541 
A Genome-wide Association Study in HIV-1 Controllers
Paul De Bakker*1,2, F Pereyra2,3, X Jia1, C Brumme1,3, N Burtt1, D Haas4, R Gulick5, D Kuritzkes2, S Deeks6, B Walker3, and Intl HIV Controllers Study
1Broad Inst of Massachusetts Inst of Tech and Harvard Univ, Cambridge, US; 2Brigham and Women`s Hosp, Harvard Med Sch, Boston, MA, US; 3Partners AIDS Res Ctr, Massachusetts Gen Hosp, Boston, US; 4Vanderbilt Univ Sch of Med, Nashville, TN, US; 5Weill Med Coll of Cornell Univ, New York, NY, US; and 6Univ of California, San Francisco, US
Background: HIV-1 controllers are characterized as
individuals who spontaneously control virus replication to levels <2000
copies/mL in the absence of ART. We conducted a genome-wide association study
in these individuals to test the hypothesis that host genetic factors are
associated with durable suppression of virus replication.
Methods: A multi-ethnic cohort of 464 HIV
controllers and 747 chronically infected individuals with high viremia from the
ACTG A5095 trial was genotyped using the Illumina HumanHap650Y platform. After
quality control and genome-wide imputation based on HapMap, we tested 3 million
SNP for association to HIV controller status in 3 ethnic groups (575 whites,
445 blacks, and 191 Hispanics) using a logistic regression model that corrects
for population structure by including EIGENSTRAT principal components as
covariates. We used stepwise logistic regression to test for independence, and
performed meta-analysis across ethnic groups in an attempt to refine the
observed association signals.
Results: Overall, 62 SNP in whites and 6 SNP in
blacks, all located in the MHC region on chromosome 6, were genome-wide
significant at p <5x10‑8. We obtain overwhelming
replication evidence for 2 SNP previously reported to be associated with lower
HIV virus load set point in whites: rs9264942 located 35kb upstream of the HLA-C
gene (odds ratio = 3.1, p = 2x10–15) and
rs2395029, a near-perfect proxy for the HLA-B*5701 allele (odds ratio = 5.5, p
= 1x10–10). Conditional on the combined effect of these 2 SNP, we
identified 1 novel associated SNP in whites. In blacks, we observe 6
genome-wide significant SNP in the MHC region, constituting 2 independent
signals of association. Meta-analysis across populations identified 4
independent signals of association in the MHC, one of which was due to
rs2395029. The absence of the –35 HLA-C SNP in this model underscores likely
allelic heterogeneity between populations.
Conclusions: We have conducted the first genome-wide
association study of a multi-ethnic cohort of HIV controllers, and have
identified 3 novel independent SNP associated with host control of HIV
infection.
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