| Abstract: | Although case-control studies suggest that African Americans with common coding variants in the APOL1 gene are 5–29 times more likely than those individuals without such variants to have focal segmental glomerulosclerosis, HIV-associated nephropathy, or ESRD, prospective studies have not yet evaluated the impact of these variants on CKD in a community-based sample of African Americans. Here, we studied whether the APOL1 G1 and G2 risk alleles associate with the development of CKD and progression to ESRD by analyzing data from 3067 African Americans in the Atherosclerosis Risk in Communities Study who did not have CKD at baseline. Carrying two risk alleles associated with a 1.49-fold increased risk of CKD (95% CI=1.02 to 2.17) and a 1.88-fold increased risk of ESRD (95% CI=1.20 to 2.93) compared with zero or one risk allele; associations persisted after adjusting for European ancestry. Among participants who developed CKD, those participants with two risk alleles were more likely to progress to ESRD than their counterparts with zero or one risk allele (HR=2.22, 95% CI=1.01 to 4.84). In conclusion, APOL1 risk variants are risk factors for the development of CKD and progression from CKD to ESRD among African Americans in the general population.African Americans suffer disproportionally from the most severe forms of CKD, including ESRD, and progress faster from CKD to ESRD, even after accounting for differences in socioeconomic factors.1–5 Recent studies show that genetic variants in the MYH9-APOL1 region on chromosome 22 that are common among individuals with African ancestry but rare in Caucasian populations are associated with prevalent ESRD,6–12 accounting for the excessive risk of kidney disease among African Americans compared with their Caucasian counterparts. In case-control studies, two risk alleles (termed G1 and G2) in the last exon of APOL1, a gene that encodes apolipoprotein-L1, are associated with 5–29 times higher odds of severe kidney disease, such as nondiabetic ESRD, hypertension-attributed ESRD, focal segmental glomerulosclerosis, and HIV-related nephropathy.8,10,11 However, it is not known whether these variants predict the development of incident CKD or ESRD events and whether the risk of progression from CKD to ESRD in a prospective community-based sample of middle-aged African Americans differs from prior work investigating associations with prevalent kidney disease in case-control studies and cross-sectional analyses of population-based or high-risk cohorts.8–14 If APOL1 G1 and G2 variants confer higher risk of incident CKD and progression to ESRD in the general population and an effective intervention is identified, then genetic screening could be used to identify high-risk individuals who can be targeted for intervention. Therefore, we sought to determine whether the APOL1 risk alleles are associated with the development of incident CKD and progression to ESRD events in over 3000 African Americans from the Atherosclerosis Risk in Communities (ARIC) Study with a baseline examination in 1987–1989 (visit 1), follow-up examinations in 1990–1992 (visit 2) and 1996–1998 (visit 4), and follow-up for ESRD hospitalizations through 2008. We hypothesized that African Americans carrying two APOL1 risk alleles would have an increased risk of CKD and ESRD progression compared with those individuals carrying zero or one risk allele. |
