In the present study we report that dietary n-6 PUFA and n-3:n-6 PUFA ratio were significantly associated with plasma Hcy concentration, although no difference in plasma Hcy based on MAT1A genotype was detected. We also identified interactions of dietary n-3:n-6 ratio and MUFA with MAT1A variants (SNP or haplotypes) in relation to plasma Hcy concentration. While these interactions have not been reported previously, several other studies provide evidence to support our findings (below).
Based on cardioprotective effects ascribed to n-3 PUFA and vascular damage attributed to plasma Hcy [3
], a growing number of recent studies have investigated the relationship between n-3 PUFA and Hcy metabolism. In the present study, we demonstrated that a high dietary n-3:n-6 ratio was significantly associated with lower plasma Hcy, which is consistent with our previous report showing that plasma Hcy concentration was significantly negatively correlated with plasma phospholipid (PL) concentration (mg/100 mL) of total n-3 (r=−0.270, p
=0.002) and with the n-3:n-6 ratio (r =−0.265, p
]. In sex-, age- and BMI-controlled partial correlations, the plasma Hcy concentration was significantly negatively correlated with platelet PL 22:6 n-3 and with n-3:n-6 ratio (p
<0.01), and positively correlated with 22:4 n-6 (p
]. These results suggest that increased consumption of dietary n-3 PUFA may be associated with lower plasma Hcy. A subsequent intervention study supported this hypothesis by demonstrating that n-3 PUFA decreased plasma Hcy concentrations in participants with diabetes and dyslipidemia who were treated with a statin-fibrate combination [24
]. Furthermore, plasma Hcy was significantly decreased in acute myocardial infarction survivors after one year of n-3 PUFA treatment [14
]. In a third study, consumption of n-3 PUFA supplements (3 g/day) over a two-month period decreased Hcy in participants with diabetes with no change in fasting blood sugar, malondialdehyde, or C-reactive protein [25
Collectively, earlier studies provide strong support for n-3 PUFA in regulating plasma Hcy concentration, but results have not been entirely consistent [15
]. Some intervention studies have observed lower plasma Hcy after n-3 PUFA supplementation [14
], while other studies did not show beneficial effects of n-3 PUFA on plasma Hcy [15
]. We hypothesize that variation in genes which encode critical enzymes in the metabolism of methionine may underlie these inconsistent results, and that intake of fatty acids may modulate Hcy through its regulation of enzyme activity and gene expression. MAT catalyzes the formation of S-adenosylmethionine from methionine and ATP. Defects in MAT1A
which partially inactivate MAT activity [26
] are one cause of hypermethioninemia [26
] and this may, therefore be expressed differentially through MAT1A
genotypes by dietary fatty acid interactions. Dietary factors may also alter MAT function, as demonstrated in our earlier animal study which showed that n-3 PUFA up-regulated MAT
gene expression and enzyme activity [27
]. While we did not observe MAT1A
3U1510 genotype-associated differences in plasma Hcy in the current study, we did show that MAT1A
3U1510 significantly interacted with the dietary n-3:n-6 ratio in modulating plasma Hcy. Further, MAT1A
haplotypes displayed strong interaction with n-3:n-6 ratio - carriers of the risk haplotype (AGA) tend to have higher plasma Hcy when the ratio is low compared to non-carriers. These results support our hypothesis that MAT1A
genotype may modulate the regulatory effect of n-3 PUFA or n-6 PUFA on Hcy metabolism. Moreover, we observed that MAT1A
i15752 interacted with total fat and total MUFA, and that MAT1A
d18777 interacted with total fat, SFA, MUFA and total PUFA in modulating plasma Hcy. Although total fat, SFA, MUFA and total PUFA were not associated with altered Hcy metabolism independent of genotype, these dietary fat intakes displayed significant interaction with MAT1A
i15752 and d18777 genotypes on plasma Hcy concentrations.
There are, however, some limitations to the present study. First, the sample size is small, which limits statistical power. Second, we calculated the dietary fatty acids using a questionnaire previously adapted from the NCI/Block food frequency form for this population. Compared with plasma fatty acids, dietary fatty acids may have some limitation. Lastly, it is debatable that elevated Hcy could be a consequence of vascular disease, instead of a cause. Higher n-3 PUFA intake may reduce vascular pathology and thus reduce plasma Hcy concentration. Therefore, the mechanisms by which n-3 PUFA regulates plasma Hcy level remains to be illustrated.
In summary, the present study confirms earlier studies reporting the relationship between PUFA intake and plasma Hcy. Our results further suggest that interactions between MAT1A variants and dietary fatty acids modulate plasma Hcy concentration. In light of strong evidence that elevated plasma Hcy is an important risk factor for cardiovascular disease, understanding the role of dietary factors in the potential amelioration of genetically based risk of hyperhomocystemia is critical. Confirmation of these interactions will require further investigation in additional populations.