Abstract 469: APOL1 Genotypes and Risk of Heart Failure: an Additive Genetic Effect in the Elderly, but Not in the Young Adults in Patients with Chronic Kidney Disease

Abstract

Objective: Apolipoprotein L1 (APOL1), the major protein component of HDL, is identified having an association with renal disease in African Americans (AA). We assessed the hypothesis that the genetic variations in APOL1 (G1 and G2 alleles) are associated with risk of heart failure (HF), and this effect is modified by age. Methods: Subjects aged 21-75, with an estimated GFR (eGFR) of 20 to 70 ml/min/1.73 m 2 at baseline recruitments (April 2003-Sept 2008), who were free of HF participating in the Chronic Renal Insufficiency Cohort (CRIC) Study and followed-up through March 2013 are analyzed (White: 1335, AA:1323). The associations of APOL1 risk genotype (assessed by either 1 of the G1 and G2, or 2 of their combinations, i.e., G1/G1, G1/G2 or G2/G2) with incident HF and mortality are examined using Cox’s regression models. Results: Within a mean 7-year (SD: 2.1) follow-up, AA had a significantly higher incidence of HF than White (2.62 vs. 1.67 per 100 person-year (PY), p=0.006) in those aged<65, and 3.94 vs. 2.71 per 100 PY (p=0.026) in those aged≥65. Cox’s models, with adjusted age, sex, eGFR and HDL, indicate that compared to White, AA aged<65 without or with 1 of either G1 or G2 had a significantly higher risk of HF [Hazard Ratio, HR: 2.15 (95%CI: 1.59-2.92, p<.0001), followed by those with either 2 of G1/G1, G1/G2 or G2/G2 alleles (1.47, 0.88-2.48, p=0.15)]. However, a significant additive genetic effect of the number of risk alleles (i.e., 0,1,2) is observed in AA aged ≥65. The corresponding HRs (95%CI) are 1.73 (1.17-2.57, p=0.007) in those without or with either 1 of the G1 or G2, and 2.17 (1.20-3.94, p=0.011) in those with either 2 of the G1 and G2 combination. A significant interaction effect of age (≥65 vs. <65) and the risk alleles (2 vs. 0/1) is observed (HR: 2.45, 95%CI: 1.14-5.28, p=0.02). Similar associations between APOL1 alleles and mortality from HF and all-cause are seen by the two age groups. Conclusion: African Americans with APOL1 risk alleles have significantly higher risk of HF and mortality than White. An additive genetic effect of the number of APOL1 risk alleles is shown among AA aged ≥65, but not in the younger adults. The modifying effect of age suggests that a possible 'different genetic-risk window' by ages warrants consideration in HF control and prevention.