes. To determine whether BAP1 predisposes to familial RCC, we sequenced the BAP1 gene in 83 unrelated probands with unexplained familial RCC. We identified a novel variant (c.41T>A; p.L14H), which cosegregated with the RCC phenotype. The p.L14H variant disrupts a highly conserved residue in the catalytic domain, a domain frequently targeted by missense mutations. The family with the BAP1 variant was characterized by early-onset clear cell RCC, occasionally of high Fuhrman grade, and lacked other features that characterize von Hippel-Lindau syndrome. These findings suggest that BAP1 is a familial RCC predisposing gene. PMID:23709298

Mester, Jessica L.; Pena-Llopis, Samuel; Pavia-Jimenez, Andrea; Christie, Alana; Vocke, Cathy D.; Ricketts, Christopher J.; Peterson, James; Middelton, Lindsay; Kinch, Lisa; Grishin, Nick; Merino, Maria J.; Metwalli, Adam R.; Xing, Chao; Xie, Xian-Jin; Dahia, Patricia L.M.; Eng, Charis

2013-01-01

164

Lack of association between methylenetetrahydrofolate reductase gene A1298C polymorphism and breast cancer susceptibility  

Microsoft Academic Search

Published data on the association between methylenetetrahydrofolate reductase gene (MTHFR) A1298C polymorphism and breast\\u000a cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Medline,\\u000a PubMed, Embase, and Web of Science were searched. Crude ORs with 95% CIs were used to assess the strength of association between\\u000a the MTHFR A1298C polymorphism and breast

Li-Xin QiuJian; Jian Zhang; Wen-Hua Li; Qun-Ling Zhang; Hui Yu; Bi-Yun Wang; Lei-Ping Wang; Jia-Lei Wang; Hui-Jie Wang; Xiao-Jian Liu; Zhi-Guo Luo; Xiang-Hua Wu

2011-01-01

165

5,10-Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms: genotype frequency and association with homocysteine and folate levels in middle-southern Italian adults.  

PubMed

Two genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene (C677T and A1298C) can influence the plasma homocysteine (Hcy) levels, especially in the presence of an inadequate folate status. The aim of this study was to evaluate the frequencies of C677T and of A1298C MTHFR polymorphisms and their correlation with Hcy and serum folate concentrations in a population of blood donors living in a region of middle-southern Italy (the Molise Region). One hundred ninety seven blood donors were studied for total plasma Hcy, serum folate and C677T and A1298C MTHFR genotypes. The frequency of C677T genotypes was 20.8% (CC), 49.8% (CT) and 29.4% (TT); for the A1298C genotypes: 48.7% (AA), 43.7% (AC) and 7.6% (CC). Hcy and serum folate concentrations were significantly different among genotypes of the C677T polymorphism (CC versus CT versus TT: <0.0001 both for Hcy and folate), with Hcy values increasing, and serum folate decreasing, from CC to TT subjects. Regarding to A1298C polymorphism, the difference among genotypes (AA versus AC versus CC; p: 0.026 for Hcy and 0.014 for serum folate), showed an opposite trend for both parameters, with Hcy higher in the wild-type and lower in the homozygotes and serum folate higher in CC than in AA subjects. In conclusion, we found a high frequency of MTHFR allele associated with high level of Hcy and low levels of folate in an Italian southern population. PMID:24277487

Zappacosta, Bruno; Graziano, Mirella; Persichilli, Silvia; Di Castelnuovo, Augusto; Mastroiacovo, Pierpaolo; Iacoviello, Licia

2014-01-01

166

Methylenetetrahydrofolate reductase C677T genotype affects promoter methylation of tumor-specific genes in sporadic colorectal cancer through an interaction with folate\\/vitamin B12 status  

Microsoft Academic Search

AIM: To evaluate joint effects of Methylentetra- hydrofolate reductase (MTHFR ) C677T genotypes, and serum folate\\/vitamin B12 concentrations on promoter methylation of tumor-associated genes among Iranian colorectal cancer patients. METHODS: We examined the associations between MTHFR C677T genotype, and promoter methylation of P16 , hMLH1 , and hMSH2 tumor-related genes among 151 sporadic colorectal cancer patients. The promoter methylation of

Pooneh Mokarram; Fakhraddin Naghibalhossaini

2008-01-01

167

Host genetic factors predisposing to HIV-associated neurocognitive disorder.  

PubMed

The success of combination antiretroviral therapy (cART) in transforming the lives of HIV-infected individuals with access to these drugs is tempered by the increasing threat of HIV-associated neurocognitive disorders (HAND) to their overall health and quality of life. Intensive investigations over the past two decades have underscored the role of host immune responses, inflammation, and monocyte-derived macrophages in HAND, but the precise pathogenic mechanisms underlying HAND remain only partially delineated. Complicating research efforts and therapeutic drug development are the sheer complexity of HAND phenotypes, diagnostic imprecision, and the growing intersection of chronic immune activation with aging-related comorbidities. Yet, genetic studies still offer a powerful means of advancing individualized care for HIV-infected individuals at risk. There is an urgent need for 1) longitudinal studies using consistent phenotypic definitions of HAND in HIV-infected subpopulations at very high risk of being adversely impacted, such as children, 2) tissue studies that correlate neuropathological changes in multiple brain regions with genomic markers in affected individuals and with changes at the RNA, epigenomic, and/or protein levels, and 3) genetic association studies using more sensitive subphenotypes of HAND. The NIH Brain Initiative and Human Connectome Project, coupled with rapidly evolving systems biology and machine learning approaches for analyzing high-throughput genetic, transcriptomic and epigenetic data, hold promise for identifying actionable biological processes and gene networks that underlie HAND. This review summarizes the current state of understanding of host genetic factors predisposing to HAND in light of past challenges and suggests some priorities for future research to advance the understanding and clinical management of HAND in the cART era. PMID:24996618

Kallianpur, Asha R; Levine, Andrew J

2014-09-01

168

The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and cancer risk: The Croatian case–control study  

Microsoft Academic Search

Objectives:Methylation abnormalities appear to be important for the pathogenesis of many cancer types. Since methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the methylation process catalyzing reduction of 5,10-methylenetetrahydrofolate to 5-methyl-tetrahydrofolate, C677T polymorphism, which decreases enzyme activity, may be associated with cancer susceptibility. The aim of this work was to investigate the distribution of MTHFR C677T polymorphism between various types

Ante Reljic; Ana-Maria Simundic; Elizabeta Topic; Nora Nikolac; Danijel Justinic; Mario Stefanovic

2007-01-01

169

Screening for C677T and A1298C MTHFR polymorphisms in patients with epilepsy and risk of hyperhomocysteinemia  

Microsoft Academic Search

Hyperhomocysteinemia can result from decreased methylenetetrahydrofolate reductase (MTHFR) enzyme activity, owing to genetic\\u000a polymorphisms and\\/or inadequate folate intake. This study was aimed at investigating the prevalence of C677T and A1298C MTHFR\\u000a polymorphisms, and their impact on hyperhomocysteinemia in 95 epileptic patients and 98 controls. Double gradient-denaturing\\u000a gradient gel electrophoresis screening revealed that the frequency of T677 polymorphic allele was similar

D. Caccamo; S. Condello; G. Gorgone; G. Crisafulli; V. Belcastro; S. Gennaro; P. Striano; F. Pisani; R. Ientile

2004-01-01

170

Association between dietary intake of folate, vitamin B6, B12 & MTHFR, MTR Genotype and breast cancer risk  

PubMed Central

Objective: we conducted a case-control study to investigate the association between dietary folate, vitamin B6 and vitamin B12 intake, MTHFR and MTR genotype, and breast cancer risk. Methods: Genotyping for MTHFR C677T and A1298C and MTR A2756G polymorphisms were performed using polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP) method. The intake of folate, vitamin B6 and vitamin B12 were calculated by each food item from questionnaire. Results: Subjects with breast cancer tended to have more first-degree relatives (?2=30.77, P<0.001) and have high intake of folate (t=2.42, P=0.008) and Vitamin B6 (t=2.94, P=0.002). Compared to the reference group, women with MTHFR 677 TT genotype and T allele had a significantly increased risk of breast cancer, with ORs (95%CI) of 1.8(1.08-2.27) and 1.39(1.02-1.92), respectively. For those who had folate intake?450 ug/day, MTHFR 667TT genotype was associated with a higher risk of breast cancer (OR=2.45, 95% CI=1.09-5.82, P=0.02). Similarly, subjects with Vitamin B6 intake?0.84 mg/day and MTHFR 667T allele genotype was correlated with a marginally increased risk of breast cancer. A significant interaction was observed between MTHFR C667T polymorphism and folate intake on the risk of breast cancer (P for interaction was 0.025). Conclusion: This case-control study found a significant association between MTHFR C667T polymorphism, folate intake and vitamin B6 and breast cancer risk, and a significant interaction was observed between MTHFR C667T polymorphism and folate intake on the risk of breast cancer. PMID:24639841

Weiwei, Zheng; Liping, Chen; Dequan, Li

2014-01-01

171

Folate intake and the MTHFR C677T genotype influence choline status in young Mexican American women  

Microsoft Academic Search

Numerous studies have reported a relationship between folate status, the methylenetetrahydrofolate reductase (MTHFR) 677C?T variant and disease risk. Although folate and choline metabolism are inter-related, only limited data are available on the relationship between choline and folate status in humans. This study sought to examine the influences of folate intake and the MTHFR 677C?T variant on choline status. Mexican-American women

Christian M. Abratte; Wei Wang; Rui Li; David J. Moriarty; Marie A. Caudill

2008-01-01

172

Effect of Riboflavin Status on the Homocysteine-lowering Effect of Folate in Relation to the MTHFR (C677T) Genotype  

Microsoft Academic Search

Background: Riboflavin (vitamin B2) is the precursor for FAD, the cofactor for methylenetetrahydrofolate reductase (MTHFR). MTHFR catalyzes the formation of 5-methyltetrahydrofolate, which acts as a methyl donor for homocysteine remethylation. Individuals with the MTHFR 677C3 T mutation have increased plasma total homocysteine (tHcy) concentrations, particularly in as- sociation with low folate status. It has been proposed that riboflavin may act

Stuart J. Moat; Pauline A. L. Ashfield-Watt; Hilary J. Powers; Robert G. Newcombe; Ian F. W. McDowell

2003-01-01

173

Analysis of the MTHFR 1298A?C and 677C?T polymorphisms as risk factors for neural tube defects  

Microsoft Academic Search

  \\u000a The thermolabile variant (677TT) of methylenetetrahydrofolate reductase (MTHFR) is a known risk factor for neural tube defects\\u000a (NTDs). The relationship between a second MTHFR polymorphism (1298A?C) and NTD risk has been inconsistent between studies.\\u000a We genotyped 276 complete NTD triads (mother, father and child affected with an NTD) and 256 controls for MTHFR 1298A?C. Our\\u000a findings do not support

Anne Parle-McDermott; James L. Mills; Peadar N. Kirke; Valerie B. O'Leary; Deborah A. Swanson; Faith Pangilinan; Mary Conley; Anne M. Molloy; Christopher Cox; John M. Scott; Lawrence C. Brody

2003-01-01

174

Are There Inherited Behavioral Traits That Predispose to Substance Abuse?  

Microsoft Academic Search

Research findings suggest that alcoholism and drug abuse may be predisposed by inherited behavioral propensities or temperaments. These inherited predispositions, through interaction with the physical and social environments, shape the development of personality. As discussed herein, there is strong evidence linking certain personality characteristics, specifically antisocial and neurotic traits, with the risk for substance abuse. Thus, personality and its precursor,

Ralph E. Tarter

1988-01-01

175

Allergy as a possible predisposing factor for hypodontia  

Microsoft Academic Search

SUMMARY The aim of this retrospective study was to identify general health problems as potential predisposing factors for hypodontia in a population of Japanese orthodontic patients. The study included 3683 individuals (1312 males and 2371 females, 13 - 42 years of age; mean, 23 years 7 months). Dental pantomograms (DPTs) were used to diagnose hypodontia. Health histories were obtained through

Tetsutaro Yamaguchi; Yoko Tomoyasu; Toshio Nakadate; Katsuji Oguchi; Koutaro Maki

176

Development and Characterization of Reference Materials for MTHFR, SERPINA1, RET, BRCA1, and BRCA2 Genetic Testing  

PubMed Central

Well-characterized reference materials (RMs) are integral in maintaining clinical laboratory quality assurance for genetic testing. These RMs can be used for quality control, monitoring of test performance, test validation, and proficiency testing of DNA-based genetic tests. To address the need for such materials, the Centers for Disease Control and Prevention established the Genetic Testing Reference Material Coordination Program (GeT-RM), which works with the genetics community to improve public availability of characterized RMs for genetic testing. To date, the GeT-RM program has coordinated the characterization of publicly available genomic DNA RMs for a number of disorders, including cystic fibrosis, Huntington disease, fragile X, and several genetic conditions with relatively high prevalence in the Ashkenazi Jewish population. Genotypic information about a number of other cell lines has been collected and is also available. The present study includes the development and commutability/genotype characterization of 10 DNA samples for clinically relevant mutations or sequence variants in the following genes: MTHFR; SERPINA1; RET; BRCA1; and BRCA2. DNA samples were analyzed by 19 clinical genetic laboratories using a variety of assays and technology platforms. Concordance was 100% for all samples, with no differences observed between laboratories using different methods. All DNA samples are available from Coriell Cell Repositories and characterization information can be found on the GeT-RM website. PMID:19767587

Barker, Shannon D.; Bale, Sherri; Booker, Jessica; Buller, Arlene; Das, Soma; Friedman, Kenneth; Godwin, Andrew K.; Grody, Wayne W.; Highsmith, Edward; Kant, Jeffery A.; Lyon, Elaine; Mao, Rong; Monaghan, Kristin G.; Payne, Deborah A.; Pratt, Victoria M.; Schrijver, Iris; Shrimpton, Antony E.; Spector, Elaine; Telatar, Milhan; Toji, Lorraine; Weck, Karen; Zehnbauer, Barbara; Kalman, Lisa V.

2009-01-01

177

DNA methylation in schizophrenia subjects: gender and MTHFR 677C/T genotype differences  

PubMed Central

Aim In schizophrenia, metabolic syndrome incidence is double that of the general population, with women having a higher incidence. Pharmacogenetically regulated folic acid may be related to this risk. DNA methylation and metabolic syndrome within this group has not been previously studied. Methods Metabolic syndrome was evaluated with fasting laboratory measurements, and dietary and lifestyle assessments. Methylation analysis used a peripheral sample for the LINE-1 assay. DNA was also genotyped for MTHFR 677C/T. Results This analysis included 133 subjects. We found a significant relationship between LINE-1 methylation, and an interaction between MTHFR and gender, controlling for serum folate (p = 0.008). Females with the 677TT genotype had the lowest methylation (56%) compared with the other groups (75%). Conclusion TT genotype females had the lowest methylation, which may explain metabolic syndrome gender differences in schizophrenia. Folate supplementation may be a suggested intervention within schizophrenia; however, additional work is required. PMID:22690662

Burghardt, Kyle J; Pilsner, J Richard; Bly, Michael J; Ellingrod, Vicki L

2012-01-01

178

Is the prevalence of MTHFR C677T polymorphism associated with ultraviolet radiation in Eurasia?  

PubMed

The methylenetetrahydrofolic acid reductase (MTHFR) C677T polymorphism causes an amino-acid change from alanine to valine and results in the enzyme becoming thermolabile and half decreased activity. Its prevalence varies among global population. We collected data about MTHFR C677T polymorphism prevalence from epidemiology studies, as well as ultraviolet (UV) radiations and some other climatological factors from the internet. The results of the correlation and quadric regression showed that there was inverse U-shape relationship between T allele frequency and UV radiation. The explanatory power of UV radiation was stronger than latitude and all climatological factors. Our results supported the hypothesis that the distribution pattern of MTFHR C677T polymorphism in Eurasia might be the result of interaction of genetic and environmental natural selection, especially the UV radiation. PMID:22992775

Yafei, Wang; Lijun, Pei; Jinfeng, Wang; Xiaoying, Zheng

2012-12-01

179

Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia  

PubMed Central

Low folate intake as well as alterations in folate metabolism as a result of polymorphisms in the enzyme methylenetetrahydrofolate reductase (MTHFR) have been associated with an increased incidence of neural tube defects, vascular disease, and some cancers. Polymorphic variants of MTHFR lead to enhanced thymidine pools and better quality DNA synthesis that could afford some protection from the development of leukemias, particularly those with translocations. We now report associations of MTHFR polymorphisms in three subgroups of pediatric leukemias: infant lymphoblastic or myeloblastic leukemias with MLL rearrangements and childhood lymphoblastic leukemias with either TEL-AML1 fusions or hyperdiploid karyotypes. Pediatric leukemia patients (n = 253 total) and healthy newborn controls (n = 200) were genotyped for MTHFR polymorphisms at nucleotides 677 (C?T) and 1,298 (A?C). A significant association for carriers of C677T was demonstrated for leukemias with MLL translocations (MLL+, n = 37) when compared with controls [adjusted odd ratios (OR) = 0.36 with a 95% confidence interval (CI) of 0.15–0.85; P = 0.017]. This protective effect was not evident for A1298C alleles (OR = 1.14). In contrast, associations for A1298C homozygotes (CC; OR = 0.26 with a 95% CI of 0.07–0.81) and C677T homozygotes (TT; OR = 0.49 with a 95% CI of 0.20–1.17) were observed for hyperdiploid leukemias (n = 138). No significant associations were evident for either polymorphism with TEL-AML1+ leukemias (n = 78). These differences in allelic associations may point to discrete attributes of the two alleles in their ability to alter folate and one-carbon metabolite pools and impact after DNA synthesis and methylation pathways, but should be viewed cautiously pending larger follow-up studies. The data provide evidence that molecularly defined subgroups of pediatric leukemias have different etiologies and also suggest a role of folate in the development of childhood leukemia. PMID:11274424

Wiemels, Joseph L.; Smith, Rosalyn N.; Taylor, G. Malcolm; Eden, Osborn B.; Alexander, Freda E.; Greaves, Mel F.

2001-01-01

180

Association between MTHFR Polymorphisms and Acute Myeloid Leukemia Risk: A Meta-Analysis  

PubMed Central

Previous observational studies investigating the association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and acute myeloid leukemia risk (AML) have yielded inconsistent results. The aim of this study is to derive a more precise estimation of the association between MTHFR (C677T and A1298C) polymorphisms and acute myeloid leukemia risk. PubMed and Embase databases were systematically searched to identify relevant studies from their inception to August 2013. Odds ratios (ORs) with 95% confidence intervals (CIs) were the metric of choice. Thirteen studies were selected for C677T polymorphism (1838 cases and 5318 controls) and 9 studies (1335 patients and 4295 controls) for A1298C polymorphism. Overall, pooled results showed that C677T polymorphism was not significant associated with AML risk(OR, 0.98–1.04; 95% CI, 0.86–0.92 to 1.09–1.25). Similar results were observed for the A1298C polymorphism and in subgroup analysis. All comparisons revealed no substantial heterogeneity nor did we detect evidence of publication bias. In summary, this meta-analysis provides evidence that MTHFR polymorphisms were not associated with AML risk. Further investigations are needed to offer better insight into the role of these polymorphisms in AML carcinogenesis. PMID:24586405

Su, Yan; Lu, Ge-Ning; Wang, Ren-Sheng

2014-01-01

181

Association between MTHFR polymorphisms and acute myeloid leukemia risk: a meta-analysis.  

PubMed

Previous observational studies investigating the association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and acute myeloid leukemia risk (AML) have yielded inconsistent results. The aim of this study is to derive a more precise estimation of the association between MTHFR (C677T and A1298C) polymorphisms and acute myeloid leukemia risk. PubMed and Embase databases were systematically searched to identify relevant studies from their inception to August 2013. Odds ratios (ORs) with 95% confidence intervals (CIs) were the metric of choice. Thirteen studies were selected for C677T polymorphism (1838 cases and 5318 controls) and 9 studies (1335 patients and 4295 controls) for A1298C polymorphism. Overall, pooled results showed that C677T polymorphism was not significant associated with AML risk(OR, 0.98-1.04; 95% CI, 0.86-0.92 to 1.09-1.25). Similar results were observed for the A1298C polymorphism and in subgroup analysis. All comparisons revealed no substantial heterogeneity nor did we detect evidence of publication bias. In summary, this meta-analysis provides evidence that MTHFR polymorphisms were not associated with AML risk. Further investigations are needed to offer better insight into the role of these polymorphisms in AML carcinogenesis. PMID:24586405

Qin, Yu-Tao; Zhang, Yong; Wu, Fang; Su, Yan; Lu, Ge-Ning; Wang, Ren-Sheng

2014-01-01

182

The Common Mutations C677T and A1298C in the Human Methylenetetrahydrofolate Reductase Gene Are Associated with Hyperhomocysteinemia and Cardiovascular Disease in Hemodialysis Patients  

Microsoft Academic Search

Background: Plasma total homocysteine (tHcy) level might be an important risk factor for the development of cardiovascular disease (CVD) in dialysis patients. While both renal failure and mutations of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene may result in hyperhomocysteinemia and CVD, the distinct roles of the thermolabile MTHFR mutation at nucleotide C677T and the more recently described mutation at nucleotide A1298C

Y. S. Haviv; V. Shpichinetsky; N. Goldschmidt; I. Abou Atta; A. Ben-Yehuda; G. Friedman

2002-01-01

183

The maize brown midrib2 (bm2) gene encodes a methylenetetrahydrofolate reductase that contributes to lignin accumulation.  

PubMed

The midribs of maize brown midrib (bm) mutants exhibit a reddish-brown color associated with reductions in lignin concentration and alterations in lignin composition. Here, we report the mapping, cloning, and functional and biochemical analyses of the bm2 gene. The bm2 gene was mapped to a small region of chromosome 1 that contains a putative methylenetetrahydrofolate reductase (MTHFR) gene, which is down-regulated in bm2 mutant plants. Analyses of multiple Mu-induced bm2-Mu mutant alleles confirmed that this constitutively expressed gene is bm2. Yeast complementation experiments and a previously published biochemical characterization show that the bm2 gene encodes a functional MTHFR. Quantitative RT-PCR analyses demonstrated that the bm2 mutants accumulate substantially reduced levels of bm2 transcript. Alteration of MTHFR function is expected to influence accumulation of the methyl donor S-adenosyl-L-methionine (SAM). Because SAM is consumed by two methyltransferases in the lignin pathway (Ye et al., ), the finding that bm2 encodes a functional MTHFR is consistent with its lignin phenotype. Consistent with this functional assignment of bm2, the expression patterns of genes in a variety of SAM-dependent or -related pathways, including lignin biosynthesis, are altered in the bm2 mutant. Biochemical assays confirmed that bm2 mutants accumulate reduced levels of lignin with altered composition compared to wild-type. Hence, this study demonstrates a role for MTHFR in lignin biosynthesis. PMID:24286468

Tang, Ho Man; Liu, Sanzhen; Hill-Skinner, Sarah; Wu, Wei; Reed, Danielle; Yeh, Cheng-Ting; Nettleton, Dan; Schnable, Patrick S

2014-02-01

184

The thermolabile variant of MTHFR is associated with depression in the British Women's Heart and Health Study and a meta-analysis  

Microsoft Academic Search

Low dietary folate intake has been implicated as a risk factor for depression. However, observational epidemiological studies are plagued by problems of confounding, reverse causality and measurement error. A common polymorphism (C677T) in MTHFR is associated with methyltetrahydrofolate reductase (MTHFR) activity and circulating folate and homocysteine levels and offers insights into whether the association between low folate and depression is

S J Lewis; D A Lawlor; G Davey Smith; R Araya; N Timpson; I N M Day; S Ebrahim

2006-01-01

185

Methylenetetrahydrofolate reductase genotypes and predisposition to atherothrombotic disease. Evidence that all three MTHFR C677T genotypes confer different levels of risk  

Microsoft Academic Search

Aims Elevated plasma homocysteine is an independent risk factor for atherothrombotic disease. Individuals homozygous for the methylenetetrahydrofolate reductase (MTHFR) 677C allele exclusively accumulate 5- methyltetrahydrofolate, the methyl donor for homocysteine remethylation, in their red blood cells; this contrasts with 677 TT homozygotes who also accumulate significant levels of non-methylated folate derivatives. Those with the MTHFR 677 TT, CT and CC

L. A. J. Kluijtmans; A. S. Whitehead

2001-01-01

186

The Methylenetetrahydrofolate Reductase Polymorphism (MTHFR c.677C > T) and Elevated Plasma Homocysteine Levels in a U.S. Pediatric Population with Incident Thromboembolism  

PubMed Central

Objective Elevated plasma homocysteine (tHcy) and the MTHFR c.677C > T variant have been postulated to increase the risk of venous thromboembolism (VTE), although mechanisms and implications to pediatrics remain incompletely understood. The objectives of this study were to determine the prevalences of elevated tHcy and MTHFR variant in a pediatric population with VTE or arterial ischemic stroke (AIS), and to determine associations with thrombus outcomes. Study Design Subjects were enrolled in an institution-based prospective cohort of children with VTE or AIS. Inclusion criteria consisted of objectively confirmed thrombus, ?21 years at diagnosis, tHcy measured and MTHFR c.677C > T mutation analysis. Clinical and laboratory data were collected. Frequencies for elevated tHcy and MTHFR variant were compared with NHANES values for healthy US children and also between study groups (VTE vs AIS, provoked vs idiopathic) and by age. Results The prevalences of hyperhomocysteinemia or MTHFR variant were not increased in comparison to NHANES. tHcy did not differ between those with wild-type MTHFR versus either c.677C > T heterozygotes or homozygotes. There was no association between tHcy or MTHFR variant and thrombus outcomes. Conclusion In this cohort of US children with VTE or AIS, neither the prevalence of hyperhomocysteinemia nor that of MTHFR variant was increased relative to reference values, and adverse thrombus outcomes were not definitively associated with either. While it is important to consider that milder forms of pyridoxine-responsive classical homocystinuria will be detected only by tHcy, we suggest that routine testing of MTHFR c.677C > T genotype as part of a thrombophilia evaluation in children with incident thromboembolismis not warranted until larger studies have been performed in order to establish or refute a link between MTHFR and adverse outcomes. PMID:23866722

Joachim, Emily; Goldenberg, Neil A.; Bernard, Timothy J.; Armstrong-Wells, Jennifer; Stabler, Sally; Manco-Johnson, Marilyn J.

2014-01-01

187

TPMT and MTHFR genotype is not associated with altered risk of thioguanine-related sinusoidal obstruction syndrome in pediatric acute lymphoblastic leukemia: a report from the Children's Oncology Group.  

PubMed

Sinusoidal obstruction syndrome is a complication of therapy for pediatric ALL and may be modified by thiopurine methyltransferase activity as well as by MTHFR genotype. We assessed TPMT *3A, *3B, *3C, and MTHFR C677T and A1298C germline genetic polymorphisms among 351 patients enrolled in the thioguanine treatment arm of CCG-1952 clinical trial. TPMT and MTHFR C677T genotypes were not associated with SOS risk. The combination of MTHFR and TPMT variant genotypes was not associated with SOS risk. These suggest that germline genetic variation in TPMT and MTHFR do not significantly alter SOS risk in patients exposed to thioguanine. PMID:24737678

Wray, Lisa; Vujkovic, Marijana; McWilliams, Thomas; Cannon, Shannon; Devidas, Meenakshi; Stork, Linda; Aplenc, Richard

2014-11-01

188

Gene Expression Differences over a Critical Period of Afferent-Dependent  

E-print Network

RNA expression of specific genes could predispose CN neurons to either death or survival after deafferentation nucleus; deafferentation; apoptosis; gene expression One poorly understood phenomenon in developmental

Rubel, Edwin

189

The association of idiopathic recurrent early pregnancy loss with polymorphisms in folic acid metabolism-related genes.  

PubMed

The aim of this study was to investigate the association between polymorphisms in folic acid metabolism-related genes and idiopathic recurrent early pregnancy loss (REPL). A prospective case-control study was performed on a cohort of 82 REPL patients and 166 healthy controls. Genotyping of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C was assessed by applying polymerase chain reaction for amplification followed by DNA sequencing, for methionine synthase reductase A66G, solute carrier family 19, member 1 (SLC19A1) G80A and C696T, and genotyping was done by utilizing the Sequenom MassARRAY system. The results revealed a significant association between MTHFR A1298C polymorphism and idiopathic REPL. Haplotype analysis indicated that the MTHFR 677C-MTHFR 1298C allele combination was associated with REPL (P < 0.001). The MTHFR 677C-MTHFR 1298A and SLC19A1 80G-SLC19A1 696C allele combinations had lower frequencies in patients with REPL, but with P > 0.05 (P = 0.093 and P = 0.084, respectively). PMID:24728915

Cao, Yunlei; Zhang, Zhaofeng; Zheng, Yanmin; Yuan, Wei; Wang, Jian; Liang, Hong; Chen, Jianping; Du, Jing; Shen, Yueping

2014-05-01

190

Adaptive developmental plasticity in methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism limits its frequency in South Indians.  

PubMed

Methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism shows considerable heterogeneity in its distribution in humans worldwide. The current study was conducted to investigate whether this polymorphism exhibited adaptive developmental plasticity in the control of the TT-genotype frequency. We screened 1,818 South Indian subjects (895 males and 923 females) for MTHFR C677T polymorphism using PCR-restriction fragment length polymorphism approach. MTHFR 677T-allele frequency in males and females was 9.1 and 11.0%, respectively. Compared to females, males had lower frequency of TT-genotype [odds ratio 0.31, 95% confidence interval (CI) 0.08-1.01]. The frequency of MTHFR 677T-allele was highest in the age group of 20-40 years and it gradually decreased from 40-60 to 60-80 years (P trend<0.0001). MTHFR 677TT-genotype was associated with 7.02-folds (95% CI: 2.12-25.63, P<0.0001) cumulative risk for recurrent pregnancy loss (RPL), neural tube defects (NTDs) and deep vein thrombosis (DVT). Linear regression model suggested that male gender exhibited increased homocysteine levels by 9.35 ?mol/L while each MTHFR 677T-allele contributed to 4.63 ?mol/L increase in homocysteine. Plasma homocysteine showed inverse correlation with dietary folate (r=-0.17, P<0.0001), B2 (r=-0.14, P<0.0001) and B6 (r=-0.07, P=0.03). Examination of the spontaneously aborted fetuses (n=35) showed no significant association of fetal genotype on its in utero viability. From the current study, it was concluded that C677T seemed to have acquired adaptive developmental plasticity among South Indians due to environmental influences thus contributing to hyperhomocysteinemia and its associated complications such as RPL, NTDs, DVT, etc. PMID:24449370

Naushad, Shaik Mohammad; Krishnaprasad, Chintakindi; Devi, Akella Radha Rama

2014-05-01

191

Matching Genes and Vitamins: A Personalized Plan May Be in Your Future  

MedlinePLUS

... a gene that contains the code for an enzyme called MTHFR. Among other things, this enzyme plays an important role in processing amino acids, ... ethnic backgrounds and found several variants of the enzyme. They inserted the genes for these variants into ...

192

Epistasis effects of COMT and MTHFR on inter-individual differences in mental health: under the inverted U-shaped prefrontal dopamine model.  

PubMed

Higher cognitive performance, maintenance of mental health and psychological well-being require adequate prefrontal cortex (PFC) function. "Inverted U-shaped" dopamine model indicates optimal PFC dopamine level is important to attain its function while high or low levels have adverse effects. Catechol-O-methyltransferase (COMT) and methylenetetrahydrofolate reductase (MTHFR) may be involved in this complex non-linear PFC dopamine regulation. We addressed whether genetic variation reflecting COMT and MTHFR activities can explain the inter-individual mental health differences in healthy Japanese men (n=188). The mental health was measured by Mental Health Inventory (MHI)-5 score. The rs4633-rs4818-rs4680 haplotypes were used to represent the multilevel COMT activities, while for MTHFR, the functional single polymorphism, rs1801133 (C677T), was used. We examined the effectiveness of haplotype-based association analysis of COMT on mental health together with studying its interaction with MTHFR-C677T. As a result, the relation between activity-ranked COMT genotype and MHI-5 score showed a tendency to fit into an "inverted U-shaped" quadratic curve (P=0.054). This curvilinear correlation was significant in the subjects with MTHFR-CC (P<0.001), but not with MTHFR T-allele carriers (P=0.793). Our pilot study implies a potential influence of COMT and MTHFR genotypic combination on normal variation of mental health. PMID:25124664

Htun, Nay Chi; Miyaki, Koichi; Zhao, Chenxi; Muramatsu, Masaaki; Sato, Noriko

2014-09-01

193

Folate Intake, MTHFR C677T Polymorphism, Alcohol Consumption, and Risk for Sporadic Colorectal Adenoma (United States)  

Microsoft Academic Search

Objective: The purpose of this study was to investigate whether folate intake is associated with risk for incident sporadic colorectal adenoma, and whether the association differs according to methylenetetrahydrofolate reductase (MTHFR) genotypes or is modified by intakes of alcohol or other micronutrients in the folate metabolism pathway.

Sonia M. Boyapati; Roberd M. Bostick; Katherine A. McGlynn; Michael F. Fina; Walter M. Roufail; Kim R. Geisinger; James R. Hebert; Ann L. Coker; Michael Wargovich

2004-01-01

194

A Hypomethylating Variant of MTHFR, 677C.T, Blunts the Neural Response to Errors in Patients with  

E-print Network

A Hypomethylating Variant of MTHFR, 677C.T, Blunts the Neural Response to Errors in Patients Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, United States of America Abstract Background: Responding to errors is a critical first step

Manoach, Dara S.

195

Genetic Polymorphisms in the Methylenetetrahydrofolate Reductase and Thymidylate Synthase Genes and Risk of Hepatocellular Carcinoma  

PubMed Central

Methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TYMS) are known to play a role in DNA methylation, synthesis, and repair. The genetic mutations in MTHFR and TYMS genes may have influences on their respective enzyme activities. Data on the association studies of the MTHFR and TYMS genetic polymorphisms and risk of hepatocellular carcinoma (HCC) are sparse. MTHFR and TYMS genotypes were determined on 365 HCC cases and 457 healthy control subjects among Hispanic and non-Hispanic whites and African-Americans in Los Angeles County, California, and among Chinese in the city of Nanning, Guangxi, China. Relative to the high-activity genotype, each low-activity genotype of MTHFR was associated with a statistically nonsignificant 30% to 50% reduction in risk of HCC. Relative to the TYMS3?UTR +6/+6 genotype, individuals with 1 or 2 copies of the deletion allele had a statistically significant 50% reduction in risk of HCC. When we examined HCC risk by the total number of mutant alleles in the 3 polymorphic loci of MTHFR/TYMS (range, 0-4), there was a monotonic decrease in risk with increasing number of mutant alleles (P for trend = 0.003). Individuals possessing the maximum number of mutant alleles (i.e., 4) had an odds ratio of 0.46 (95% confidence interval = 0.23-0.93) for HCC compared with those with no or only 1 mutant allele. Conclusion This study supports the hypothesis that reduced MTHFR activity and enhanced TYMS activity, both of which are essential elements in minimizing uracil misincorporation into DNA, may protect against the development of HCC. PMID:17659576

Yuan, Jian-Min; Lu, Shelly C.; Van Den Berg, David; Govindarajan, Sugantha; Zhang, Zhen-Quan; Mato, Jose M.; Yu, Mimi C.

2008-01-01

196

POT1 loss-of-function variants predispose to familial melanoma.  

PubMed

Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease. Here we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene (POT1), with a proportion of family members presenting with an early age of onset and multiple primary tumors. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres. PMID:24686849

Robles-Espinoza, Carla Daniela; Harland, Mark; Ramsay, Andrew J; Aoude, Lauren G; Quesada, Víctor; Ding, Zhihao; Pooley, Karen A; Pritchard, Antonia L; Tiffen, Jessamy C; Petljak, Mia; Palmer, Jane M; Symmons, Judith; Johansson, Peter; Stark, Mitchell S; Gartside, Michael G; Snowden, Helen; Montgomery, Grant W; Martin, Nicholas G; Liu, Jimmy Z; Choi, Jiyeon; Makowski, Matthew; Brown, Kevin M; Dunning, Alison M; Keane, Thomas M; López-Otín, Carlos; Gruis, Nelleke A; Hayward, Nicholas K; Bishop, D Timothy; Newton-Bishop, Julia A; Adams, David J

2014-05-01

197

Mass hysteria among schoolchildren. Early loss as a predisposing factor.  

