Homocysteine-reducing B vitamins and ischemic heart disease: a separate-sample Mendelian randomization analysis.

Abstract

Observationally, homocysteine is positively associated with ischemic heart disease (IHD) and unhealthy lipids; folate and vitamin B12, which reduce homocysteine, are associated with lower IHD risk and healthy lipids. Randomized controlled trials have shown no benefits of folate and vitamin B12 for IHD. To clarify the role of these potential targets of intervention in IHD we assessed how genetically determined homocysteine, folate and vitamin-B12-affected IHD and lipids. Separate-sample instrumental variable analysis with genetic instruments, that is, Mendelian randomization, was used to obtain unconfounded estimates (based on strongly related single-nucleotide polymorphisms (SNPs)) using CARDIoGRAMplusC4D, a large coronary artery disease/myocardial infarction (CAD/MI) case (n=64 374)-control (n=130 681) study with extensive genotyping, and the Global Lipids Genetics Consortium Results (n=196 475). Homocysteine was unrelated to CAD/MI (odds ratio (OR) 1.07 per log-transformed s.d., 95% confidence interval (CI) 0.96 to 1.19) based on 14 SNPs, as was folate (OR 1.18 per s.d., 95% CI 0.80 to 1.75) based on rs153734, and vitamin B12 (OR 0.98 per log-transformed s.d., 95% CI 0.85 to 1.14) based on rs602662, rs9473555, rs526934 and rs11254363. Homocysteine and folate were not clearly associated with lipids, vitamin B12 was associated with higher inverse normal transformed low-density lipoprotein cholesterol (0.07, 95% CI 0.02 to 0.12) and triglycerides (0.05, 95% CI 0.004 to 0.09). Our findings do not corroborate the observed positive association of homocysteine or negative associations of folate and vitamin B12 with CAD/MI. Vitamin B12 might be associated with an unfavorable lipid profile.