None of the loci showing more modest associations with CAD (Table 4) includes genes hitherto strongly implicated in the pathogenesis of CAD. A potentially interesting association is at rs6922269 (P=6.3×10-6), an intronic SNP in MTHFD1L, which encodes methylenetetrahydrofolate dehydrogenase (NADP+-dependent) 1-like, the mitochondrial isozyme of C1-tetrahydrofolate (THF) synthase48,49. C1-THF synthases interconvert the one carbon units carried by the biologically active form of folic acid, C1-tetrahydrofolate. These are used in a variety of cellular processes including purine and methionine synthesis48. Another enzyme in the same pathway, methylene THF reductase (encoded by MTHFR) is subject to a common mutation which influences plasma homocysteine level50 and has been associated with increased risk of coronary and other atherosclerotic disease51. The possibility of a link between variants in MTHFD1L and CAD risk is supported by evidence that MTHFD1L activity also contributes to plasma homocysteine52 and that defects in the MTHFD1L pathway may increase plasma homocysteine level48,53.