PubMed

On May 21, 1979, an outbreak of illness spread swiftly among elementary school students in a Boston suburb. Of 224 boys and girls attending an assembly, 34 were hospitalized with severe dizziness, weakness, hyperventilation, headache, nausea, and abdominal pain. Sudden remission of symptoms, preponderance in girls, and failure of an extensive epidemiological investigation to detect an organic cause indicated mass hysteria. To test the hypothesis that previous loss influenced a child's vulnerability to current loss and predisposed that child to mass hysteria, we compared the incidence of family disruption in the hospitalized children with that in the nonhospitalized children. A significantly higher rate of parental divorce (P less than .00005) and death within the family (P less than .0005) occurred among the hospitalized children. These findings suggest a relationship between childhood loss and susceptibility to mass hysteria. PMID:7092505

Small, G W; Nicholi, A M

1982-06-01

198

Subclinical Mastitis in Dairy Animals: Incidence, Economics, and Predisposing Factors  

PubMed Central

A study was conducted to assess the incidence and economics of subclinical form of bovine mastitis in Central Region of India. Daily milk records of 187 animals during three seasons were collected and subjected to analysis. The economic loss due to reduction in yield, clinical expenses, and additional resources used were quantified and aggregated. The losses due to mastitis in monetary terms were estimated to be INR1390 per lactation, among which around 49% was owing to loss of value from milk and 37% on account of veterinary expenses. Higher losses were observed in crossbred cows due to their high production potential that was affected during mastitis period. The cost of treating an animal was estimated to be INR509 which includes cost of medicine (31.10%) and services (5.47%). Inadequate sanitation, hygiene, and veterinary services were the main predisposing factors for incidence and spread of mastitis as perceived by the respondents. PMID:25093203

Sinha, Mukesh Kr.; Thombare, N. N.; Mondal, Biswajit

2014-01-01

199

Genetic skin diseases predisposing to basal cell carcinoma.  

PubMed

Basal cell carcinoma (BCC) is the commonest cancer in humans. Predisposing factors reflect common genetic variations and environmental influences in most cases. However, an underlying Mendelian disorder should be suspected in a specific subset of patients, namely those with multiple, early onset lesions. Some specific conditions, including Gorlin, Bazex-Dupré-Christol and Rombo syndromes, and Xeroderma Pigmentosum, show BCC as a prominent feature. In addition, BCC may represent a relatively common, although less specific, finding in many other genodermatoses. These include disorders of DNA replication/repair functions (Bloom, Werner, Rothmund-Thomson and Muir-Torre syndromes), genodermatoses affecting the folliculo-sebaceus unit (Brooke-Spiegler, Schöpf-Schulz-Passarge and Cowden syndromes), immune response (cartilage-hair hypoplasia and epidermodysplasia verruciformis) and melanin biosynthesis (oculocutaneous albinism and Hermansky-Pudlak syndrome), and some epidermal nevus syndromes. Further conditions occasionally associated with BCCs exist, but the significance of the association remains to be proven. PMID:22391625

Castori, Marco; Morrone, Aldo; Kanitakis, Jean; Grammatico, Paola

2012-01-01

200

Hyperhomocyst(e)inaemia, but not MTHFR C677T mutation, as a risk factor for non-arteritic ischaemic optic neuropathy  

Microsoft Academic Search

BACKGROUND\\/AIMSHyperhomocyst(e)inaemia has been identified as a strong risk factor for stroke, myocardial infarction, and deep vein thrombosis. A point mutation of methylene tetrahydrofolate reductase (MTHFR C677T) has been associated with increased plasma homocyst(e)ine levels. To investigate whether hyperhomocyst(e)inaemia and\\/or MTHFR C677T mutation are associated with non-arteritic ischaemic optic neuropathy (NAION), a case-control study including 59 consecutive patients with NAION and

Martin Weger; Olaf Stanger; Hannes Deutschmann; Michael Simon; Wilfried Renner; Otto Schmut; Jürgen Semmelrock; Anton Haas

2001-01-01

201

Association of the MTHFR C677T and A1298C polymorphisms with methotrexate toxicity in rheumatoid arthritis: a meta-analysis.  

PubMed

The aim of this study was to explore whether the C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase (MTHFR) play a role in methotrexate (MTX) toxicity in rheumatoid arthritis (RA). MEDLINE and EMBASE database searches and subsequent manual searches were utilized to identify articles in which C677T and A1298C MTHFR polymorphisms were evaluated in RA patients taking MTX. A meta-analysis was conducted to identify associations between MTHFR polymorphisms and MTX toxicity. Twelve studies comprising a total of 2,288 RA patients were included in our meta-analysis. Meta-analysis revealed an association between the overall toxicity of MTX and the MTHFR 677TT genotype (odds ratio [OR]?=?1.615, 95 % confidence interval [CI]?=?1.185-2.200, p?=?0.002). Stratification by ethnicity indicated an association between the MTHFR 677TT genotype and the overall toxicity of MTX in East Asians (OR?=?1.583, 95 % CI?=?1.075-2.331, p?=?0.020). The toxicity of MTX also was found to be associated with the TT genotype in patients taking folate (OR?=?1.893, 95 % CI?=?1.283-2.793, p?=?0.001). Stratification by toxicity type indicated an association between the MTHFR 677TT genotype and any adverse effects (OR?=?1.716, 95 % CI?=?1.127-2.612, p?=?0.012). Meta-analysis stratified by toxicity type indicated an association between the MTHFR 1298CC genotype and any adverse effects (OR?=?0.501, 95 % CI?=?0.284-0.886, p?=?0.017). The results of our meta-analysis suggest that the MTHFR C677T and A1298C polymorphisms are associated with MTX toxicity in RA patients. PMID:24794492

Song, Gwan Gyu; Bae, Sang-Cheol; Lee, Young Ho

2014-12-01

202

Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and the risk of primary Hepatocellular Carcinoma (HCC) in a Chinese population  

Microsoft Academic Search

Objectives  Methylenetetrahydrofolate reductase (MTHFR), which is expressed in the liver, may be involved in both DNA methylation and\\u000a DNA synthesis. It is also indicated as a potential risk factor of liver cancer in patients with chronic liver disease. To\\u000a date, no study has been conducted on MTHFR and hepatocellular carcinoma (HCC) using a population-based design. The objective\\u000a of this study was

Li-Na Mu; Wei Cao; Zuo-Feng Zhang; Lin Cai; Qing-Wu Jiang; Nai-Chieh You; Binh Yang Goldstein; Guo-Rong Wei; Chuan-Wei Chen; Qing-Yi Lu; Xue-Fu Zhou; Bao-Guo Ding; Jun Chang; Shun-Zhang Yu

2007-01-01

203

Association of polymorphisms MTHFR C677T and A1298C with risk of colorectal cancer, genetic and epigenetic characteristic of tumors, and response to chemotherapy  

Microsoft Academic Search

Background and aims  The enzyme MTHFR plays an important role in folate metabolism, and folate is implicated in carcinogenesis due to its role in DNA methylation,\\u000a repair, and synthesis. We analyze the relationship of MTHFR C677T and A1298C polymorphisms with biological, clinicopathological, genetic and epigenetic features of tumors, and the patient\\u000a outcome after treatment with 5-FU-based chemotherapy to determine the contribution

Antonia M. Fernández-Peralta; Lydia Daimiel; Nargisse Nejda; Daniel Iglesias; Vicente Medina Arana; Juan J. González-Aguilera

2010-01-01

204

Polymorphisms in methylenetetrahydrofolate reductase gene and risk of non-Hodgkin lymphoma in a multi-ethnic population.  

PubMed

An imbalance in folate metabolism can adversely affect DNA synthesis and methylation systems which can lead to susceptibility to non-Hodgkin lymphoma (NHL). Whether single nucleotide polymorphisms (SNPs) and their haplotypes in the methylenetetrahydrofolate reductase (MTHFR) are associated with NHL, remain inconclusive. We investigated the association between MTHFR C677T and A1298C SNPs and NHL risk in a population which is made up of Malay, Chinese and Indian ethnic subgroups. A total of 372 NHL patients and 722 controls were genotyped using the Sequenom MassARRAY platform. Our results of the pooled subjects failed to demonstrate significant association between the MTHFR C677T and A1298C SNPs with NHL and its subtypes. The results were in agreement with the previous meta-analyses. In the Indian ethnic subgroup however, single locus analysis of MTHFR A1298C appears to confer risk to NHL (Odds ratio (OR) 1.91, 95% confidence interval (95% CI) 1.22-3.00, P=0.006). The risk is almost doubled in homozygous carrier of MTHFR 1298CC (OR 4.03, 95% CI 1.56-10.43, P=0.004). Haplotype analysis revealed higher frequency of CC in the Indian NHL patients compared with controls (OR 1.86, 95% CI 1.18-2.93, P=0.007). There is lack of evidence to suggest an association between MTHFR C677T and A1298C with the risk of NHL in the Malays and Chinese. In the Indians however, the MTHFR A1298C confers risk to NHL. This study suggests ethnicity modifies the relationship between polymorphisms in the folate-metabolizing gene and NHL. PMID:24646728

Suthandiram, Sujatha; Gan, Gin Gin; Zain, Shamsul Mohd; Haerian, Batoul Sadat; Bee, Ping Chong; Lian, Lay Hoong; Chang, Kian Meng; Ong, Tee Chuan; Mohamed, Zahurin

2014-05-01

205

Methylenetetrahydrofolate reductase gene polymorphism as a risk factor for diabetic nephropathy: a meta-analysis  

Microsoft Academic Search

Investigations into the association between diabetic nephropathy (DN) and MTHFR C677T gene polymorphism in several case–control\\u000a studies has yielded contradictory results. To shed light on these inconclusive findings, a meta-analysis of all available\\u000a studies relating the C677T polymorphism to the risk of developing DN was conducted. The PubMed database was searched, and\\u000a case–control studies investigating the association between MTHFR C677T

Elias Zintzaras; Katrin Uhlig; George N. Koukoulis; Afroditi A. Papathanasiou; Ioannis Stefanidis

2007-01-01

206

Methyltetrahydrofolate reductase C677T gene mutation and hyperhomocysteinemia as a novel risk factor for diabetic nephropathy.  

PubMed

Hyperhomocysteinemia is a well-defined risk factor for endothelial dysfunction and atherosclerosis. A point mutation (677 C-T) of MTHFR gene results in a significant increase at plasma homocysteine levels. In this study we aimed to evaluate the effects of MTHFR gene mutation and consequent hyperhomocysteinemia on the development of diabetic microvascular complications in comparison with the other defined risk factors. Diabetic patients without a history of macrovascular complication or overt nephropathy enrolled into the study. The presence of MTHFR 677 C-T point mutation was evaluated by Real-Time PCR technique by using a LightCycler. MTHFR heterozygous mutation was present in 24 patients over 52. Patients with diabetes were divided into two groups according to the presence of MTHFR gene mutation. Both groups were well matched regarding age and diabetes duration. Metabolic parameters, plasma homocysteine, microalbuminuria, folic acid, and vitamin B12 levels were also studied. Presence of neuropathy and retinopathy were evaluated by specific tests. Duration of diabetes, BMI, systolic and diastolic blood pressure, plasma CRP, HbA1c, and lipid levels were not different between the two groups. Plasma homocysteine (12.89 +/- 1.74 and 8.98 +/- 1.91 micromol/l; P < 0.0001) and microalbuminuria levels (73.40 +/- 98.15 and 29.53 +/- 5.08 mg/day; P = 0.021) were significantly higher in the group with MTHFR gene mutation while creatinine clearance levels (101.1 +/- 42.6 and 136.21 +/- 51.50 ml/min; P = 0.008) were significantly lower. Sixteen over 22 (73%) of the patients with diabetic nephropathy had MTHFR gene mutation, while this was only 27% (8 over 30) in normoalbuminuric patients (P = 0.017). There was a significant correlation of plasma homocysteine level with microalbuminuria (r = 0.54; P = 0.031) in the patients with diabetic nephropathy who had C677T polymorphism. We did not find any specific association of MTHFR gene mutation and hyperhomocysteinemia with retinopathy or neuropathy. PMID:19598005

Ukinc, Kubilay; Ersoz, Halil Onder; Karahan, Caner; Erem, Cihangir; Eminagaoglu, Selcuk; Hacihasanoglu, Arif Bayram; Yilmaz, Mustafa; Kocak, Mustafa

2009-10-01

207

Role of plasma homocysteine levels and MTHFR polymorphisms on IQ scores in children and young adults with epilepsy treated with antiepileptic drugs.  

PubMed

Homocysteine (Hcy) is a sulfur-containing amino acid involved in methionine metabolism. High plasma total Hcy (tHcy) has been quite frequently reported in patients with epilepsy treated with antiepileptic drugs (AEDs) mainly related to plasma folate reduction induced by AEDs themselves. The role of C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene (MTHFR) on the increase of plasma tHcy in patients with epilepsy taking AEDs is still controversial. Cognitive impairment may be associated with epilepsy either as the result of the epileptic syndrome per se or as a side effect induced by the AEDs. High plasma tHcy levels were associated with lower cognitive performances in patients affected by Alzheimer's disease and mild cognitive impairment and in healthy elderly. We searched for a correlation between plasma tHcy levels with the intelligence quotient (IQ) scores in a population of children and young adults with epilepsy treated with old and/or newer AEDs. The study group encompassed 179 patients (92 M, 51.5%) followed at our Unit of Child Neuropsychiatry and aged between 4 and 25years (mean+SD: 14.03±4.25). The inclusion criteria included the following: 1) diagnosis of epilepsy of "unknown cause" (cryptogenic) according to the ILAE classification, 2) age older than 3years, 3) stabilized antiepileptic treatment for at least 6months, and 4) clinical records of cognitive tests, plasma tHcy value, and results of MTHFR polymorphisms. Patients' mean tHcy value was 9.71±3.13?M/L (tHcy<9?M/L as our laboratory cutoff in nonepileptic controls). The mean TIQ score was 85.22 (SD±24.12); the mean VIQ score was 86.32 (SD±20.86); and the mean PIQ score was 86.94 (SD±21.51). C677T and A1298C MTHFR polymorphisms were detected in 74/92 (80%) examined patients and distributed into the following: CT (22.3%), TT (14.9%), CC (10.3%) for C677T, AC (16%), CC (1.1%), and AA (30.3%) for A1298C. Plasma tHcy levels were not significantly related to the IQ scores (TIQ, VIQ, or PIQ). Two significant findings came out. First, patients on AED polytherapy showed significantly lower TIQ, VIQ, and PIQ scores compared with the ones with AED monotherapy (p=0.032; p=0.008; p=0.005, respectively). However, this significant difference was not observed with the plasma tHcy levels compared with AED treatment. Second, patients with the 677TT genotype showed significantly higher tHcy levels versus those with the wt ones (p=0.049). In the latter group of patients, although the mean TIQ score was lower compared with the mean TIQ score in those with the wt ones, the difference only approached statistical significance (p=0.056). To our knowledge, this is the first study investigating the relationship between tHcy levels and cognitive scores in children with epilepsy treated with AEDs. Analysis of wider samples, selective neuropsychological tests, and prospective recruitment of patients might be encouraged. PMID:24183735

Di Rosa, Gabriella; Lenzo, Patrizia; Parisi, Eleonora; Neri, Milena; Guerrera, Silvia; Nicotera, Antonio; Alibrandi, Angela; Germanò, Eva; Caccamo, Daniela; Spanò, Maria; Tortorella, Gaetano

2013-12-01

208

?????? ??? ???????? MTHFR ??? MTRR ???? ???????? ???????????? ??? ?????????????? ?????.  

E-print Network

??Osteoporosis and atherosclerosis are two multifactorial and degenerative diseases, which constitute major problems to the public health. These age-related diseases, share common risk factors and… (more)

?????????, ?????????? ???????

2011-01-01

209

Association of the C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene with schizophrenia: Association is significant in men but not in women  

Microsoft Academic Search

Schizophrenia is a complex and common psychiatric disorder with a polygenic inheritance. In our previous report, we showed an association between the methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms and schizophrenia in patients from Bakirkoy in Istanbul, Turkey [Sazci, A., Ergul, E., Guzelhan, Y., Kaya, G., Kara, I., 2003. Methylenetetrahydrofolate reductase gene polymorphisms in patients with schizophrenia. Mol. Brain

Ali Sazci; Emel Ergul; Ismail Kucukali; Ihsan Kara; Guner Kaya

2005-01-01

210

The 4G\\/4G polymorphism of the hypofibrinolytic plasminogen activator inhibitor type 1 gene: An independent risk factor for serious pregnancy complications  

Microsoft Academic Search

The specific aim of the current study of 133 women with at least 1 pregnancy and measures of hypofibrinolytic and thrombophilic gene mutations was to determine retrospectively whether the mutations were associated with adverse pregnancy outcomes including prematurity, miscarriage, stillbirth, intrauterine growth retardation (IUGR), eclampsia, and abruptio placentae. Four gene mutations (factor V Leiden, methylenetetrahydrofolate reductase [MTHFR], prothrombin, and 4G\\/5G

C. J. Glueck; Harvey Phillips; Dan Cameron; Ping Wang; Robert N. Fontaine; Sarah K. Moore; Luann Sieve-Smith; Trent Tracy

2000-01-01

211

Molecular amino acid signatures in the MHC class II peptide-binding pocket predispose to autoimmune thyroiditis in humans and in mice  

Microsoft Academic Search

Hashimoto's thyroiditis (HT) is associated with HLA, but the associated allele is still controversial. We hypothesized that specific HLA-DR pocket-sequence variants are associated with HT and that similar variants in the murine I-E locus (homologous to HLA-DR) predispose to experimental autoimmune thyroiditis (EAT), a classical mouse model of HT. Therefore, we sequenced the polymorphic exon 2 of the HLA-DR gene

Francesca Menconi; Maria C. Monti; David A. Greenberg; Taiji Oashi; Roman Osman; Terry F. Davies; Yoshiyuki Ban; Eric M. Jacobson; Erlinda S. Concepcion; Cheuk Wun Li; Yaron Tomer

2008-01-01

212

Hyperhomocyst(e)inemia and MTHFR C677T genotypes in patients with central retinal vein occlusion  

Microsoft Academic Search

Background: Elevated plasma homocyst(e)ine is a major risk factor for venous thrombosis and cardiovascular disease. Homozygosity for the MTHFR C677T mutation and low plasma folate levels increase plasma homocyst(e)ine concentrations. The aim of this retrospective case-control study was to investigate a possible association between hyperhomocyst(e)inemia and central retinal vein occlusion. Methods: Our study included 78 consecutive patients with central retinal

Martin Weger; Olaf Stanger; Hannes Deutschmann; Werner Temmel; Wilfried Renner; Otto Schmut; Jürgen Semmelrock; Anton Haas

2002-01-01

213

The role of hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) C677T mutation in patients with retinal artery occlusion  

Microsoft Academic Search

PURPOSE: Hyperhomocysteinemia has been established as an important risk factor for cardiovascular diseases. The aim of the present study was to investigate whether hyperhomocysteinemia and\\/or homozygosity for the methylenetetrahydrofolate reductase (MTHFR) C677T mutation are associated with an increased risk for retinal artery occlusion (RAO).DESIGN: Retrospective case-control study.METHODS: We studied 105 consecutive patients with retinal artery occlusion and 105 age and

Martin Weger; Olaf Stanger; Hannes Deutschmann; Franz Josef Leitner; Wilfried Renner; Otto Schmut; Jürgen Semmelrock; Anton Haas

2002-01-01

214

Methylenetetrahydrofolate reductase (MTHFR) C677T and thymidylate synthase promoter (TSER) polymorphisms in Indonesian children with and without leukemia  

Microsoft Academic Search

Genetic variations in the polymorphic tandem repeat sequence of the enhancer region of the thymidylate synthase promoter (TSER), as well as in methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, influence methotrexate sensitivity. We studied these polymorphisms in children with acute lymphoblastic leukaemia (ALL) and in subjects without malignancy in Indonesia and Holland.The frequencies of TT and CT genotypes were two-fold higher in

Elisa Giovannetti; Dewa G. Ugrasena; Eddy Supriyadi; Laura Vroling; Antonino Azzarello; Desiree de Lange; Godefridus J. Peters; Anjo J. P. Veerman; Jacqueline Cloos

2008-01-01

215

C677T and A1298C MTHFR polymorphisms, a challenge for antifolate and fluoropyrimidine-based therapy personalisation  

Microsoft Academic Search

Pharmacogenetics represents an exciting, new promising tool for the individualisation of therapy. Several genetic polymorphisms and haplotypes have been considered in an attempt to optimise therapy with specific drugs but, up to now, their clinical applications remain limited.5,10-Methylenetetrahydrofolate reductase (MTHFR), a key enzyme of one-carbon metabolism, catalyses the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Two common non-synonymous variants, the C677T

Elena De Mattia; Giuseppe Toffoli

2009-01-01

216

Prediction of Methotrexate Clinical Response in Portuguese Rheumatoid Arthritis Patients: Implication of MTHFR rs1801133 and ATIC rs4673993 Polymorphisms  

PubMed Central

Objective. Methotrexate (MTX), the most used drug in rheumatoid arthritis (RA) treatment, showing variability in clinical response, is often associated with genetic polymorphisms. This study aimed to elucidate the role of methylenetetrahydrofolate reductase (MTHFR) C677T and aminoimidazole carboxamide adenosine ribonucleotide transformylase (ATIC) T675C polymorphisms and clinicopathological variables in clinical response to MTX in Portuguese RA patients. Methods. Study included 233 RA patients treated with MTX for at least six months. MTHFR C677T and ATIC T675C polymorphisms were genotyped and clinicopathological variables were collected. Statistical analyses were performed and binary logistic regression method adjusted to possible confounding variables. Results. Multivariate analyses demonstrated that MTHFR 677TT (OR = 4.63; P = 0.013) and ATIC 675T carriers (OR = 5.16; P = 0.013) were associated with over 4-fold increased risk for nonresponse. For clinicopathological variables, noncurrent smokers (OR = 7.98; P = 0.001), patients positive to anti-cyclic citrullinated peptide (OR = 3.53; P = 0.004) and antinuclear antibodies (OR = 2.28; P = 0.045), with higher health assessment questionnaire score (OR = 2.42; P = 0.007), and nonsteroidal anti-inflammatory drug users (OR = 2.77; P = 0.018) were also associated with nonresponse. Contrarily, subcutaneous administration route (OR = 0.11; P < 0.001) was associated with response. Conclusion. Our study suggests that MTHFR C677T and ATIC T675C genotyping combined with clinicopathological data may help to identify patients whom will not benefit from MTX treatment and, therefore, assist clinicians in personalizing RA treatment. PMID:24967362

Lima, Aurea; Monteiro, Joaquim; Bernardes, Miguel; Sousa, Hugo; Azevedo, Rita; Seabra, Vitor; Medeiros, Rui

2014-01-01

217

Genetic Association Analyses of Nitric Oxide Synthase Genes and Neural Tube Defects Vary by Phenotype  

PubMed Central

Neural tube defects (NTDs) are caused by improper neural tube closure during the early stages of embryonic development. NTDs are hypothesized to have a complex genetic origin and numerous candidate genes have been proposed. The nitric oxide synthase 3 (NOS3) G594T polymorphism has been implicated in risk for spina bifida, and interactions between that single nucleotide polymorphism (SNP) and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism have also been observed. To evaluate other genetic variation in the NO pathway in the development of NTDs, we examined all three NOS genes: NOS1, NOS2, and NOS3. Using 3109 Caucasian samples in 745 families, we evaluated association in the overall dataset and within specific phenotypic subsets. Haplotype tagging SNPs in the NOS genes were tested for genetic association with NTD subtypes, both for main effects as well as for the presence of interactions with the MTHFR C677T polymorphism. Nominal main effect associations were found with all subtypes, across all three NOS genes, and interactions were observed between SNPs in all three NOS genes and MTHFR C677T. Unlike the previous report, the most significant associations in our dataset were with cranial subtypes and the AG genotype of rs4795067 in NOS2 (p = 0.0014) and the interaction between the rs9658490 G allele in NOS1 and MTHFR 677TT genotype (p = 0.0014). Our data extend the previous findings by implicating a role for all three NOS genes, independently and through interactions with MTHFR, in risk not only for spina bifida, but all NTD subtypes. PMID:24323870

Soldano, Karen L.; Garrett, Melanie E.; Cope, Heidi L.; Rusnak, J. Michael; Ellis, Nathen J.; Dunlap, Kaitlyn L.; Speer, Marcy C.; Gregory, Simon G.; Ashley-Koch, Allison E.

2014-01-01

218

Effect of the MTHFR 677C/T polymorphism on homocysteinemia in response to creatine supplementation: a case study.  

PubMed

Creatine (Cr) is recommended as a dietary supplement especially for athletes but its therapeutic potential is also discussed. It is assumed that human body uses Cr for the formation of phosphocreatine, which is necessary for muscular work as a source of energy. Production of Cr in a body is closely connected to methionine cycle where guanidinoacetate (GAA) is in a final step methylated from S-adenosylmethionine (SAM). Increased availability of SAM for phosphatidylcholine (PC) and sarcosine synthesis can potentially stimulate endogenous production of betaine a thus methylation of homocysteine (HCy) to form methionine. Our subject who was methylenetetrahydrofolate reductase (MTHFR) 677TT homozygote lowered plasma HCy from 33.3 micromol/l to 17.1 micromol/l following one-month Cr supplementation (5 g/day) opposite to 677CC and CT genotypes whose HCy levels tended to increase (but still in normal ranges). We suppose that Cr supplementation stimulates pathways leading to production of sarcosine which can serve to regenerate tetrahydrofolate (THF) to form 5,10-methylene-THF. This could potentially increase MTHFR enzyme activity which may later result in increased HCy methylation. Cr supplementation significantly effects metabolism of one carbon unit and potentially lower body´s demands for methyl groups. This could be beneficial as in the case of reduced enzyme activity such as MTHFR 677C/T polymorphism. PMID:23869894

Petr, M; Steffl, M; Kohlíková, E

2013-12-20

219

Folate Intake, MTHFR Polymorphisms, and the Risk of Colorectal Cancer: A Systematic Review and Meta-Analysis  

PubMed Central

Background. The objective was to determine whether relationships exist between the methylene-tetrahydrofolate reductase (MTHFR) polymorphisms and risk of colorectal cancer (CRC) and examine whether the risk is modified by level of folate intake. Methods. MEDLINE, Embase, and SCOPUS were searched to May 2012 using the terms “folic acid,” “folate,” “colorectal cancer,” “methylenetetrahydrofolate reductase,” “MTHFR.” Observational studies were included which (1) assessed the risk of CRC for each polymorphism and/or (2) had defined levels of folate intake for each polymorphism and assessed the risk of CRC. Results. From 910 references, 67 studies met our criteria; hand searching yielded 10 studies. The summary risk estimate comparing the 677CT versus CC genotype was 1.02 (95% CI 0.95–1.10) and for 677TT versus CC was 0.88 (95% CI 0.80–0.96) both with heterogeneity. The summary risk estimates for A1298C polymorphisms suggested no reduced risk. The summary risk estimate for high versus low total folate for the 677CC genotype was 0.70 (95% CI 0.56–0.89) and the 677TT genotype 0.63 (95% CI 0.41–0.97). Conclusion. These results suggest that the 677TT genotype is associated with a reduced risk of developing CRC, under conditions of high total folate intake, and this associated risk remains reduced for both MTHFR 677 CC and TT genotypes. PMID:23125859

Kennedy, Deborah A.; Stern, Seth J.; Matok, Ilan; Moretti, Myla E.; Sarkar, Moumita; Adams-Webber, Thomasin; Koren, Gideon

2012-01-01

220

Somatic Overgrowth Predisposes to Seizures in Autism Spectrum Disorders  

PubMed Central

Background Comorbidity of Autism Spectrum Disorders with seizures or abnormal EEG (Autism-Epilepsy Phenotype) suggests shared pathomechanisms, and might be a starting point to identify distinct populations within the clinical complexity of the autistic spectrum. In this study, we tried to assess whether distinct subgroups, having distinctive clinical hallmarks, emerge from this comorbid condition. Methods Two-hundred and six individuals with idiopathic Autism Spectrum Disorders were subgrouped into three experimental classes depending on the presence of seizures and EEG abnormalities. Neurobehavioral, electroclinical and auxological parameters were investigated to identify differences among groups and features which increase the risk of seizures. Our statistical analyses used ANOVA, post-hoc multiple comparisons, and the Chi-squared test to analyze continuous and categorical variables. A correspondence analysis was also used to decompose significant Chi-squared and reduce variables dimensions. Results The high percentage of children with seizures (28.2% of our whole cohort) and EEG abnormalities (64.1%) confirmed that the prevalence of epilepsy in Autism Spectrum Disorders exceeds that of the general population. Seizures were associated with severe intellectual disability, and not with autism severity. Interestingly, tall stature (without macrocephaly) was significantly associated with EEG abnormalities or later onset seizures. However, isolated macrocephaly was equally distributed among groups or associated with early onset seizures when accompanied by tall stature. Conclusions Tall stature seems to be a phenotypic “biomarker” of susceptibility to EEG abnormalities or late epilepsy in Autism Spectrum Disorders and, when concurring with macrocephaly, predisposes to early onset seizures. Growth pattern might act as an endophenotypic marker in Autism-Epilepsy comorbidity, delineating distinct pathophysiological subtypes and addressing personalized diagnostic work-up and therapeutic approaches. PMID:24086423

Brachini, Francesca; Apicella, Fabio; Cosenza, Angela; Ferrari, Anna Rita; Guerrini, Renzo; Muratori, Filippo; Romano, Maria Francesca; Santorelli, Filippo M.; Tancredi, Raffaella; Sicca, Federico

2013-01-01

221

Hiatal hernia predisposes to nocturnal gastro-oesophageal reflux  

PubMed Central

Background Nocturnal reflux has been associated with severe complications of gastro-oesophageal reflux disease and a poorer quality of life. Hiatal hernia predisposes to increased oesophageal acid exposure, but the effect on night reflux symptoms has never been investigated. The aim of the study was to investigate if hiatal hernia is associated with more frequent and severe night reflux symptoms. Methods A total of 215 consecutive patients (110 male, mean age 52.6?±?14.7 years) answered a detailed questionnaire on frequency and severity of specific day and night reflux symptoms. Subsequently, all patients underwent upper endoscopy and were categorized in two groups based on the endoscopic presence of hiatal hernia. Results Patients with hiatal hernia were more likely to have nocturnal symptoms compared to those without hiatal hernia (78.6 vs. 51.8%, p?=?0.0001); 59.2% of patients with hiatal hernia reported heartburn and 60.2% regurgitation compared to 43.8 and 39.3% of those without hiatal hernia, respectively (p?=?0.033 and p?=?0.003). The proportions of patients with day heartburn or regurgitation were not significantly different between the two groups. Night heartburn and regurgitation were graded as significantly more severe by patients with hiatal hernia (4.9?±?4.2 vs. 3.2?±?3.7, p?=?0.002, and 3.8?±?4.2 vs. 2.2?±?3.5, p?=?0.001, respectively). Patients with hiatal hernia had more frequent weekly night heartburn and regurgitation compared to those without hiatal hernia (p?=?0.004 and p?=?0.008, respectively). Conclusions More patients with hiatal hernia reported nocturnal reflux symptoms compared to those without hiatal hernia. Furthermore, nocturnal reflux symptoms were significantly more frequent and graded as significantly more severe in patients with presence of hiatal hernia rather than in those without hiatal hernia. PMID:24917956

Karamanolis, Georgios; Polymeros, Dimitrios; Triantafyllou, Konstantinos; Adamopoulos, Adam; Barbatzas, Charalampos; Vafiadis, Irini

2013-01-01

222

Germline SMARCB1 mutation predisposes to multiple meningiomas and schwannomas with preferential location of cranial meningiomas at the falx cerebri.  

PubMed

Schwannomatosis is a rare hereditary cancer syndrome in which patients develop multiple non-vestibular schwannomas. The chromatin remodelling gene SMARCB1 (also known as INI1, hSNF5, and BAF47) has been identified as a schwannomatosis predisposing gene, being involved in a subset of sporadic and familial cases. Recent studies have shown that SMARCB1 may also be involved in the development of multiple meningiomas. Previously, we demonstrated that the SMARCB1 exon 2 missense mutation c.143 C?>?T segregates with the presence of meningiomas in five members of a large family with multiple meningiomas and schwannomas. We extended our genetic analyses by screening 44 additional at-risk family members and identified 13 new carriers. Eleven of these were subjected to magnetic resonance imaging (MRI) of brain and spine. In addition, we analyzed four meningiomas and two schwannomas from family members for the presence of schwannomatosis-specific changes. We found in each tumor retention of the SMARCB1 exon 2 mutation, acquisition of an independent neurofibromatosis type 2 (NF2) gene mutation, and loss of heterozygosity at SMARCB1 and NF2 by loss of the wild-type copy of both genes. The MRI scans revealed one or more falx meningiomas in seven of 11 (64%) newly identified SMARCB1 mutation carriers. We conclude that the SMARCB1 exon 2 missense mutation in this family predisposes to the development of meningiomas as well as schwannomas, occurring via the same genetic pathways, and that this mutation preferentially induces cranial meningiomas located at the falx cerebri. PMID:22038540

van den Munckhof, Pepijn; Christiaans, Imke; Kenter, Susan B; Baas, Frank; Hulsebos, Theo J M

2012-02-01

223

Relationship of the FKBP5 C/T polymorphism with dysfunctional attitudes predisposing to depression.  

PubMed

FK506-binding protein 51 (FKBP5) is a co-chaperone of the glucocorticoid receptor, and plays an important role in the negative feedback regulation of the hypothalamic-pituitary-adrenal axis. The C/T single nucleotide polymorphism in the intron 2 of the FKBP5 gene affects cortisol secretion, and has been implicated in the pathophysiology of depression. In this study, the relationship of the FKBP5 C/T polymorphism with dysfunctional attitudes predisposing to depression was examined. The subjects were 300 healthy Japanese. The FKBP5 genotypes were determined by a real-time PCR and cycling probe technology for SNP typing. Dysfunctional attitudes were assessed by the 24-item version of the Dysfunctional Attitude Scale (DAS-24), which has the Achievement, Self-control, and Dependency subscales. DAS-24 total scores were significantly higher in the group with the T allele than in that without this allele (p=0.001). Regarding the subscales, scores of the Achievement (p=0.003) and Self-control (p=0.009) subscales, but not those of the Dependency subscale, were significantly higher in the former group than in the latter group. The present study suggests that the FKBP5 C/T polymorphism is implicated in formation of dysfunctional attitudes, especially those about achievement and self-control. PMID:24889341

Suzuki, Akihito; Matsumoto, Yoshihiko; Sadahiro, Ryoichi; Enokido, Masanori; Goto, Kaoru; Otani, Koichi

2014-08-01

224

Chromosome 21 Scan in Down Syndrome Reveals DSCAM as a Predisposing Locus in Hirschsprung Disease  

PubMed Central

Hirschsprung disease (HSCR) genetics is a paradigm for the study and understanding of multigenic disorders. Association between Down syndrome and HSCR suggests that genetic factors that predispose to HSCR map to chromosome 21. To identify these additional factors, we performed a dose-dependent association study on chromosome 21 in Down syndrome patients with HSCR. Assessing 10,895 SNPs in 26 Caucasian cases and their parents led to identify two associated SNPs (rs2837770 and rs8134673) at chromosome-wide level. Those SNPs, which were located in intron 3 of the DSCAM gene within a 19 kb-linkage disequilibrium block region were in complete association and are consistent with DSCAM expression during enteric nervous system development. We replicated the association of HSCR with this region in an independent sample of 220 non-syndromic HSCR Caucasian patients and their parents. At last, we provide the functional rationale to the involvement of DSCAM by network analysis and assessment of SOX10 regulation. Our results reveal the involvement of DSCAM as a HSCR susceptibility locus, both in Down syndrome and HSCR isolated cases. This study further ascertains the chromosome-scan dose-dependent methodology used herein as a mean to map the genetic bases of other sub-phenotypes both in Down syndrome and other aneuploidies. PMID:23671607

Jannot, Anne-Sophie; Chaoui, Asma; Masse-Morel, Marine; Arnold, Stacey; Sanlaville, Damien; Ceccherini, Isabella; Borrego, Salud; Hofstra, Robert M. W.; Munnich, Arnold; Bondurand, Nadege; Chakravarti, Aravinda; Clerget-Darpoux, Francoise; Amiel, Jeanne; Lyonnet, Stanislas

2013-01-01

225

Genome-wide association study identifies novel loci predisposing to cutaneous melanoma.  

