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Association analyses suggest multiple interaction effects of the methylenetetrahydrofolate reductase polymorphisms on timing of menarche and natural menopause in white women.

ABSTRACT: OBJECTIVE:This study aimed to investigate whether polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene are associated with age at menarche and age at natural menopause in white women. METHODS:In a cross-sectional study, a total of 305 randomly selected unrelated white women were genotyped for six single nucleotide polymorphisms (SNPs) of the MTHFR gene (including one common replacement, rs1801133). This sample was comprehensively analyzed for the association of the SNPs with age at menarche. Then a subsample of 210 women who experienced natural menopause was analyzed for the association of the MTHFR gene with age at natural menopause. RESULTS:Duration of breast-feeding was a significant predictor of earlier natural menopause (P < 0.05). No individual SNPs were associated with either age at menarche or age at natural menopause. However, three significant (P < 0.05) SNP-SNP interaction effects (rs2066470/rs1476413, rs2066470/rs4846049, and rs17037390/rs4846049) on the onset of menarche were determined. Three haplotypes were significantly associated with age at menopause (P < 0.05). Four SNPs (rs2066470, rs17037390, rs1801133, and rs4846048) indicated significant interaction effects with various lifestyle factors on age at natural menopause. CONCLUSIONS:The results of our study suggest that the MTHFR gene may influence the onset of menarche and natural menopause. This effect is probably due to the multiple SNP-SNP and SNP-environment interactions. More independent studies are needed to further clarify the possible contribution of this gene to the timing of menarche and menopause.

SUBMITTER: Liu P

PROVIDER: S-EPMC2806497 | biostudies-literature | 2010 Jan-Feb

REPOSITORIES: biostudies-literature

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Association analyses suggest multiple interaction effects of the methylenetetrahydrofolate reductase polymorphisms on timing of menarche and natural menopause in white women.

Liu Pengyuan P Lu Yan Y Recker Robert R RR Deng Hong-Wen HW Dvornyk Volodymyr V

Menopause (New York, N.Y.) 20100101 1

<h4>Objective</h4>This study aimed to investigate whether polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene are associated with age at menarche and age at natural menopause in white women.<h4>Methods</h4>In a cross-sectional study, a total of 305 randomly selected unrelated white women were genotyped for six single nucleotide polymorphisms (SNPs) of the MTHFR gene (including one common replacement, rs1801133). This sample was comprehensively analyzed for the association of th ...[more]

PMID: 19593234

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Project description:What is already known about this subject* Numerous clinical studies, including a few prospective ones, have reported conflicting results on the impact of gene polymorphisms related to fluorouracil (FU) and oxaliplatin pharmacodynamics.What this study adds* This prospective study is the first to report that clinical response to FOLFOX is significantly related to methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms (677C-->T and 1298A-->C), with a response rate of 37, 53, 63 and 80% in patients harbouring no, one, two or three favourable MTHFR alleles, respectively. * Only polymorphisms of genes related to oxaliplatin pharmacodynamics (GSTpi 105Ile-->Val and XPD 751Ly-->Gln) influenced progression-free survival. * These results corroborate the observation that response was related to the cumulative FU dose, whereas progression-free survival was related to the cumulative oxaliplatin dose.AimsTo test prospectively the predictive value of germinal gene polymorphisms related to fluorouracil (FU) and oxaliplatin (Oxa) pharmacodynamics on toxicity and responsiveness of colorectal cancer (CRC) patients receiving FOLFOX therapy.MethodsAdvanced CRC patients (n= 117) receiving FOLFOX 7 therapy were enrolled. Gene polymorphisms relevant for FU [thymidylate synthase (TYMS, 28 bp repeats including the G-->C mutation + 6 bp deletion in 3'UTR), methylenetetrahydrofolate reductase (MTHFR, 677C-->T, 1298A-->C), dihydropyrimidine deshydrogenase (IVS14+1G-->A) and Oxa: glutathione S-transferase (GST) pi (105Ile-->Val, 114Ala-->Val), excision repair cross-complementing group 1 (ERCC1) (118AAT-->AAC), ERCC2 (XPD, 751Lys-->Gln) and XRCC1 (399Arg-->Gln)] were determined (blood mononuclear cells).ResultsNone of the genotypes was predictive of toxicity. Response rate (54.7% complete response + partial response) was related to FU pharmacogenetics, with both 677C-->T (P= 0.042) and 1298A-->C (P= 0.004) MTHFR genotypes linked to clinical response. Importantly, the score of favourable MTHFR alleles (677T and 1298C) was positively linked to response, with response rates of 37.1, 53.3, 62.5 and 80.0% in patients bearing no, one, two or three favourable alleles, respectively (P= 0.040). Polymorphisms of genes related to Oxa pharmacodynamics showed an influence on progression-free survival, with a better outcome in patients bearing GSTpi 105 Val/Val genotype or XPD 751Lys-containing genotype (P= 0.054).ConclusionsThese results show that response to FOLFOX therapy in CRC patients may be driven by MTHFR germinal polymorphisms.

Project description:BackgroundThe association between the methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and the susceptibility to cervical lesions was unclear. This study was designed to investigate their precise association using a large-scale meta-analysis.MethodsThe previous 16 studies were identified by searching PubMed, Embase and CBM databases. The crude odds ratios and their corresponding 95% confidence intervals (CIs) were used to estimate the association between the MTHFR C677T/A1298C polymorphisms and the susceptibility to the cervical lesions. The subgroup analyses were made on the following: pathological history, geographic region, ethnicity, source of controls and source of DNA for genotyping.ResultsNeither of the polymorphisms had a significant association with the susceptibility to the cervical lesions in all genetic models. Similar results were found in the subgroup analyses. No association was found between the MTHFR C677T polymorphism and the cervical lesions in the Asia or the America populations though a significant inverse association was found in the Europe population (additive model: P = 0.006, OR = 0.83, 95% CI = 0.72-0.95; CT vs. CC: P = 0.05, OR = 0.83, 95% CI = 0.69-1.00; TT vs. CC: P = 0.05, OR = 0.73, 95% CI = 0.53-1.00). Interestingly, women with the MTHFR A1298C polymorphisms had a marginally increased susceptibility to invasive cancer (ICC) when compared with no carriers but no statistically significant difference in the dominant model (P = 0.06, OR = 1.21, 95% CI = 0.99-1.49) and AC vs. AA (P = 0.09, OR = 1.21, 95% CI = 0.97-1.51).ConclusionsThe MTHFR C677T and A1298C polymorphisms may not increase the susceptibility to cervical lesions. However, the meta-analysis reveals a negative association between the MTHFR C677T polymorphisms and the cervical lesions, especially in the European populations. The marginal association between the MTHFR A1298C polymorphisms and the susceptibility to cervical cancer requires a further study.

Dataset Information

Association analyses suggest multiple interaction effects of the methylenetetrahydrofolate reductase polymorphisms on timing of menarche and natural menopause in white women.

Publications

Association analyses suggest multiple interaction effects of the methylenetetrahydrofolate reductase polymorphisms on timing of menarche and natural menopause in white women.

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