African ancestry influences CCR5 -2459G>A genotype-associated virologic success of highly active antiretroviral therapy.
BACKGROUND
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.
*Department of Biostatistics, Environmental Health Sciences, and Epidemiology, College of Public Health, Kent State University, Kent, OH; †Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH; ‡Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, OH; §Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH; ‖Center for Global Health and Diseases, Case Western Reserve University School of Medicine, Cleveland, OH; and ¶Department of Medicine, Division of Infectious Diseases and HIV Medicine, Case Western Reserve University School of Medicine, Cleveland, OH (Dr Richard J. Jurevic, DDS, PhD, is now with the Department of Oral Diagnostics, School of Dentistry, West Virginia University, Morgantown, WV).
Vinay K
VK
Cheruvu
Robert P
RP
Igo
Richard J
RJ
Jurevic
David
D
Serre
Peter A
PA
Zimmerman
Benigno
B
Rodriguez
Rajeev K
RK
Mehlotra
D000328:Adult; D001741:Black or African American; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019713:Receptors, CCR5 / Q000235:genetics*; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load
D044966:Anti-Retroviral Agents; C584933:CCR5 protein, human; D019713:Receptors, CCR5