rs1076991

Case-control study of 501 young stroke patients and 1,211 controls examining 58 polymorphisms in 17 genes involved in methionine metabolism. Multiple logistic regression identified four independent risk factors for early-onset ischaemic stroke: rs10037045 BHMT (OR 1.38, p=0.033), rs682985 BHMT2 (OR 1.46, p=0.017), rs1051319 CBS (OR 3.75, p<0.0001), and rs202680 FOLH1 (OR 3.00, p<0.0001). Haplotype analyses identified significant associations with BHMT, CBS, FOLH1, MTR, PON2, TCN2 and TYMS haplotypes and stroke risk.

This case-control study examined 29 polymorphisms in four folate-mediated one-carbon metabolism pathway genes (MTHFD1, SHMT1, MTHFR, DHFR) in Hispanic and non-Hispanic white populations to assess their association with conotruncal heart defects. MTHFD1 rs11627387 was associated with a 1.7-fold increased 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). MTHFR rs1801133 (C677T) showed a 2.8-fold increased risk among Hispanic mothers with low dietary folate intake, while rs1801131 (A1298C) showed a 2.0-fold increased risk among those with higher folate intake. Gene-folate interactions were observed, suggesting maternal multivitamin use and dietary folate intake may modify conotruncal heart defect risk.

Case-control study (222 cases, 454 controls) examining gene-folate interactions in five folate-related genes (MTHFD1, MTHFR, SHMT1, DHFR, TYMS) and neural tube defect risk. Maternal MTHFR SNPs rs1476413, rs1801131, and rs1801133 showed decreased NTD risk with low folate intake (OR=0.55-0.69, 80% CI); infant MTHFD1 SNPs rs2236224, rs2236225, and rs11627387 showed increased risk (OR=1.53-4.25, 80% CI); maternal SHMT1 rs669340 showed protective gene-only effect (OR=0.69, 95% CI: 0.49-0.96).

This family-based association study examined 14 folate pathway genes using 89 SNPs in 445 NSCLP families (317 non-Hispanic White, 128 Hispanic) to identify genetic variants contributing to nonsyndromic cleft lip and palate. Evidence for association was found with SNPs in NOS3 and TYMS in the non-Hispanic White group (rs2373929/NOS3, rs502396/TYMS, and others), and with MTR, BHMT2, MTHFS, and SLC19A1 in the Hispanic group (rs1422086/BHMT2, rs2115540/MTHFS significant after Bonferroni correction). Multiple gene-gene interactions were detected, with CBS and MTHFD1 showing the most extensive interactions. Significant interactions were also found between several SNPs and maternal smoking and one SNP (rs651646/FOLR2) with offspring sex.

This study examined the MTHFD1 gene promoter in relation to neural tube defects (NTDs) in an Irish population (2462 samples). The authors characterized the MTHFD1 promoter and identified that SNP rs1076991 (C>T) has a significant functional effect on promoter activity in vitro, with the T allele showing ~1.6-fold reduced transcriptional activity. While rs1076991 alone is not an independent risk factor for NTDs, it significantly increases case (χ² = 11.06, P = 0.001) and maternal (χ² = 6.68, P = 0.01) risk when analyzed in combination with the previously identified R653Q polymorphism (rs2236225).