PubMed

We performed a multistage genome-wide association study of melanoma. In a discovery cohort of 1804 melanoma cases and 1026 controls, we identified loci at chromosomes 15q13.1 (HERC2/OCA2 region) and 16q24.3 (MC1R) regions that reached genome-wide significance within this study and also found strong evidence for genetic effects on susceptibility to melanoma from markers on chromosome 9p21.3 in the p16/ARF region and on chromosome 1q21.3 (ARNT/LASS2/ANXA9 region). The most significant single-nucleotide polymorphisms (SNPs) in the 15q13.1 locus (rs1129038 and rs12913832) lie within a genomic region that has profound effects on eye and skin color; notably, 50% of variability in eye color is associated with variation in the SNP rs12913832. Because eye and skin colors vary across European populations, we further evaluated the associations of the significant SNPs after carefully adjusting for European substructure. We also evaluated the top 10 most significant SNPs by using data from three other genome-wide scans. Additional in silico data provided replication of the findings from the most significant region on chromosome 1q21.3 rs7412746 (P = 6 × 10(-10)). Together, these data identified several candidate genes for additional studies to identify causal variants predisposing to increased risk for developing melanoma. PMID:21926416

Amos, Christopher I; Wang, Li-E; Lee, Jeffrey E; Gershenwald, Jeffrey E; Chen, Wei V; Fang, Shenying; Kosoy, Roman; Zhang, Mingfeng; Qureshi, Abrar A; Vattathil, Selina; Schacherer, Christopher W; Gardner, Julie M; Wang, Yuling; Bishop, D Tim; Barrett, Jennifer H; MacGregor, Stuart; Hayward, Nicholas K; Martin, Nicholas G; Duffy, David L; Mann, Graham J; Cust, Anne; Hopper, John; Brown, Kevin M; Grimm, Elizabeth A; Xu, Yaji; Han, Younghun; Jing, Kaiyan; McHugh, Caitlin; Laurie, Cathy C; Doheny, Kim F; Pugh, Elizabeth W; Seldin, Michael F; Han, Jiali; Wei, Qingyi

2011-12-15

226

Genome-wide association study identifies novel loci predisposing to cutaneous melanoma†  

PubMed Central

We performed a multistage genome-wide association study of melanoma. In a discovery cohort of 1804 melanoma cases and 1026 controls, we identified loci at chromosomes 15q13.1 (HERC2/OCA2 region) and 16q24.3 (MC1R) regions that reached genome-wide significance within this study and also found strong evidence for genetic effects on susceptibility to melanoma from markers on chromosome 9p21.3 in the p16/ARF region and on chromosome 1q21.3 (ARNT/LASS2/ANXA9 region). The most significant single-nucleotide polymorphisms (SNPs) in the 15q13.1 locus (rs1129038 and rs12913832) lie within a genomic region that has profound effects on eye and skin color; notably, 50% of variability in eye color is associated with variation in the SNP rs12913832. Because eye and skin colors vary across European populations, we further evaluated the associations of the significant SNPs after carefully adjusting for European substructure. We also evaluated the top 10 most significant SNPs by using data from three other genome-wide scans. Additional in silico data provided replication of the findings from the most significant region on chromosome 1q21.3 rs7412746 (P = 6 × 10?10). Together, these data identified several candidate genes for additional studies to identify causal variants predisposing to increased risk for developing melanoma. PMID:21926416

Amos, Christopher I.; Wang, Li-E; Lee, Jeffrey E.; Gershenwald, Jeffrey E.; Chen, Wei V.; Fang, Shenying; Kosoy, Roman; Zhang, Mingfeng; Qureshi, Abrar A.; Vattathil, Selina; Schacherer, Christopher W.; Gardner, Julie M.; Wang, Yuling; Tim Bishop, D.; Barrett, Jennifer H.; MacGregor, Stuart; Hayward, Nicholas K.; Martin, Nicholas G.; Duffy, David L.; Mann, Graham J.; Cust, Anne; Hopper, John; Brown, Kevin M.; Grimm, Elizabeth A.; Xu, Yaji; Han, Younghun; Jing, Kaiyan; McHugh, Caitlin; Laurie, Cathy C.; Doheny, Kim F.; Pugh, Elizabeth W.; Seldin, Michael F.; Han, Jiali; Wei, Qingyi

2011-01-01

227

Riboflavin status modifies the effects of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms on homocysteine.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR), riboflavin-dependent enzymes, participate in homocysteine metabolism. Reported effects of riboflavin status on the association between the MTHFR 677C>T polymorphism and homocysteine vary, and the effects of the MTRR 66A>G or MTRR 524C>T polymorphisms on homocysteine are unclear. We tested the hypothesis that the effects of the MTHFR 677C>T, MTRR 66A>G and MTRR 524C>T polymorphisms on fasting plasma total homocysteine (tHcy) depend on riboflavin status (erythrocyte glutathionine reductase activation coefficient, optimum: <1.2; marginally deficient: 1.2-1.4; deficient: ?1.4) in 771 adults aged 18-75 years. MTHFR 677T allele carriers with middle or low tertile plasma folate (<14.7 nmol/L) had 8.2 % higher tHcy compared to the 677CC genotype (p < 0.01). This effect was eliminated when riboflavin status was optimal (p for interaction: 0.048). In the lowest cobalamin quartile (?273 pmol/L), riboflavin status modifies the relationship between the MTRR 66 A>G polymorphism and tHcy (p for interaction: 0.034). tHcy was 6.6 % higher in MTRR 66G allele carriers compared to the 66AA genotype with marginally deficient or optimal riboflavin status, but there was no difference when riboflavin status was deficient (p for interaction: 0.059). tHcy was 13.7 % higher in MTRR 524T allele carriers compared to the 524CC genotype when cobalamin status was low (p < 0.01), but no difference was observed when we stratified by riboflavin status. The effect of the MTHFR 677C>T polymorphism on tHcy depends on riboflavin status, that of the MTRR 66A>G polymorphism on cobalamin and riboflavin status and that of the MTRR 524C>T polymorphism on cobalamin status. PMID:25322900

García-Minguillán, Carlos J; Fernandez-Ballart, Joan D; Ceruelo, Santiago; Ríos, Lídia; Bueno, Olalla; Berrocal-Zaragoza, Maria Isabel; Molloy, Anne M; Ueland, Per M; Meyer, Klaus; Murphy, Michelle M

2014-11-01

228

Association between MTHFR C677T and A1298C Polymorphisms and NSCL/P Risk in Asians: A Meta-Analysis  

PubMed Central

Objective Several studies have reported the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and nonsyndromic cleft lip with or without palate (NSCL/P) in Asian populations. However, findings have been conflicting. In order to investigate the association, a meta-analysis was performed. Methods We searched Pubmed, MedLine and EmBase database to selected eligible studies. The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were calculated using fixed effects model or random effects model to assess the association between MTHFR polymorphisms and NSCL/P in both Asian children and mothers. Results Finally, nine case-control studies were included. Overall, the MTHFR C677T polymorphism and NSCL/P showed pooled ORs (95%CI) of 1.41(1.23–1.61) in Asian children, and 1.70(1.19–2.42) in Asian mothers. Subgroup analyses by geographical locations further identified the association in Eastern Asian children, Western/Central Asian children and mothers, but not in Eastern Asian mothers. However, no significant relationship between MTHFR A1298C polymorphism and NSCL/P was found in this meta-analysis. Conclusions The MTHFR 677T allele was associated with an increased risk of NSCL/P in Asian populations. PMID:24658649

Zhao, Mengmeng; Ren, Yangwu; Shen, Li; Zhang, Yue; Zhou, Baosen

2014-01-01

229

Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus  

PubMed Central

Barrett’s Esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia. Barrett’s Esophagus strongly predisposes to esophageal adenocarcinoma (EAC), a tumour with a very poor prognosis. We have undertaken the first genome-wide association study on Barrett’s Esophagus, comprising 1,852 UK cases and 5,172 UK controls in discovery and 5,986 cases and 12,825 controls in the replication. Two regions were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined=4.09×10?9, OR(95%CI) =1.21(1.13-1.28)) and chromosome 16q24, rs9936833 (Pcombined=2.74×10?10, OR(95%CI) =1.14(1.10-1.19)). The top SNP on chromosome 6p21 is within the major histocompatibility complex, and the closest protein-coding gene to rs9936833 on chromosome 16q24 is FOXF1, which is implicated in esophageal development and structure. We found evidence that the genetic component of Barrett’s Esophagus is mediated by many common variants of small effect and that SNP alleles predisposing to obesity also increase risk for Barrett’s Esophagus. PMID:22961001

2012-01-01

230

Both Host and Pathogen Factors Predispose to Escherichia coli Urinary-Source Bacteremia in Hospitalized Patients  

PubMed Central

Background.?The urinary tract is the most common source for Escherichia coli bacteremia. Mortality from E. coli urinary-source bacteremia is higher than that from urinary tract infection. Predisposing factors for urinary-source E. coli bacteremia are poorly characterized. Methods.?In order to identify urinary-source bacteremia risk factors, we conducted a 12-month prospective cohort study of adult inpatients with E. coli bacteriuria that were tested for bacteremia within ±1 day of the bacteriuria. Patients with bacteremia were compared with those without bacteremia. Bacterial isolates from urine were screened for 16 putative virulence genes using high-throughput dot-blot hybridization. Results.?Twenty-four of 156 subjects (15%) had E. coli bacteremia. Bacteremic patients were more likely to have benign prostatic hyperplasia (56% vs 19%; P = .04), a history of urogenital surgery (63% vs 28%; P = .001), and presentation with hesitancy/retention (21% vs 4%; P = .002), fever (63% vs 38%; P = .02), and pyelonephritis (67% vs 41%; P = .02). The genes kpsMT (group II capsule) (17 [71%] vs 62 [47%]; P = .03) and prf (P-fimbriae family) (13 [54%] vs 40 [30%]; P = .02) were more frequent in the urinary strains from bacteremic patients. Symptoms of hesitancy/retention (odds ratio [OR], 7.8; 95% confidence interval [CI], 1.6–37), history of a urogenital procedure (OR, 5.4; 95% CI, 2–14.7), and presence of kpsMT (OR, 2.9; 95% CI, 1–8.2) independently predicted bacteremia. Conclusions.?Bacteremia secondary to E. coli bacteriuria was frequent (15%) in those tested for it. Urinary stasis, surgical disruption of urogenital tissues, and a bacterial capsule characteristic contribute to systemic invasion by uropathogenic E. coli. PMID:22431806

Marschall, Jonas; Zhang, Lixin; Foxman, Betsy; Warren, David K.; Henderson, Jeffrey P.

2012-01-01

231

Prenatal Exposure to the Environmental Obesogen Tributyltin Predisposes Multipotent Stem Cells to  

E-print Network

human and mouse multipotent stromal stem cells derived from white adipose tissue [adipose cells to differentiate into adipocytes, an effect that could likely increase adipose mass over timePrenatal Exposure to the Environmental Obesogen Tributyltin Predisposes Multipotent Stem Cells

Blumberg, Bruce

232

COMPARATIVE EVALUATION OF RISK FACTORS FOR CARDIOVASCULAR DISEASE (CVD) IN GENETICALLY PREDISPOSED RATS  

EPA Science Inventory

Rodent CVD models are increasingly used for understanding individual differences in susceptibility to environmental stressors such as air pollution. We characterized pathologies and a number of known human risk factors of CVD in genetically predisposed, male young adult Spontaneo...

233

Why are women predisposed to autoimmune rheumatic diseases?  

Microsoft Academic Search

The majority of autoimmune diseases predominate in females. In searching for an explanation for this female excess, most attention has focused on hormonal changes - both exogenous changes (for example, oral contraceptive pill) and fluctuations in endogenous hormone levels particularly related to menstruation and pregnancy history. Other reasons include genetic differences, both direct (influence of genes on sex chromosomes) and

Jacqueline E Oliver; Alan J Silman

2009-01-01

234

[Rasopathies: developmental disorders that predispose to cancer and skin manifestations].  

PubMed

Proteins belonging to the RAS/mitogen activated protein kinase (MAPK) pathway play key roles in cell proliferation, differentiation, survival, and death. For more than 30 years now we have known that 30% of human cancers carry somatic mutations in genes encoding proteins from this pathway. Whereas somatic mutations have a high malignant potential, germline mutations are linked to developmental abnormalities that are often poorly clinically differentiated, although each is dependent upon the specific gene affected. Thus, all patients share varying degrees of mental retardation or learning difficulties, heart disease, facial dysmorphism, skin anomalies, and, in some cases, predisposition to cancer. These syndromes, known as rasopathies, include Noonan syndrome, Costello syndrome, neurofibromatosis-1, LEOPARD syndrome, cardiofaciocutaneous syndrome, and Legius syndrome. Recognizing the skin manifestations of rasopathies can facilitate diagnosis of these syndromes. PMID:21536246

Hernández-Martín, A; Torrelo, A

2011-01-01

235

A non-coding mutation in the 5' untranslated region of patched homologue 1 predisposes to basal cell carcinoma.  

PubMed

Mutations in the human homolog of the Drosophila patched gene, patched homologue 1 (PTCH-1), are responsible for most hereditary and sporadic basal cell carcinomas. Here, we present a father and daughter with a high propensity for the development of basal cell carcinoma who were heterozygous for a non-coding germline mutation in the 5' untranslated region (UTR) of PTCH-1 (insertion of a surplus CGG triplet at the site of a seven times CGG repeat). We analysed the impact of this mutation on PTCH translation using a luciferase-based reporter vector. Insertion of an eighth CGG in the 5' UTR repressed protein translation dramatically when compared to the wild-type sequence. Our results suggest that this non-coding variant in the 5' UTR represents a mutation predisposing to basal cell carcinoma. PMID:24131384

Tietze, Julia K; Pfob, Martina; Eggert, Marlene; von Preußen, Anna; Mehraein, Yasmin; Ruzicka, Thomas; Herzinger, Thomas

2013-12-01

236

Effect of the methylenetetrahydrofolate reductase gene polymorphisms on homocysteine, folate and vitamin B12 in patients with bipolar disorder and relatives  

Microsoft Academic Search

We investigated the effect of polymorphic variants of c.1298A>C (Glu429Ala) and c.677C>T (Ala222Val) in methylenetetrahydrofolate (MTHFR) gene on the total homocysteine (tHcy), folate and B12 levels in patients with bipolar disorder, first-degree relatives of patients, and controls. The c.677C>T and c.1298A>C polymorphisms in MTHFR were determined by polymerase chain reaction-restriction fragment length polymorphism in 197 bipolar patients, 278 relatives and

Zeynep Ozbek; Cem Ismail Kucukali; Elif Ozkok; Nurcan Orhan; Makbule Aydin; Gamze Kilic; Ali Sazci; Ihsan Kara

2008-01-01

237

A new classification of HLA-DRB1 alleles differentiates predisposing and protective alleles for autoantibody production in rheumatoid arthritis  

PubMed Central

The HLA-DRB1 gene was reported to be associated with anticitrullinated protein/peptide autoantibody (ACPA) production in rheumatoid arthritis (RA) patients. A new classification of HLA-DRB1 alleles, reshaping the shared epitope (SE) hypothesis, was recently found relevant in terms of RA susceptibility and structural severity. We investigated the relevance of this new classification of HLA-DRB1 SE+ alleles in terms of rheumatoid factor (RF) and ACPA production in a sample of French RA patients. We studied 160 early RA patients included in a prospective longitudinal cohort of French Caucasian patients with recent-onset arthritis. RF, anticyclic citrullinated peptide 2 (anti-CCP2) and antideiminated human fibrinogen autoantibodies (AhFibA) were assessed in all patients at inclusion. The HLA-DRB1 gene was typed by PCR-sequence specific oligonucleotides probes (PCR-SSOP), and SE+ alleles were classified into four groups (S1, S2, S3P, S3D) according to the new classification. The new classification of HLA-DRB1 SE+ alleles distinguishes predisposing and protective alleles for RF, anti-CCP2 or AhFibA production. The presence of S2 or S3P alleles is associated with both RF, anti-CCP2 or AhFibA positivity, whereas the presence of S3D or S1 alleles appears to be protective for RF, anti-CCP2 or AhFibA positivity. The new classification of HLA-DRB1 SE+ alleles is relevant in terms of autoantibody production in early RA patients by differentiating predisposing and protective alleles for RF or ACPA production. PMID:17328818

Gourraud, Pierre-Antoine; Dieude, Philippe; Boyer, Jean-Frederic; Nogueira, Leonor; Cambon-Thomsen, Anne; Mazieres, Bernard; Cornelis, Francois; Serre, Guy; Cantagrel, Alain; Constantin, Arnaud

2007-01-01

238

Changes in lifestyle and total homocysteine in relation to MTHFR(C677T) genotype: the Inter99 study  

Microsoft Academic Search

Background:Reduction in total homocysteine (tHcy) may be clinically relevant in the prevention of cardiovascular disease (CVD) in the general population.Objective:To examine the effects of changes in various lifestyle habits and lifestyle related biological CVD risk markers on changes in tHcy in relation to MTHFR(C677T) genotype.Design:A 1 year follow-up study.Setting:Copenhagen County, Denmark.Subjects:Statistical analyses were based on a population-based sample of 915

L L N Husemoen; T F Thomsen; M Fenger; T Jørgensen; LLN Husemoen

2006-01-01

239

The effect of MTHFR(C677T) genotype on plasma homocysteine concentrations in healthy children is influenced by gender  

Microsoft Academic Search

Objective:To explore the influence of gender, together with folate status, on the relation between the common methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and plasma total homocysteine (tHcy) concentrations in healthy children.Design:Cross-sectional study by face-to-face interview.Setting and subjects:A total of 186 sixth-grade students participated from twelve randomly selected primary schools in Volos, Greece.Methods:Fasting tHcy, folate, and vitamin B12 were measured in plasma.

C Papoutsakis; N Yiannakouris; Y Manios; E Papaconstantinou; F Magkos; K H Schulpis; A Zampelas; A L Matalas

2006-01-01

240

Gene Polymorphisms of Homocysteine Metabolism-Related Enzymes in Chinese Patients with Occlusive Coronary Artery or Cerebral Vascular Diseases  

Microsoft Academic Search

The mutations in homocysteine (Hcy) metabolism-related enzyme genes including methylenetetrahydrofolate reductase (MTHFR) C677T, cystathionine ?-synthase (CBS) 844ins68, and methionine synthase (MS) A2756G have been identified as genetic risk factors for thromboembolic events. It has been noticed that these gene mutations have heterogeneous distributions among different ethnic groups or geographic areas. The data on the prevalence of the gene mutations in

Guangsen Zhang; Chongwen Dai

2001-01-01

241

NKX2-6 mutation predisposes to familial atrial fibrillation.  

PubMed

Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia and is associated with substantially increased morbidity and mortality rates. Aggregating evidence demonstrates that genetic defects are involved in the pathogenesis of AF and a number of AF-associated genes have been identified. Nevertheless, AF is a genetically heterogeneous disorder and the genetic components underpinning AF in an overwhelming majority of patients remain unclear. In this study, the entire coding exons and splice junction sites of the NK2 homeobox 6 (NKX2-6) gene, which encodes a homeodomain transcription factor important for cardiovascular development, were sequenced in 150 unrelated patients with lone AF, and a novel heterozygous NKX2-6 mutation, p.Q175H, was identified in an index patient. Genetic analysis of the available family members of the mutation carrier revealed that the mutation co-segregated with AF transmitted in an autosomal dominant pattern. The missense mutation was absent in the 200 unrelated ethnically matched healthy individuals used as controls and the altered amino acid was completely conserved evolutionarily among species. Due to unknown transcriptional targets of NKX2-6, the functional characteristics of the mutation as regards transcriptional activity were analyzed using NKX2-5 as a surrogate. Alignment between human NKX2-6 and NKX2-5 proteins displayed that the Q175H-mutant NKX2-6 was equivalent to the Q181H-mutant NKX2-5, and the introduction of Q181H into NKX2-5 significantly decreased its transcriptional activity at the atrial natriuretic factor promoter. The present study firstly associates genetically defective NKX2-6 with enhanced susceptibility to AF, providing novel insight into the molecular mechanisms underlying AF and suggesting potential strategies for the antenatal prophylaxis and personalized treatment of AF. PMID:25319568

Wang, Jun; Zhang, Dai-Fu; Sun, Yu-Min; Li, Ruo-Gu; Qiu, Xing-Biao; Qu, Xin-Kai; Liu, Xu; Fang, Wei-Yi; Yang, Yi-Qing

2014-12-01

242

A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk  

Microsoft Academic Search

Excessive estrogen stimulation unopposed by progesterone strongly predisposes to endometrial cancer. Because the antiproliferative effect of progesterone requires the progesterone receptor (PR), which exists in two isoforms, PR-A and -B, we reasoned that variants in the PR gene may predispose to endometrial cancer. We found six variable sites, including four polymorphisms in the hPR gene and five common haplotypes. One

Immaculata de Vivo; Gordon S. Huggins; Susan E. Hankinson; Pamela J. Lescault; Marike Boezen; Graham A. Colditz; David J. Hunter

2002-01-01

243

Predisposing, enabling and need correlates of mental health treatment utilization among homeless men.  

PubMed

There is significant unmet need for mental health treatment among homeless men, but little is known about the correlates of treatment utilization in this population. Within the framework of the Behavioral Model for Vulnerable Populations, this study examines predisposing, enabling and need factors that may be associated with mental health care utilization. Participants were a representative sample of 305 heterosexually active homeless men utilizing meal programs in the Skid Row region of LA. Logistic regression examined the association between predisposing, enabling and need factors and past 30 day mental health service utilization on Skid Row. Results indicated that while need, operationalized as positive screens for posttraumatic stress disorder or depression, was associated with recent mental health care utilization, predisposing and enabling factors were also related to utilization. African-American homeless men, and those men who also reported substance abuse treatment and drop-in center use, had increased odds of reporting mental health care utilization. PMID:24595594

Rhoades, Harmony; Wenzel, Suzanne L; Golinelli, Daniela; Tucker, Joan S; Kennedy, David P; Ewing, Brett

2014-11-01

244

Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency  

SciTech Connect

5-Methyltetrahydrofolate, the major form of folate in plasma, is a carbon donor for the remethylation of homocysteine to methionine. This form of folate is generated from 5,10-methylenetetrahydrofolate through the action of 5,10-methylenetetrahydrofolate reductase (MTHFR), a cytosolic flavoprotein. Patients with an autosomal recessive severe deficiency of MTHFR have homocystinuria and a wide range of neurological and vascular disturbances. We have recently described the isolation of a cDNA for MTHFR and the identification of two mutations in patients with severe MTHFR deficiency. We report here the characterization of seven novel mutations in this gene: six missense mutations and a 5{prime} splice-site defect that activates a cryptic splice in the coding sequence. We also present a preliminary analysis of the relationship between genotype and phenotype for all nine mutations identified thus far in this gene. A nonsense mutation and two missense mutations (proline to leucine and threonine to methionine) in the homozygous state are associated with extremely low activity (0%-3%) and onset of symptoms within the 1st year of age. Other missense mutations (arginine to cysteine and arginine to glutamine) are associated with higher enzyme activity and later onset of symptoms. 19 refs., 4 figs., 2 tabs.

Goyette, P.; Frosst, P.; Rosenblatt, D.S.; Rozen. R. [McGill Univ., Montreal (Canada)

1995-05-01

245

Hyperhomocysteinemia and MTHFR C677T and A1298C polymorphisms are associated with chronic allograft nephropathy in renal transplant recipients  

Microsoft Academic Search

Hyperhomocysteine has been reported to be an important risk factor for the development of atherosclerosis. Identification of risk factors, such as hyperhomocysteinemia, is crucial for a better understanding of the events that lead to degenerative processes in the vascular system and for a correct understanding of the potential role of methylene-tetrahydrofolate reductase enzymes (MTHFR) to help in the treatment of

E. C. Pavarino-Bertelli; M. P. Sanches de Alvarenga; E. M. Goloni-Bertollo; M. A. S. F. Baptista; R. Haddad; N. F. Hoerh; M. N. Eberlin; M. Abbud-Filho

2004-01-01

246

Plasma homocysteine, MTHFR C677T, CBS 844ins68bp, and MTHFD1 G1958A polymorphisms in spontaneous cervical artery dissections  

Microsoft Academic Search

Mild hyperhomocysteinemia is a probable risk factor for atherosclerotic diseases and stroke. Recently, associations of elevated plasma homocysteine concentrations in the acute phase and of MTHFR 677 TT genotype with spontaneous cervical artery dissections (sCAD) have been reported. The purpose of this study was to test this hypothesis in the currently largest sample of patients with sCAD, taking into account

Carsten Konrad; Georg A. Müller; Claus Langer; Gregor Kuhlenbäumer; Klaus Berger; Darius G. Nabavi; Rainer Dziewas; Florian Stögbauer; Erich B. Ringelstein; Ralf Junker

2004-01-01

247

The association of p53 mutations and p53 codon 72, Her 2 codon 655 and MTHFR C677T polymorphisms with breast cancer in Northern Greece  

Microsoft Academic Search

The aim of this study was to explore a possible association between p53 codon 72, Her 2 codon 655 and MTHFR C677T polymorphisms and breast cancer in Northern Greece. We examined 42 women with breast cancer and 51 controls. A total of 42 women with breast cancer as well as healthy controls were investigated and results showed that p53 codon

Theodora G. Kalemi; Alexandros F. Lambropoulos; Maria Gueorguiev; Sofia Chrisafi; Konstantinos T. Papazisis; Alexandros Kotsis

2005-01-01

248

Effect of the methylenetetrahydrofolate reductase ( MTHFR 677C>T) polymorphism on plasma homocysteine concentrations in healthy children is influenced by consumption of folate-fortified foods  

Microsoft Academic Search

ObjectiveTo explore the influence of folate-fortified foods (ready-to-eat [RTE] breakfast cereals or fruit-juice drinks) on the relation between the methylenetetrahydrofolate reductase (MTHFR 677C>T) polymorphism and plasma total homocysteine (tHcy) concentrations in healthy children.

Constantina Papoutsakis; Yannis Manios; Faidon Magkos; Evaggelos Papaconstantinou; Kleopatra H. Schulpis; Antonis Zampelas; Antonia L. Matalas; Nikos Yiannakouris

2010-01-01

249

Predisposing factors for individuals' Lyme disease prevention practices: Connecticut, Maine, and Montana.  

PubMed Central

OBJECTIVES: This study examined factors that predispose individuals to protect against Lyme disease. METHODS: Knowledge, attitude, and practice questions concerning Lyme disease prevention were included in the Behavioral Risk Factor Surveillance surveys in Connecticut, Maine, and Montana. A total of 4246 persons were interviewed. RESULTS: Perceived risk of acquiring Lyme disease, knowing anyone with Lyme disease, knowledge about Lyme disease, and believing Lyme disease to be a common problem were significantly associated with prevention practices. CONCLUSIONS: Predisposing factors differ substantially between states and appear related to disease incidence. Personal risk, knowing someone with Lyme disease, and cognizance about Lyme disease and acting on this information are consistent with social learning theories. PMID:9431299

Herrington, J E; Campbell, G L; Bailey, R E; Cartter, M L; Adams, M; Frazier, E L; Damrow, T A; Gensheimer, K F

1997-01-01

250

Assessing predictive capacity and conditional independence of landslide predisposing factors for shallow landslides susceptibility models  

NASA Astrophysics Data System (ADS)

The aim of this study is to identify the landslide predisposing factors combination, using a bivariate statistical model that best predict landslide susceptibility. The best predictive model should have a good performance in terms of suitability and predictive power, and should be based on landslide predisposing factors that are conditionally independent. The study area is the Santa Marta de Penaguião council (70 km2) located in the Northern Portugal. Several destructive landslides occurred in this area in the last decades promoting landscape degradation and other negative human and economic impacts. A landslide inventory was built in 2005-2009 using aerial photo-interpretation (1/5.000 scale) and field work validation. This inventory contains 767 shallow translational slides. The landslide density is 11 events/square kilometre, and each landslide has, on average, 136 m2 and the depth of the slip surface typically ranges from 1 to 1.5 m. The landslide layer was crossed individually with seven landslide predisposing factors (Aspect; Curvature; Slope Angle; Geomorphological Units; Land Use; Inverse Wetness Index; Lithology) and each class within each predisposing theme was weighted using the Information Value Method. In order to identify the best combination of landslide predisposing factors, all possible combinations were tested which resulted in 120 predictive models. The goodness of fit of each landslide susceptibility model was evaluated by constructing the Success Rate Curves and by computing the Area Under the Curve (AUC). The best landslide susceptibility model was selected according to the model degree of fitness and on the basis of a conditional independence criterion. Two tests were performed to the entire dataset to assess conditional independence: the Overall Conditional Independence (OCI) and the Agterberg & Cheng Conditional Independence Test (ACCIT) (Agterberg and Cheng, 2002). The best landslide susceptibility model was constructed with only three landslide predisposing factors (slope angle, inverse wetness index and land use) and was compared with a model developed using the total set of landslide predisposing factors. Finally, the predictive capacity of the selected landslide susceptibility model was evaluated by computing Prediction Rate Curves based on the partitioning of landslide inventory using temporal, spatial and random criteria. The same procedure was applied to the seven-factors model for comparison purposes. Results showed that the model of spatial distribution of landslide susceptibility built with three factors is not significantly different from the one produced with the total set of factors. Therefore, it is shown that it is possible to produce a reliable landslide susceptibility model using only a few landslides predisposing factors and fulfilling the conditional independence hypothesis.

Pereira, S.; Zêzere, J. L.; Bateira, C.

2012-04-01

251

Meta-analyses of blood homocysteine levels for gender and genetic association studies of the MTHFR C677T polymorphism in schizophrenia.  

PubMed

Previous studies suggest that elevated blood homocysteine levels and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism are risk factors for schizophrenia. However, the effects of gender and MTHFR C677T genotypes on blood homocysteine levels in schizophrenia have not been consistent. We first investigated whether plasma total homocysteine levels were higher in patients with schizophrenia than in controls with stratification by gender and by the MTHFR C677T genotypes in a large cohort (N = 1379). Second, we conducted a meta-analysis of association studies between blood homocysteine levels and schizophrenia separately by gender (N = 4714). Third, we performed a case-control association study between the MTHFR C677T polymorphism and schizophrenia (N = 4998) and conducted a meta-analysis of genetic association studies based on Japanese subjects (N = 10 378). Finally, we assessed the effect of plasma total homocysteine levels on schizophrenia by a mendelian randomization approach. The ANCOVA after adjustment for age demonstrated a significant effect of diagnosis on the plasma total homocysteine levels in all strata, and the subsequent meta-analysis for gender demonstrated elevated blood homocysteine levels in both male and female patients with schizophrenia although antipsychotic medication might influence the outcome. The meta-analysis of the Japanese genetic association studies demonstrated a significant association between the MTHFR C677T polymorphism and schizophrenia. The mendelian randomization analysis in the Japanese populations yielded an OR of 1.15 for schizophrenia per 1-SD increase in plasma total homocysteine. Our study suggests that increased plasma total homocysteine levels may be associated with an increased risk of schizophrenia. PMID:24535549

Nishi, Akira; Numata, Shusuke; Tajima, Atsushi; Kinoshita, Makoto; Kikuchi, Kumiko; Shimodera, Shinji; Tomotake, Masahito; Ohi, Kazutaka; Hashimoto, Ryota; Imoto, Issei; Takeda, Masatoshi; Ohmori, Tetsuro

2014-09-01

252

Significance of dietary folate intake, homocysteine levels and MTHFR 677 C>T genotyping in South African patients diagnosed with depression: test development for clinical application.  

PubMed

Low folate intake in the presence of the functional MTHFR 677 C > T (rs1801133) polymorphism is an important cause of elevated homocysteine levels previously implicated in major depressive disorder (MDD) and many other chronic diseases. In this study the clinical relevance and inter-relationship of these aspects were evaluated in 86 South African patients diagnosed with MDD and 97 population-matched controls participating in a chronic diseases screening program. A questionnaire-based clinical and nutrition assessment was performed, homocysteine levels determined, and all study participants genotyped for MTHFR 677 C > T (rs1801133) using allele-specific TaqMan technology. The folate score was found to be significantly lower in the patient group compared to controls (p?=?0.003) and correlated with increased body mass index (BMI), particularly in females with MDD (p?=?0.009). BMI was significantly higher in the MDD patients compared with controls after adjustment for age and sex (p?=?0.015), but this association was no longer significant after further adjustment for the level of folate intake in the diet. In MDD patients but not controls, the minor T-allele of MTHFR 677 C > T was associated with increased BMI (p?=?0.032), which in turn correlated significantly with increased homocysteine levels. The significant association between BMI and homocysteine levels was observed in both the MDD patient (p?=?0.049) and control (p?=?0.018) study groups. The significantly higher homocysteine levels observed in MDD patients compared to controls after adjustment for age and sex (p?=?0.030), therefore appears to be mediated by the effects of MTHFR 677 C > T and low folate intake on BMI. Detection of the low-penetrance MTHFR 677 C > T mutation reinforces the importance of folate intake above the recommended daily dose to prevent or restore dysfunction of the methylation pathway. PMID:24532086

Delport, Darnielle; Schoeman, Renata; van der Merwe, Nicole; van der Merwe, Lize; Fisher, Leslie R; Geiger, Dieter; Kotze, Maritha J

2014-06-01

253

Meta-analyses of Blood Homocysteine Levels for Gender and Genetic Association Studies of the MTHFR C677T Polymorphism in Schizophrenia  

PubMed Central

Previous studies suggest that elevated blood homocysteine levels and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism are risk factors for schizophrenia. However, the effects of gender and MTHFR C677T genotypes on blood homocysteine levels in schizophrenia have not been consistent. We first investigated whether plasma total homocysteine levels were higher in patients with schizophrenia than in controls with stratification by gender and by the MTHFR C677T genotypes in a large cohort (N = 1379). Second, we conducted a meta-analysis of association studies between blood homocysteine levels and schizophrenia separately by gender (N = 4714). Third, we performed a case-control association study between the MTHFR C677T polymorphism and schizophrenia (N = 4998) and conducted a meta-analysis of genetic association studies based on Japanese subjects (N = 10 378). Finally, we assessed the effect of plasma total homocysteine levels on schizophrenia by a mendelian randomization approach. The ANCOVA after adjustment for age demonstrated a significant effect of diagnosis on the plasma total homocysteine levels in all strata, and the subsequent meta-analysis for gender demonstrated elevated blood homocysteine levels in both male and female patients with schizophrenia although antipsychotic medication might influence the outcome. The meta-analysis of the Japanese genetic association studies demonstrated a significant association between the MTHFR C677T polymorphism and schizophrenia. The mendelian randomization analysis in the Japanese populations yielded an OR of 1.15 for schizophrenia per 1-SD increase in plasma total homocysteine. Our study suggests that increased plasma total homocysteine levels may be associated with an increased risk of schizophrenia. PMID:24535549

Nishi, Akira; Numata, Shusuke; Tajima, Atsushi; Kinoshita, Makoto; Kikuchi, Kumiko; Shimodera, Shinji; Tomotake, Masahito; Ohi, Kazutaka; Hashimoto, Ryota; Imoto, Issei; Takeda, Masatoshi; Ohmori, Tetsuro

2014-01-01

254

The Influence of Predisposing, Enabling and Need Factors on Condom Use in Ivory Coast  

ERIC Educational Resources Information Center

The main objective of this study was to identify key determinants of condom use in Ivory Coast. Data stem from Ivory Coast Demographic Health Survey (DHS) conducted by ORC Macro in 2005 among a representative sample of 9,686 persons aged 15 - 49. Following the behavioral model, we use logistic regression to assess the effect of predisposing

Ngamini Ngui, Andre

2010-01-01

255

Vronique Deroche-Gamonet High novelty preference rats are predisposed to compulsive cocaine self-administration  

E-print Network

Véronique Deroche-Gamonet High novelty preference rats are predisposed to compulsive cocaine self ­ France. Running title: novelty preference predicts cocaine addiction Correspondence to : Véronique/novelty seeking is amongst the best markers of cocaine addiction in humans. However, its implication

Paris-Sud XI, Université de

256

Genetic factors affect the tendency to develop cancer. Predisposing mutations often influence DNA repair,cell-  

E-print Network

Genetic factors affect the tendency to develop cancer. Predisposing mutations often influence DNA is known about genetic predisposition to cancer.The key facts fall into four cat- egories.First,major (that of the genetic tendency to develop cancer, at least in the late-onset epithelial cancers such as breast and colon

Frank, Steven A.

257

Bilateral and Simultaneous Rupture of the Triceps Tendon in a Patient without Predisposing Factors  

PubMed Central

Tendon rupture is typically associated with predisposing features including renal failure, hyperparathyroidism, and connective tissue elastosis. We present a case in which none of these risk factors is present and in a completely healthy patient. To our knowledge, this has never been reported in the literature. PMID:23326731

Desai, Bobby; Slish, John; Allen, Brandon

2012-01-01

258

Predisposing, Precipitating, Perpetuating, Professional Help, and Prevention Factors of Eating Disorders.  

