Correlation between total homocysteine and cerebral small vessel disease: A Mendelian randomization study

Cerebral small vessel disease (CSVD) is a clinical imaging syndrome with diverse etiology. Total homocysteine (HCY) level might increase the risk of myocardial and cerebral infarction by damaging the vascular endothelium. We aimed to explore the correlation between total HCY and CSVD imaging burden, based on Mendelian randomization methods.A total of 1,023 participants of the Shunyi study, a population-based cohort study, were included. Vascular risk factors, total HCY levels and methylenetetrahydrofolate reductase (MTHFR) gene mutations (C677T and A1298C) were examined. CSVD imaging markers, including lacunes, cerebral microbleeds, white matter hyperintensity, enlarged perivascular space and brain parenchymal fraction (BPF) were also assessed.Mutations of C677T were significantly correlated with increased total HCY levels (CC→TT: β = 0.28, p < 0.0001), while mutations of A1298C were correlated with decreased total HCY levels (AA→AC: β = -0.13, p < 0.0001; AA→CC: β = -0.25, p = 0.004). In the Mendelian randomization study, the C677T genotype was significantly associated with lacunes (CC→CT: odds ratio [OR] 2.76, p = 0.008; CC→TT: OR 2.50, p = 0.018), and the A1298C genotype was significantly correlated with BPF (AA→CC: β = 1.32, p = 0.015). Similarly, in multivariate regression analysis, total HCY levels were significantly correlated with lacunes (OR 2.14, p < 0.0001) and negatively correlated with BPF (β = -0.55, p = 0.004). Age, sex and vascular risk factors were adjusted for.Total HCY level was correlated with imaging burden of CSVD, especially with lacunes and brain volume loss. For individuals with risk genetic predisposition, enhanced homocysteine-lowering strategies might be necessary to reduce the risk and progress of CSVD.