Abstract
BackgroundWhether a modestly elevated homocysteine level is causally associated with an increased risk of cardiovascular disease remains unestablished. We conducted a Mendelian randomization study to assess the associations of circulating total homocysteine (tHcy) and B vitamin levels with cardiovascular diseases in the general population.MethodsIndependent single nucleotide polymorphisms associated with tHcy (n = 14), folate (n = 2), vitamin B6 (n = 1), and vitamin B12 (n = 14) at the genome-wide significance level were selected as instrumental variables. Summary-level data for 12 cardiovascular endpoints were obtained from genetic consortia, the UK Biobank study, and the FinnGen consortium.ResultsHigher genetically predicted circulating tHcy levels were associated with an increased risk of stroke. For each one standard deviation (SD) increase in genetically predicted tHcy levels, the odds ratio (OR) was 1.11 (95% confidence interval (CI), 1.03, 1.21; p = 0.008) for any stroke, 1.26 (95% CI, 1.05, 1.51; p = 0.013) for subarachnoid hemorrhage, and 1.11 (95% CI, 1.03, 1.21; p = 0.011) for ischemic stroke. Higher genetically predicted folate levels were associated with decreased risk of coronary artery disease (ORSD, 0.88; 95% CI, 0.78, 1.00, p = 0.049) and any stroke (ORSD, 0.86; 95% CI, 0.76, 0.97, p = 0.012). Genetically predicted increased vitamin B6 levels were associated with a reduced risk of ischemic stroke (ORSD, 0.88; 95% CI, 0.81, 0.97, p = 0.009). None of these associations persisted after multiple testing correction. There was no association between genetically predicted vitamin B12 and cardiovascular disease.ConclusionsThis study reveals suggestive evidence that B vitamin therapy and lowering of tHcy may reduce the risk of stroke, particularly subarachnoid hemorrhage and ischemic stroke.
Highlights
Whether a modestly elevated homocysteine level is causally associated with an increased risk of cardiovascular disease remains unestablished
Instrument selection single nucleotide polymorphism (SNP) associated with total homocysteine (tHcy) and B vitamins were identified at the genome-wide significance threshold (p < 5 × 10−8) from meta-analyses of genome-wide association studies on tHcy (n = 44,147 individuals) [29], folate (n = 37,465 individuals) [30], vitamin B6 (n = 1864 individuals) [31], and vitamin B12 (n = 45,576 individuals) [30] in individuals of European ancestry
For 1-standard deviation (SD) increase in genetically predicted tHcy levels, the combined odds ratio (OR) was 1.11 for stroke, 1.26 for subarachnoid hemorrhage, and 1.11 for ischemic stroke
Summary
Whether a modestly elevated homocysteine level is causally associated with an increased risk of cardiovascular disease remains unestablished. We conducted a Mendelian randomization study to assess the associations of circulating total homocysteine (tHcy) and B vitamin levels with cardiovascular diseases in the general population. Deficiency of either of these B vitamins can lead to an elevated circulating level of total homocysteine (tHcy), which has been implicated in the development of cardiovascular disease (CVD) [2,3,4,5]. Randomized controlled trials (RCTs) have generally not detected a protective effect of homocysteine-lowering therapy with B vitamins on total CVD [6,7,8] or coronary artery disease [4, 6]. Potential explanations for the inconsistent results may be related to small sample sizes, low adherence to the treatment, and different study populations and CVD outcomes
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