ERIC Educational Resources Information Center

This report describes an eating disorder as a multi-dimensional physiological, psychological, social, and cultural illness. A chart describing the typical anorexic and bulimic is included which has on its horizontal axis the predisposing, precipitating, perpetuating, professional help, and prevention factors of anorexia nervosa and bulimia. On its…

Moriarty, Dick; Chanko, Cathy

259

Synergistic effects of the MTHFR C677T and A1298C polymorphisms on the increased risk of micro- and macro-albuminuria and progression of diabetic nephropathy among Iranians with type 2 diabetes mellitus  

Microsoft Academic Search

ObjectivesTo find whether polymorphisms of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C are risk factors for diabetic nephropathy (DN) among type 2 diabetes mellitus (T2DM) patients from Western Iran.

Mehrali Rahimi; Ali Hasanvand; Zohreh Rahimi; Asad Vaisi-Raygani; Hadi Mozafari; Mansour Rezaei; Javad Zargooshi; Farid Najafi; Ebrahim Shakiba

2010-01-01

260

The chosen genes : Jews, genetics, and the future of ethnic medicine  

E-print Network

All humans have certain genes that cause or predispose them to various diseases. In the ideal medical future, scientists will have hyperfast gene analyzers able to sequence anyone's DNA in a matter of minutes. In that ...

Anthes, Emily Kennedy

2006-01-01

261

Gene Identification in Asthma and Allergy  

Microsoft Academic Search

Asthma and atopy are due to the interaction between genetic and environmental factors. The genetic basis of asthma and atopy is becoming more certain, with the promise of improvements in the diagnosis and treatment of these disorders. A combination of candidate gene and positional cloning studies has already identified several genes which influence allergic disease. These genes predispose in general

Miriam F. Moffatt; William O. C. M. Cookson

1998-01-01

262

The Alu-rich genomic architecture of SPAST predisposes to diverse and functionally distinct disease-associated CNV alleles.  

PubMed

Intragenic copy-number variants (CNVs) contribute to the allelic spectrum of both Mendelian and complex disorders. Although pathogenic deletions and duplications in SPAST (mutations in which cause autosomal-dominant spastic paraplegia 4 [SPG4]) have been described, their origins and molecular consequences remain obscure. We mapped breakpoint junctions of 54 SPAST CNVs at nucleotide resolution. Diverse combinations of exons are deleted or duplicated, highlighting the importance of particular exons for spastin function. Of the 54 CNVs, 38 (70%) appear to be mediated by an Alu-based mechanism, suggesting that the Alu-rich genomic architecture of SPAST renders this locus susceptible to various genome rearrangements. Analysis of breakpoint Alus further informs a model of Alu-mediated CNV formation characterized by small CNV size and potential involvement of mechanisms other than homologous recombination. Twelve deletions (22%) overlap part of SPAST and a portion of a nearby, directly oriented gene, predicting novel chimeric genes in these subjects' genomes. cDNA from a subject with a SPAST final exon deletion contained multiple SPAST:SLC30A6 fusion transcripts, indicating that SPAST CNVs can have transcriptional effects beyond the gene itself. SLC30A6 has been implicated in Alzheimer disease, so these fusion gene data could explain a report of spastic paraplegia and dementia cosegregating in a family with deletion of the final exon of SPAST. Our findings provide evidence that the Alu genomic architecture of SPAST predisposes to diverse CNV alleles with distinct transcriptional--and possibly phenotypic--consequences. Moreover, we provide further mechanistic insights into Alu-mediated copy-number change that are extendable to other loci. PMID:25065914

Boone, Philip M; Yuan, Bo; Campbell, Ian M; Scull, Jennifer C; Withers, Marjorie A; Baggett, Brett C; Beck, Christine R; Shaw, Christine J; Stankiewicz, Pawel; Moretti, Paolo; Goodwin, Wendy E; Hein, Nichole; Fink, John K; Seong, Moon-Woo; Seo, Soo Hyun; Park, Sung Sup; Karbassi, Izabela D; Batish, Sat Dev; Ordóñez-Ugalde, Andrés; Quintáns, Beatriz; Sobrido, María-Jesús; Stemmler, Susanne; Lupski, James R

2014-08-01

263

Genes  

NSDL National Science Digital Library

Illustration of the placement of genes in a chromosome. A gene can be defined as a region of DNA that controls a hereditary characteristic. It usually corresponds to a sequence used in the production of a specific protein or RNA. A gene carries biological information in a form that must be copied and transmitted from each cell to all its progeny. This includes the entire functional unit: coding DNA sequences, non-coding regulatory DNA sequences, and introns. Genes can be as short as 1000 base pairs or as long as several hundred thousand base pairs. It can even be carried by more than one chromosome. The estimate for the number of genes in humans has decreased as our knowledge has increased. As of 2001, humans are thought to have between 30,000 and 40,000 genes.

Excellence, Access

2005-03-12

264

Involvement of gene polymorphisms of the folate pathway enzymes in gene expression and anticancer drug sensitivity using the NCI60 panel as a model  

Microsoft Academic Search

Folate, a vitamin of the B group involved in one-carbon group metabolism, plays an important role in DNA synthesis and methylation. Several polymorphisms in the genes involved in folate uptake and biotransformations have been shown to be associated to the risk of cancer and to anticancer drug response. We studied common polymorphisms in MTHFR (N5,10-methylene-tetrahydrofolate reductase), MTHFD1 (N5,10-methylene-tetrahydrofolate dehydrogenase), MTR

Virginie Charasson; Dominique Hillaire-Buys; Isabelle Solassol; Armelle Laurand-Quancard; Frédéric Pinguet; Valérie Le Morvan; Jacques Robert

2009-01-01

265

Plasminogen activator inhibitor-1 4G/5G and the MTHFR 677C/T polymorphisms and susceptibility to polycystic ovary syndrome: a meta-analysis.  

PubMed

The aim of this study was to explore whether the plasminogen activator inhibitor-1 (PAI-1) 4G/5G and the methylenetetrahydrofolate reductase (MTHFR) 677C/T polymorphisms are associated with susceptibility to polycystic ovary syndrome (PCOS). Meta-analyses were conducted to determine the association between the PAI-1 4G/5G and MTHFR 677C/T polymorphisms and PCOS using: (1) allele contrast (2) homozygote contrast, (3) recessive, and (4) dominant models. For meta-analysis, nine studies of the PAI-1 4G/5G polymorphism with 2384 subjects (PCOS, 1615; controls, 769) and eight studies of the MTHFR 677C/T polymorphism with 1270 study subjects were included. Meta-analysis of all study subjects showed no association between PCOS and the PAI-1 4G allele (OR=0.949, 95% CI=0.671-1.343, p=0.767). Stratification by ethnicity, however, indicated a significant association between the PAI-1 4G allele and PCOS in Turkish and Asian populations (OR=0.776, 95% CI=0.602-0.999, p=0.049; OR=1.749, 95% CI=1.297-2.359, p=2.5×10(-5) respectively). In addition, meta-analysis indicated an association between PCOS and the PAI-1 4G4G+4G5G genotype in Europeans (OR=1.406, 95% CI=1.025-1.928, p=0.035). However, meta-analysis of all study subjects showed no association between PCOS and the MTHFR 677T allele (OR=0.998, 95% CI=0.762-1.307, p=0.989), including Europeans (OR=0.806, 95% CI=0.610-1.063, p=0.126). Meta-analysis showed no association between PCOS and the MTHFR 677C/T polymorphism using homozygote contrast, and recessive and dominant models. In conclusion, meta-analysis suggests the PAI-1 4G/5G polymorphism is associated with susceptibility to PCOS in European, Turkish, and Asian populations, but the MTHFR 677C/T polymorphism is not associated with susceptibility to PCOS in Europeans. PMID:24439532

Lee, Young Ho; Song, Gwan Gyu

2014-04-01

266

Combined choroidal neovascularization and hypopituitarism in a patient with homozygous mutation in methylenetetrahydrofolate reductase gene  

PubMed Central

We report a case of choroidal neovascularization (CNV) secondary to methylenetetrahydrofolate reductase (MTHFR) gene mutation in a 20-year-old male patient with hypopituitarism. Treatment with three consecutive injections of intravitreal ranibizumab (anti-vascular endothelial growth factor) resulted in significant improvement of the patient's vision and the appearance of the macula. A search of the literature produced no previously reported case of MTHFR gene mutation associated both CNV and possibly hypopituitarism. With hormone replacement therapy of hypopituitarism, acetyl salicylic acid 100 mg/day also was started. The patient was clinically stable both for CNV and other thromboembolic disorders over a 6-month follow-up and also 1-year follow-up period. PMID:24672570

Aydogdu, Aydogan; Haymana, Cem; Baskoy, Kamil; Durukan, Ali H.; Ozgur, Gokhan; Azal, Omer

2014-01-01

267

[Brain monoaminoxidase during late ontogenesis in rats genetically predisposed to pendulum-like movements].  

PubMed

Rats genetically predisposed (PM+) and non-predisposed (PM-) to pendulum movement (spontaneous nystagm) were studied at different age. In old PM+ and PM- rats the brain MAO-A activity did not differ, unlike between young PM+ and PM- rats. In old PM+ and PM- rats, brain stem MAO-A activity was higher than in young ones. Actinomycin D lowered brain stem MAO-A activity in PM+ and PM- rats. In the absence of actinomycin D, stress elevated MAO-B activity in the brain stem of PM- rats, and a preliminary actinomycin D administration prevent the MAO-B activating effect of stress. Possible differences in MAO-A and MAO-B regulation at transcription level in PM+ and PM- are discussed. PMID:10432556

Vo?tenko, N N; Barykina, N N; Kolpakov, V G

1999-01-01

268

Predisposing, Enabling and Pregnancy-Related Determinants of Late Initiation of Prenatal Care  

Microsoft Academic Search

Prenatal care is important for the health and wellbeing of women and their babies. There is international consensus that prenatal\\u000a care should begin in the first trimester. This study aims to analyze the effects of predisposing, enabling and pregnancy-related\\u000a determinants of late prenatal care initiation. In this prospective observational study, 333 women were recruited consecutively\\u000a at the beginning of their

Katrien Beeckman; Fred Louckx; Koen Putman

269

Dietary intake of folate and riboflavin, MTHFR C677T Genotype, and colorectal adenoma risk: a Dutch case-control study  

Microsoft Academic Search

We investigated the associations between dietary intake of folate and vitamin B2, MTHFR C677T genotype, and colorectal adenomas in a Dutch case-control study. Data of cases with at least one histologically confirmed colorectal adenoma (n = 768) and controls with no history of any type of colorectal polyp (n = 709) were included. Dietary intake was assessed using a food-frequency

M. van den Donk; G. M. Buijsse; S. W. van den Berg; M. C. Ocké; J. L. Harryvan; F. M. Nagengast; F. J. Kok; E. Kampman

2005-01-01

270

Assessment of tailor-made prevention of atherosclerosis with folic acid supplementation: randomized, double-blind, placebo-controlled trials in each MTHFR C677T genotype  

Microsoft Academic Search

This study aimed at assessing the effect of folic acid supplementation quantitatively in each MTHFR C677T genotype and considered the efficiency of tailor-made prevention of atherosclerosis. Study design was genotype-stratified, randomized, double-blind, placebo-controlled trials. The setting was a Japanese company in the chemical industry. Subjects were 203 healthy men after exclusion of those who took folic acid or drugs known

Koichi Miyaki; Mitsuru Murata; Haruhito Kikuchi; Izumi Takei; Takeo Nakayama; Kiyoaki Watanabe; Kazuyuki Omae

2005-01-01

271

Methylenetetrahydrofolate reductase (MTHFR) genetic variation and major depressive disorder prognosis: A five-year prospective cohort study of primary care attendees.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) genetic variation has been associated with the diagnosis of major depressive disorder (MDD) but no study to date has examined the effect MTHFR variation has on MDD prognosis. We sought to examine the prospective effects of two common MTHFR variants (C677T and A1298C) as well as seven haplotype-tagging single nucleotide polymorphisms (htSNPs) on MDD prognosis over a 5-year (60-month) period. Participants were 147 depressed primary care attendees enrolled in the Diagnosis, Management and Outcomes of Depression in Primary Care (diamond) prospective cohort study. Prognosis of MDD was measured using three methods: (1) DSM-IV criteria, (2) Primary Care Evaluation of Mental Disorders Patient Health Questionnaire-9 (PHQ-9), and (3) Center for Epidemiologic Studies Depression Scale (CESD). DSM-IV criteria for MDD was assessed using the Composite International Diagnostic Interview at baseline and 24, 36, 48, and 60 months post-baseline; whereas, PHQ-9 and CESD measures were employed at baseline and 12, 24, 36, 48, and 60 months post-baseline. Repeated measures analysis of variance showed that PHQ-9 symptom severity trajectories differed by C677T genotype (F?=?3.34, df?=?2,144, P?=?0.038), with 677CC genotype showing the most severe symptom severity course over the 60 months of observation. Neither the A1298C polymorphism nor any of the htSNPs were associated with MDD prognosis regardless of measure used. Our results suggest that the MTHFR C677T polymorphism may serve as a marker for MDD prognosis pending independent replication. PMID:24123968

Bousman, Chad A; Potiriadis, Maria; Everall, Ian P; Gunn, Jane M

2014-01-01

272

MTHFR 677T Is a Strong Determinant of the Degree of Hearing Loss Among Polish Males with Postlingual Sensorineural Hearing Impairment  

PubMed Central

Hearing impairment (HI) is the most common sensory handicap. Congenital HI often has a genetic basis, whereas the etiology of nonsyndromic postlingual HI (npHI) usually remains unidentified. Our purpose was to test whether the MTHFR C677T (rs1801133) polymorphism affecting folate metabolism is associated with the occurrence or severity of npHI. We studied rs1801133 genotypes in 647 npHI patients (age <40, sudden sensorineural loss excluded, HI characterized as mean of better ear hearing thresholds for 0.5–8 kHz) and 3273 adult controls from the background population. Genotype distribution among patients and controls was similar, but among male cases (n=302) we found a dose-dependent correlation of MTHFR 677T with the degree of HI (mean thresholds in dB: 38.8, 44.9, and 53.3, for CC, CT, and TT genotypes, respectively; p=0.0013, pcor.=0.017). Among male patients rs1801133 TT significantly increased the risk of severe/profound HI (odds ratio=4.88, p=0.001). Among controls the known effect of MTHFR 677T on plasma total homocysteine was more pronounced in men than in women (p<0.00004 for genotype-sex interaction) suggesting that in Poland folate deficiency is more prevalent in males. In conclusion, we report a novel strong effect of MTHFR 677T among males with npHI. The functional significance of rs1801133 suggests that these patients may benefit from folate supplementation—an intervention which is simple, cheap, and devoid of side effects. PMID:22424391

Pollak, Agnieszka; Mueller-Malesinska, Malgorzata; Lechowicz, Urszula; Skorka, Agata; Korniszewski, Lech; Sobczyk-Kopciol, Agnieszka; Waskiewicz, Anna; Broda, Grazyna; Iwanicka-Pronicka, Katarzyna; Oldak, Monika; Skarzynski, Henryk

2012-01-01

273

Developmental androgen excess programs sympathetic tone and adipose tissue dysfunction and predisposes to a cardiometabolic syndrome in female mice  

PubMed Central

Among women, the polycystic ovarian syndrome (PCOS) is considered a form of metabolic syndrome with reproductive abnormalities. Women with PCOS show increased sympathetic tone, visceral adiposity with enlarged adipocytes, hypoadiponectinemia, insulin resistance, glucose intolerance, increased inactive osteocalcin, and hypertension. Excess fetal exposure to androgens has been hypothesized to play a role in the pathogenesis of PCOS. Previously, we showed that neonatal exposure to the androgen testosterone (NT) programs leptin resistance in adult female mice. Here, we studied the impact of NT on lean and adipose tissues, sympathetic tone in cardiometabolic tissues, and the development of metabolic dysfunction in mice. Neonatally androgenized adult female mice (NTF) displayed masculinization of lean tissues with increased cardiac and skeletal muscle as well as kidney masses. NTF mice showed increased and dysfunctional white adipose tissue with increased sympathetic tone in both visceral and subcutaneous fat as well as increased number of enlarged and insulin-resistant adipocytes that displayed altered expression of developmental genes and hypoadiponectinemia. NTF exhibited dysfunctional brown adipose tissue with increased mass and decreased energy expenditure. They also displayed decreased undercarboxylated and active osteocalcin and were predisposed to obesity during chronic androgen excess. NTF showed increased renal sympathetic tone associated with increased blood pressure, and they developed glucose intolerance and insulin resistance. Thus, developmental exposure to testosterone in female mice programs features of cardiometabolic dysfunction, as can be observed in women with PCOS, including increased sympathetic tone, visceral adiposity, insulin resistance, prediabetes, and hypertension. PMID:23612996

Nohara, Kazunari; Waraich, Rizwana S.; Liu, Suhuan; Ferron, Mathieu; Waget, Aurelie; Meyers, Matthew S.; Karsenty, Gerard; Burcelin, Remy

2013-01-01

274

Identifying multiple causative genes at a single GWAS locus  

PubMed Central

Genome-wide association studies (GWAS) are useful for nominating candidate genes, but typically are unable to establish disease causality or differentiate between the effects of variants in linkage disequilibrium (LD). Additionally, some GWAS loci might contain multiple causative variants or genes that contribute to the overall disease susceptibility at a single locus. However, the majority of current GWAS lack the statistical power to test whether multiple causative genes underlie the same locus, prompting us to adopt an alternative approach to testing multiple GWAS genes empirically. We used gene targeting in a disease-susceptible rat model of genetic hypertension to test all six genes at the Agtrap-Plod1 locus (Agtrap, Mthfr, Clcn6, Nppa, Nppb, and Plod1) for blood pressure (BP) and renal phenotypes. This revealed that the majority of genes at this locus (five out of six) can impact hypertension by modifying BP and renal phenotypes. Mutations of Nppa, Plod1, and Mthfr increased disease susceptibility, whereas Agtrap and Clcn6 mutations decreased hypertension risk. Reanalysis of the human AGTRAP-PLOD1 locus also implied that disease-associated haplotype blocks with polygenic effects were not only possible, but rather were highly plausible. Combined, these data demonstrate for the first time that multiple modifiers of hypertension can cosegregate at a single GWAS locus. PMID:24006081

Flister, Michael J.; Tsaih, Shirng-Wern; O'Meara, Caitlin C.; Endres, Bradley; Hoffman, Matthew J.; Geurts, Aron M.; Dwinell, Melinda R.; Lazar, Jozef; Jacob, Howard J.; Moreno, Carol

2013-01-01

275

Gene polymorphisms in association with emerging cardiovascular risk markers in adult women  

PubMed Central

Background Evidence on the associations of emerging cardiovascular disease risk factors/markers with genes may help identify intermediate pathways of disease susceptibility in the general population. This population-based study is aimed to determine the presence of associations between a wide array of genetic variants and emerging cardiovascular risk markers among adult US women. Methods The current analysis was performed among the National Health and Nutrition Examination Survey (NHANES) III phase 2 samples of adult women aged 17 years and older (sample size n = 3409). Fourteen candidate genes within ADRB2, ADRB3, CAT, CRP, F2, F5, FGB, ITGB3, MTHFR, NOS3, PON1, PPARG, TLR4, and TNF were examined for associations with emerging cardiovascular risk markers such as serum C-reactive protein, homocysteine, uric acid, and plasma fibrinogen. Linear regression models were performed using SAS-callable SUDAAN 9.0. The covariates included age, race/ethnicity, education, menopausal status, female hormone use, aspirin use, and lifestyle factors. Results In covariate-adjusted models, serum C-reactive protein concentrations were significantly (P value controlling for false-discovery rate ? 0.05) associated with polymorphisms in CRP (rs3093058, rs1205), MTHFR (rs1801131), and ADRB3 (rs4994). Serum homocysteine levels were significantly associated with MTHFR (rs1801133). Conclusion The significant associations between certain gene variants with concentration variations in serum C-reactive protein and homocysteine among adult women need to be confirmed in further genetic association studies. PMID:20078877

2010-01-01

276

Association of MTHFR C677T and A1298C polymorphisms with non-Hodgkin lymphoma susceptibility: evidence from a meta-analysis.  

PubMed

Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism and DNA synthesis. A number of studies have examined the association of MTHFR C677T and A1298C polymorphisms with non-Hodgkin lymphoma (NHL) susceptibility; however, the conclusions were contradictory. We searched available publications assessing the polymorphisms of MTHFR and NHL susceptibility from MEDLINE, EMBASE and CBM. Genotype-based mRNA expression analysis was performed using data from 270 individuals with three different ethnicities. Ultimately, a total of 7448 cases and 11146 controls from 25 studies were included for the C677T polymorphism, 6173 cases and 9725 controls from 19 studies for the A1298C polymorphism. Pooled results indicated that neither C677T nor A1298C polymorphism was associated with NHL susceptibility. However, C677T polymorphism showed a statistically significantly increased risk for Caucasians, but a decreased risk for Asians in the subgroup analysis by ethnicity. The same variants may confer increased susceptibility to develop follicular lymphoma (FL). Moreover, A1298C polymorphism was associated with increased NHL risk for Asians. This meta-analysis indicated that C677T polymorphism was associated with altered NHL susceptibility for Caucasians, Asians and FL. Increased NHL risk was also shown for A1298C among Asians. These findings warrant validation in large and well-designed prospective studies. PMID:25146845

He, Jing; Liao, Xiao-Yu; Zhu, Jin-Hong; Xue, Wen-Qiong; Shen, Guo-Ping; Huang, Shao-Yi; Chen, Wei; Jia, Wei-Hua

2014-01-01

277

Association of the methylenetetrahydrofolate reductase gene A1298C polymorphism with stroke risk based on a meta-analysis.  

PubMed

Several independent studies have reported the role of the methylenetetrahydrofolate reductase gene (MTHFR) A1298C polymorphism in strokes, but the results are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed in the present study. In this meta-analysis, a total of 13 studies, including 1974 cases and 2660 controls, were selected to evaluate the possible association. Crude odds ratios (ORs) with 95% confidence intervals (CI) were used to assess the strength of the association in additive, dominant, and recessive models. The overall analysis showed that MTHFR A1298C was associated with a significant increase in the risk of stroke in the heterozygote comparison (AC vs AA: OR = 1.17; 95%CI = 1.03-1.34) and in the dominant model (AC/CC vs AA: OR = 1.22; 95%CI = 1.01-1.49). Stratified analysis showed a significantly strong association between the MTHFR A1298C polymorphism and stroke risk in Asian populations (OR = 1.32 for AC vs AA; OR = 1.94 for CC vs AA; OR = 1.37 for AC/CC vs AA; OR = 1.33 for C vs A allele), but not in Caucasian populations. Additionally, the MTHFR 1298C allele was found to be a risk factor for developing ischemic strokes. However, no statistically significant increased risk of hemorrhagic stroke was found in any of the genetic models. In conclusion, this meta-analysis supported that the MTHFR A1298C polymorphism could be capable of increasing stroke susceptibility in Asian, but not in Caucasian, populations. PMID:24391036

Lv, Q; Lu, J; Wu, W; Sun, H; Zhang, J

2013-01-01

278

Fluorescence resonance energy transfer-based real-time polymerase chain reaction method without DNA extraction for the genotyping of F5, F2, F12, MTHFR, and HFE  

PubMed Central

Blood samples are extensively used for the molecular diagnosis of many hematological diseases. The daily practice in a clinical laboratory of molecular diagnosis in hematology involves using a variety of techniques, based on the amplification of nucleic acids. Current methods for polymerase chain reaction (PCR) use purified genomic DNA, mostly isolated from total peripheral blood cells or white blood cells (WBC). In this paper we describe a real-time fluorescence resonance energy transfer-based method for genotyping directly from blood cells. Our strategy is based on an initial isolation of the WBCs, allowing the removal of PCR inhibitors, such as the heme group, present in the erythrocytes. Once the erythrocytes have been lysed, in the LightCycler® 2.0 Instrument, we perform a real-time PCR followed by a melting curve analysis for different genes (Factors 2, 5, 12, MTHFR, and HFE). After testing 34 samples comparing the real-time crossing point (CP) values between WBC (5×106 WBC/mL) and purified DNA (20 ng/?L), the results for F5 Leiden were as follows: CP mean value for WBC was 29.26±0.566 versus purified DNA 24.79±0.56. Thus, when PCR was performed from WBC (5×106 WBC/mL) instead of DNA (20 ng/?L), we observed a delay of about 4 cycles. These small differences in CP values were similar for all genes tested and did not significantly affect the subsequent analysis by melting curves. In both cases the fluorescence values were high enough, allowing a robust genotyping of all these genes without a previous DNA purification/extraction. PMID:25028568

Martinez-Serra, Jordi; Robles, Juan; Nicolàs, Antoni; Gutierrez, Antonio; Ros, Teresa; Amat, Juan Carlos; Alemany, Regina; Vögler, Oliver; Abelló, Aina; Noguera, Aina; Besalduch, Joan

2014-01-01

279

Methylenetetrahydrofolate reductase gene variants and antipsychotic-induced weight gain and metabolic disturbances.  

PubMed

Weight gain and metabolic disturbances represent serious side-effects in antipsychotic (AP) treatment, particularly with clozapine and olanzapine. The methylenetetrahydrofolate reductase (MTHFR) gene is a key determinant in the folate metabolism and previous studies reported a significant effect on AP-induced weight gain and related metabolic abnormalities. Thus, we investigated MTHFR gene variants and changes in several important metabolic parameters in AP-treated patients. In this study, two functional MTHFR polymorphisms, rs1801133 (C677T) and rs1801131 (A1298C), were investigated for changes in weight and metabolic parameters. Genotypic associations were evaluated in a large population (n = 347 including 66 first episode psychosis, FEP patients) treated mostly with clozapine and olanzapine. We did not detect any genotypic association with weight changes (p > 0.05) in our total sample and in the sample refined for ancestry and medication. In our allelic analyses, we observed a trend for the 677-C allele to be associated with weight gain in the total sample (p = 0.03). This effect appeared to be driven by the FEP patients where those carrying the C-allele gained, on average, twice as much weight. Exploratory analyses revealed a significant association between the C677T and the A1298C polymorphism with HDL cholesterol serum levels in patients (p = 0.031). Overall we did not detect a major effect of two functional MTHFR gene variants and AP-induced weight gain. However, our findings suggest an effect of the C677T polymorphism in FEP patients and changes in weight and cholesterol levels. Further investigations in a larger sample are required. PMID:24725652

Kao, A C C; Rojnic Kuzman, M; Tiwari, A K; Zivkovic, M V; Chowdhury, N I; Medved, V; Kekin, I; Zai, C C; Lieberman, J A; Meltzer, H Y; Bozina, T; Bozina, N; Kennedy, J L; Sertic, J; Müller, D J

2014-07-01

280

Maternal air pollution exposure induces fetal neuroinflammation and predisposes offspring to obesity in aduthood in a sex-specific manner  

EPA Science Inventory

Emerging evidence suggests environmental chemical exposures during critical windows of development may contribute to the escalating prevalence of obesity. We tested the hypothesis that prenatal air pollution exposure would predispose the offspring to weight gain in adulthood. Pre...

281

Severe Arterial Thrombophilia Associated With a Homozygous MTHFR Gene Mutation (A1298C) in a Young Man With Klinefelter Syndrome  

Microsoft Academic Search

Klinefelter syndrome (KS) is the most common sex chromosome disorder in men. It may be associated with an increased risk for venous thrombosis and thromboembolism, which is partially explained by hypofibrinolysis due to androgen deficiency. Additional genetic or acquired thrombophilic states have been shown in KS patients complicated with venous thrombosis as isolated case reports. Arterial thrombotic events had not

Mustafa Ozbek; M. Akif Öztürk; Kemal Ureten; Ozcan Ceneli; Mehmet Erdogan; Ibrahim C. Haznedaroglu

2008-01-01

282

Study on Salmonella Typhi occurrence in gallbladder of patients suffering from chronic cholelithiasis-a predisposing factor for carcinoma of gallbladder.  

PubMed

Cholelithiasis is frequently associated with carcinoma of gallbladder, and the presence of Salmonella Typhi in gallbladder of patients suffering from cholelithiasis is implicated as a predisposing factor for carcinogenesis. This study was conducted on patients suffering from chronic cholelithiasis from a region in North India-endemic area for enteric fever with high incidence of gallstones and gallbladder cancer. Since culture studies rarely reveal the chronic Salmonella Typhi persistence, we use PCR assay to specifically amplify the H1-d flagellin gene sequence homologous with Salmonella Typhi. Seven cases (17.5%), none of which were positive for culture, showed positive PCR results for Salmonella Typhi, 4 (10%) of which were tissue, 2 bile (5%), and 1 gallstone (2.5%). The chronic existence of Salmonella Typhi in gallbladder disease was confirmed. Thus, the study would indicate the importance of vaccination so as to prevent chronic infection and need for early diagnostic tools to prevent any further complications. PMID:23790418

Walawalkar, Yogesh D; Gaind, Rajni; Nayak, Vijayashree

2013-09-01

283

Factors predisposing to adjacent 2 and 3:1 disjunctions: study of 161 human reciprocal translocations.  

PubMed Central

Reciprocal translocations produce imbalances by three types of disjunction which are, in decreasing frequency, adjacent 1, 3:1, and adjacent 2. Adjacent 1 disjunction produces duplication deficiencies of inverse topography to those of adjacent 2. The imbalanced chromosome segments in one of these types are balanced in the other. The disjunction 3:1 produces pure trisomies and monosomies. The following situations predispose to adjacent 2 disjunction: translocations between the long arms of two acrocentric chromosomes or between one of these and that of a No 9 chromosome; centric segments, either short or carrying a heterochromatic zone (9qh); a balanced translocation in the mother. The factors predisposing to the disjunction adjacent 2 operate by selection, or directly on the meiotic configuration. Some of them (shortness of the interstitial segment, shortness of the short arms of translocation chromosomes) act in both these ways. Their influence is probably responsible for the repetitive and exclusive character of this disjunction. The conditions for the occurrence of the 3:1 disjunctions seem less strict than those for adjacent 2, although they should be of the same nature (involvement of acrocentrics or a chromosome 9 in the translocation, maternal origin). Images PMID:395305

Jalbert, P; Sele, B

1979-01-01

284

Primary otomycosis in the Indian subcontinent: predisposing factors, microbiology, and classification.  

PubMed

Objective. To define otomycosis and determine the predisposing factors and microbiology in primary otomycosis. Study Design. Prospective study of two years and review of the literature. Setting. Academic Department of Otolaryngology in a coastal city in India. Patients. 150 immunocompetent individuals of whom 100 consecutive patients with a clinical diagnosis of otomycosis are considered as the study group and 50 consecutive patients with no otomycosis are considered as the control group. Results and Observations. Instillation of coconut oil (42%), use of topical antibiotic eardrops (20%), and compulsive cleaning of external ear with hard objects (32%) appeared to be the main predisposing factors in otomycosis. Aspergilli were the most common isolates (80%) followed by Penicillium (8%), Candida albicans (4%), Rhizopus (1%), and Chrysosporium (1%), the last being reported for the first time in otomycosis. Among aspergilli, A. niger complex (38%) was the most common followed by A. fumigatus complex (27%) and A. flavus complex (15%). Bacterial isolates associated with fungi in otomycosis were S. aureus, P. aeruginosa, and Proteus spp. In 42% of healthy external ears fungi were isolated. Conclusion. Aspergillus spp. were the most common fungi isolated, followed by Penicillium. Otomycotic ears are often associated with bacterial isolates when compared to normal ears. Fungi are also present in a significant number of healthy external auditory canals and their profiles match those in cases of otomycosis. The use of terms "primary" and "secondary" otomycosis is important to standardize reporting. PMID:24949016

Prasad, Sampath Chandra; Kotigadde, Subbannayya; Shekhar, Manisha; Thada, Nikhil Dinaker; Prabhu, Prashanth; D' Souza, Tina; Prasad, Kishore Chandra

2014-01-01

285

Primary Otomycosis in the Indian Subcontinent: Predisposing Factors, Microbiology, and Classification  

PubMed Central

Objective. To define otomycosis and determine the predisposing factors and microbiology in primary otomycosis. Study Design. Prospective study of two years and review of the literature. Setting. Academic Department of Otolaryngology in a coastal city in India. Patients. 150 immunocompetent individuals of whom 100 consecutive patients with a clinical diagnosis of otomycosis are considered as the study group and 50 consecutive patients with no otomycosis are considered as the control group. Results and Observations. Instillation of coconut oil (42%), use of topical antibiotic eardrops (20%), and compulsive cleaning of external ear with hard objects (32%) appeared to be the main predisposing factors in otomycosis. Aspergilli were the most common isolates (80%) followed by Penicillium (8%), Candida albicans (4%), Rhizopus (1%), and Chrysosporium (1%), the last being reported for the first time in otomycosis. Among aspergilli, A. niger complex (38%) was the most common followed by A. fumigatus complex (27%) and A. flavus complex (15%). Bacterial isolates associated with fungi in otomycosis were S. aureus, P. aeruginosa, and Proteus spp. In 42% of healthy external ears fungi were isolated. Conclusion. Aspergillus spp. were the most common fungi isolated, followed by Penicillium. Otomycotic ears are often associated with bacterial isolates when compared to normal ears. Fungi are also present in a significant number of healthy external auditory canals and their profiles match those in cases of otomycosis. The use of terms “primary” and “secondary” otomycosis is important to standardize reporting. PMID:24949016

Kotigadde, Subbannayya; Shekhar, Manisha; Thada, Nikhil Dinaker; Prabhu, Prashanth; D' Souza, Tina; Prasad, Kishore Chandra

2014-01-01

286

In utero exposure to benzo(a)pyrene predisposes offspring to cardiovascular dysfunction in later-life  

PubMed Central

In utero exposure of the fetus to benzo(a)pyrene [B(a)P], a polycyclic aromatic hydrocarbon, is thought to dysregulate cardiovascular development. To investigate the effects of in utero B(a)P exposure on cardiovascular development, timed-pregnant Long Evans Hooded (LEH) rats were exposed to diluent or B(a)P (150, 300, 600 and 1200 ?g/kg/BW) by oral gavage on embryonic (E) days E14 (the metamorphosing embryo stage) through E17 (the 1st fetal stage). There were no significant effects of in utero exposure to B(a)P on the number of pups born per litter or in pre-weaning growth curves. Pre-weaning profiles for B(a)P metabolite generation from cardiovascular tissue were shown to be dose-dependent and elimination of these metabolites was shown to be time-dependent in exposed offspring. Systolic blood pressure on postnatal day P53 in the middle and high exposure groups of offspring were significantly elevated as compared to controls. Microarray and quantitative real-time PCR results were directly relevant to a biological process pathway in animal models for “regulation of blood pressure”. Microarray and quantitative real-time PCR analysis revealed upregulation of mRNA expression for angiotensin (AngII), angiotensinogen (AGT) and endothelial nitric oxide synthase (eNOS) in exposed offspring. Biological network analysis and gene set enrichment analysis subsequently identified potential signaling mechanisms and molecular pathways that might explain the elevated systolic blood pressures observed in B(a)P-exposed offspring. Our findings suggest that in utero exposure to B(a)P predispose offspring to functional deficits in cardiovascular development that may contribute to cardiovascular dysfunction in later life. PMID:22374506

G.E., Jules; Pratap, S.; Ramesh, A.; Hood, D.B.

2013-01-01

287

Gene Variants in the Folate-mediated One-carbon Metabolism (FOCM) Pathway as Risk Factors for Conotruncal Heart Defects  

PubMed Central

We evaluated 35 variants among four folate-mediated one-carbon metabolism pathway genes, MTHFD1, SHMT1, MTHFR, and DHFR as risk factors for conotruncal heart defects. Cases with a diagnosis of single gene disorders or chromosomal aneusomies were excluded. Controls were randomly selected from area hospitals in proportion to their contribution to the total population of live-born infants. Odds Ratios (OR) and the 95% confidence intervals were computed for each genotype (homozygous variant or heterozygote, versus homozygous wildtype) and for increase of each less common allele (log-additive model). Interactions between each variant and three folate intake variables (maternal multivitamin use, maternal dietary folate intake, and combined maternal folate intake) were also evaluated under the log-additive model. In general, we did not identify notable associations. The A allele of MTHFD1 rs11627387 was associated with a 1.7-fold increase in conotruncal defects risk in both Hispanic mothers (OR=1.7, 95% CI=1.1?2.5) and Hispanic infants (OR=1.7, 95% CI=1.2?2.3). The T allele of MTHFR rs1801133 was associated with a 2.8-fold increase of risk among Hispanic women whose dietary folate intake was ? 25th centile. The C allele of MTHFR rs1801131 was associated with a two-fold increase of risk (OR=2.0, 95%CI=1.0?3.9) only among those whose dietary folate intake was >25th centile. Our study suggested that MTHFD1 rs11627387 may be associated with risk of conotruncal defects through both maternal and offspring genotype effect among the Hispanics. Maternal functional variants in MTHFR gene may interact with dietary folate intake and modify the conotruncal defects risk in the offspring. PMID:22495907

Zhu, Huiping; Yang, Wei; Lu, Wei; Etheredge, Analee; Lammer, Edward J; Finnell, Richard; Carmichael, Suzan L.; Shaw, Gary

2012-01-01

288

Maternal dietary intake of folate, vitamin B12 and MTHFR 677C>T genotype: their impact on newborn's anthropometric parameters.  

