Premium
Homocysteine and small vessel stroke: A mendelian randomization analysis
Author(s) -
Larsson Susanna C.,
Traylor Matthew,
Markus Hugh S.
Publication year - 2019
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25440
Subject(s) - mendelian randomization , odds ratio , stroke (engine) , medicine , homocysteine , methylenetetrahydrofolate reductase , single nucleotide polymorphism , confidence interval , gastroenterology , biology , genetics , allele , genotype , gene , genetic variants , mechanical engineering , engineering
Objective Trials of B vitamin therapy to lower blood total homocysteine (tHcy) levels for prevention of stroke are inconclusive. Secondary analyses of trial data and epidemiological studies suggest that tHcy levels may be particularly associated with small vessel stroke (SVS). We assessed whether circulating tHcy and B vitamin levels are selectively associated with SVS, but not other stroke subtypes, using Mendelian randomization. Methods We used summary statistics data for single‐nucleotide polymorphisms (SNPs) associated with tHcy (n = 18), folate (n = 3), vitamin B 6 (n = 1), and vitamin B 12 (n = 14) levels, and the corresponding data for stroke from the MEGASTROKE consortium (n = 16,952 subtyped ischemic stroke cases and 404,630 noncases). Results Genetically predicted tHcy was associated with SVS, with an odds ratio of 1.34 (95% confidence interval [CI], 1.13–1.58; p = 6.7 × 10 –4 ) per 1 standard deviation (SD) increase in genetically predicted tHcy levels, but was not associated with large artery or cardioembolic stroke. The association was mainly driven by SNPs at or near the MTHFR and MUT genes. The odds ratios of SVS per 1 SD increase in genetically predicted folate and vitamin B 6 levels were 0.49 (95% CI, 0.34–0.71; p = 1.3 × 10 –4 ) and 0.70 (95% CI, 0.52–0.94; p = 0.02), respectively. Genetically higher vitamin B 12 levels were not associated with any stroke subtype. Interpretation These findings suggest that any effect of homocysteine‐lowering treatment in preventing stroke will be confined to the SVS subtype. Whether genetic variants at or near the MTHFR and MUT genes influence SVS risk through pathways other than homocysteine levels and downstream effects require further investigation. Ann Neurol 2019;85:495–501