Is the Heat Labile Variant of Methylene Tetrahydrofolate Reductase (MTHFR-HL) Associated with Elevated Plasma Total Homocysteine (tHcy) and Premature Coronary Artery Disease (CAD)?
Patients with premature CAD (onset ≤55 in males, ≤65 in females) generally have higher tHcy while MTHFR-HL has been inconsistently associated with CAD. To address this issue we determined MTHFR genotype (HL vs wild type = WT), and measured tHcy, plasma folate, vitamins B12 and B6, and standard risk factors in 224 (74% male, mean age 56.0 ± 6.0) patients with premature, familial CAD (cases) and in 146 controls (56% male, mean age 48.7 ± 6.5). As expected, tHcy was significantly higher in cases (p < 0.0001) and in subjects with low folate (<16 nmol/L, p <0.0001). Furthermore, there was a significant interaction between case status, MTHFR-HL homozygosity (HL/HL), and low folate as shown in the ⇓figure (shown are least-square means ± 95% CI; p = 0.0072 for interaction term; “other” refers to WT/WT and WT/HL genotypes). However, the frequency of MTHFR-HL homozygosity was not different in cases (10.71%) versus controls (10.96%), nor was there an excess of risk associated with having both HL/HL and low folate though numbers were small (4.9% of cases versus 4.1% of controls). Thus, the MTHFR-HL variant may contribute to high tHcy in premature CAD cases with low folate status, but a direct effect of MTHFR-HL on CAD risk appears to be unlikely, at least in populations with sufficient folate intake.