PubMed

In this study, we evaluated the effects of dietary intake of vitamin B12 and folate during pregnancy and their interactions with maternal polymorphism of MTHFR (677C>T; 1298A>C) on intrauterine development. Anthropometric parameters were obtained from 231 newborns that belong to a prospective birth cohort in Morelos, Mexico. Maternal dietary intake of vitamin B12 and folate was assessed using a semi-quantitative questionnaire administered during the first and third trimesters of the pregnancy. Maternal MTHFR 677C>T and 1298 A>C genotypes were determined by PCR-RFLP. The associations between deficient dietary intake of vitamin B12 (<2.0 ?g/d) and folate (<400 ?g/d) in the first and third trimesters and maternal polymorphisms of MTHFR on anthropometric parameters at birth were estimated using a multivariate linear regression model. During pregnancy, the deficient dietary intake was roughly 60 % for folate and 19 % for vitamin B12. Allelic frequencies of 677T and 1298C were 59 and 10 %, respectively. After adjusting for confounders, deficiency in maternal dietary intake of vitamin B12 (<2.0 ?g/d) was associated with a significant reduction in length (? ~ -2.4; 95 % CI -4.3; -0.6) and length-for-age at birth (? ~ -1.2; 95 % CI -2.3; -0.1) among infants whose mothers were carriers of the 677TT genotype (p for interaction = 0.02). In contrast, no association was observed between deficiency in maternal dietary intake of folate (<400 ?g/d) and any anthropometric parameter of newborns. These results suggest that supplementation with vitamin B12 during pregnancy could have a favorable impact on intrauterine fetal development mainly in populations that are genetically susceptible. PMID:25173112

Torres-Sánchez, Luisa; López-Carrillo, Lizbeth; Blanco-Muñoz, Julia; Chen, Jia

2014-09-01

289

Effect of lifestyle factors on plasma total homocysteine concentrations in relation to MTHFR(C677T) genotype. Inter99 (7)  

Microsoft Academic Search

Objective: To examine the associations between various lifestyle factors—smoking habits, physical activity, dietary habits, coffee, tea, and alcohol consumption—and homocysteine (tHcy) in relation to MTHFR(C677T) genotype.Design: Cross-sectional population-based study.Setting: Residents of Copenhagen County, Denmark.Subjects: A random sample of 6457 men and women aged 30–60 years drawn from the Civil Registration System and invited to a health examination in 1999–2001. A

L L N Husemoen; T F Thomsen; M Fenger; T Jørgensen; LLN Husemoen

2004-01-01

290

Different roles of MTHFR C677T and A1298C polymorphisms in colorectal adenoma and colorectal cancer: a meta-analysis  

Microsoft Academic Search

Association studies on the MTHFR polymorphisms (C677T and A1298C) in colorectal cancer (CRC) and colorectal adenoma have shown conflicting results. We performed\\u000a a meta-analysis to better assess the purported associations. Overall, the 677T allele (10,131 patients and 15,362 controls)\\u000a showed a small but significant protective effect against CRC compared to the 677C allele [P=0.0003, odds ratio (OR)=0.93; 95% confidence interval

Yan Huang; Shizhong Han; Yao Li; Yumin Mao; Yi Xie

2007-01-01

291

Methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms, plasma homocysteine, folate, and vitamin B 12 levels and the extent of coronary artery disease  

Microsoft Academic Search

The question of whether mild hyperhomocysteinemia is a risk factor for coronary artery disease (CAD) has long been debated and is still unclear. We investigated whether there is a link between methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms or plasma homocysteine and CAD. This is a case-control study that included 2,121 consecutive patients (cases) with angiographically proved CAD and

Klaus Kölling; Gjin Ndrepepa; Werner Koch; Siegmund Braun; Julinda Mehilli; Albert Schömig; Adnan Kastrati

2004-01-01

292

Exploring the Effects of Methylenetetrahydrofolate Reductase Gene Variants C677T and A1298C on the Risk of Orofacial Clefts in 261 Norwegian Case-Parent Triads  

Microsoft Academic Search

Folic acid and the methylenetetrahydrofolate reductase (MTHFR) gene have both been implicated in the etiology of orofacial clefts. The authors selected 261 case-parent triads (173 cases with cleft lip with or without cleft palate (CL\\/P) and 88 cases with cleft palate only (CPO)) from a Norwegian population-based study of orofacial clefts (May 1996-1998). A case-parent triad design was used to

Astanand Jugessur; Allen J. Wilcox; Rolv T. Lie; Jeffrey C. Murray; Jack A. Taylor

2003-01-01

293

The epidemiology of bovine respiratory disease: What is the evidence for predisposing factors?  

PubMed Central

Bovine respiratory disease (BRD) is the most costly disease of beef cattle in North America. It is multi-factorial, with a variety of physical and physiological stressors combining to predispose cattle to pneumonia. However, efforts to discern which factors are most important have frequently failed to establish definitive answers. Calves are at highest risk shortly after transport. Risk factors include purchasing from sale barns and commingling. It is unclear whether or not these practices increase susceptibility, increase exposure, or are proxies for poor management. Lighter-weight calves appear to be at greater risk, although this has not been consistent. Persistent infection (PI) with bovine virus diarrhea virus increases BRD occurrence, but it is unclear if PI calves affect other cattle in the feedlot. The complexity of BRD has made it difficult to define involvement of individual factors. Stressors may play a role as “necessary but not sufficient” components, requiring additive effects to cause disease. PMID:21197200

Taylor, Jared D.; Fulton, Robert W.; Lehenbauer, Terry W.; Step, Douglas L.; Confer, Anthony W.

2010-01-01

294

Interactions among bone, liver, and adipose tissue predisposing to diabesity and fatty liver.  

PubMed

Growing epidemiological evidence connects obesity and its complications, including metabolic syndrome, diabetes, and nonalcoholic fatty liver disease (NAFLD) to reduced bone health and osteoporosis. Parallel to human studies, experimental data disclosed a complex network of interaction among adipose tissue, the liver, and the bone, which reciprocally modulate the function of each other. The main mediators of such crosstalk include hormonal/cytokine signals from the bone (osteopontin, osteocalcin, and osteoprotegerin), the liver (fetuin-A), and adipose tissue [leptin, tumor necrosis factor-? (TNF-?), and adiponectin]. Dysregulation of this network promotes the development of diabesity, NAFLD, and osteoporosis. We will review recent advances in understanding the mechanisms of bone-liver-adipose tissue interaction predisposing to obesity, diabetes, NAFLD, and osteoporosis and their potential clinical implications. PMID:23816817

Musso, Giovanni; Paschetta, Elena; Gambino, Roberto; Cassader, Maurizio; Molinaro, Federica

2013-09-01

295

Comparison of lesions predisposing to rhegmatogenous retinal detachment by race of subjects.  

PubMed

Because rhegmatogenous retinal detachments are thought to be much less common in blacks than in whites, we compared the incidence of various lesions known to cause or predispose to this condition (synchysis senilis, posterior vitreous detachment, breaks, tears, and holes of the peripheral fundus, and lattice degeneration of the retina) in a series of postmortem eyes on the basis of race. Our statistical analysis also included trauma, myopia, and chorioretinitis. The series included 322 black subjects and 2,012 white subjects. The subjects ranged in age from 20 to 93 years at the time of death. Although the initial data showed a racial difference in the incidence of synchysis senilis of grade 3 (50% destruction) or higher and posterior vitreous detachment (P = .033 and P = .021, respectively), we found no difference when the data were age-corrected. PMID:6638131

Foos, R Y; Simons, K B; Wheeler, N C

1983-11-01

296

Hearing impairment risk and interaction of folate metabolism related gene polymorphisms in an aging study  

PubMed Central

Background Recent investigations demonstrated many genetic contributions to the development of human age-related hearing impairment (ARHI), however, reports of factors associated with a reduction in the ARHI risk are rare. Folate metabolism is essential for cellular functioning. Despite the extensive investigations regarding the roles of folate metabolism related gene polymorphisms in the pathophysiology of complex diseases, such as cancer, cardio-cerebrovascular disease, and atherosclerosis, little is known about the association with ARHI. The aim of this study is to investigate the effects of the methionine synthase (MTR) A2756G and methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphisms on the risk of hearing impairment in middle-aged and elderly Japanese. Methods Data were collected from community-dwelling Japanese adults aged 40-84 years who participated in the Longitudinal Study of Aging biennially between 1997 and 2008. We analyzed cumulative data (5,167 samples in accumulated total) using generalized estimating equations. Results The MTHFR 677T allele was significantly associated with a reduced risk of hearing impairment only when the subjects were wild-type homozygotes for MTR A2756G. The per-T allele odds ratio of MTHFR for the risk of developing hearing impairment was 0.7609 (95% CI: 0.6178-0.9372) in the MTR AA genotype. In addition, a subgroup analysis demonstrated that the favorable effect of the MTHFR 677T allele on the risk of developing hearing impairment was independent of folate and homocysteine level, whereas plasma total homocysteine level was independently associated with an increased risk of developing hearing impairment. The interactive effect of gene polymorphisms associated with folate metabolism may modify the risk of developing hearing impairment after middle age. These results contribute to the elucidation of the causes of ARHI. Conclusions The present study has found that the MTHFR 677T allele has a favorable effect on a risk of hearing impairment in the middle-aged and elderly population, only when the individuals were wild-type homozygotes for MTR A2756G. PMID:21385350

2011-01-01

297

Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia.  

PubMed

Polymorphisms in folate pathway genes may influence the susceptibility to acute lymphoblastic leukemia (ALL). DNA was isolated from 245 pediatric ALL patients (cases) and from 500 blood bank donors (controls). Polymorphisms in methylene-tetrahydrofolate reductase (MTHFR 677C>T, 1298A>C), methionine synthase (MTR 2756A>G), methionine synthase reductase (MTRR 66A>G), methylenetetrahydrofolate dehydrogenase (MTHFD1 1958G>A), nicotinamide N-methyltransferase (NNMT IVS -151C>T), serine hydroxymethyl transferase (SHMT1 1420C>T), thymidylate synthase (TS 2R3R), and the reduced folate carrier (RFC1 80G>A) were detected. In ALL patients, an increased occurrence was observed of the RFC1 80AA variant (odds ratio [OR] = 2.1; 95% confidence interval [CI] = 1.3-3.2; P = .002) and the RFC1 80A allele (OR = 1.5; 95% CI, 1.1-2.1; P = .02). Likewise, the NNMT IVS -151TT genotype showed a 2.2-fold increased ALL risk (OR = 2.2; 95% CI, 1.1-4.6; P = .04). A 1.4-fold reduction in ALL risk was observed for (heterozygous or homozygous) carriers of the TS 2R allele and the MTHFR 677T allele (OR = 0.7; 95% CI, 0.5-1.0; P < .05). Furthermore, interactions between NNMT and MTHFR 677C>T and RFC1 were observed. NNMT IVS -151CC/MTHFR 677CT + TT patients exhibited a 2-fold reduction in ALL risk whereas RFC1 80AA/NNMT IVS -151CT + TT subjects had a 4.2-fold increase in ALL risk (P = .001). For the first time, we associate the RFC1 80G>A and NNMT IVS -151C>T variants to an increased ALL susceptibility. PMID:19020309

de Jonge, Robert; Tissing, Wim J E; Hooijberg, Jan Hendrik; Jansen, Gerrit; Kaspers, Gertjan J L; Lindemans, Jan; Peters, Godefridus J; Pieters, Rob

2009-03-01

298

Congenital anomaly of the inferior vena cava and factor V Leiden mutation predisposing to deep vein thrombosis  

PubMed Central

A previously healthy 21-year-old man presented with back pain, bilateral extremity pain, and right lower extremity weakness, paresthesias, and swelling. Sonographic examination revealed diffuse deep vein thrombosis (DVT) in the femoral and popliteal venous system. CT imaging revealed hypoplasia of the hepatic inferior vena cava (IVC) segment with formation of multiple varices and collateral veins around the kidneys. Hematologic workup also discovered a factor V Leiden mutation, further predisposing the patient to DVT. The rare, often overlooked occurrence of attenuated IVC, especially in the setting of hypercoagulable state, can predispose patients to significant thrombosis.

Lamparello, Brooke M; Erickson, Cameron R; Kulthia, Arun; Virparia, Vasudev; Thet, Zeyar

2014-01-01

299

Evidence for homosexuality gene  

SciTech Connect

A genetic analysis of 40 pairs of homosexual brothers has uncovered a region on the X chromosome that appears to contain a gene or genes for homosexuality. When analyzing the pedigrees of homosexual males, the researcheres found evidence that the trait has a higher likelihood of being passed through maternal genes. This led them to search the X chromosome for genes predisposing to homosexuality. The researchers examined the X chromosomes of pairs of homosexual brothers for regions of DNA that most or all had in common. Of the 40 sets of brothers, 33 shared a set of five markers in the q28 region of the long arm of the X chromosome. The linkage has a LOD score of 4.0, which translates into a 99.5% certainty that there is a gene or genes in this area that predispose males to homosexuality. The chief researcher warns, however, that this one site cannot explain all instances of homosexuality, since there were some cases where the trait seemed to be passed paternally. And even among those brothers where there was no evidence that the trait was passed paternally, seven sets of brothers did not share the Xq28 markers. It seems likely that homosexuality arises from a variety of causes.

Pool, R.

1993-07-16

300

Folate-metabolizing gene variants and pregnancy outcome of IVF.  

PubMed

There is growing evidence that folate status and variation in folate-metabolizing genes are involved in female reproductive functions. This study evaluated the influence of maternal blood folate, vitamin B(12), homocysteine and 10 folate pathway gene variants on IVF outcome. Also, the prevalence of these polymorphisms was compared in 439 female IVF patients and 225 fertile controls. MTHFR 677 CT heterozygotes had a higher proportion of good-quality embryos and an increased chance of pregnancy. MTHFR 1793 GA heterozygosity was associated with a lower percentage of previously failed IVF treatments. Heterozygosity for FOLR1 1816 C/delC and 1841 G/A was associated with a raised risk of pregnancy loss. The CTH 1208 GT genotype was associated with an increased chance of pregnancy and a smaller number of previously failed IVF cycles and the genotype frequency was lower in IVF patients with three or more previously failed IVF treatments compared with fertile controls. SLC19A1 80 GA heterozygotes had a decreased number of previously failed IVF treatments and were more prevalent among fertile controls. In conclusion, polymorphisms in folate-metabolizing genes may affect ovarian stimulation and pregnancy outcome of IVF, and heterozygous individuals, rather than the wild-type homozygotes, appeared to have more favourable outcomes. PMID:21507721

Laanpere, M; Altmäe, S; Kaart, T; Stavreus-Evers, A; Nilsson, T K; Salumets, A

2011-06-01

301

Are effects of MTHFR (C677T) genotype on BMD confined to women with low folate and riboflavin intake? Analysis of food records from the Danish osteoporosis prevention study  

Microsoft Academic Search

We have previously found BMD and fracture risk to be significantly associated with the MTHFR (C677T) polymorphism in healthy postmenopausal women in the first years after menopause. Since then, other cohort studies have suggested that sufficient intake of riboflavin and\\/or folate may have the potential to prevent development of low BMD in women with the TT genotype. This could to

Bo Abrahamsen; Jonna Skov Madsen; Charlotte Landbo Tofteng; Lis Stilgren; Else Marie Bladbjerg; Søren Risom Kristensen; Kim Brixen; Leif Mosekilde

2005-01-01

302

Bacterial blight (Pseudomonas pisi Sackett) of peas in South Africa, with special reference to frost as a predisposing factor  

Microsoft Academic Search

In the beginning of the nineteen fifties bacterial blight caused much damage to pea crops in South Africa, particularly to those grown for seed production. A study has been made of the causal organism and the conditioning factors of the disease, special attention being paid to frost as a predisposing factor.The symptoms of the disease vary according to weather conditions

B. H. Boelema

1972-01-01

303

Predisposing factors for renal scarring in children with urinary tract infection.  

PubMed

This study was undertaken to determine the predisposing factors for renal scarring in children with urinary tract infection. In this prospective cohort study, 176 children with documented urinary tract infection were categorized into four groups: ?1 year old, 1-2 years old, 2-7 years and 7-14 years old. Ultrasonography and Technetium-99 m-DMSA scan were used to detect the possible abnormalities. Infants under 12 months old presented as the most common group for renal scarring (27 cases, 52.9%), and vesicoureteral reflux (VUR) was diagnosed in 29 cases (56.8%). Fifteen (41.67%) children between the ages of one and two years had renal scar, and VUR was detected in half of the patients. In the third group, 36.3%, and in fourth group, 41.6% of the patients had renal scar. Also, 38.6% in group three and 50% in the final group had VUR. A co-incidental finding that was observed in this study was the high incidence of pseudohypoaldesteronism (PHA) in our patients: in 39.2% of the children in group one, 22.2% in group two and 4% in group three. In group four however, none of the patients had PHA. Risk of scar formation with urinary tract infection (UTI) was higher in the younger age group and in those with recurrent UTIs. PMID:22569440

Beiraghdar, Fatemeh; Panahi, Yunes; Einollahi, Behzad; Moharamzad, Yashar; Nemati, Eghlim; Amirsalari, Susan

2012-05-01

304

Putting the brakes on mammary tumorigenesis: Loss of STAT1 predisposes to intraepithelial neoplasias  

PubMed Central

Multiparous Stat1?/? mice spontaneously develop mammary tumors with increased incidence: at an average age of 12 months, 55% of the animals suffer from mammary cancer, although the histopathology is heterogeneous. We consistently observed mosaic expression or down-regulation of STAT1 protein in wild-type mammary cancer evolving in the control group. Transplantation experiments show that tumorigenesis in Stat1?/? mice is partially influenced by impaired CTL mediated tumor surveillance. Additionally, STAT1 exerts an intrinsic tumor suppressing role by controlling and blocking proliferation of the mammary epithelium. Loss of STAT1 in epithelial cells enhances cell growth in both transformed and primary cells. The increased proliferative capacity leads to the loss of structured acini formation in 3D-cultures. Analogous effects were observed when Irf1?/? epithelial cells were used. Accordingly, the rate of mammary intraepithelial neoplasias (MINs) is increased in Stat1?/? animals: MINs represent the first step towards mammary tumors. The experiments characterize STAT1/IRF1 as a key growth inhibitory and tumor suppressive signaling pathway that prevents mammary cancer formation by maintaining growth control. Furthermore, they define the loss of STAT1 as a predisposing event via enhanced MIN formation. PMID:22185785

Schneckenleithner, Christine; Bago-Horvath, Zsuzsanna; Dolznig, Helmut; Neugebauer, Nina; Kollmann, Karoline; Kolbe, Thomas; Decker, Thomas; Kerjaschki, Dontscho; Wagner, Kay-Uwe; Muller, Mathias; Stoiber, Dagmar; Sexl, Veronika

2011-01-01

305

Exacerbated Mechanical Hyperalgesia in Rats with Genetically Predisposed Depressive Behavior: Role of Melatonin and NMDA Receptors  

PubMed Central

A connection between pain and depression has long been recognized in the clinical setting; however, its mechanism remains unclear. In this study, we showed that mechanical hyperalgesia induced by unilateral temporomandibular joint (TMJ) inflammation was exacerbated in Wistar-Kyoto (WKY) rats with genetically predisposed depressive behavior. Reciprocally, TMJ inflammation enhanced depressive behavior such that a lower nociceptive threshold correlated with a higher score of depressive behavior in the same WKY rats. As compared with Wistar rats, WKY rats exhibited a lower plasma melatonin level, downregulation of the melatonin MT1 receptor, but upregulation of the NR1 subunit of the NMDA receptor in the ipsilateral trigeminal subnucleus caudalis (Sp5C). Intracisternal administration of 6-chloromelatonin (250?g, twice daily × 7 days) concurrently attenuated mechanical hyperalgesia and depressive behavior in WKY rats as well as downregulated the NR1 expression in the ipsilateral Sp5C. In patch-clamp recordings, melatonin dose-dependently decreased NMDA-induced currents in spinal cord dorsal horn substantia gelatinosa neurons. These results demonstrate a reciprocal relationship between TMJ inflammation-induced mechanical hyperalgesia and depressive behavior and suggest that the central melatoninergic system, through modulation of the NMDA receptor expression and activity, may play a role in the mechanisms of the comorbidity between pain and depression. PMID:23046768

Wang, Shuxing; Tian, Yinghong; Song, Li; Lim, Grewo; Tan, Yonghui; You, Zerong; Chen, Lucy; Mao, Jianren

2012-01-01

306

Helminth infections predispose mice to pneumococcal pneumonia but not to other pneumonic pathogens.  

PubMed

Pneumonia is the leading killer of children worldwide. Here, we report that helminth-infected mice develop fatal pneumonia when challenged with Streptococcus pneumoniae. Mice were chronically infected with either the flatworm Taenia crassiceps or the roundworm Heligmosomoides polygyrus. Upon challenge with a pneumonic type 3 strain of S. pneumoniae (A66.1), the worm-infected mice developed pneumonia at a rate and to a degree higher than age-matched control mice as measured by bioluminescent imaging and lung titers. This predisposition to pneumonia appears to be specific to S. pneumoniae, as worm-infected mice did not show evidence of increased morbidity when challenged with a lethal dose of influenza virus or sublethal doses of Staphylococcus aureus or Listeria monocytogenes. The defect was also present when worm-infected mice were challenged with a type 2 sepsis-causing strain (D39); an increased rate of pneumonia, decreased survival, and increased lung and blood titers were found. Pneumococcal colonization and immunity against acute otitis media were unaffected. Anti-helminthic treatment in the H. polygyrus model reversed this susceptibility. We conclude that helminth coinfection predisposes mice to fatal pneumococcal pneumonia by promoting increased outgrowth of bacteria in the lungs and blood. These data have broad implications for the prevention and treatment for pneumonia in the developing world, where helminth infections are endemic and pneumococcal pneumonia is common. PMID:24952091

Apiwattanakul, Nopporn; Thomas, Paul G; Kuhn, Raymond E; Herbert, De'Broski R; McCullers, Jonathan A

2014-10-01

307

Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress.  

PubMed

Intestinal dysfunction is related to stress and early life events, but the mechanisms are largely unknown. Our aim was to determine whether early trauma predisposes adult rats to intestinal mucosal dysfunction in response to stress. Neonatal Sprague-Dawley rats were individually separated from their mothers for 3 h/day at 4-21 days of age. Between days 80 and 90, separated and control rats were subjected to mild acute stress (30-min water avoidance) or sham stress. Mucosal barrier function and ion transport were assessed in colonic tissues mounted in Ussing chambers. Mild stress increased short-circuit current, conductance, and transepithelial transport of macromolecules in separated rats, while having minimal effects in controls. Pretreatment of the separated rats with a corticotropin-releasing hormone (CRH) antagonist, the peptide alpha-helical CRH(9-41) injected intraperitoneally 20 min before stress, abolished the stress-induced mucosal changes. Our results indicate that neonatal trauma can induce phenotypic changes in adulthood, including enhanced vulnerability of the gut mucosa to stress via mechanisms involving peripherally located CRH receptors. PMID:12388189

Söderholm, Johan D; Yates, Derrick A; Gareau, Mélanie G; Yang, Ping-Chang; MacQueen, Glenda; Perdue, Mary H

2002-12-01

308

Perceptions of predisposing and protective factors for perinatal depression in same-sex parents.  

PubMed

Increasing numbers of women are choosing to have children in the context of same-sex relationships or as "out" lesbian or bisexual individuals. This study used qualitative methods to assess perceived predisposing and protective factors for perinatal depression in lesbian, gay, bisexual, and queer (LGBQ) women. Two focus groups with LGBQ women were conducted: 1) biological parents of young children and 2) nonbiological parents of young children or whose partners were currently pregnant. Three major themes emerged. Issues related to social support were primary, particularly related to disappointment with the lack of support provided by members of the family of origin. Participants also described issues related to the couple relationship, such as challenges in negotiating parenting roles. Finally, legal and policy barriers (e.g., second parent adoption) were identified as a significant source of stress during the transition to parenthood. Both lack of social support and relationship problems have previously been identified as risk factors for perinatal depression in heterosexual women, and legal and policy barriers may represent a unique risk factor for this population. Therefore, additional study of perinatal mental health among LGBQ women is warranted. PMID:16260356

Ross, Lori E; Steele, Leah; Sapiro, Beth

2005-01-01

309

Caloric restriction followed by high fat feeding predisposes to oxidative stress in skeletal muscle mitochondria.  

PubMed

The purpose of the present study was to assess the impact of previous period of caloric restriction on energy balance and skeletal muscle mitochondrial energetics in response to high-fat (HF) diet. To this end, 1 group of rats was subjected to 2 weeks of caloric restriction with nonpurified diet and then fed HF diet (430?kJ metabolizable energy/day) for 1 week, while the second group was fed ad libitum with nonpurified diet for 2 weeks and then fed HF diet (430?kJ metabolizable energy/day) for 1 week. Body composition, energy balance, and glucose homeostasis were measured. Mitochondrial mass, oxidative capacity and efficiency, parameters of oxidative stress, and antioxidant defense were evaluated in subsarcolemmal and intermyofibrillar mitochondria from skeletal muscle. Body energy and lipid content, plasma insulin, and metabolic efficiency were significantly higher, while energy expenditure significantly decreased, in food-restricted rats fed HF diet compared to controls. Mitochondrial efficiency and oxidative damage in skeletal muscle were significantly increased, while antioxidant defence was significantly lower in food-restricted rats fed HF diet, compared with controls. Finally, food-restricted rats fed HF diet exhibited significant reduction in subsarcolemmal mitochondrial mass. In conclusion, caloric restriction elicits higher mitochondrial efficiency and predisposes skeletal muscle to high fat-induced oxidative damage, which in turn could lead to impaired glucose homeostasis in food-restricted rats fed HF diet. PMID:23918688

Crescenzo, R; Bianco, F; Coppola, P; Mazzoli, A; Liverini, G; Iossa, S

2013-11-01

310

C677T and A1298C Polymorphisms of the Methylenetetrahydrofolate Reductase Gene: Incidence and Effect of Combined Genotypes on Plasma Fasting and Post-Methionine Load Homocysteine in Vascular Disease  

Microsoft Academic Search

Background: Moderately increased plasma concentra- tions of total homocysteine (tHcy) have been shown to be an important risk factor for vascular diseases. Two common polymorphisms of the methylenetetrahydro- folate reductase (MTHFR) gene, the thermolabile C677T and a more recently reported A1298C polymorphism, may contribute to hyperhomocysteinemia. Methods: Using PCR and restriction fragment length polymorphism analysis, we studied the prevalence of

Naomi Q. Hanson; Omer Aras; Feng Yang; Michael Y. Tsai

311

Combination of Thrombophilic Gene Polymorphisms as a Cause of Increased the Risk of Recurrent Pregnancy Loss  

PubMed Central

Background Recurrent pregnancy loss is (RPL) a heterogeneous condition. While the role of acquired thrombophilia has been accepted as an etiology for RPL, the contribution of specific inherited thrombophilic gene polymorphisms to the disorder has been remained controversial. Methods One hundred women with a history of two or more consecutive abortions and 100 women with at least two live births and no miscarriages were included in the study and evaluated for the presence of 11 thrombophilic gene polymorphisms (Factor V LEIDEN, Factor V 4070 A/G, Factor V 5279 A/G, Factor XIII 103 G/T, Factor XIII 614 A/T, Factor XIII 1694 C/T, PAI-1 -675 4G/5G, ITGB3 1565 T/C, ?-Fibrinogen -455G/A, MTHFR 677 C/T, MTHFR 1298 A/C) using PCR-RFLP technique. The data were statistically analyzed using Mann-Whitney test and logistic regression model. Results There was no relation between factor XIII 103G/T gene polymorphism with increased risk of RPL. However, the other 10 gene polymorphisms were found to be associated with increased/decreased risk of RPL. Multiple logistic regression model for analyzing the simultaneous effects of these polymorphisms on the risk of RPL showed that six of these 11 polymorphisms (Factor V 1691G/A, Factor V 5279A/G, Factor XIII 614A/T, ?-Fibrinogen -455G/A, ITGB3 1565T/C, and MTHFR 1298A/ C) were associated with RPL. Conclusion It is possible to calculate the risk of abortion in a patient with RPL by determining only six of the 10 polymorphisms that are individually associated with RPL. PMID:23926530

Torabi, Raheleh; Zarei, Saeed; Zeraati, Hojjat; Zarnani, Amir Hassan; Akhondi, Mohammad Mehdi; Hadavi, Reza; Shiraz, Elham Savadi; Jeddi-Tehrani, Mahmood

2012-01-01

312

A Genome-wide Admixture Scan for Ancestry-linked Genes Predisposing to Sarcoidosis in African Americans  

PubMed Central

Genome-wide linkage and association studies have uncovered variants associated with sarcoidosis, a multi-organ granulomatous inflammatory disease. African ancestry may influence disease pathogenesis since African Americans are more commonly affected by sarcoidosis. Therefore, we conducted the first sarcoidosis genome-wide ancestry scan using a map of 1,384 highly ancestry informative single nucleotide polymorphisms genotyped on 1,357 sarcoidosis cases and 703 unaffected controls self-identified as African American. The most significant ancestry association was at marker rs11966463 on chromosome 6p22.3 (ancestry association risk ratio (aRR)= 1.90; p=0.0002). When we restricted the analysis to biopsy-confirmed cases, the aRR for this marker increased to 2.01; p=0.00007. Among the eight other markers that demonstrated suggestive ancestry associations with sarcoidosis were rs1462906 on chromosome 8p12 which had the most significant association with European ancestry (aRR=0.65; p=0.002), and markers on chromosomes 5p13 (aRR=1.46; p=0.005) and 5q31 (aRR=0.67; p=0.005), which correspond to regions we previously identified through sib pair linkage analyses. Overall, the most significant ancestry association for Scadding stage IV cases was to marker rs7919137 on chromosome 10p11.22 (aRR=0.27; p=2×10?5), a region not associated with disease susceptibility. In summary, through admixture mapping of sarcoidosis we have confirmed previous genetic linkages and identified several novel putative candidate loci for sarcoidosis. PMID:21179114

Rybicki, Benjamin A.; Levin, Albert M.; McKeigue, Paul; Datta, Indrani; Gray-McGuire, Courtney; Colombo, Marco; Reich, David; Burke, Robert R.; Iannuzzi, Michael C.

2010-01-01

313

Predisposing Factors for Fibroids and Outcome of Laparoscopic Myomectomy in Infertility  

PubMed Central

Introduction: Fibroids are very common tumors affecting women for centuries, however surprising that no significant data is still available as to what could be the cause of fibroid? What could be the predisposing or risk factors? Does it has any impact on fertility? Outcomes of Laparoscopic myomectomy in infertility? Setting: Advanced Tertiary Gynecologic endoscopic unit. Aims and Objectives: 1) What are the predisposing factors to develop fibroids? 2) Do fibroids lead to infertility? 3) What are the indications for removal of fibroids in infertility? 4) Is laparoscopic surgery better than open surgery? 5) Is the risk of rupture uterus more after laparoscopic myomectomy? 6) What is the success in terms of pregnancy rate after myomectomy? 7) What are the chances of abortions with or without myomectomy? Materials and Methods: A retrospective research study was carried out on 2540 women at the National Institute of Laser and Endoscopic Surgery and Aakar IVF Centre, Mumbai, a referral centre in India. This study was done over a period of 14 years. Women varied in age from 23 to 51 years and infertility of at least more than three years. The woman had fibroids from one to seventeen in number and two centimeters to eighteen centimeters in size which were either submucous, intramural, serosal, cervical or broad ligament. The women requiring hysteroscopic myoma resection were excluded in this study and Laparoscopic myomectomy done in woman other than infertility are also excluded from the study. Results: During the course of our study we found that the diet, weight, hypertension, habits had a bearing on incidence of fibroid. In one of the most promising research fact we found that fibroids itself produce prolactin and due to three times high level of aromatase had higher level of estradiol locally compared to normal myometrium. This was detrimental to fertility. A mild elevation of blood levels of prolactin usually in the range of 40 – 60 ng/ml was noticed in nearly 42% of the cases. Fibroids with infertility as a major complaint along with excessive vaginal bleeding in 33%, pain abdomen and dysmenorhea 10%, pressure symptoms in 3%, accidental finding of a large mass in 5% were the major indications for laparoscopic myomectomy. The pregnancy rate after removal of fibroids with active fertility treatment was 42 % and in donor oocyte IVF was 50%, abortion rate was 5%, 64% LSCS, 31% vaginal deliveries. There was no scar rupture in all pregnancies post laparoscopic myomectomy. Conclusion: Presence of fibroids in first degree female relative, predominantly red meat eating women, excess weight and high Blood pressure increased incidence of fibroids. Pregnancies & oral contraceptives decreased chances of fibroids. In infertile patient fibroids of significant size, multiple, had high local prolactin & aromatase level affecting fertility. Laparoscopic removal of fibroids increased pregnancy rate to 37.2% & 50% in donor oocyte IVF. PMID:22442511

Trivedi, Prakash; Abreo, Mohini

2009-01-01

314

Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials  

PubMed Central

Summary Background The MTHFR 677C?T polymorphism has been associated with raised homocysteine concentration and increased risk of stroke. A previous overview showed that the effects were greatest in regions with low dietary folate consumption, but differentiation between the effect of folate and small-study bias was difficult. A meta-analysis of randomised trials of homocysteine-lowering interventions showed no reduction in coronary heart disease events or stroke, but the trials were generally set in populations with high folate consumption. We aimed to reduce the effect of small-study bias and investigate whether folate status modifies the association between MTHFR 677C?T and stroke in a genetic analysis and meta-analysis of randomised controlled trials. Methods We established a collaboration of genetic studies consisting of 237 datasets including 59?995 individuals with data for homocysteine and 20?885 stroke events. We compared the genetic findings with a meta-analysis of 13 randomised trials of homocysteine-lowering treatments and stroke risk (45?549 individuals, 2314 stroke events, 269 transient ischaemic attacks). Findings The effect of the MTHFR 677C?T variant on homocysteine concentration was larger in low folate regions (Asia; difference between individuals with TT versus CC genotype, 3·12 ?mol/L, 95% CI 2·23 to 4·01) than in areas with folate fortification (America, Australia, and New Zealand, high; 0·13 ?mol/L, ?0·85 to 1·11). The odds ratio (OR) for stroke was also higher in Asia (1·68, 95% CI 1·44 to 1·97) than in America, Australia, and New Zealand, high (1·03, 0·84 to 1·25). Most randomised trials took place in regions with high or increasing population folate concentrations. The summary relative risk (RR) of stroke in trials of homocysteine-lowering interventions (0·94, 95% CI 0·85 to 1·04) was similar to that predicted for the same extent of homocysteine reduction in large genetic studies in populations with similar folate status (predicted RR 1·00, 95% CI 0·90 to 1·11). Although the predicted effect of homocysteine reduction from large genetic studies in low folate regions (Asia) was larger (RR 0·78, 95% CI 0·68 to 0·90), no trial has evaluated the effect of lowering of homocysteine on stroke risk exclusively in a low folate region. Interpretation In regions with increasing levels or established policies of population folate supplementation, evidence from genetic studies and randomised trials is concordant in suggesting an absence of benefit from lowering of homocysteine for prevention of stroke. Further large-scale genetic studies of the association between MTHFR 677C?T and stroke in low folate settings are needed to distinguish effect modification by folate from small-study bias. If future randomised trials of homocysteine-lowering interventions for stroke prevention are undertaken, they should take place in regions with low folate consumption. Funding Full funding sources listed at end of paper (see Acknowledgments). PMID:21803414

Holmes, Michael V; Newcombe, Paul; Hubacek, Jaroslav A; Sofat, Reecha; Ricketts, Sally L; Cooper, Jackie; Breteler, Monique MB; Bautista, Leonelo E; Sharma, Pankaj; Whittaker, John C; Smeeth, Liam; Fowkes, F Gerald R; Algra, Ale; Shmeleva, Veronika; Szolnoki, Zoltan; Roest, Mark; Linnebank, Michael; Zacho, Jeppe; Nalls, Michael A; Singleton, Andrew B; Ferrucci, Luigi; Hardy, John; Worrall, Bradford B; Rich, Stephen S; Matarin, Mar; Norman, Paul E; Flicker, Leon; Almeida, Osvaldo P; van Bockxmeer, Frank M; Shimokata, Hiroshi; Khaw, Kay-Tee; Wareham, Nicholas J; Bobak, Martin; Sterne, Jonathan AC; Smith, George Davey; Talmud, Philippa J; van Duijn, Cornelia; Humphries, Steve E; Price, Jackie F; Ebrahim, Shah; Lawlor, Debbie A; Hankey, Graeme J; Meschia, James F; Sandhu, Manjinder S; Hingorani, Aroon D; Casas, Juan P

2011-01-01

315

Excess NO Predisposes Mitochondrial Succinate-Cytochrome c Reductase to Produce Hydroxyl Radical†  

PubMed Central

Mitochondria–derived oxygen free radical(s) are important mediators of oxidative cellular injury. It is widely hypothesized that excess NO enhances O2•? generated by mitochondria under certain pathological conditions. In the mitochondrial electron transport chain, succinate-cytochrome c reductase (SCR) catalyzes the electron transfer reaction from succinate to cytochrome c. To gain the insights into the molecular mechanism of how NO overproduction may mediate the oxygen free radical generation by SCR, we employed isolated SCR, cardiac myoblast H9c2, and endothelial cells to study the interaction of NO with SCR in vitro and ex vivo. Under the conditions of enzyme turnover in the presence of NO donor (DEANO), SCR gained pro-oxidant function for generating hydroxyl radical as detected by EPR spin trapping using DEPMPO. The EPR signal associated with DEPMPO/•OH adduct was nearly completely abolished in the presence of catalase or an iron chelator and partially inhibited by SOD, suggesting the involvement of the iron-H2O2 dependent Fenton reaction or O2•?–dependent Haber-Weiss mechanism. Direct EPR measurement of SCR at 77 °K indicated the formation of a nonheme iron-NO complex, implying that electron leakage to molecular oxygen was enhanced at the FAD cofactor, and that excess NO predisposed SCR to produce •OH. In H9c2 cells, SCR dependent oxygen free radical generation was stimulated by NO released from DEANO or produced by the cells following exposure to hypoxia/reoxygenation. With shear exposure that led to overproduction of NO by the endothelium, SCR mediated oxygen free radical production was also detected in cultured vascular endothelial cells. PMID:21406178

Chen, Jingfeng; Chen, Chwen-Lih; Alevriadou, B. Rita; Zweier, Jay L.; Chen, Yeong-Renn

2011-01-01

316

Sexual activity does not predispose to reflux episodes in patients with gastroesophageal reflux disease  

PubMed Central

Background The role of sexual activity on gastroesophageal reflux disease (GERD) is an under-recognized concern of patients, and one rarely assessed by physicians. Objective The objective of this article is to determine the influence of sexual activity on the intraesophageal acid exposure and acid reflux events in GERD patients. Methods Twenty-one patients with the diagnosis of GERD were prospectively enrolled. Intraesophageal pH monitoring was recorded for 48 hours with a Bravo capsule. All patients were instructed to have sexual intercourse or abstain in a random order two hours after the same refluxogenic dinner within two consecutive nights. Patients were requested to have sex in the standard “missionary position” and women were warned to avoid abdominal compression. The patients completed a diary reporting the time of the sexual intercourse and GERD symptoms. The percentage of reflux time and acid reflux events were compared in two ways: within 30 and 60 minutes prior to and after sexual intercourse on the day of sexual intercourse and in the same time frame of the day without sexual intercourse. Results Fifteen of 21 GERD patients were analyzed. The percentage of reflux time and number of acid reflux events did not show a significant difference within the 30- and 60-minute periods prior to and after sexual intercourse on the day of sexual intercourse and on the day without sexual intercourse, as well. Conclusion Sexual activity does not predispose to increased intraesophageal acid exposure and acid reflux events. Larger studies are needed to confirm our findings in patients who define reflux symptoms during sexual intercourse.

