APOL1 Kidney Risk Variants and Cardiovascular Disease: An Individual Participant Data Meta-Analysis

Abstract

BackgroundTwo 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.MethodsWe 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.ResultsOver 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.ConclusionsIn 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.

Phenome-wide association analysis suggests the APOL1 linked disease spectrum primarily drives kidney-specific pathways

“…This method may overcorrect for these associations because of the lack of independence across phenotypes when each is defined by a phecode. Prior reports [28][29][30] show mixed findings on the association between the APOL1 high-risk genotype and CVD. Differences in study design, definition of CVD outcomes, and assessment of confounders, particularly the confounding effect of APOL1-associated CKD on development of CVD, make it difficult to conclude whether an association may exist.…”

<b><i>APOL1</i></b> Genetic Variants Are Associated with Serum-Oxidized Low-Density Lipoprotein Levels and Subclinical Atherosclerosis in South African CKD Patients

“…Recently, two studies which included 52,208 African-American participants did not support the previously reported associations between APOL1 renal-risk variants and increased burden of CVD [25,26]. Moreover, the findings of the 2 reports suggest that the observed increased CVD risk in the studied populations is likely related to APOL1 association with CKD.…”

The function of apolipoproteins L (APOLs): relevance for kidney disease, neurotransmission disorders, cancer and viral infection

“…In addition to the risk of kidney disease, the C-terminal APOL1 variants were significantly associated with other pathologies. A linkage with increased cardiovascular mortality was observed, but this could occur through the effects of the APOL1 variants on kidney disease itself [80]. Either fetal or maternal expression of the APOL1 variants was significantly linked to maternal preeclampsia, likely through trophoblast dysfunction [81,82].…”