Type 2 diabetes, glycaemic indexes, and cerebral small vessel disease: genetic overlap, causal relationship and drug targets

초록

Background and aims: Type 2 diabetes (T2DM) is a potential risk factor for cerebral small vessel disease (cSVD), but the relationship between glycemic indexes and cSVD is unclear. We examined the linkage and causal relationship between T2DM, glycemic indexes, and cSVD phenotypes using large, recently published genome-wide association studies (GWAS). Materials and methods: We analyzed GWAS data on T2DM, glycemic indexes (including glycated hemoglobin, fasting glucose, 2-hour glucose after an oral glucose challenge, and fasting insulin levels), and cSVD phenotypes (white matter hyperintensity volume, lacunar stroke, and cerebral microbleeds). Our analysis involved: 1) identifying pleiotropic SNPs, 2) global genetic correlation analysis, 3) two-sample Mendelian randomization analysis, and 4) drug-target Mendelian randomization analysis with expression quantitative trait loci (eQTL) data. Results: We found 11 pleiotropic SNPs with shared associations among T2DM, glycemic indexes, and cSVD phenotypes, including three unreported SNPs (rs2361543, rs12542733, rs713286). Genetic correlation analysis revealed T2DM and 2-hour glucose after an oral glucose challenge correlated with white matter hyperintensity volume and lacunar stroke. Fasting glucose also correlated with lacunar stroke. In the two-sample Mendelian randomization analysis, only T2DM and 2-hour glucose after an oral glucose challenge increased the risk of lacunar stroke (Odds ratio [95% CI], 1.10 [1.05-1.16] and 1.28 [1.05-1.57], respectively). In the drug-target Mendelian randomization analysis, sodium-glucose cotransporter-2 (SGLT2) inhibitors appeared to lower the risk of white matter hyperintensity volume and lacunar stroke (0.78 [0.63-0.98] and 0.39 [0.18-0.88], respectively), and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists lowered the risk of cerebral microbleeds (0.52 [0.27-0.98]). Conclusion: Our analysis demonstrated the linkage between T2DM, glycemic indexes, and cSVD phenotypes, as well as the potential preventive role of antidiabetic agents in cSVD.