Bor, Serhat; Valytova, Elen; Yildirim, Esra; Vardar, Rukiye

2014-01-01

317

Cannabis Use Disorders Predispose to the Development of Sexually Transmitted Diseases among Youth  

PubMed Central

Background Previous cross-sectional studies involving adults suggest that sexually transmitted diseases (STD) such as cocaine use disorders and opioid use disorders are associated with the development of sexually transmitted diseases (STD). However, it is less clear whether cannabis use disorders (CUD) are associated with the development of STDs, or whether those associations extend to adolescent populations. Longitudinal studies examining those associations are particularly scarce. The current report provides findings from a longitudinal study that examined the relationship between STD and CUD among youth transitioning to young adulthood. Method The subjects in this longitudinal study were initially recruited when the index sons of these fathers were 10-12 years of age, and subsequent assessments were conducted at age 12-14, 16, 19, and 22. Multivariate logistic regression and path analyses were conducted. Results At age 22, of the 345 subjects, 30 subjects were diagnosed with one or more STD, and 105 were diagnosed with a CUD. STDs were almost four times as common among those with a CUD as among those without a CUD, which was a significant difference. Path analyses demonstrated that peer deviance mediated the association between a measure of risk for SUD knows as the TLI and CUD, and that peer deviance mediated the association between TLI and STD. Risky sexual behaviors were common. Conclusions These finding suggest that cannabis use disorders (CUD) predispose to the development of sexually transmitted disorders (STD) among youth. These findings also suggest that peer deviance mediates the development of STD and of CUD among teenagers making the transition to young adulthood.

Cornelius, Jack R.; Kirisci, Levent; Clark, Duncan B.

2013-01-01

318

Exploring genetic variants predisposing to diabetes mellitus and their association with indicators of socioeconomic status  

PubMed Central

Background The relevance of disease-related genetic variants for the explanation of social inequalities in complex diseases is unclear and empirical analyses are largely missing. The aim of our study was to examine whether genetic variants predisposing to diabetes mellitus are associated with socioeconomic status in a population-based cohort. Methods We genotyped 11 selected diabetes-related single nucleotide polymorphisms in 4655 participants (age 45-75 years) of the Heinz Nixdorf Recall study. Diabetes status was self-reported or defined by blood glucose levels. Education, income and paternal occupation were assessed as indicators of socioeconomic status. Multiple regression analyses were used to examine the association of socioeconomic status and diabetes by estimating sex-specific and age-adjusted prevalence ratios and their corresponding 95%-confidence intervals. To explore the relationship between individual single nucleotide polymorphisms and socioeconomic status sex- and age-adjusted odds ratios were computed. We adjusted the alpha-level for multiple testing of 11 single nucleotide polymorphisms using Bonferroni’s method ( ? BF?~?0.005). In addition, we explored the association of a genetic risk score with socioeconomic status. Results Social inequalities in diabetes were observed for all indicators of socioeconomic status. However, there were no significant associations between individual diabetes-related risk alleles and socioeconomic status with odds ratios ranging from 0.87 to 1.23. Similarly, the genetic risk score analysis revealed no evidence for an association. Conclusions Our data provide no evidence for an association between 11 diabetes-related risk alleles and different indicators of socioeconomic status in a population-based cohort, suggesting that the explored genetic variants do not contribute to health inequalities in diabetes. PMID:24935819

2014-01-01

319

Predisposing Factors Related to Shunt-Dependent Chronic Hydrocephalus after Aneurysmal Subarachnoid Hemorrhage  

PubMed Central

Objective Hydrocephalus is a common sequelae of aneurysmal subarachnoid hemorrhage (SAH) and patients who develop hydrocephalus after SAH typically have a worse prognosis than those who do not. This study was designed to identify factors predictive of shunt-dependent chronic hydrocephalus among patients with aneurysmal SAH, and patients who require permanent cerebrospinal fluid diversion. Methods Seven-hundred-and-thirty-four patients with aneurysmal SAH who were treated surgically between 1990 and 2006 were retrospectively studied. Three stages of hydrocephalus have been categorized in this paper, i.e., acute (0-3 days after SAH), subacute (4-13 days after SAH), chronic (?14 days after SAH). Criteria indicating the occurrence of hydrocephalus were the presence of significantly enlarged temporal horns or ratio of frontal horn to maximal biparietal diameter more than 30% in computerized tomography. Results Overall, 66 of the 734 patients (8.9%) underwent shunting procedures for the treatment of chronic hydrocephalus. Statistically significant associations among the following factors and shunt-dependent chronic hydrocephalus were observed. (1) Increased age (p < 0.05), (2) poor Hunt and Hess grade at admission (p < 0.05), (3) intraventricular hemorrhage (p < 0.05), (4) Fisher grade III, IV at admission (p < 0.05), (5) radiological hydrocephalus at admission (p < 0.05), and (6) post surgery meningitis (p < 0.05) did affect development of chronic hydrocephalus. However the presence of intracerebral hemorrhage, multiple aneurysms, vasospasm, and gender did not influence on the development of shunt-dependent chronic hydrocephalus. In addition, the location of the ruptured aneurysms in posterior cerebral circulation did not correlate with the development of shunt-dependent chronic hydrocephalus. Conclusion Hydrocephalus after aneurysmal SAH seems to have a multifactorial etiology. Understanding predisposing factors related to the shunt-dependent chronic hydrocephalus may help to guide neurosurgeons for better treatment outcomes. PMID:19096639

Kwon, Jae-Hyun; Sung, Soon-Ki; Song, Young-Jin; Choi, Hyu-Jin; Huh, Jae-Taeck

2008-01-01

320

A Lower Degree of PBMC L1 Methylation in Women with Lower Folate Status May Explain the MTHFR C677T Polymorphism Associated Higher Risk of CIN in the US Post Folic Acid Fortification Era  

PubMed Central

Background Studies in populations unexposed to folic acid (FA) fortification have demonstrated that MTHFR C677T polymorphism is associated with increased risk of higher grades of cervical intraepithelial neoplasia (CIN 2+). However, it is unknown whether exposure to higher folate as a result of the FA fortification program has altered the association between MTHFR C677T and risk of CIN, or the mechanisms involved with such alterations. The current study investigated the following in a FA fortified population: 1) The association between MTHFR C677T polymorphism and risk of CIN 2+; 2) The modifying effects of plasma folate concentrations on this association; and 3) The modifying effects of plasma folate on the association between the polymorphism and degree of methylation of long interspersed nucleotide elements (L1s), in peripheral blood mononuclear cell (PBMC) DNA, a documented biomarker of CIN risk. Methods The study included 457 US women diagnosed with either CIN 2+ (cases) or ? CIN 1 (non-cases). Unconditional logistic regression models were used to test the associations after adjusting for relevant risk factors for CIN. Results The 677CT/TT MTHFR genotypes were not associated with the risk of CIN 2+. Women with CT/TT genotype with lower folate, however, were more likely to be diagnosed with CIN 2+ compared to women with CT/TT genotype with higher folate (OR?=?2.41, P?=?0.030). Women with CT/TT genotype with lower folate were less likely to have a higher degree of PBMC L1 methylation compared to women with CT/TT genotype with higher folate (OR?=?0.28, P?=?0.017). Conclusions This study provides the first evidence that the MTHFR 677CT/TT genotype-associated lower degree of PBMC L1 methylation increases the risk of CIN 2+ in women in the US post-FA fortification era. Thus, even in the post-FA fortification era, not all women have adequate folate status to overcome MTHFR 677CT/TT genotype-associated lower degree of L1 methylation. PMID:25302494

Badiga, Suguna; Johanning, Gary L.; Macaluso, Maurizio; Azuero, Andres; Chambers, Michelle M.; Siddiqui, Nuzhat R.; Piyathilake, Chandrika J.

2014-01-01

321

Perinatal iron deficiency predisposes the developing rat hippocampus to greater injury from mild to moderate hypoxia–ischemia  

Microsoft Academic Search

The hippocampus is injured in both hypoxia–ischemia (HI) and perinatal iron deficiency that are co-morbidities in infants of diabetic mothers and intrauterine growth restricted infants. We hypothesized that preexisting perinatal iron deficiency predisposes the hippocampus to greater injury when exposed to a relatively mild HI injury. Iron-sufficient and iron-deficient rats (hematocrit 40% lower and brain iron concentration 55% lower) were

Raghavendra Rao; Ivan Tkac; Elise L Townsend; Kathleen Ennis; Rolf Gruetter; Michael K Georgieff; R Rao

2007-01-01

322

Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus  

Microsoft Academic Search

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986

Z Su; LJ Gay; A Strange; C Palles; G Band; DC Whiteman; F Lescai; C Langford; M Nanji; S Edkins; A van der Winkel; D Levine; P Sasieni; C Bellenguez; K Howarth; C Freeman; N Trudgill; M Pirinen; MP Peppelenbosch; LJ van der Laan; EJ Kuipers; JP Drenth; WH Peters; JV Reynolds; DP Kelleher; R McManus; H Grabsch; H Prenen; R Bisschops; K Krishnadath; PD Siersema; JW van Baal; M Middleton; R Petty; R Gillies; N Burch; P Bhandari; S Paterson; C Edwards; I Penman; K Vaidya; Y Ang; I Murray; P Patel; W Ye; P Mullins; AH Wu; NC Bird; H Dallal; NJ Shaheen; LJ Murray; K Koss; L Bernstein; Y Romero; LJ Hardie; R Zhang; H Winter; DA Corley; S Panter; HA Risch; BJ Reid; I Sargeant; H Smart; A Dhar; H McMurtry; H Ali; G Liu; AG Casson; WH Chow; M Rutter; A Tawil; D Morris; C Nwokolo; P Isaacs; C Rodgers; K Ragunath; C MacDonald; C Haigh; D Monk; G Davies; S Wajed; D Johnston; M Gibbons; S Cullen; N Church; R Langley; M Griffin; D Alderson; P Deloukas; SE Hunt; E Gray; S Dronov; SC Potter; A Tashakkori-Ghanbaria; M Anderson; C Brooks; JM Blackwell; E Bramon; MA Brown; JP Casas; A Corvin; A Duncanson; HS Markus; CG Mathew; CN Palmer; R Plomin; A Rautanen; SJ Sawcer; RC Trembath; AC Viswanathan; N Wood; G Trynka; C Wijmenga; JB Cazier; P Atherfold; AM Nicholson; NL Gellatly; D Glancy; SC Cooper; D Cunningham; T Lind; J Hapeshi; D Ferry; B Rathbone; J Brown; S Love; S Attwood; S MacGregor; P Watson; S Sanders; W Ek; RF Harrison; P Moayyedi; J de Caestecker; H Barr; E Stupka; TL Vaughan; L Peltonen; CC Spencer; I Tomlinson; P Donnelly; JA Jankowski

2012-01-01

323

A Case of Candida albicans Endophthalmitis with No Predisposing Risk Factors and a Distant Source of Infection  

PubMed Central

Purpose To report a case of Candida albicans endophthalmitis with no identifiable predisposing risk factors. Case Report A 57-year-old male presented with a 3-day history of worsening floaters and reduced visual acuity. Fundoscopy and optical coherence tomography showed presence of fluffy white preretinal and intraretinal infiltrates. With no past medical history or evidence of immunosuppression but having travelled abroad and suffered from diarrhoea, fungal aetiology was thought to be unlikely and as a result, treatment was commenced for toxoplasma. Despite treatment, his vision did not improve. Initial investigations including inflammatory markers, serology for toxoplasmosis, blood culture, chest radiograph and aqueous sampling could not identify a source of infection. However, polymerase chain reaction results from vitreous sampling revealed C. albicans. As a result, the patient was treated with intravenous voriconazole and intravitreal amphotericin B. As initial clinical improvement was limited, a vitrectomy was performed with further intravitreal amphotericin B. Clinical improvement was rapid following vitrectomy. After repeated Gram staining and culture of infected toenails, Gram-positive yeast cells were isolated. Conclusion Although C. albicans is a frequent cause of endogenous endophthalmitis, patients often have one or more predisposing systemic condition assisting the diagnosis. The present case illustrates that (1) even in the absence of any predisposing risk factors, C. albicans should be considered as a possible differential diagnosis in recalcitrant uveitis, and (2) endogenous candida endophthalmitis can be a result of fungal infections from distant sites such as the toenails. PMID:23275788

Chavan, Randhir; Mustafa, Mohammad Z.; Narendran, Nirodhini; Tarin, Shoaib; Yang, Yit

2012-01-01

324

Acquired hypermethylation of the P16INK4A promoter in abdominal paraganglioma: relation to adverse tumor phenotype and predisposing mutation  

PubMed Central

Recurrent alterations in promoter methylation of tumor suppressor genes (TSGs) and LINE1 (L1RE1) repeat elements were previously reported in pheochromocytoma and abdominal paraganglioma. This study was undertaken to explore CpG methylation abnormalities in an extended tumor panel and assess possible relationships between metastatic disease and mutation status. CpG methylation was quantified by bisulfite pyrosequencing for selected TSG promoters and LINE1 repeats. Methylation indices above normal reference were observed for DCR2 (TNFRSF10D), CDH1, P16 (CDKN2A), RARB, and RASSF1A. Z-scores for overall TSG, and individual TSG methylation levels, but not LINE1, were significantly correlated with metastatic disease, paraganglioma, disease predisposition, or outcome. Most strikingly, P16 hypermethylation was strongly associated with SDHB mutation as opposed to RET/MEN2, VHL/VHL, or NF1-related disease. Parallel analyses of constitutional, tumor, and metastasis DNA implicate an order of events where constitutional SDHB mutations are followed by TSG hypermethylation and 1p loss in primary tumors, later transferred to metastatic tissue. In the combined material, P16 hypermethylation was prevalent in SDHB-mutated samples and was associated with short disease-related survival. The findings verify the previously reported importance of P16 and other TSG hypermethylation in an independent tumor series. Furthermore, a constitutional SDHB mutation is proposed to predispose for an epigenetic tumor phenotype occurring before the emanation of clinically recognized malignancy. PMID:23154831

Kiss, Nimrod B; Muth, Andreas; Andreasson, Adam; Juhlin, C Christofer; Geli, Janos; Backdahl, Martin; Hoog, Anders; Wangberg, Bo; Nilsson, Ola; Ahlman, Hakan; Larsson, Catharina

2013-01-01

325

Haploid Insufficiency of Suppressor Enhancer Lin12 1-like (SEL1L) Protein Predisposes Mice to High Fat Diet-induced Hyperglycemia*  

PubMed Central

Increasing evidence suggests that endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of type 2 diabetes mellitus. SEL1L is an ER membrane protein that is highly expressed in the pancreatic islet and acinar cells. We have recently reported that a deficiency of SEL1L causes systemic ER stress and leads to embryonic lethality in mice. Here we show that mice with one functional allele of Sel1l (Sel1l+/?) are more susceptible to high fat diet (HFD)-induced hyperglycemia. Sel1l+/? mice have a markedly reduced ?-cell mass as a result of decreased ?-cell proliferation. Consequently, Sel1l+/? mice are severely glucose-intolerant and exhibit significantly retarded glucose-stimulated insulin secretion. Pancreatic islets from Sel1l+/? mice stimulated with a high concentration of glucose in vitro express significantly higher levels of unfolded protein response genes than those from wild-type control mice. Furthermore, dominant-negative interference of SEL1L function in insulinoma cell lines severely impairs, whereas overexpression of SEL1L efficiently improves protein secretion. Taken together, our results indicate that haploid insufficiency of SEL1L predispose mice to high fat diet-induced hyperglycemia. Our findings highlight a critical and previously unknown function for SEL1L in regulating adult ?-cell function and growth. PMID:21536682

Francisco, Adam B.; Singh, Rajni; Sha, Haibo; Yan, Xi; Qi, Ling; Lei, Xingen; Long, Qiaoming

2011-01-01

326

Elevated total plasma homocysteine and 667C{r_arrow}T mutation of the 5,10-methylenetetrahydrofolate reductase gene in thrombotic vascular disease  

SciTech Connect

Moderate elevation of total plasma homocysteine (tHcy) has been reported as an independent risk factor for thrombotic vascular disease, a well-known multifactorial disorder. Possible genetic causes of elevated tHcy include defects of the sulfur-containing amino acids metabolism due to deficiencies of cystathionine {Beta}-synthase, of 5,10-methylenetetrahydrofolate reductase (MTHFR), and of the enzymes of cobalamin metabolism. An impaired activity of MTHFR due to a thermolabile form of the enzyme has been observed in {le}28% of hyperhomocysteinemic patients with premature vascular disease. More recently, the molecular basis of such enzymatic thermolability has been related to a common mutation of the MTHFR gene, causing a C-to-T substitution at nt 677 (677C{r_arrow}T). This mutation was found in 38% of unselected chromosomes from 57 French Canadian individuals. The homozygous state for the mutation was present in 12% of these subjects and correlated with significantly elevated tHcy. Preliminary evidence indicates that the frequency of homozygotes for the 677C{r_arrow}T mutation may vary significantly in populations from different geographic areas. 5 refs., 2 tabs.

De Franchis, R.; Sebastio, G.; Andria, G. [Universita Federico II, Naples (Italy)] [and others

1996-07-01

327

A Case Control Study on the Contribution of Factor V-Leiden, Prothrombin G20210A, and MTHFR C677T Mutations to the Genetic Susceptibility of Deep Venous Thrombosis  

Microsoft Academic Search

Background: Insofar as the inherited prothrombotic single nucleotide polymorphisms (SNPs) factor V G1691A (FV-Leiden), prothrombin (PRT) G20210A, and methylenetetrahydrofolate reductase (MTHFR), C677T are inherited risk factors of venous thromboembolism (VTE), the aim of this study was to determine the prevalence of single and combined SNPs in 198 patients with documented deep venous thrombosis (DVT), and 697 control subjects, and to

Wassim Y. Almawi; Hala Tamim; Raghid Kreidy; Georgina Timson; Elias Rahal; Malak Nabulsi; Ramzi R. Finan; Noha Irani-Hakime

2005-01-01

328

Molecular amino acid signatures in the MHC class II peptide-binding pocket predispose to autoimmune thyroiditis in humans and in mice.  

PubMed

Hashimoto's thyroiditis (HT) is associated with HLA, but the associated allele is still controversial. We hypothesized that specific HLA-DR pocket-sequence variants are associated with HT and that similar variants in the murine I-E locus (homologous to HLA-DR) predispose to experimental autoimmune thyroiditis (EAT), a classical mouse model of HT. Therefore, we sequenced the polymorphic exon 2 of the HLA-DR gene in 94 HT patients and 149 controls. In addition, we sequenced exon 2 of the I-E gene in 22 strains of mice, 12 susceptible to EAT and 10 resistant. Using logistic regression analysis, we identified a pocket amino acid signature, Tyr-26, Tyr-30, Gln-70, Lys-71, strongly associated with HT (P = 6.18 x 10(-5), OR = 3.73). Lys-71 showed the strongest association (P = 1.7 x 10(-8), OR = 2.98). This association was seen across HLA-DR types. The 5-aa haplotype Tyr-26, Tyr-30, Gln-70, Lys-71, Arg-74 also was associated with HT (P = 3.66 x 10(-4)). In mice, the I-E pocket amino acids Val-28, Phe-86, and Asn-88 were strongly associated with EAT. Structural modeling studies demonstrated that pocket P4 was critical for the development of HT, and pockets P1 and P4 influenced susceptibility to EAT. Surprisingly, the structures of the HT- and EAT-susceptible pockets were different. We conclude that specific MHC II pocket amino acid signatures determine susceptibility to HT and EAT by causing structural changes in peptide-binding pockets that may influence peptide binding, selectivity, and presentation. Because the HT- and EAT-associated pockets are structurally different, it is likely that distinct antigenic peptides are associated with HT and EAT. PMID:18779568

Menconi, Francesca; Monti, Maria C; Greenberg, David A; Oashi, Taiji; Osman, Roman; Davies, Terry F; Ban, Yoshiyuki; Jacobson, Eric M; Concepcion, Erlinda S; Li, Cheuk Wun; Tomer, Yaron

2008-09-16

329

Epigenetic Genes and Emotional Reactivity to Daily Life Events: A Multi-Step Gene-Environment Interaction Study  

PubMed Central

Recent human and animal studies suggest that epigenetic mechanisms mediate the impact of environment on development of mental disorders. Therefore, we hypothesized that polymorphisms in epigenetic-regulatory genes impact stress-induced emotional changes. A multi-step, multi-sample gene-environment interaction analysis was conducted to test whether 31 single nucleotide polymorphisms (SNPs) in epigenetic-regulatory genes, i.e. three DNA methyltransferase genes DNMT1, DNMT3A, DNMT3B, and methylenetetrahydrofolate reductase (MTHFR), moderate emotional responses to stressful and pleasant stimuli in daily life as measured by Experience Sampling Methodology (ESM). In the first step, main and interactive effects were tested in a sample of 112 healthy individuals. Significant associations in this discovery sample were then investigated in a population-based sample of 434 individuals for replication. SNPs showing significant effects in both the discovery and replication samples were subsequently tested in three other samples of: (i) 85 unaffected siblings of patients with psychosis, (ii) 110 patients with psychotic disorders, and iii) 126 patients with a history of major depressive disorder. Multilevel linear regression analyses showed no significant association between SNPs and negative affect or positive affect. No SNPs moderated the effect of pleasant stimuli on positive affect. Three SNPs of DNMT3A (rs11683424, rs1465764, rs1465825) and 1 SNP of MTHFR (rs1801131) moderated the effect of stressful events on negative affect. Only rs11683424 of DNMT3A showed consistent directions of effect in the majority of the 5 samples. These data provide the first evidence that emotional responses to daily life stressors may be moderated by genetic variation in the genes involved in the epigenetic machinery. PMID:24967710

Pishva, Ehsan; Drukker, Marjan; Viechtbauer, Wolfgang; Decoster, Jeroen; Collip, Dina; van Winkel, Ruud; Wichers, Marieke; Jacobs, Nele; Thiery, Evert; Derom, Catherine; Geschwind, Nicole; van den Hove, Daniel; Lataster, Tineke; Myin-Germeys, Inez; van Os, Jim

2014-01-01

330

Reduced folate carrier-1 G80a gene polymorphism is associated with neuroblastoma's development.  

PubMed

Neuroblastoma is a malignant embryonal tumor of neural crest cells that give rise to the sympathetic nervous system, responsible for 10-70% of all cases of childhood cancer. Because of its early appearance, it has been suggested that risk factors active in the prenatal can be associated with the pathogenesis of neuroblastoma. The aim of this study was to investigate whether the genetic polymorphisms MTHFR C677T and A1298C, MTR A2756G, TYMS 2R/3R and SLC19A1 G80A, involved in folate metabolism, increase the risk of neuroblastoma in Brazilian children. This study comprised 31 Brazilian children (0-14 years old) diagnosed with neuroblastoma compared with 92 controls. Investigation of polymorphisms MTHFR C677T, MTR A2756G and SLC19A1 A80G was performed using PCR-RFLP, the TYMS 2R/3R using PCR and MTHFR A1298C using AS-PCR. The SLC19A1 A80A genotype was significantly associated with the development of neuroblastoma, compared with the control group (Williams G-Test = 0.0286; OR = 5.1667; 95% CI = 1.4481-18.4338; p = 0.0175). When analyzed together, the 80AG+AA genotypes showed a trend toward association (OR = 3.3033; 95% CI = 1.0586-10.3080; p = 0.0563). Our results suggest that individuals carriers of genotype AA for the SLC19A1 gene present risk for the development of neuroblastoma and possibly have difficulty in absorption of folic acid by the cells, and this may adversely affect the metabolism of folate causing genomic instability and promoting the development of cancer. This is the first retrospective/prospective study to examine the relationship between polymorphisms of folate pathway genes and risk of neuroblastoma. PMID:24771227

de Miranda, Dyego O; Barros, Jemima E X S; Vieira, Maria Madalena S; Lima, Elker L S; Moraes, Vera L L; da Silva, Helker A; Garcia, Helder L B O; Lima, Cássia A; Gomes, Adriana V; Santos, Neide; Muniz, Maria T C

2014-08-01

331

Interactions of Several Lipid-Related Gene Polymorphisms and Cigarette Smoking on Blood Pressure Levels  

PubMed Central

The interactions of single nucleotide polymorphisms (SNPs) and cigarette smoking on blood pressure levels are limited. The present study was undertaken to detect nine lipid-related SNPs and their interactions with cigarette smoking on blood pressure levels. Genotyping of ATP-binding cassette transporter A1 (ABCA-1) V825I, acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) rs1044925, low density lipoprotein receptor (LDL-R) Ava?, hepatic lipase gene (LIPC) -250G>A, endothelial lipase gene (LIPG) 584C>T, methylenetetrahydrofolate reductase (MTHFR) 677C>T, proprotein convertase subtilisin-like kexin type 9 (PCSK9) E670G, peroxisome proliferator-activated receptor delta (PPARD) +294T>C, and Scavenger receptor class B type 1 (SCARB1) rs5888 was performed in 935 nonsmokers and 845 smokers. The interactions were detected by factorial regression analysis. The frequencies of genotypes (ACAT-1 and LIPG), alleles (ABCA-1), and both genotypes and alleles (LDL-R, LIPC, PPARD and SCARB1) were different between nonsmokers and smokers (P < 0.05-0.001). The levels of pulse pressure (PP, ABCA-1), and systolic, diastolic blood pressure (SBP, DBP) and PP (LIPC) in nonsmokers were different among the genotypes (P < 0.01-0.001). The levels of SBP (ABCA-1, ACAT-1, LIPG and PCSK9), DBP (ACAT-1, LDL-R, LIPC, PCSK9 and PPARD), and PP (LIPC, LIPG, MTHFR and PCSK9) in smokers were different among the genotypes (P < 0.01-0.001). The SNPs of ABCA-1, ACAT-1 and PCSK9; ACAT-1, LDL-R, MTHFR and PCSK9; and ABCA-1, LIPC, PCSK9 and PPARD were shown interactions with cigarette smoking to influence SBP, DBP and PP levels (P < 0.05-0.001); respectively. The differences in blood pressure levels between the nonsmokers and smokers might partly result from different interactions of several SNPs and cigarette smoking. PMID:22606049

Yin, Rui-Xing; Wu, Dong-Feng; Wu, Jin-Zhen; Cao, Xiao-Li; Aung, Lynn Htet Htet; Miao, Lin; Long, Xing-Jiang; Liu, Wan-Ying; Zhang, Lin; Li, Meng

2012-01-01

332

Carbamazepine Hypersensitivity Syndrome Triggered by a Human Herpes Virus Reactivation in a Genetically Predisposed Patient  

Microsoft Academic Search

A case of severe hypersensitivity syndrome, triggered by carbamazepine in the presence of a concomitant active human herpes virus (HHV) 6 and 7 infection is described. To further understand the molecular mechanism of this adverse reaction, analyses of the genetic variants of human leukocyte antigen (HLA) and of the epoxide hydrolase gene (EPHX1), previously associated with carbamazepine hypersensitivity, were performed.

Lorenzo Calligaris; Gabriele Stocco; Sara De Iudicibus; Sara Marino; Giuliana Decorti; Egidio Barbi; Marco Carrozzi; Federico Marchetti; Fiora Bartoli; Alessandro Ventura

2009-01-01

333

Genetic Modifiers Predisposing to Congenital Heart Disease in the Sensitized Down Syndrome Population  

PubMed Central

Background About half of people with Down syndrome (DS) exhibit some form of congenital heart disease (CHD). However, trisomy for human chromosome 21 (Hsa21) alone is insufficient to cause CHD as half of all people with DS have a normal heart, suggesting that genetic modifiers interact with dosage sensitive gene(s) on Hsa21 to result in CHD. We hypothesize that a threshold exists in both Down syndrome and euploid populations for the number of genetic perturbations that can be tolerated before CHD results. Methods and Results We ascertained a group of individuals with DS and complete atrioventricular septal defect (AVSD) and sequenced two candidate genes for CHD, CRELD1, which is associated with AVSD in people with or without DS, and HEY2, whose mouse ortholog produces septal defects when mutated. Several deleterious variants were identified but the frequency of these potential modifiers was low. We crossed mice with mutant forms of these potential modifiers to the Ts65Dn mouse model of Down syndrome. Crossing loss-of-function alleles of either Creld1 or Hey2 onto the trisomic background caused a significant increase in the frequency of CHD, demonstrating an interaction between the modifiers and trisomic genes. We showed further that although either of these mutant modifiers is benign by itself, they interact to affect heart development when inherited together. Conclusions Using mouse models of Down syndrome and of genes associated with congenital heart disease we demonstrate a biological basis for an interaction that supports a threshold hypothesis for additive effects of genetic modifiers in the sensitized trisomic population. PMID:22523272

Li, Huiqing; Cherry, Sheila; Klinedinst, Donna; DeLeon, Valerie; Redig, Jennifer; Reshey, Benjamin; Chin, Michael T.; Sherman, Stephanie L.; Maslen, Cheryl L.; Reeves, Roger H.

2012-01-01

334

Methylenetetrahydrofolate reductase C677T gene polymorphism and essential hypertension: A meta-analysis of 10,415 subjects  

PubMed Central

The methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism has been suggested to be associated with the risk of essential hypertension (EH), however, results remain inconclusive. To investigate this association, the present meta-analysis of 27 studies including 5,418 cases and 4,997 controls was performed. The pooled odds ratio (OR) and its corresponding 95% confidence interval were calculated using the random-effects model. A significant association between the MTHFR C677T gene polymorphism and EH was found under the allelic (OR, 1.32; 95% CI, 1.20–1.45; P=0.000), dominant (OR, 1.39; 95% CI, 1.25–1.55; P=0.000), recessive (OR, 1.38; 95% CI, 1.18–1.62; P=0.000), homozygote (OR, 1.59; 95% CI, 1.32–1.92; P=0.000), and heterozygote (OR, 1.32; 95% CI, 1.20–1.45; P=0.000) genetic models. A strong association was also revealed in subgroups, including Asian, Caucasian and Chinese. The Japanese subgroup did not show any significant association under all models. Meta-regression analyses suggested that the study design was a potential source of heterogeneity, whereas the subgroup analysis additionally indicated that the population origin may also be an explanation. Another subgroup analysis revealed that hospital-based studies have a stronger association than population-based studies, however, the former suffered a greater heterogeneity. Funnel plot and Egger’s test manifested no evidence of publication bias. In conclusion, the present study supports the evidence for the association between the MTHFR C677T gene polymorphism and EH in the whole population, as well as in subgroups, such as Asian, Caucasian and Chinese. The carriers of the 677T allele are susceptible to EH. PMID:25054014

YANG, KE-MING; JIA, JIAN; MAO, LI-NA; MEN, CHEN; TANG, KANG-TING; LI, YAN-YAN; DING, HAI-XIA; ZHAN, YI-YANG

2014-01-01

335

Characterization of a naturally-occurring p27 mutation predisposing to multiple endocrine tumors  

Microsoft Academic Search

BACKGROUND: p27Kip1 (p27) is an important negative regulator of the cell cycle and a putative tumor suppressor. The finding that a spontaneous germline frameshift mutation in Cdkn1b (encoding p27) causes the MENX multiple endocrine neoplasia syndrome in the rat provided the first evidence that Cdkn1b is a tumor susceptibility gene for endocrine tumors. Noteworthy, germline p27 mutations were also identified

Sara Molatore; Eva Kiermaier; Christian B Jung; Misu Lee; Elke Pulz; Heinz Höfler; Michael J Atkinson; Natalia S Pellegata

2010-01-01

336

Prenatal Exposure to the Environmental Obesogen Tributyltin Predisposes Multipotent Stem Cells to Become Adipocytes  

PubMed Central

The environmental obesogen hypothesis proposes that pre- and postnatal exposure to environmental chemicals contributes to adipogenesis and the development of obesity. Tributyltin (TBT) is an agonist of both retinoid X receptor (RXR) and peroxisome proliferator-activated receptor ? (PPAR?). Activation of these receptors can elevate adipose mass in adult mice exposed to the chemical in utero. Here we show that TBT sensitizes human and mouse multipotent stromal stem cells derived from white adipose tissue [adipose-derived stromal stem cells (ADSCs)] to undergo adipogenesis. In vitro exposure to TBT, or the PPAR? activator rosiglitazone increases adipogenesis, cellular lipid content, and expression of adipogenic genes. The adipogenic effects of TBT and rosiglitazone were blocked by the addition of PPAR? antagonists, suggesting that activation of PPAR? mediates the effect of both compounds on adipogenesis. ADSCs from mice exposed to TBT in utero showed increased adipogenic capacity and reduced osteogenic capacity with enhanced lipid accumulation in response to adipogenic induction. ADSCs retrieved from animals exposed to TBT in utero showed increased expression of PPAR? target genes such as the early adipogenic differentiation gene marker fatty acid-binding protein 4 and hypomethylation of the promoter/enhancer region of the fatty acid-binding protein 4 locus. Hence, TBT alters the stem cell compartment by sensitizing multipotent stromal stem cells to differentiate into adipocytes, an effect that could likely increase adipose mass over time. PMID:20160124

Kirchner, Severine; Kieu, Tiffany; Chow, Connie; Casey, Stephanie; Blumberg, Bruce

2010-01-01

337

Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma  

PubMed Central

Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin POT1 gene (g.7:124493086 C>T, Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere length and elevated fragile telomeres suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two other Italian families, yielding a frequency of POT1 variants comparable to that of CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in American and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations. PMID:24686846

Shi, Jianxin; Yang, Xiaohong R.; Ballew, Bari; Rotunno, Melissa; Calista, Donato; Fargnoli, Maria Concetta; Ghiorzo, Paola; Paillerets, Brigitte Bressac-de; Nagore, Eduardo; Avril, Marie Francoise; Caporaso, Neil E.; McMaster, Mary L.; Cullen, Michael; Wang, Zhaoming; Zhang, Xijun; Bruno, William; Pastorino, Lorenza; Queirolo, Paola; Banuls-Roca, Jose; Garcia-Casado, Zaida; Vaysse, Amaury; Mohamdi, Hamida; Riazalhosseini, Yasser; Foglio, Mario; Jouenne, Fanelie; Hua, Xing; Hyland, Paula L.; Yin, Jinhu; Vallabhaneni, Haritha; Chai, Weihang; Minghetti, Paola; Pellegrini, Cristina; Ravichandran, Sarangan; Eggermont, Alexander; Lathrop, Mark; Peris, Ketty; Scarra, Giovanna Bianchi; Landi, Giorgio; Savage, Sharon A.; Sampson, Joshua N.; He, Ji; Yeager, Meredith; Goldin, Lynn R.; Demenais, Florence; Chanock, Stephen J.; Tucker, Margaret A.; Goldstein, Alisa M.; Liu, Yie; Landi, Maria Teresa

2014-01-01

338

Obesity genes: so close and yet so far...  

