African Ancestry Influences CCR5-2459G>A Genotype-Associated Virologic Success of Highly Active Antiretroviral Therapy

Introduction: In a North American, HIV-positive, highly active antiretroviral therapy (HAART)-treated, adherent cohort of self-identified white and black patients, we previously observed that chemokine (C-C motif) receptor 5 (CCR5) -2459G>A genotype had a strong association with time to achieve virologic success (TVLS) in black but not in white patients. Methods: Using 128 genome-wide ancestry informative markers, we performed a quantitative assessment of ancestry in these patients (n = 310) to determine (1) whether CCR5 -2459G>A genotype is still associated with TVLS of HAART when ancestry, not self-identified race, is considered and (2) whether this association is influenced by varying African ancestry. Results: We found that the interaction between CCR5 -2459G>A genotype and African ancestry (<= 0.125 vs. >= 0.425 and <0.71 vs. >= 0.71) was significantly associated with TVLS (GG compared with AA, P = 0.044 and 0.018, respectively). Furthermore, the association between CCR5 -2459G>A genotype and TVLS was stronger in patients with African ancestry >= 0.71 than in patients with African ancestry >= 0.452, in both Kaplan-Meier (log-rank P = 0.039 and 0.057, respectively, for AA, GA, and GG) and Cox proportional hazards regression (relative hazard for GG compared with AA 2.59 [95% confidence interval: 1.27 to 5.22; P = 0.01] and 2.26 [95% confidence interval: 1.18 to 4.32; P = 0.01], respectively) analyses. Conclusions: We observed that the association between CCR5 -2459G>A genotype and TVLS of HAART increased with stronger African ancestry. Understanding the genomic mechanisms by which African ancestry influences this association is critical and requires further studies.