Methylenetetrahydrofolate Reductase Variants Associated with Hypertension and Cardiovascular Disease Interact with Dietary Polyunsaturated Fatty Acids to Modulate Plasma Homocysteine in Puerto Rican Adults

Department of Food Science and Nutrition, Zhejiang University, Hangzhou, 310029 China.
Journal of Nutrition (Impact Factor: 3.88). 02/2011; 141(4):654-9. DOI: 10.3945/jn.110.134353
Source: PubMed


Although methylenetetrahydrofolate reductase (MTHFR) genetic variants are associated with plasma homocysteine (Hcy) and cardiovascular disease (CVD), little is known whether dietary fatty acid intake modulates these associations. The goal was to examine the interaction of MTHFR variants with dietary fatty acids influencing plasma Hcy in 995 Boston Puerto Rican adults. We found that plasma Hcy concentration was negatively correlated with (n-3) PUFA intake (r = -0.117; P = 0.022), and the ratio of (n-3):(n-6) PUFA in the diet (r = -0.122; P = 0.009). Further, 2 functional MTHFR variants, 1298A>C and 677C>T, which are not in linkage disequilibrium in this population, were significantly associated with hypertension (OR = 1.72, P = 0.024, and OR = 1.60, P = 0.002, respectively). In addition, the 1298A>C variant was significantly associated with CVD (OR = 3.32; P = 0.030). Importantly, this variant exhibited significant interactions with intakes of total and (n-6) PUFA and the (n-3):(n-6) PUFA ratio of the diet. The plasma Hcy concentration of carriers of risk allele 1298C was greater than that of noncarriers only when participants had consumed a high-PUFA diet (>7.8% energy) but was not greater when they had low intake of PUFA (≤7.8% energy). In addition, participants with combined genotypes of both SNP (677 TT with 1298 AC or CC) who consumed high levels of (n-3) PUFA (>0.66% energy) had lower plasma Hcy compared with those who had the same genotype and consumed low levels of (n-3) PUFA (≤0.66% energy). Our study suggests that dietary PUFA intake modulates the effect of 2 MTHFR variants on plasma Hcy in Boston Puerto Rican adults.

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    • ") were found to be associated with Hcy concentration [13]. However, studies have been limited to one or a few SNPs with joint effects [11, 14–16]. "
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    ABSTRACT: 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.
    Full-text · Article · Jan 2014
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    • "In the Mendelian randomization paradigm, an instrumental variable has to satisfy the following three criteria [42,43]: 1) the MTHFR 677C > T should be robustly associated with Hcy; 2) the genotype should not be associated with confounding factors that bias the association between intermediate Hcy and T2DM; 3) absence of pleiotropy, as the MTHFR 677C > T should exert its effect on the T2DM only through the specific intermediate Hcy. Based on available evidence, MTHFR 677C > T seemed to meet these assumptions well [6,39,44,45]. Thus, the Mendelian randomization coefficient estimates using MTHFR 677C > T as instruments would provide the causal association between Hcy and T2DM risk free of bias due to reverse causation and residual confounding. "
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    ABSTRACT: We tested the hypothesis that elevated homocysteine (Hcy) level is causally associated with increased risk of type 2 diabetes mellitus (T2DM). The meta-analysis and Mendelian randomization analysis were performed among 4011 cases and 4303 controls. The absolute pooled mean Hcy concentration in subjects with MTHFR 677TT was 5.55 mumol/L (95% CI, 1.33 to 9.77) greater than that in subjects with MTHFR 677CC in T2DM. Overall, the T allele of the MTHFR 677 C > T conferred a greater risk for T2DM [Random effect (RE) OR = 1.31(1.17-1.64), I2 = 41.0%, p = 0.055]. The random effect (RE) pooled OR associated with T2DM for MTHFR 677TT relative to the 677CC was [RE OR = 1.38(1.18-1.62)]. The fixed-effect pooled OR of the association for the MTHFR 677 TT vs CT was 1.29 (95% CI, 1.09-1.51). MTHFR 677 TT showed a significantly higher risk for T2DM compared with MTHFR 677 CC + CT [Fixed effect (FE) OR = 1.32(1.14-1.54), I2 = 0.0%, p = 0.686]. The absolute pooled mean Hcy concentration in individuals with T2DM was 0.94 mumol/L (95% CI, 0.40-1.48) greater than that in control subjects. The estimated causal OR associated with T2DM was 1.29 for 5 mumol/L increment in Hcy. Our findings provided strong evidence on the causal association of Hcy level with the development of T2DM.
    Full-text · Article · Dec 2013 · BMC Genomics
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    • "Furthermore, in Chinese diets, meat and chicken are main sources of saturated fat. It has been shown that an increased dietary intake of saturated fat caused an increase in plasma tHcy concentrations [10,29]. Moreover, fish and fish oil supplements are rich sources of very-long-chain n-3 fatty acids. "
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    ABSTRACT: Dietary patterns are associated with plasma total homocysteine (tHcy) concentrations in healthy populations, but the associations between dietary protein and tHcy, total cysteine (tCys) in high risk populations are unclear. We therefore examined the association between dietary protein and tHcy and tCys concentrations in coronary angiographic subjects. We conducted a cross-sectional study of 1015 Chinese patients who underwent coronary angiography (40--85 y old). With the use of food-frequency questionnaires, we divided the total protein intakes into high animal-protein and high plant-protein diets. Circulating concentrations of tHcy and tCys were simultaneously measured by high-performance liquid chromatography with fluorescence detection. We found that high animal-protein diet was positively associated with hyperhomocysteinemia after adjustment for potential confounders, with the subjects in the highest quartile of intake having the greatest increase in risk (OR: 4.14, 95% CI: 2.67-6.43), whereas high plant-protein diet was inversely related to hyperhomocysteinemia, with a higher intake being protective. Compared with the first quartile of intake, the adjusted OR was 0.59 (95% CI: 0.38-0.91) for the fourth quartile. The total protein intake was positively associated with the risk of hypercysteinemia and the participants in highest quartile had significant OR of 1.69 (95% CI: 1.02-2.87) compared with those in lowest quartile. In multivariate linear regression analyses, high animal-protein and total-protein intakes were positively associated with plasma tHcy and tCys concentrations. The plant-protein intake was a negative determinant of plasma tHcy concentrations. High animal-protein diet was positively associated with high tHcy concentrations, whereas high plant-protein diet was inversely associated with tHcy concentrations. Furthermore the total protein intake was strongly related to tCys concentrations.
    Full-text · Article · Nov 2013 · Nutrition Journal
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