Chronic Kidney Disease and Risk of Intracerebral Hemorrhage: The Role of Hypertension as a Mediator
Kevin Vanent1, Cyprien Rivier2, Charles Matouk2, Michael Levitt1, Thabele Leslie-Mazwi1, Thomas Gill2, Kevin Sheth2, Guido Falcone2
1University of Washington, 2Yale University
Objective:
To assess for mediators of the association between chronic kidney disease (CKD) and risk of spontaneous intracerebral hemorrhage (ICH).
Background:
CKD is a well-established risk factor for ICH. However, the biological pathway underlying this association remains unclear.
Design/Methods:
We conducted a PheWAS using data from the UK Biobank (UKB), a large cohort study that enrolled over 500,000 Britons aged 40-69. We first developed a polygenic risk score that contained 27 independent (r2 <0.1) genetic risk variants known to be associated with CKD at genome-wide significant levels (p<5x10-8). We subsequently tested for associations between this CKD genetic risk score and the 1,840 disease phenotypes available through the UKB baseline assessment. We used a Bonferroni corrected p<2.7x10-5 as our threshold for significance. For all phenotypes that reached statistical significance in the PheWAS, we obtained summary results from previously published genome-wide association studies and implemented multivariable Mendelian Randomization (MR) to evaluate the proportion of the total effect of CKD on ICH risk mediated through these phenotypes. The indirect effect of CKD on ICH risk was calculated using the difference in coefficients method.
Results:
Excluding renal-related diseases, hypertension was the only significant phenotype in the PheWAS (p=3.2x10-21). Genetically determined CKD was associated with a total increase in ICH risk of 38% in univariable MR (OR 1.38; 95% CI 1.12-1.71; p=0.002). This association was reduced to a 19% increase after adjusting for hypertension in multivariable MR (OR 1.19; 95% CI 1.03-1.39; p=0.021). The proportion of the total effect of CKD on ICH risk mediated through hypertension was estimated to be 55%.
Conclusions:
Hypertension accounts for approximately 55% of the total effect of CKD on ICH risk in genetic analyses. This aligns with existing knowledge that CKD can worsen hypertension. Further studies are needed to identify other pathways that mediate the remaining effect of CKD on ICH risk.