APOL1 Kidney Risk Variants and Cardiovascular Disease: An Individual Participant Data Meta-Analysis
Authors: Grams Morgan E. , Surapaneni Aditya , Ballew Shoshana H. , Appel Lawrence J. , Boerwinkle Eric , Boulware L. Ebony , Chen Teresa K. , Coresh Josef , Cushman Mary , Divers Jasmin , Gutiérrez Orlando M. , Irvin Marguerite R. , Ix Joachim H. , Kopp Jeffrey B. , Kuller Lewis H. , Langefeld Carl D. , Lipkowitz Michael S. , Mukamal Kenneth J. , Musani Solomon K. , Naik Rakhi P. , Pajewski Nicholas M. , Peralta Carmen A. , Tin Adrienne , Wassel Christina L. , Wilson James G. , Winkler Cheryl A. , Young Bessie A. , Zakai Neil A. , Freedman Barry I. 
Published: August 2019

Significance Statement
Two variations in the apo L1 gene (APOL1) common in West African and African American populations are strongly associated with development of ESKD. Studies evaluating whether these APOL1 kidney-risk variants increase the risk of cardiovascular disease have had inconsistent results. The authors conducted a two-stage meta-analysis of individual participant data from eight large cohorts with data on APOL1 kidney-risk variants. The analysis included 21,305 blacks and assessed the relationship between APOL1 kidney-risk variants and several types of cardiovascular disease and death. In a recessive genetic model adjusted for demographics, comorbidities, and kidney measures, there were no significant associations between APOL1 kidney-risk genotypes and death or the composite outcome of incident cardiovascular disease, which included coronary heart disease, stroke, myocardial infarction, and heart failure. There were also no significant associations between these variants and coronary heart disease, stroke, myocardial infarction, and heart failure when the conditions were considered individually. This study suggests that the APOL1 kidney-risk variants may not have a direct effect on cardiovascular disease separate from the effects of kidney disease itself.

Background
Two coding variants in the apo L1 gene (APOL1) are strongly associated with kidney disease in blacks. Kidney disease itself increases the risk of cardiovascular disease, but whether these variants have an independent direct effect on the risk of cardiovascular disease is unclear. Previous studies have had inconsistent results.

Methods
We conducted a two-stage individual participant data meta-analysis to assess the association of APOL1 kidney-risk variants with adjudicated cardiovascular disease events and death, independent of kidney measures. The analysis included 21,305 blacks from eight large cohorts.

Results
Over 8.9±5.0 years of follow-up, 2076 incident cardiovascular disease events occurred in the 16,216 participants who did not have cardiovascular disease at study enrollment. In fully-adjusted analyses, individuals possessing two APOL1 kidney-risk variants had similar risk of incident cardiovascular disease (coronary heart disease, myocardial infarction, stroke and heart failure; hazard ratio 1.11, 95% confidence interval, 0.96 to 1.28) compared to individuals with zero or one kidney-risk variant. The risk of coronary heart disease, myocardial infarction, stroke and heart failure considered individually was also comparable by APOL1 genotype. APOL1 genotype was also not associated with death. There was no difference in adjusted associations by level of kidney function, age, diabetes status, or body-mass index.

Conclusions
In this large, two-stage individual participant data meta-analysis, APOL1 kidney-risk variants were not associated with incident cardiovascular disease or death independent of kidney measures.