PubMed Central

Little is known about genetic variants that predispose individuals toward leanness or fatness. This minireview highlights recent advances in the study of human populations, animal models and synergistic efforts as described by De Luca and colleagues in BMC Genetics, which are beginning to harvest low-hanging fruit in the search for obesity genes. PMID:19046411

Pomp, Daniel; Mohlke, Karen L

2008-01-01

339

Gene Conversion in Human Genetic Disease  

PubMed Central

Gene conversion is a specific type of homologous recombination that involves the unidirectional transfer of genetic material from a ‘donor’ sequence to a highly homologous ‘acceptor’. We have recently reviewed the molecular mechanisms underlying gene conversion, explored the key part that this process has played in fashioning extant human genes, and performed a meta-analysis of gene-conversion events known to have caused human genetic disease. Here we shall briefly summarize some of the latest developments in the study of pathogenic gene conversion events, including (i) the emerging idea of minimal efficient sequence homology (MESH) for homologous recombination, (ii) the local DNA sequence features that appear to predispose to gene conversion, (iii) a mechanistic comparison of gene conversion and transient hypermutability, and (iv) recently reported examples of pathogenic gene conversion events. PMID:24710102

Chen, Jian-Min; Ferec, Claude; Cooper, David N.

2010-01-01

340

Impact of Methionine Synthase Gene and Methylenetetrahydrofolate Reductase Gene Polymorphisms on the Risk of Sudden Sensorineural Hearing Loss  

Microsoft Academic Search

Idiopathic sudden sensorineural hearing loss (SSNHL) represents a frequently encountered otological disease of unknown etiology. In recent years, several inherited risk factors have been found in the pathogenesis of vascular diseases. In the present study, we determined whether specific polymorphism or the combination of polymorphisms in folate-dependent homocysteine metabolism genes can act as predisposing inherited vascular risk factors in the

Menachem Gross; Gideon Friedman; Ron Eliashar; Nira Koren-Morag; Neta Goldschmidt; Iman Abou Atta; Arie Ben-Yehuda

2006-01-01

341

Behavioral training and predisposed coping strategies interact to influence resilience in male Long-Evans rats: implications for depression.  

PubMed

Effective coping strategies and adaptive behavioral training build resilience against stress-induced pathology. Both predisposed and acquired coping strategies were investigated in rats to determine their impact on stress responsiveness and emotional resilience. Male Long-Evans rats were assigned to one of the three coping groups: passive, active, or variable copers. Rats were then randomly assigned to either an effort-based reward (EBR) contingent training group or a non-contingent training group. Following EBR training, rats were tested in appetitive and stressful challenge tasks. Physiological responses included changes in fecal corticosterone and dehydroepiandrosterone (DHEA) metabolites as well as neuropeptide Y (NPY)-immunoreactivity in the hippocampus and amygdala. Regardless of a rat's predisposed coping strategy, EBR rats persisted longer than non-contingent rats in the appetitive problem-solving task. Furthermore, training and coping styles interacted to yield the seemingly most adaptive DHEA/corticosterone ratios in the EBR-trained variable copers. Regardless of training group, variable copers exhibited increased NPY-immunoreactivity in the CA1 region. PMID:22257065

Bardi, Massimo; Rhone, Alexandra P; Franssen, Catherine L; Hampton, Joseph E; Shea, Eleanor A; Hyer, Molly M; Huber, Jordan; Lambert, Kelly G

2012-05-01

342

Genetic variants in the complement system predisposing to age-related macular degeneration: a review.  

PubMed

Age-related macular degeneration (AMD) is a major cause of visual impairment in the western world. It is characterized by the presence of lipoproteinaceous deposits (drusen) in the inner layers of the retina. Immunohistochemistry studies identified deposition of complement proteins in the drusen as well as in the choroid. In the last decade, genetic studies have linked both common and rare variants in genes of the complement system to increased risk of development of AMD. Here, we review the variants described to date and discuss the functional implications of dysregulation of the alternative pathway of complement in AMD. PMID:25034031

Schramm, Elizabeth C; Clark, Simon J; Triebwasser, Michael P; Raychaudhuri, Soumya; Seddon, Johanna M; Atkinson, John P

2014-10-01

343

Ectopic expression of HOXC6 blocks myeloid differentiation and predisposes to malignant transformation.  

PubMed

Insertional mutagenesis resulting from the integration of retroviral vectors has led to the discovery of many oncogenes associated with leukemia. We investigated the role of HOXC6, identified by proximal provirus integration in a large animal hematopoietic stem cell gene therapy study, for a potential involvement in hematopoietic stem cell activity and hematopoietic cell fate decision. HOXC6 was overexpressed in the murine bone marrow transplantation model and tested in a competitive repopulation assay in comparison to the known hematopoietic stem cell expansion factor, HOXB4. We have identified HOXC6 as a factor that enhances competitive repopulation capacity in vivo and colony formation in vitro. Ectopic HOXC6 expression also induced strong myeloid differentiation and expansion of granulocyte-macrophage progenitors/common myeloid progenitors (GMPs/CMPs) in vivo, resulting in myeloid malignancies with low penetrance (3 of 17 mice), likely in collaboration with Meis1 because of a provirus integration mapped to the 3' region in the malignant clone. We characterized the molecular basis of HOXC6-induced myeloid differentiation and malignant cell transformation with complementary DNA microarray analysis. Overexpression of HOXC6 induced a gene expression signature similar to several acute myeloid leukemia subtypes when compared with normal GMPs/CMPs. These results demonstrate that HOXC6 acts as a regulator in hematopoiesis and is involved in malignant transformation. PMID:24513167

Wurm, Melanie; Kowalski, John; Heckl, Dirk; Zhang, Xiao-Bing; Nelson, Veronica; Beard, Brian C; Kiem, Hans-Peter

2014-02-01

344

Congenital heart defects and genetic variants in the methylenetetrahydroflate reductase gene  

PubMed Central

Background Most non?syndromic congenital heart defects (CHD) are caused by a complex interaction between maternal lifestyle factors, environmental exposures, and maternal and fetal genetic variants. Maternal periconceptional intake of folic acid containing vitamin supplements is reported to decrease the risk of CHD. The 677C?T and 1298A?C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene decrease enzyme activity. Objective To examine the relation between CHD and maternal and fetal MTHFR polymorphisms Methods 375 nuclear families were studied. The transmission/disequilibrium test was used to test for transmission distortion in complete triads. A log?linear approach was used to test for associations between CHD and maternal and offspring polymorphisms, and to estimate independently the contributions of maternal and fetal variants to relative risks. Haplotype frequencies were estimated and a haplotype transmission disequilibrium test carried out. Results The 1298C allele was transmitted less often than expected (p?=?0.0013). There was no distortion in the transmission of the 677T allele, neither was there evidence of a parent of origin effect in the transmission of either of the single nucleotide polymorphisms. The 677C–1298C haplotype was also transmitted less often than expected (p?=?0.0020). The relative risk associated with inheriting one copy of the 1298C allele was 0.64 (95% confidence interval, 0.48 to 0.87) and the that associated with inheriting two copies of the 1298C allele, 0.38 (0.21 to 0.70). Conclusions The apparent protective effect of the MTHFR 1298C allele against CHD could have several explanations and further study is needed. PMID:15951337

Hobbs, C A; James, S J; Parsian, A; Krakowiak, P A; Jernigan, S; Greenhaw, J J; Lu, Y; Cleves, M A

2006-01-01

345

Gene-environment interactions in severe intraventricular hemorrhage of preterm neonates.  

PubMed

Intraventricular hemorrhage (IVH) of the preterm neonate is a complex developmental disorder, with contributions from both the environment and the genome. IVH, or hemorrhage into the germinal matrix of the developing brain with secondary periventricular infarction, occurs in that critical period of time before the 32nd to 33rd wk postconception and has been attributed to changes in cerebral blood flow to the immature germinal matrix microvasculature. Emerging data suggest that genes subserving coagulation, inflammatory, and vascular pathways and their interactions with environmental triggers may influence both the incidence and severity of cerebral injury and are the subject of this review. Polymorphisms in the Factor V Leiden gene are associated with the atypical timing of IVH, suggesting an as yet unknown environmental trigger. The methylenetetrahydrofolate reductase (MTHFR) variants render neonates more vulnerable to cerebral injury in the presence of perinatal hypoxia. The present study demonstrates that the MTHFR 677C>T polymorphism and low 5-min Apgar score additively increase the risk of IVH. Finally, review of published preclinical data suggests the stressors of delivery result in hemorrhage in the presence of mutations in collagen 4A1, a major structural protein of the developing cerebral vasculature. Maternal genetics and fetal environment may also play a role. PMID:24192699

Ment, Laura R; Adén, Ulrika; Lin, Aiping; Kwon, Soo Hyun; Choi, Murim; Hallman, Mikko; Lifton, Richard P; Zhang, Heping; Bauer, Charles R

2014-01-01

346

The Effect of Multiple Single Nucleotide Polymorphisms in the Folic Acid Pathway Genes on Homocysteine Metabolism  

PubMed Central

Objective. To investigate the joint effects of the single nucleotide polymorphisms (SNPs) of genes in the folic acid pathway on homocysteine (Hcy) metabolism. Methods. Four hundred women with normal pregnancies were enrolled in this study. SNPs were identified by MassARRAY. Serum folic acid and Hcy concentration were measured. Analysis of variance (ANOVA) and support vector machine (SVM) regressions were used to analyze the joint effects of SNPs on the Hcy level. Results. SNPs of MTHFR (rs1801133 and rs3733965) were significantly associated with maternal serum Hcy level. In the different genotypes of MTHFR (rs1801133), SNPs of RFC1 (rs1051266), TCN2 (rs9606756), BHMT (rs3733890), and CBS (rs234713 and rs2851391) were linked with the Hcy level adjusted for folic acid concentration. The integrated SNPs scores were significantly associated with the residual Hcy concentration (RHC) (r = 0.247). The Hcy level was significantly higher in the group with high SNP scores than that in other groups with SNP scores of less than 0.2 (P = 0.000). Moreover, this difference was even more significant in moderate and high levels of folic acid. Conclusion. SNPs of genes in the folic acid pathway possibly affect the Hcy metabolism in the presence of moderate and high levels of folic acid. PMID:24524080

Liang, Shuang; Zhou, Yuanpeng; Wang, Huijun; Qian, Yanyan; Ma, Duan; Tian, Weidong; Persaud-Sharma, Vishwani; Yu, Chen; Ren, Yunyun; Zhou, Shufeng; Li, Xiaotian

2014-01-01

347

Analysis of 30 Genes (355 SNPS) Related to Energy Homeostasis for Association with Adiposity in European-American and Yup’ik Eskimo Populations  

Microsoft Academic Search

Objective: Human adiposity is highly heritable, but few of the genes that predispose to obesity in most humans are known. We tested candidate genes in pathways related to food intake and energy expenditure for association with measures of adiposity. Methods: We studied 355 genetic variants in 30 candidate genes in 7 molecular pathways related to obesity in two groups of

Wendy K. Chung; Amit Patki; Naoki Matsuoka; Bert B. Boyer; Nianjun Liu; Solomon K. Musani; Anna V. Goropashnaya; Perciliz L. Tan; Nicholas Katsanis; Stephen B. Johnson; Peter K. Gregersen; David B. Allison; Rudolph L. Leibel; Hemant K. Tiwari

2009-01-01

348

Need, Enabling, Predisposing, and Behavioral Determinants of Access to Preventative Care in Argentina: Analysis of the National Survey of Risk Factors  

PubMed Central

Introduction Health care utilization is an important step to disease management, providing opportunities for prevention and treatment. Anderson’s Health Behavior Model has defined utilization by need, predisposing, and enabling determinants. We hypothesize that need, predisposing, and enabling, highlighting behavioral factors are associated with utilization in Argentina. Methods We performed a logistic regression analysis of the 2005 and 2009 Argentinean Survey of Risk Factors, a cohort of 41,392 and 34,732 individuals, to explore the association between need, enabling, predisposing, and behavioral factors to blood pressure measurement in the last year. Results In the 2005 cohort, blood pressure measurement was associated with perception of health, insurance coverage, basic needs met, and income. Additionally, female sex, civil state, household type, older age groups, education, and alcohol use were associated with utilization. The 2009 cohort showed similar associations with only minor differences between the models. Conclusions We explored the association between utilization of clinical preventive services with need, enabling, predisposing, and behavioral factors. While predisposing and need determinants are associated with utilization, enabling factors such as insurance coverage provides an area for public intervention. These are important findings where policies should be focused to improve utilization of preventive services in Argentina. PMID:22984608

Jahangir, Eiman; Irazola, Vilma; Rubinstein, Adolfo

2012-01-01

349

Polymorphisms in thymidylate synthase and reduced folate carrier (SLC19A1) genes predict survival outcome in advanced non-small cell lung cancer patients treated with pemetrexed-based chemotherapy  

PubMed Central

The aim of this study was to evaluate the association between thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR) and reduced folate carrier (SLC19A1) gene polymorphisms and the treatment efficacy of pemetrexed-based chemotherapy in advanced non-small cell lung cancer (NSCLC). Advanced NSCLC patients received pemetrexed and cisplatin every three weeks. Polymorphisms in the TS, MTHFR and SLC19A1 genes were detected in peripheral blood samples using DNA sequencing and Taqman PCR. An analysis of gene polymorphisms was performed with respect to the progression-free survival (PFS), response rate (RR) and overall survival (OS) of patients treated with pemetrexed. The median PFS times for patients with the TS 2R/2R, 2R/3C or 3C/3C genotypes were significantly longer than those of patients with the 2R/3G, 3C/3G or 3G/3G genotypes (P=0.036). Patients with the SLC19A1 CC genotype had a significantly longer median OS compared with individuals with the homozygous and heterozygous genotypes (12.2 vs. 8.9 and 7.3 months, respectively; P=0.022). The PFS and OS did not differ for the three genotypes of MTHFR assessed. The RR was higher in patients with the TS 2R/2R, 2R/3C or 3C/3C genotypes than in the other groups (P=0.044). The polymorphisms of the 5?-UTR of the TS gene and exon 6 (2522) C/T of the SLC19A1 gene predict the survival of advanced NSCLC patients treated with pemetrexed. However, a large scale clinical trial is required to validate these findings. PMID:23599757

LI, WEN-JUAN; JIANG, HUA; FANG, XIN-JIAN; YE, HONG-LING; LIU, MING-HUAN; LIU, YAN-WEN; CHEN, QIAN; ZHANG, LI; ZHANG, JIN-YU; YUAN, CHUN-LUAN; ZHANG, QIU-YUN

2013-01-01

350

The Mycotoxin Deoxynivalenol Predisposes for the Development of Clostridium perfringens-Induced Necrotic Enteritis in Broiler Chickens  

PubMed Central

Both mycotoxin contamination of feed and Clostridium perfringens-induced necrotic enteritis have an increasing global economic impact on poultry production. Especially the Fusarium mycotoxin deoxynivalenol (DON) is a common feed contaminant. This study aimed at examining the predisposing effect of DON on the development of necrotic enteritis in broiler chickens. An experimental Clostridium perfringens infection study revealed that DON, at a contamination level of 3,000 to 4,000 µg/kg feed, increased the percentage of birds with subclinical necrotic enteritis from 20±2.6% to 47±3.0% (P<0.001). DON significantly reduced the transepithelial electrical resistance in duodenal segments (P<0.001) and decreased duodenal villus height (P?=?0.014) indicating intestinal barrier disruption and intestinal epithelial damage, respectively. This may lead to an increased permeability of the intestinal epithelium and decreased absorption of dietary proteins. Protein analysis of duodenal content indeed showed that DON contamination resulted in a significant increase in total protein concentration (P?=?0.023). Furthermore, DON had no effect on in vitro growth, alpha toxin production and netB toxin transcription of Clostridium perfringens. In conclusion, feed contamination with DON at concentrations below the European maximum guidance level of 5,000 µg/kg feed, is a predisposing factor for the development of necrotic enteritis in broilers. These results are associated with a negative effect of DON on the intestinal barrier function and increased intestinal protein availability, which may stimulate growth and toxin production of Clostridium perfringens. PMID:25268498

Antonissen, Gunther; Ducatelle, Richard; Haesebrouck, Freddy; Timbermont, Leen; Verlinden, Marc; Janssens, Geert Paul Jules; Eeckhaut, Venessa; Eeckhout, Mia; De Saeger, Sarah; Hessenberger, Sabine; Martel, An; Croubels, Siska

2014-01-01

351

Estudo do polimorfismo C677T do gene da metilenotetrahidrofolato redutase (MTHFR) em pacientes com mucosite de trato gastrointestinal após transplante alogênico de medula óssea.  

E-print Network

??Oral mucositis remains an important side-effect and life-threatening complication of hematopoietic stem cell transplantation. It can occurs in 100% of patients underwenting allogeneic stem cell… (more)

Fabio Luiz Coracin

2009-01-01

352

Age-Related Changes in the Global DNA Methylation Profile of Leukocytes Are Linked to Nutrition but Are Not Associated with the MTHFR C677T Genotype or to Functional Capacities  

PubMed Central

Global DNA methylation of peripheral blood leukocytes has been recently proposed as a potential biomarker for disease risk. However, the amplitude of the changes in DNA methylation associated with normal aging and the impacts of environmental changes on this variation are still unclear. In this context, we evaluated the association of global DNA methylation with nutritional habits, tobacco smoking, body mass index (BMI), clinical laboratory parameters, polymorphism C677T MTHFR, functional cognition and the daily practice of physical activity in a cancer-free older population. Leukocyte global DNA methylation from 126 older individuals was quantified using a high-throughput ELISA-based method. Global DNA hypomethylation was observed in older individuals when compared to a younger population (p?=?0.0469), confirming changes in DNA methylation in the aging process. Furthermore, the methylation profile of elders was correlated with the daily ingestion of carbohydrates (p?=?0.0494), lipids (p?=?0.0494), vitamin B6 (p?=?0.0421), magnesium (p?=?0.0302), and also to the serum levels of total protein (p?=?0.0004), alpha 2 globulin (p?=?0.0013) and albumin (p?=?0.0015). No statistically significant difference was observed when global DNA methylation were stratified according to C677T MTHFR genotypes (p?=?0.7200), BMI (p?=?0.1170), smoking habit (p?=?0.4382), physical activity in daily life (p?=?0.8492), scored cognitive function (p?=?0.7229) or depression state (p?=?0.8301). Our data indicate that age-related variations in the global DNA methylation profile of leukocytes might be modulated by the daily intake of carbohydrates, lipids, vitamin B6, and magnesium and be associated with serum protein levels, however it is independent of C677T MTHFR genotype and not correlated with BMI, smoking habit, cognitive function or the routine physical activities. PMID:23285094

Gomes, Marcus V. M.; Toffoli, Leandro V.; Arruda, Douglas W.; Soldera, Larissa M.; Pelosi, Gislaine G.; Neves-Souza, Rejane D.; Freitas, Eliane R.; Castro, Denilson T.; Marquez, Audrey S.

2012-01-01

353

Mutations in AXIN2 Cause Familial Tooth Agenesis and Predispose to Colorectal Cancer  

PubMed Central

Wnt signaling regulates embryonic pattern formation and morphogenesis of most organs. Aberrations of regulation of Wnt signaling may lead to cancer. Here, we have used positional cloning to identify the causative mutation in a Finnish family in which severe permanent tooth agenesis (oligodontia) and colorectal neoplasia segregate with dominant inheritance. Eleven members of the family lacked at least eight permanent teeth, two of whom developed only three permanent teeth. Colorectal cancer or precancerous lesions of variable types were found in eight of the patients with oligodontia. We show that oligodontia and predisposition to cancer are caused by a nonsense mutation, Arg656Stop, in the Wnt-signaling regulator AXIN2. In addition, we identified a de novo frameshift mutation 1994-1995insG in AXIN2 in an unrelated young patient with severe tooth agenesis. Both mutations are expected to activate Wnt signaling. The results provide the first evidence of the importance of Wnt signaling for the development of dentition in humans and suggest that an intricate control of Wnt-signal activity is necessary for normal tooth development, since both inhibition and stimulation of Wnt signaling may lead to tooth agenesis. Our findings introduce a new gene for hereditary colorectal cancer and suggest that tooth agenesis may be an indicator of cancer susceptibility. PMID:15042511

Lammi, Laura; Arte, Sirpa; Somer, Mirja; Jarvinen, Heikki; Lahermo, Paivi; Thesleff, Irma; Pirinen, Sinikka; Nieminen, Pekka

2004-01-01

354

Extracellular Matrix Defects in Aneurysmal Fibulin-4 Mice Predispose to Lung Emphysema  

PubMed Central

Background In this study we set out to investigate the clinically observed relationship between chronic obstructive pulmonary disease (COPD) and aortic aneurysms. We tested the hypothesis that an inherited deficiency of connective tissue might play a role in the combined development of pulmonary emphysema and vascular disease. Methods We first determined the prevalence of chronic obstructive pulmonary disease in a clinical cohort of aortic aneurysms patients and arterial occlusive disease patients. Subsequently, we used a combined approach comprising pathological, functional, molecular imaging, immunological and gene expression analysis to reveal the sequence of events that culminates in pulmonary emphysema in aneurysmal Fibulin-4 deficient (Fibulin-4R) mice. Results Here we show that COPD is significantly more prevalent in aneurysm patients compared to arterial occlusive disease patients, independent of smoking, other clinical risk factors and inflammation. In addition, we demonstrate that aneurysmal Fibulin-4R/R mice display severe developmental lung emphysema, whereas Fibulin-4+/R mice acquire alveolar breakdown with age and upon infectious stress. This vicious circle is further exacerbated by the diminished antiprotease capacity of the lungs and ultimately results in the development of pulmonary emphysema. Conclusions Our experimental data identify genetic susceptibility to extracellular matrix degradation and secondary inflammation as the common mechanisms in both COPD and aneurysm formation. PMID:25255451

Ramnath, Natasja W. M.; van de Luijtgaarden, Koen M.; van der Pluijm, Ingrid; van Nimwegen, Menno; van Heijningen, Paula M.; Swagemakers, Sigrid M. A.; van Thiel, Bibi S.; Ridwan, Ruziedi Y.; van Vliet, Nicole; Vermeij, Marcel; Hawinkels, Luuk J. A. C.; de Munck, Anne; Dzyubachyk, Oleh; Meijering, Erik; van der Spek, Peter; Rottier, Robbert; Yanagisawa, Hiromi; Hendriks, Rudi W.; Kanaar, Roland; Rouwet, Ellen V.; Kleinjan, Alex; Essers, Jeroen

2014-01-01

355

Germline SMARCE1 mutations predispose to both spinal and cranial clear cell meningiomas.  

PubMed

We recently reported SMARCE1 mutations as a cause of spinal clear cell meningiomas. Here, we have identified five further cases with non-NF2 spinal meningiomas and six with non-NF2 cranial meningiomas. Three of the spinal cases and three of the cranial cases were clear cell tumours. We screened them for SMARCE1 mutations and investigated copy number changes in all point mutation-negative samples. We identified two novel mutations in individuals with spinal clear cell meningiomas and three mutations in individuals with cranial clear cell meningiomas. Copy number analysis identified a large deletion of the 5' end of SMARCE1 in two unrelated probands with spinal clear cell meningiomas. Testing of affected and unaffected relatives of one of these individuals identified the same deletion in two affected female siblings and their unaffected father, providing further evidence of incomplete penetrance of meningioma disease in males. In addition, we found loss of SMARCE1 protein in three of 10 paraffin-embedded cranial clear cell meningiomas. Together, these results demonstrate that loss of SMARCE1 is relevant to cranial as well as spinal meningiomas. Our study broadens the spectrum of mutations in the SMARCE1 gene and expands the phenotype to include cranial clear cell meningiomas. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:25143307

Smith, Miriam J; Wallace, Andrew J; Bennett, Chris; Hasselblatt, Martin; Elert-Dobkowska, Ewelina; Evans, Linton T; Hickey, William F; van Hoff, Jack; Bauer, David; Lee, Amy; Hevner, Robert F; Beetz, Christian; du Plessis, Daniel; Kilday, John-Paul; Newman, William G; Evans, D Gareth

2014-12-01

356

Functional variations modulating PRKCA expression and alternative splicing predispose to multiple sclerosis.  

PubMed

The protein kinase C alpha (PRKCA) gene, encoding a Th17-cell-selective kinase, was repeatedly associated with multiple sclerosis (MS), but the underlying pathogenic mechanism remains unknown. We replicated the association in Italians (409 cases, 723 controls), identifying a protective signal in the PRKCA promoter (P = 0.033), and a risk haplotype in intron 3 (P = 7.7 × 10(-4); meta-analysis with previously published data: P = 4.01 × 10(-8)). Expression experiments demonstrated that the protective signal is associated with alleles conferring higher PRKCA expression levels, well fitting our observation that MS patients have significantly lower PRKCA mRNA levels in blood. The risk haplotype was shown to be driven by a GGTG ins/del polymorphism influencing the heterogeneous nuclear ribonucleoprotein H-dependent inclusion/skipping of a PRKCA alternative exon 3*. Indeed, exon 3* can be present in two different versions in PRKCA mRNAs (out-of-frame 61 bp or in-frame 66 bp long), and is preferentially included in transcripts generated through a premature polyadenylation event. The GGTG insertion downregulates 3* inclusion and shifts splicing towards the 66 bp isoform. Both events reduce the nonsense-mediated mRNA-decay-induced degradation of exon 3*-containing mRNAs. Since we demonstrated that the protein isoform produced through premature polyadenylation aberrantly localizes to the plasma membrane and/or in cytoplasmic clusters, dysregulated PRKCA 3* inclusion may represent an additional mechanism relevant to MS susceptibility. PMID:25080502

Paraboschi, Elvezia M; Rimoldi, Valeria; Soldà, Giulia; Tabaglio, Tommaso; Dall'Osso, Claudia; Saba, Elena; Vigliano, Marco; Salviati, Alessandro; Leone, Maurizio; Benedetti, Maria D; Fornasari, Diego; Saarela, Janna; De Jager, Philip L; Patsopoulos, Nikolaos A; D'Alfonso, Sandra; Gemmati, Donato; Duga, Stefano; Asselta, Rosanna

2014-12-20

357

Rnf8 deficiency impairs class switch recombination, spermatogenesis, and genomic integrity and predisposes for cancer  

PubMed Central

Signaling and repair of DNA double-strand breaks (DSBs) are critical for preventing immunodeficiency and cancer. These DNA breaks result from exogenous and endogenous DNA insults but are also programmed to occur during physiological processes such as meiosis and immunoglobulin heavy chain (IgH) class switch recombination (CSR). Recent studies reported that the E3 ligase RNF8 plays important roles in propagating DNA DSB signals and thereby facilitating the recruitment of various DNA damage response proteins, such as 53BP1 and BRCA1, to sites of damage. Using mouse models for Rnf8 mutation, we report that Rnf8 deficiency leads to impaired spermatogenesis and increased sensitivity to ionizing radiation both in vitro and in vivo. We also demonstrate the existence of alternative Rnf8-independent mechanisms that respond to irradiation and accounts for the partial recruitment of 53bp1 to sites of DNA damage in activated Rnf8?/? B cells. Remarkably, IgH CSR is impaired in a gene dose-dependent manner in Rnf8 mutant mice, revealing that these mice are immunodeficient. In addition, Rnf8?/? mice exhibit increased genomic instability and elevated risks for tumorigenesis indicating that Rnf8 is a novel tumor suppressor. These data unravel the in vivo pleiotropic effects of Rnf8. PMID:20385750

Li, Li; Halaby, Marie-Jo; Hakem, Anne; Cardoso, Renato; El Ghamrasni, Samah; Harding, Shane; Chan, Norman; Bristow, Robert; Sanchez, Otto; Durocher, Daniel

2010-01-01

358

A meta-analysis of genotypes and haplotypes of methylenetetrahydrofolate reductase gene polymorphisms in breast cancer.  

PubMed

The association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and breast cancer risk has been extensively explored, but their results are conflicting rather than conclusive. To derive a more precise estimation, we carried out not only an updated meta-analysis but also a combined analysis based on all the available studies estimating the association between MTHFR C677T and/or A1298C and breast cancer risk. With respect to C677T polymorphism, the results suggested that 677T allele was associated with significantly elevated breast cancer risk in overall analysis (T vs. C: OR 1.073, 95 % CI 1.028-1.120; TT vs. CC: OR 1.177, 95 % CI 1.072-1.293; TT vs. CC + CT: OR 1.175, 95 % CI 1.073-1.288); Stratifying by ethnicity, significantly increased risk was only found in East Asians (T vs. C: OR 1.150, 95 % CI 1.039-1.273; TT vs. CC: OR 1.441, 95 % CI 1.145-1.814; TT vs. CC + CT: OR 1.413, 95 % CI 1.148-1.739); When stratified by menopausal status, statistically significant association was found for postmenopausal women (CT + TT vs. CC: OR 1.092, 95 % CI 1.011-1.179). In regard to A1298C polymorphism, no significant associations were found between the polymorphism and breast cancer risk. With respect to MTHFR haplotypes, significantly elevated breast cancer risk was associated with 677T-1298C for overall result (OR 1.498, 95 % CI 1.143-1.962) and for Caucasians (OR 2.088, 95 % CI 1.277-3.416) when compared with 677C-1298A; Haplotype 677C-1298C might provide higher protection than 677C-1298A in East Asians (OR 0.840, 95 % CI 0.742-0.949). The combined genotypes for C677T and A1298C produced a significant OR for the 677TT/1298AC relative to 677CC/1298AA in overall population (OR 2.047, 95 % CI 1.275-3.288); When stratified by ethnicity, significant ORs were only found for East Asians (677CC/1298CC vs. 677CC/1298AA: OR 0.686, 95 % CI 0.478-0.985; 677TT/1298AC vs. 677CC/1298AA: OR 2.181, 95 % CI 1.179-4.035). The findings suggest that the MTHFR C677T polymorphism but not A1298C, and some variants on their combined genotypes or haplotypes may be involved with the development of breast cancer. PMID:24973876

Zhong, Shanliang; Chen, Zhiyuan; Yu, Xinnian; Li, Wenjing; Tang, Jinhai; Zhao, Jianhua

2014-09-01

359

Mutations in the Filaggrin are Predisposing Factor in Korean Children With Atopic Dermatitis  

PubMed Central

Purpose Filaggrin (FLG) is a key protein that facilitates the terminal differentiation of the epidermis and the formation of the skin barrier. Recent studies showed that atopic dermatitis (AD) associates closely with loss-of-function mutations in the FLG gene. Asian and European populations differ in the frequencies of FLG mutations. Several FLG mutations, including 3321delA, E2422X, K4671X, S2554X, and R501X, occur frequently in Chinese and Japanese populations. The association between three FLG null mutations and AD in Korean children was investigated. Methods The FLG mutations in 1,430 children (aged 0-18 years) with AD and 862 control subjects were genotyped by using the TaqMan assay. Results The FLG null mutation E2422X was not detected in any patients with AD or control subjects. The R501X null mutation was detected in only one child with AD (0.1%). Children with AD had the 3321delA deletion significantly more frequently (2.4%) than the control subjects (0.0%, P<0.001). Children with AD also had a significantly higher combined allele frequency of the three FLG null mutations (2.6%) than the controls (0.0%, P<0.001). The 3321delA null mutation did not associate significantly with AD severity (P=0.842). When the patients with AD were divided into allergic AD and non-allergic AD patient groups, these two groups did not differ in terms of the frequency of 3321delA. Conclusions The Korean children had a lower frequency of FLG mutations than European populations. FLG null mutations may be associated with the development of AD in Korean children. PMID:23814674

Yu, Ho-Sung; Kang, Mi-Jin; Jung, Young-Ho; Kim, Hyung-Young; Seo, Ju-Hee; Kim, Young-Joon; Lee, Seung-Hwa; Kim, Ha-Jung; Kwon, Ji-Won; Kim, Byoung-Ju; Yu, Jinho

2013-01-01

360

Blood pressure loci identified with a gene-centric array.  

PubMed

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies. PMID:22100073

Johnson, Toby; Gaunt, Tom R; Newhouse, Stephen J; Padmanabhan, Sandosh; Tomaszewski, Maciej; Kumari, Meena; Morris, Richard W; Tzoulaki, Ioanna; O'Brien, Eoin T; Poulter, Neil R; Sever, Peter; Shields, Denis C; Thom, Simon; Wannamethee, Sasiwarang G; Whincup, Peter H; Brown, Morris J; Connell, John M; Dobson, Richard J; Howard, Philip J; Mein, Charles A; Onipinla, Abiodun; Shaw-Hawkins, Sue; Zhang, Yun; Davey Smith, George; Day, Ian N M; Lawlor, Debbie A; Goodall, Alison H; Fowkes, F Gerald; Abecasis, Gonçalo R; Elliott, Paul; Gateva, Vesela; Braund, Peter S; Burton, Paul R; Nelson, Christopher P; Tobin, Martin D; van der Harst, Pim; Glorioso, Nicola; Neuvrith, Hani; Salvi, Erika; Staessen, Jan A; Stucchi, Andrea; Devos, Nabila; Jeunemaitre, Xavier; Plouin, Pierre-François; Tichet, Jean; Juhanson, Peeter; Org, Elin; Putku, Margus; Sõber, Siim; Veldre, Gudrun; Viigimaa, Margus; Levinsson, Anna; Rosengren, Annika; Thelle, Dag S; Hastie, Claire E; Hedner, Thomas; Lee, Wai K; Melander, Olle; Wahlstrand, Björn; Hardy, Rebecca; Wong, Andrew; Cooper, Jackie A; Palmen, Jutta; Chen, Li; Stewart, Alexandre F R; Wells, George A; Westra, Harm-Jan; Wolfs, Marcel G M; Clarke, Robert; Franzosi, Maria Grazia; Goel, Anuj; Hamsten, Anders; Lathrop, Mark; Peden, John F; Seedorf, Udo; Watkins, Hugh; Ouwehand, Willem H; Sambrook, Jennifer; Stephens, Jonathan; Casas, Juan-Pablo; Drenos, Fotios; Holmes, Michael V; Kivimaki, Mika; Shah, Sonia; Shah, Tina; Talmud, Philippa J; Whittaker, John; Wallace, Chris; Delles, Christian; Laan, Maris; Kuh, Diana; Humphries, Steve E; Nyberg, Fredrik; Cusi, Daniele; Roberts, Robert; Newton-Cheh, Christopher; Franke, Lude; Stanton, Alice V; Dominiczak, Anna F; Farrall, Martin; Hingorani, Aroon D; Samani, Nilesh J; Caulfield, Mark J; Munroe, Patricia B

2011-12-01

361

LQTS gene LOVD database.  

