A multiethnic genome-wide association study of HIV-1 viral load among injection drug users
Hancock, D. B., Levy, J. L., Page, G. P., Novak, S. P., Glasheen, C., Gaddis, N. C., ... Johnson, E. O. (2012, November). A multiethnic genome-wide association study of HIV-1 viral load among injection drug users. Presented at American Society of Human Genetics Annual Meeting, San Francisco, CA, November 6-10, .
Among those infected with HIV-1, there is considerable variation in the amount of circulating virus during the asymptomatic phase after acute infection and prior to development of AIDS. Genome-wide association (GWA) studies have discovered genetic risk factors of HIV-1 viral load, most notably single nucleotide polymorphisms (SNPs) in the human leukocyte antigen (HLA) region on chromosome 6. However, much of the population variability in disease progression remains unexplained. The previous GWA studies have generally not focused on viral load among active injection drug users, who may have additional biological challenges controlling the virus due to their drug use. To identify novel genetic risk factors of HIV-1 viral load, we conducted GWA studies in African American and European American HIV-1-positive injection drug users from the Urban Health Study. DNA was extracted from stored serum at RUCDR and treated with Illumina FFPE restoration prior to genotyping at CIDR on the Illumina Omni1-Quad array. Following quality control procedures for genotyped SNPs and participants, the analysis data set included ~700,000 autosomal SNPs in 569 African Americans and 314 European Americans. In the separate ethnic groups, additive SNP genotypes were tested for association with log-transformed viral load using linear regression models adjusted for age, gender, behavioral risk class (based on a latent class analysis of several important behavioral and demographic risk factors), recruitment pre- or post-availability of antiretroviral therapy, and 10 principal component eigenvalues for population stratification. The ethnic-specific GWA results were then combined in a fixed-effects meta-analysis. The lowest meta-analysis P-value (P=5x10-7) was observed for an intergenic SNP located between two genes on chromosome 3p14 not previously associated with HIV-1 viral load. However, one of the novel genes has been directly linked to HIV protease inhibitor treatment responsiveness, providing further evidence to support its role in regulation of viral load. Several SNPs on chromosome 6 in the previously implicated HLA region had nominally significant meta-analysis P-values (lowest P=4x10-5). Further analyses based on 1000 Genomes-imputed SNPs and genotyping of Hispanic American samples are underway to characterize these and other loci that may offer insights into the control of HIV-1 viral load and clinical progression towards AIDS.