Assessing causality between carotid-femoral pulse wave velocity and cognitive function: a mendelian randomization study

Objective: Arterial stiffness is usually significantly associated with cognitive function. We conducted a Mendelian randomization study to investigate the causal relationship between measures of arterial stiffness and cognitive function in a cross-sectional survey. Design and method: A total of 1516 adults aged more 30 years old in the CardioVascular Disease risk FACTors in two townships Study (CVDFACTS) with wave 6 and wave 7 during 2013-2020 were evaluated for artery stiffness with carotid-femoral pulse wave velocity (CFPWV) and cognitive function with Mine-Mental Short Evaluation (MMSE). A genome-wide association study was used to identify the genetic variants associated with CFPWV. Mendelian Randomization analysis was conducted using the R software. Results: A total of 87 SNP were identified (p-value<10-6) in the KDM4B gene (Chromosome-19) and 3 SNPs [rs10085112, rs2613776 and rs147498368] of them were independently associated with CFPWV. We constructed a polygenetic risk score (PRS, 1-6) with the 3 significant SNPs. PRS was the genetic variant and instrumental variable in the Mendelian Randomization. PRS was significantly associated with CFPWV (beta = -0.37, p = 0.0003), the “exposure”, and MMSE (beta = 0.14, p = 0.031), the “outcome”. In contrast, PRS was not associated with age, sex, systolic/diastolic blood pressure, body mass index, fasting glucose, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, C-reactive protein, creatinine and uric acid, the “confounders”. Mendelian Randomization estimate (95% confidence intervals) of the causal effect of the exposure (CFPWV) on the outcome (MMSE) was -0.433 (-0.810, -0.056, p-value = 0.0244). Conclusions: Our study provides evidence that KDM4B gene may be instrumental in the causal relationship between artery stiffness measured by CFPWV and cognitive function measured by MMSE in a Han Chinese population.