PubMed

The Long QT Syndrome (LQTS) is a group of genetically heterogeneous disorders that predisposes young individuals to ventricular arrhythmias and sudden death. LQTS is mainly caused by mutations in genes encoding subunits of cardiac ion channels (KCNQ1, KCNH2,SCN5A, KCNE1, and KCNE2). Many other genes involved in LQTS have been described recently(KCNJ2, AKAP9, ANK2, CACNA1C, SCNA4B, SNTA1, and CAV3). We created an online database(http://www.genomed.org/LOVD/introduction.html) that provides information on variants in LQTS-associated genes. As of February 2010, the database contains 1738 unique variants in 12 genes. A total of 950 variants are considered pathogenic, 265 are possible pathogenic, 131 are unknown/unclassified, and 292 have no known pathogenicity. In addition to these mutations collected from published literature, we also submitted information on gene variants, including one possible novel pathogenic mutation in the KCNH2 splice site found in ten Chinese families with documented arrhythmias. The remote user is able to search the data and is encouraged to submit new mutations into the database. The LQTS database will become a powerful tool for both researchers and clinicians. PMID:20809527

Zhang, Tao; Moss, Arthur; Cong, Peikuan; Pan, Min; Chang, Bingxi; Zheng, Liangrong; Fang, Quan; Zareba, Wojciech; Robinson, Jennifer; Lin, Changsong; Li, Zhongxiang; Wei, Junfang; Zeng, Qiang; Qi, Ming

2010-11-01

362

Examining the Diet of Post-Migrant Hispanic Males Using the Precede-Proceed Model: Predisposing, Reinforcing, and Enabling Dietary Factors  

ERIC Educational Resources Information Center

Objective: To examine socio-environmental, behavioral, and predisposing, reinforcing, and enabling (PRE) factors contributing to post-migration dietary behavior change among a sample of traditional Hispanic males. Design: In this descriptive study, semistructured interviews, a group interview, and photovoice, followed by group interviews, were…

Castellanos, Diana Cuy; Downey, Laura; Graham-Kresge, Susan; Yadrick, Kathleen; Zoellner, Jamie; Connell, Carol L.

2013-01-01

363

Decision-Making after Prenatal Diagnosis of a Syndrome Predisposing to Intellectual Disability: What Prospective Parents Need to Know and the Importance of Non-Medical Information  

ERIC Educational Resources Information Center

Background: Recently researchers have suggested that non-medical information may impact the decision to continue or terminate a pregnancy after a prenatal diagnosis. This study is an investigation of what type of information prospective parents need for this decision-making in the case of a condition predisposing to intellectual disability.…

Huyard, Caroline

2012-01-01

364

Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival  

PubMed Central

Background The antifolate agent methotrexate is an important component of maintenance therapy in acute lymphoblastic leukemia, although methotrexate-related toxicity is often a reason for interruption of chemotherapy. Prediction of toxicity is difficult because of inter-individual variability susceptibility to antileukemic agents. Methotrexate interferes with folate metabolism leading to depletion of reduced folates. Design and Methods The aim of this study was to investigate the influence of polymorphisms for folate metabolizing enzymes with respect to toxicity and survival in adult patients with acute lymphoblastic leukemia treated with methotrexate maintenance therapy. To this purpose, we evaluated possible associations between genotype and hematologic and non-hematologic toxicity and effects on survival at 2 years of follow-up in patients with acute lymphoblastic leukemia. Results Polymorphisms in the genes encoding for methylenetetrahydrofolate reductase (MTHFR 677C>T) and in dihydrofolate reductase (DHFR 19 bp deletion) significantly increased the risk of hepatotoxicity in single (odds ratio 5.23, 95% confidence interval 1.13–21.95 and odds ratio 4.57, 95% confidence interval 1.01–20.77, respectively) and in combined analysis (odds ratio 6.82, 95% confidence interval 1.38–33.59). MTHFR 677C>T also increased the risk of leukopenia and gastrointestinal toxicity, whilst thymidylate synthase 28 bp repeat polymorphism increased the risk of anemia (odds ratio 8.48, 95% confidence interval 2.00–36.09). Finally, patients with MTHFR 677TT had a decreased overall survival rate (hazard ratio 2.37, 95% confidence interval 1.46–8.45). Conclusions Genotyping of folate polymorphisms might be useful in adult acute lymphoblastic leukemia to optimize methotrexate therapy, reducing the associated toxicity with possible effects on survival. PMID:19648163

Ongaro, Alessia; De Mattei, Monica; Della Porta, Matteo Giovanni; Rigolin, GianMatteo; Ambrosio, Cristina; Di Raimondo, Francesco; Pellati, Agnese; Masieri, Federica Francesca; Caruso, Angelo; Catozzi, Linda; Gemmati, Donato

2009-01-01

365

Effect of n-3 polyunsaturated fatty acid on gene expression of the critical enzymes involved in homocysteine metabolism  

PubMed Central

Background Previous studies showed that plasma n-3 polyunsaturated fatty acid (PUFA) was negatively associated with plasma homocysteine (Hcy). Objective We investigated the regulatory effect of n-3 PUFA on mRNA expression of the critical genes encoding the enzymes involved in Hcy metabolism. Methods HepG2 cells were treated with docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), alpha-linolenic acid (ALA) respectively for 48 h. The cells were collected and total RNA was isolated. The mRNA expression levels of the genes were determined by using Real Time-PCR. Results Compared with controls, the mRNA expression levels of 5-methyltetrahydrofolate reductase (MTHFR) were significantly increased in the DHA group (p < 0.05) and ALA group (p < 0.05); Significantly down-regulated mRNA expression of methionine adenosyltransferase (MAT) was observed with the treatments compared with the controls; the level of MAT expression was significant lower in the DHA group than the ALA group (p < 0.05); Cystathionine-?-lyase (CSE) expression was significantly increased in the DHA (p < 0.05) and EPA groups (p < 0.05) compared with control. No significant changes were shown in mRNA expression levels of S-adenosylhomocysteine hydrolases (SAHH), cystathionine ?-synthase (CBS), and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR). Conclusions Our results suggest that DHA up-regulates CSE and MTHFR mRNA expression and down-regulates MAT mRNA expression involved in Hcy metabolism. PMID:22260268

2012-01-01

366

Folate and Vitamin B12 Related Genes and Risk for Omphalocele  

PubMed Central

Both taking folic acid-containing vitamins around conception and consuming food fortified with folic acid have been reported to reduce omphalocele rates. Genetic factors are etiologically important in omphalocele as well; our pilot study showed a relationship with the folate metabolic enzyme gene methylenetetrahydrofolate reductase (MTHFR). We studied 169 non-aneuploid omphalocele cases and 761 unaffected, matched controls from all New York State births occurring between 1998 and 2005 to look for associations with single nucleotide polymorphisms (SNPs) known to be important in folate, vitamin B12, or choline metabolism. In the total study population, variants in the transcobalamin receptor gene (TCblR), rs2232775 (Q8R), and the MTHFR gene, rs1801131 (1298A>C), were significantly associated with omphalocele. In African-Americans significant associations were found with SNPs in genes for the vitamin B12 transporter (TCN2) and the vitamin B12 receptor (TCblR). A SNP in the homocysteine-related gene, betaine-homocysteine S-methyltransferase (BHMT), rs3733890 (R239Q), was significantly associated with omphalocele in both African-Americans and Asians. Only the TCblR association in the total population remained statistically significant if Bonferroni correction was applied. The finding that transcobalamin receptor (TCblR) and transporter (TCN2) SNPs and a BHMT SNP were associated with omphalocele suggests that disruption of methylation reactions, in which folate, vitamin B12, and homocysteine play critical parts, may be a risk factor for omphalocele. Our data, if confirmed, suggest that supplements containing both folic acid and vitamin B12 may be beneficial in preventing omphaloceles. PMID:22116453

Mills, James L.; Carter, Tonia C.; Kay, Denise M.; Browne, Marilyn; Brody, Lawrence C.; Liu, Aiyi; Romitti, Paul A.; Caggana, Michele; Druschel, Charlotte

2012-01-01

367

Clinical evaluation of tumor characteristics predisposing serum thyroglobulin to be undetectable in patients with differentiated thyroid cancer  

SciTech Connect

This study delineates tumor characteristics which predispose serum thyroglobulin (TG) to be undetectable in patients in spite of persistent or recurrent differentiated thyroid cancer. Three hundred seventy four thyroid carcinoma patients with completed thyroid ablation were investigated by means of conventional diagnostic procedures (iodine-131 total-body scan, x-ray, TG determination) and, in addition, with high-resolution sonographic study of the neck. Sensitivity of TG for the detection of metastases amounted to 83% under TSH stimulation and 50% under thyroxine (T4) treatment. Specificity proved to be 95% under TSH stimulation and 99% under T4 treatment. Common features of the tumors associated with false-negative TG determinations (n = 16) were papillary histologic characteristics, manifestation in lymph nodes of the neck or mediastinum, and small size. It is therefore necessary for the early detection of persistent or recurrent papillary cancer metastases to perform in addition to iodine-131 scans high-resolution sonography of the neck in combination with the determination of TG serum concentrations under endogenous TSH stimulation.

Mueller-Gaertner, H.W.Sc.; Schneider, C.

1988-03-01

368

[Does the Tako-Tsubo syndrome need a certain coronary anatomy in the apical ventricular region as predisposing factor?].  

PubMed

The Tako-Tsubo transient left ventricular apical ballooning was born as a clinical profile in the year 2001. This syndrome occurs mainly in women older than 60 years and it is frequently preceded by a physical or emotional stress. Its presentation simulates a myocardial infarction, although with some differences: the pain is not always typical, and its intensity is moderate. The electrocardiogram reveals an elevation of ST in the anterior face in 90% of the cases; from the second day on, negative T waves in V2 through V6 leads are present, along with prolongation of the QTc interval. Enzymes are poorly elevated as expected from the electrical alterations. The alteration that defines the syndrome is the hypokinesis or akinesis of the apical segments with hyperkinesis of the basal ones. The main uncertainty of the Tako-Tsubo syndrome is its pathogenesis, its elucidation will provide advances in the practical handling of this syndrome2. We present the clinical case of a patient with this syndrome and a review of the existing medical literature on the possible association with a predisposing coronary anatomy in the apical segment. PMID:17500191

Nevado Portero, Jaime; Fernández Quero, Mónica; Jiménez Díaz, Javier; Benezet Mazuecos, Javier; Campos Pareja, Ana

2007-01-01

369

Uterine rupture revisited: Predisposing factors, clinical features, management and outcomes from a tertiary care center in Turkey  

PubMed Central

Objective: To determine the predisposing factors, modes of clinical presentation, management modalities and fetomaternal outcomes of uterine rupture cases at a tertiary care center in Turkey. Methodology: A 14-year retrospective analysis of 61 gravid (>20 weeks of gestation) uterine rupture cases between January 1998 to March 2012 was carried out. Results: The incidence of ruptured uteri was calculated to be 0.116%. Persistence for vaginal delivery after cesarean was the most common cause of uterine rupture (31.1%). Ablatio placenta was the most common co-existent obstetric pathology (4.9%). Bleeding was the main symptom at presentation (44.3%) and complete type of uterine rupture (93.4%) was more likely to occur. Isthmus was the most vulnerable part of uterus (39.3%) for rupture. The longer the interval between rupture and surgical intervention, the longer the duration of hospitalization was. Older patients with increased number of previous pregnancies were likely to have longer hospitalization periods. Conclusion: Rupture of gravid uterus brings about potentially hazardous risks. Regular antenatal care, hospital deliveries and vigilance during labor with quick referral to a well-equipped center may reduce the incidence of this condition. PMID:24353622

Turgut, Abdulkadir; Ozler, Ali; Siddik Evsen, Mehmet; Ender Soydinc, Hatice; Yaman Goruk, Neval; Karacor, Talip; Gul, Talip

2013-01-01

370

?-Catenin stabilization stalls the transition from double-positive to single-positive stage and predisposes thymocytes to malignant transformation  

PubMed Central

Activation of ?-catenin has been causatively linked to the etiology of colon cancer. Conditional stabilization of this molecule in pro-T cells promotes thymocyte development without the requirement for pre-TCR signaling. We show here that activated ?-catenin stalls the developmental transition from the double-positive (DP) to the single-positive (SP) thymocyte stage and predisposes DP thymocytes to transformation. ?-Catenin–induced thymic lymphomas have a leukemic arrest at the early DP stage. Lymphomagenesis requires Rag activity, which peaks at this developmental stage, as well as additional secondary genetic events. A consistent secondary event is the transcriptional up-regulation of c-Myc, whose activity is required for transformation because its conditional ablation abrogates lymphomagenesis. In contrast, the expression of Notch receptors as well as targets is reduced in DP thymocytes with stabilized ?-catenin and remains low in the lymphomas, indicating that Notch activation is not required or selected for in ?-catenin–induced lymphomas. Thus, ?-catenin activation may provide a mechanism for the induction of T-cell–acute lymphoblastic leukemia (T-ALL) that does not depend on Notch activation. PMID:17317856

Guo, Zhuyan; Dose, Marei; Kovalovsky, Damian; Chang, Rui; O'Neil, Jennifer; Look, A. Thomas; von Boehmer, Harald; Khazaie, Khashayarsha

2007-01-01

371

A structural bioinformatics approach for identifying proteins predisposed to bind linear epitopes on pre-selected target proteins  

PubMed Central

We have developed a protocol for identifying proteins that are predisposed to bind linear epitopes on target proteins of interest. The protocol searches through the protein database for proteins (scaffolds) that are bound to peptides with sequences similar to accessible, linear epitopes on the target protein. The sequence match is considered more significant if residues calculated to be important in the scaffold–peptide interaction are present in the target epitope. The crystal structure of the scaffold–peptide complex is then used as a template for creating a model of the scaffold bound to the target epitope. This model can then be used in conjunction with sequence optimization algorithms or directed evolution methods to search for scaffold mutations that further increase affinity for the target protein. To test the applicability of this approach we targeted three disease-causing proteins: a tuberculosis virulence factor (TVF), the apical membrane antigen (AMA) from malaria, and hemagglutinin from influenza. In each case the best scoring scaffold was tested, and binders with Kds equal to 37 ?M and 50 nM for TVF and AMA, respectively, were identified. A web server (http://rosettadesign.med.unc.edu/scaffold/) has been created for performing the scaffold search process with user-defined target sequences. PMID:23341643

Choi, Eun Jung; Jacak, Ron; Kuhlman, Brian

2013-01-01

372

Chronic stress exposure may affect the brain's response to high calorie food cues and predispose to obesogenic eating habits.  

PubMed

Exaggerated reactivity to food cues involving calorically-dense foods may significantly contribute to food consumption beyond caloric need. Chronic stress, which can induce palatable "comfort" food consumption, may trigger or reinforce neural pathways leading to stronger reactions to highly rewarding foods. We implemented functional magnetic resonance imaging (fMRI) to assess whether chronic stress influences activation in reward, motivation and executive brain regions in response to pictures of high calorie and low calorie foods in thirty women. On separate lab visits, we also assessed food intake from a snack food buffet and circulating cortisol. In women reporting higher chronic stress (HCS), pictures of high calorie foods elicited exaggerated activity in regions of the brain involving reward, motivation, and habitual decision-making. In response to pictures of high calorie food, higher chronic stress was also associated with significant deactivation in frontal regions (BA10; BA46) linked to strategic planning and emotional control. In functional connectivity analysis, HCS strengthened connectivity between amygdala and the putamen, while LCS enhanced connectivity between amygdala and the anterior cingulate and anterior prefrontal cortex (BA10). A hypocortisolemic signature and more consumption of high calorie foods from the snack buffet were observed in the HCS group. These results suggest that persistent stress exposure may alter the brain's response to food in ways that predispose individuals to poor eating habits which, if sustained, may increase risk for obesity. PMID:23954410

Tryon, Matthew S; Carter, Cameron S; Decant, Rashel; Laugero, Kevin D

2013-08-15

373

Germline Missense Changes in the APC Gene and Their Relationship to Disease  

Microsoft Academic Search

Familial adenomatous polyposis (FAP) is characterized by the presence of hundreds to thousands of adenomas that carpet the entire colon and rectum. Nonsense and frameshift mutations in the adenomatous polyposis coli (APC) gene account for the majority of mutations identified to date and predispose primarily to the typical disease phenotype. Some APC mutations are associated with a milder form of

Rodney J Scott; Renee Crooks; Lindy Rose; John Attia; Ammarin Thakkinstian; Lesley Thomas; Allan D Spigelman; Cliff J Meldrum

2004-01-01

374

Factors Predisposing to Infection  

Microsoft Academic Search

In the old, age-related changes in host defenses play a key role in the increased susceptibility and severity of infections.\\u000a \\u000a Comorbidities are common in older persons and may further compromise host defenses.\\u000a \\u000a \\u000a Innate and adaptive immunity are now known to be interactive systems; both are affected by age and disease, and changes in\\u000a innate immunity affects adaptive immunity.\\u000a \\u000a \\u000a \\u000a Recent studies

Dean C. Norman

375

Polymorphisms of Pyrimidine Pathway Enzymes Encoding Genes and HLA-B*40:01 Carriage in Stavudine-Associated Lipodystrophy in HIV-Infected Patients  

PubMed Central

Purpose To assess in a cohort of Caucasian patients exposed to stavudine (d4T) the association of polymorphisms in pyrimidine pathway enzymes and HLA-B*40?01 carriage with HIV/Highly active antiretroviral therapy (HAART)-associated lipodystrophy syndrome (HALS). Methods Three-hundred and thirty-six patients, 187 with HALS and 149 without HALS, and 72 uninfected subjects were recruited. The diagnosis of HALS was performed following the criteria of the Lipodystrophy Severity Grading Scale. Polymorphisms in the thymidylate synthase (TS) and methylene-tetrahydrofolate reductase (MTHFR) genes were determined by direct sequencing, HLA-B genotyping by PCR-SSOr Luminex Technology, and intracellular levels of stavudine triphosphate (d4T-TP) by a LC-MS/MS assay method. Results HALS was associated with the presence of a low expression TS genotype polymorphism (64.7% vs. 42.9%, OR?=?2.43; 95%CI: 1.53–3.88, P<0.0001). MTHFR gene polymorphisms and HLA-B*40?01 carriage were not associated with HALS or d4T-TP intracellular levels. Low and high expression TS polymorphisms had different d4T-TP intracellular levels (25.60 vs. 13.60 fmol/106 cells, P<0.0001). Independent factors associated with HALS were(OR [95%CI]: (a) Combined TS and MTHFR genotypes (p?=?0.006, reference category (ref.): ‘A+A’; OR for ‘A+B’ vs. ref.: 1.39 [0.69–2.80]; OR for ‘B+A’ vs. ref.: 2.16 [1.22–3.83]; OR for ‘B+B’ vs. ref.: 3.13, 95%CI: 1.54–6.35), (b) maximum viral load ?5 log10 (OR: 2.55, 95%CI: 1.56–4.14, P?=?0.001), (c) use of EFV (1.10 [1.00–1.21], P?=?0.008, per year of use). Conclusion HALS is associated with combined low-expression TS and MTHFR associated with high activity polymorphisms but not with HLA-B*40?01 carriage in Caucasian patients with long-term exposure to stavudine. PMID:23840581

Pruvost, Alain; Torres, Ferran; Salazar, Juliana; Gutierrez, Maria del Mar; Domingo, Joan Carles; Fernandez, Irene; Villarroya, Francesc; Vidal, Francesc; Baiget, Montserrat; de la Calle-Martin, Oscar

2013-01-01

376

Predisposing trees to die during drought: How physiology and climate history influence mortality in southwestern U.S. piñon pine  

NASA Astrophysics Data System (ADS)

Detailed physical and chemical studies of trees that die and survive during drought provide insight into the historic conditions and physiological mechanisms that underpin episodes of tree mortality. We seek to deduce key physiological parameters that influenced the mortality and survival of piñon pine (Pinus edulis) during relatively warmer (2000's) and cooler (1950's) droughts in the southwestern U.S. Using recently sampled and archived tree-ring specimens of trees that died and survived during the 2000's and 1950's droughts, we constructed time series from two measurements that serve as integrated parameters of whole-tree physiological function: radial growth and stable carbon isotope ratios (?13C) in tree-ring cellulose. We focused our efforts on addressing two hypotheses: 1) piñon trees that died had hydraulic characteristics that predisposed them to succumb to drought and associated bark beetle outbreaks through either hydraulic failure or carbon starvation; 2) dead tree growth and ?13C should be more responsive to climate than surviving trees if drought and temperature driven stress are the ultimate drivers of tree death. We further hypothesize that if dying trees respond to drought by closing their stomata to avoid hydraulic failure, they limit their ability to photosynthesize and should exhibit lower growth and more positive ?13C than trees that survive. Conversely, if trees that died maintained relatively open stomata and succumbed to drought via hydraulic failure, they should exhibit more negative ?13C than trees that survive. Leading up to the 2000's drought, growth in trees that died was lower than in surviving trees, consistent with our expectation. ?13C in trees that died was more negative than in surviving trees but both growth and ?13C of trees that died were less responsive to climate than surviving trees, counter to our initial hypotheses. Our ?13C results are consistent with the hypothesis that the trees that died maintained higher stomatal conductance during drought and hence ran a greater risk of hydraulic failure than trees that survived. An alternative hypothesis is that trees that died had lower leaf area per unit root area, which could also explain higher growth in surviving trees. However, this explanation is inconsistent with previous published results on leaf area of piñon pines that died and survived during the 2000's drought. Notably, tree growth data extending back further in time reveals that growth of live and dead trees was similar until the 1950's drought, when growth trajectories diverged. The mechanism underlying this growth divergence is not yet clear, but this result suggests an important role of previous droughts in predisposing trees to die during subsequent droughts. This raises the possibility of increased future mortality if drought frequency increases even in the absence of changes in drought severity. We are currently expanding our analyses to trees that died and survived across multiple sites covering both the 2000's and the 1950's drought, which will allow us to compare mortality mechanisms across landscapes and between droughts of different magnitudes and temperature profiles.

Macalady, A. K.; English, N. B.; McDowell, N. G.; Swetnam, T. W.

2011-12-01

377

Early life nutrient restriction impairs blood-brain metabolic profile and neurobehavior predisposing to Alzheimer's disease with aging.  

PubMed

Prenatal nutrient restriction (NR) culminating in intra-uterine growth restriction (IUGR) with postnatal catch up growth leads to diabesity. In contrast, postnatal NR with growth restriction (PNGR) superimposed on IUGR (IPGR) protects young and aging adults from this phenotype. We hypothesized that PNGR/IPGR will compromise the blood-brain metabolic profile impairing neurobehavior and predisposing to Alzheimer's disease (AD). NR (50%) in late gestation followed by cross-fostering of rat pups to either ad lib fed (CON) or NR (50%) lactating mothers generated CON, IUGR, PNGR and IPGR male (M) and female (F) offspring that were examined through the life span. In PNGR/IPGR plasma/CSF glucose and lactate decreased while ketones increased in (M) and (F) (PN21, PN50). In addition increased brain glucose transporters, Glut1 & Glut3, greater brain derived neurotrophic factor (BDNF), reduced Glut4, with unchanged serotonin transporter concentrations were noted in (F) (PN50-60). While (F) displayed more hyperactivity, both (F) and (M) exhibited anxiety although socially and cognitively unimpaired (PN25-28&50). Aging (15-17 m) (F) not (M), expressed low plasma insulin, reduced brain IRS-2, pAkt, and pGSK-3?(Ser9), unchanged pPDK1, pTau or lipoprotein receptor related protein 1 (LRP1), higher glial fibrillary acidic protein (GFAP) and spinophilin but a 10-fold increased amyloid-?42. We conclude that therapeutically superimposing PNGR on IUGR (IPGR) should be carefully weighed in light of unintended consequences related to perturbed neurobehavior and potential predilection for AD. PMID:23228723

Tomi, Masatoshi; Zhao, Yuanzi; Thamotharan, Shanthie; Shin, Bo-Chul; Devaskar, Sherin U

2013-02-01

378

Early Life Nutrient Restriction Impairs Blood-Brain Metabolic Profile and Neurobehavior Predisposing to Alzheimer's disease with Aging  

PubMed Central

Prenatal nutrient restriction (NR) culminating in intra-uterine growth restriction (IUGR) with postnatal catch up growth leads to diabesity. In contrast, postnatal NR with growth restriction (PNGR) superimposed on IUGR (IPGR) protects young and aging adults from this phenotype. We hypothesized that PNGR/IPGR will compromise the blood-brain metabolic profile impairing neurobehavior and predisposing to Alzheimer’s disease (AD). NR (50%) in late gestation followed by cross-fostering of rat pups to either ad lib fed (CON) or NR (50%) lactating mothers generated CON, IUGR, PNGR and IPGR male (M) and female (F) offspring that were examined through the life span. In PNGR/IPGR plasma/CSF glucose and lactate decreased while ketones increased in (M) and (F) (PN21, PN50). In addition increased brain glucose transporters, Glut1 & Glut3, greater brain derived neurotrophic factor (BDNF), reduced Glut4, with unchanged serotonin transporter concentrations were noted in (F) (PN50-60). While (F) displayed more hyperactivity, both (F) and (M) exhibited anxiety although socially and cognitively unimpaired (PN25-28&50). Aging (15-17m) (F) not (M), expressed low plasma insulin, reduced brain IRS-2, pAkt, and pGSK-3pSer9, unchanged pPDK1, pTau or lipoprotein receptor related protein 1 (LRP1), higher glial fibrillary acidic protein (GFAP) and spinophilin but a 10-fold increased amyloid-p42. We conclude that therapeutically superimposing PNGR on IUGR (IPGR) should be carefully weighed in light of unintended consequences related to perturbed neurobehavior and potential predilection for AD. PMID:23228723

Tomi, Masatoshi; Zhao, Yuanzi; Thamotharan, Shanthie; Shin, Bo-Chul; Devaskar, Sherin U.

2014-01-01

379

Hormonal regulation of energy-protein homeostasis in hemodialysis patients: an anorexigenic profile that may predispose to adverse cardiovascular outcomes  

PubMed Central

To assess whether endocrine dysfunction may cause derangement in energy homeostasis in patients undergoing hemodialysis (HD), we profiled hormones, during a 3-day period, from the adipose tissue and the gut and the nervous system around the circadian clock in 10 otherwise healthy HD patients and 8 normal controls. The protocol included a 40-h fast. We also measured energy-protein intake and output and assessed appetite and body composition. We found many hormonal abnormalities in HD patients: 1) leptin levels were elevated, due, in part, to increased production, and nocturnal surge in response to daytime feeding, exaggerated. 2) Peptide YY (PYY), an anorexigenic gut hormone, was markedly elevated and displayed an augmented response to feeding. 3) Acylated ghrelin, an orexigenic gut hormone, was lower and did not exhibit the premeal spike as observed in the controls. 4) neuropeptide Y (NPY), a potent orexigenic peptide, was markedly elevated and did not display any circadian variation. 5) Norepinephrine, marginally elevated, did not exhibit the normal nocturnal dip. By contrast, ?-melanocyte-stimulating hormone and glucagon-like peptide-1 were not different between the two groups. Despite these hormonal abnormalities, HD patients maintained a good appetite and had normal body lean and fat mass, and there was no evidence of increased energy expenditure or protein catabolism. We explain the hormonal abnormalities as well as the absence of anorexia on suppression of parasympathetic activity (vagus nerve dysfunction), a phenomenon well documented in dialysis patients. Unexpectedly, we noted that the combination of high leptin, PYY, and NPY with suppressed ghrelin may increase arterial blood pressure, impair vasodilatation, and induce cardiac hypertrophy, and thus could predispose to adverse cardiovascular events that are the major causes of morbidity and mortality in the HD population. This is the first report attempting to link hormonal abnormalities associated with energy homeostasis to adverse cardiovascular outcome in the HD patients. PMID:20959536

Suneja, Manish; Murry, Daryl J.; Stokes, John B.

2011-01-01

380

Macrophages and Dendritic Cells Emerge in the Liver during Intestinal Inflammation and Predispose the Liver to Inflammation  

PubMed Central

The liver is a physiological site of immune tolerance, the breakdown of which induces immunity. Liver antigen-presenting cells may be involved in both immune tolerance and activation. Although inflammatory diseases of the liver are frequently associated with inflammatory bowel diseases, the underlying immunological mechanisms remain to be elucidated. Here we report two murine models of inflammatory bowel disease: RAG-2?/? mice adoptively transferred with CD4+CD45RBhigh T cells; and IL-10?/? mice, accompanied by the infiltration of mononuclear cells in the liver. Notably, CD11b?CD11clowPDCA-1+ plasmacytoid dendritic cells (DCs) abundantly residing in the liver of normal wild-type mice disappeared in colitic CD4+CD45RBhigh T cell-transferred RAG-2?/? mice and IL-10?/? mice in parallel with the emergence of macrophages (M?s) and conventional DCs (cDCs). Furthermore, liver M?/cDCs emerging during intestinal inflammation not only promote the proliferation of naïve CD4+ T cells, but also instruct them to differentiate into IFN-?-producing Th1 cells in vitro. The emergence of pathological M?/cDCs in the liver also occurred in a model of acute dextran sulfate sodium (DSS)-induced colitis under specific pathogen-free conditions, but was canceled in germ-free conditions. Last, the M?/cDCs that emerged in acute DSS colitis significantly exacerbated Fas-mediated hepatitis. Collectively, intestinal inflammation skews the composition of antigen-presenting cells in the liver through signaling from commensal bacteria and predisposes the liver to inflammation. PMID:24392145

Mikami, Yohei; Mizuno, Shinta; Nakamoto, Nobuhiro; Hayashi, Atsushi; Sujino, Tomohisa; Sato, Toshiro; Kamada, Nobuhiko; Matsuoka, Katsuyoshi; Hisamatsu, Tadakazu; Ebinuma, Hirotoshi; Hibi, Toshifumi; Yoshimura, Akihiko; Kanai, Takanori

2014-01-01

381

The human adult subtype ACh receptor channel has high Ca2+ permeability and predisposes to endplate Ca2+ overloading.  

PubMed

Slow-channel congenital myasthenic syndrome, caused by mutations in subunits of the endplate ACh receptor (AChR), results in prolonged synaptic currents and excitotoxic injury of the postsynaptic region by Ca2+ overloading. The Ca2+ overloading could be due entirely to the prolonged openings of the AChR channel or could be abetted by enhanced Ca2+ permeability of the mutant channels. We therefore measured the fractional Ca2+ current, defined as the percentage of the total ACh-evoked current carried by Ca2+ ions (Pf), for AChRs harbouring the alphaG153S or the alphaV249F slow-channel mutation, and for wild-type human AChRs in which Pf has not yet been determined. Experiments were performed in transiently transfected GH4C1 cells and human myotubes with simultaneous recording of ACh-evoked whole-cell currents and fura-2 fluorescence signals. We found that the Pf of the wild-type human endplate AChR was unexpectedly high (Pf approximately 7%), but neither the alphaV249F nor the alphaG153S mutation altered Pf. Fetal human AChRs containing either the wild-type or the mutated alpha subunit had a much lower Pf (2-3%). We conclude that the Ca2+ permeability of human endplate AChRs is higher than that reported for any other human nicotinic AChR, with the exception of alpha7-containing AChRs (Pf > 10%); and that neither the alphaG153S nor the alphaV249F mutations affect the Pf of fetal or adult endplate AChRs. However, the intrinsically high Ca2+ permeability of human AChRs probably predisposes to development of the endplate myopathy when opening events of the AChR channel are prolonged by altered AChR-channel kinetics. PMID:16527851

Fucile, Sergio; Sucapane, Antonietta; Grassi, Francesca; Eusebi, Fabrizio; Engel, Andrew G

2006-05-15

382

Cancer-predisposing mutations within the RING domain of BRCA1: Loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity  

Microsoft Academic Search

BRCA1 is a breast and ovarian cancer-specific tumor suppressor that seems to be involved in transcription and DNA repair. Here we report that BRCA1 exhibits a bona fide ubiquitin (Ub) protein ligase (E3) activity, and that cancer-predisposing mutations within the BRCA1 RING domain abolish its Ub ligase activity. Furthermore, these mutants are unable to reverse -radiation hypersensitivity of BRCA1-null human

Heinz Ruffner; Claudio A. P. Joazeiro; Dan Hemmati; Tony Hunter; Inder M. Verma

2001-01-01

383

Effect of polyunsaturated fatty acids on homocysteine metabolism through regulating the gene expressions involved in methionine metabolism.  

PubMed

The objective was to investigate the regulatory effect of polyunsaturated fatty acids (PUFAs) on mRNA expression of key genes involved in homocysteine (Hcy) metabolism. Eighty male Sprague Dawley rats were randomly divided into eight groups. The oils were orally administered daily for 8 weeks. Plasma Hcy, phospholipids fatty acids, and mRNA expression were determined. Compared with the control group, plasma Hcy was significantly decreased in the 22:6n-3 and conjugated linoleic acid (CLA) groups; mRNA expression of Mthfr was significantly upregulated in the 22:6n-3, 20:5n-3, and 18:3n-3 groups and downregulated in the 18:2n-6 and stearolic acid (SO) groups. Mat1a was upregulated in the 22:6n-3, 20:5n-3, 18:3n-3, and CLA groups. In addition, Cbs was upregulated in the 22:6n-3, 20:5n-3, 18:3n-3 and CLA groups while downregulated in 18:2n-6 and SO groups. Dietary 22:6n-3 and CLA decrease the plasma concentration of Hcy. mRNA expression of Mthfr, Mat1a, Cbs and Pemt, Gnmt, Mtrr, and Bad is upregulated by n-3 PUFA and downregulated by n-6 PUFA. CLA upregulates mRNA expression of Mat1a and Cbs. PMID:23766724

Huang, Tao; Hu, Xiaojie; Khan, Nicholas; Yang, Jing; Li, Duo

2013-01-01

384

Effect of Polyunsaturated Fatty Acids on Homocysteine Metabolism through Regulating the Gene Expressions Involved in Methionine Metabolism  

PubMed Central

The objective was to investigate the regulatory effect of polyunsaturated fatty acids (PUFAs) on mRNA expression of key genes involved in homocysteine (Hcy) metabolism. Eighty male Sprague Dawley rats were randomly divided into eight groups. The oils were orally administered daily for 8 weeks. Plasma Hcy, phospholipids fatty acids, and mRNA expression were determined. Compared with the control group, plasma Hcy was significantly decreased in the 22:6n-3 and conjugated linoleic acid (CLA) groups; mRNA expression of Mthfr was significantly upregulated in the 22:6n-3, 20:5n-3, and 18:3n-3 groups and downregulated in the 18:2n-6 and stearolic acid (SO) groups. Mat1a was upregulated in the 22:6n-3, 20:5n-3, 18:3n-3, and CLA groups. In addition, Cbs was upregulated in the 22:6n-3, 20:5n-3, 18:3n-3 and CLA groups while downregulated in 18:2n-6 and SO groups. Dietary 22:6n-3 and CLA decrease the plasma concentration of Hcy. mRNA expression of Mthfr, Mat1a, Cbs and Pemt, Gnmt, Mtrr, and Bad is upregulated by n-3 PUFA and downregulated by n-6 PUFA. CLA upregulates mRNA expression of Mat1a and Cbs. PMID:23766724

Huang, Tao; Hu, Xiaojie; Khan, Nicholas; Yang, Jing; Li, Duo

2013-01-01

385

Evaluation of Factor V G1691A, prothrombin G20210A, Factor XIII V34L, MTHFR A1298C, MTHFR C677T and PAI-1 4G/5G genotype frequencies of patients subjected to cardiovascular disease (CVD) panel in south-east region of Turkey.  

PubMed

Cardiovascular disease (CVD) risk factors, such as arterial hypertension, obesity, dyslipidemia or diabetes mellitus, as well as CVDs, including myocardial infarction, coronary artery disease or stroke, are the most prevalent diseases and account for the major causes of death worldwide. In the present study, 4,709 unrelated patients subjected to CVD panel in south-east part of Turkey between the years 2010 and 2013 were enrolled and DNA was isolated from the blood samples of these patients. Mutation analyses were conducted using the real-time polymerase chain reaction method to screen six common mutations (Factor V G1691A, PT G20210A, Factor XIII V34L, MTHFR A1298C and C677T and PAI-1 -675 4G/5G) found in CVD panel. The prevalence of these mutations were 0.57, 0.25, 2.61, 13.78, 9.34 and 24.27 % in homozygous form, respectively. Similarly, the mutation percent of them in heterozygous form were 7.43, 3.44, 24.91, 44.94, 41.09 and 45.66%, respectively. No mutation was detected in 92 (1.95%) patients in total. Because of the fact that this is the fi