Study 33 – Genome-wide Association Study of HIV-1 Host Genetics Among Injection Drug Users

Investigator:  Eric Johnson, Ph.D. (RTI International)

Status: Available at dbGaP

Abstract:  Vancouver Injection Drug User Study (VIDUS)

The overaching goal of this project remains to identify and characterize genetic deteminants of HIV-1 susceptibility and resistance in a large sample of injection drug users (IDUs).  We plan to expand beyond our initial GWAS and replication of HIV acquisition and viral control phenotypes by conducting (1) a case/control targeted NexGen sequencing study of HIV-1 infection (positive/negative), (2) replication in an independent sample, and (3) assessment of altered gene expression by HIV status for replicating loci to better understand potentially biological function underlying observed statistical associations.  To conduct these follow-up studies, we will use the 3,136 UHS IDUs from our GWAS and 1,200 new samples being collected in collaboration with VIDUS (500 HIV+ and 700 HIV- IDUs). VIDUS samples will include whole blood for DNA extraction and sequencing as well as mRNA for whole genome expression.

Host genetics influence susceptibility to HIV-1.  Identifying genetic associations with HIV acquisition provides targets for medication and vaccine development.  For example, the only well-replicated genetic association with HIV acquisition, a 32-base pair deletion in the CCR5 gene, gave rise to maraviroc, an antiretroviral drug.  We recently indentified 8 genetic regions of interest through a genome-wide association study (GWAS) of HIV-1 acquisition among IDUs.  We found significant independent replication for FRMDP1 and nominal replication for KDM3B and KDM4C.  Our novel regions span genes with biological roles in the immune system, some known mechanisms affecting viral replication and infectivity during acute HIV exposure.  However, the genetic variants with the most statistically significant associations with a disease are often not functional but instead serve as markers for regions that harbor variants that functionally impact risk for disease.  NexGen sequencing is a highly promising approach to discovering the functional variants in disease-associated gene regions. It is widely hypothesized that rare and structural variants not captured in GWAS but found in sequencing will highlight important biological mechanisms contributing to disease.

Specific Aim 1:  To extend discovery of genetic associations with HIV acquisition by targeted NexGen sequencing of genomic regions identified in our recent GWAS.

Specific Aim 2:  To validate genetic associations with HIV acquisition in an independent cohort.

Specific Aim 3:  Investigate function of genetic variants having replicated associations using gene expression and bioinformatics.

The proposed study is novel: capitalizing on a case-control cohort of ancestrally diverse and highly exposed IDUs, using targeted sequencing, and testing for validation in an independent cohort with both genotype and expression data.  Hypothesizing that important functional variants affecting HIV acquisition lay under our GWAS signals and ignoring the potential effects of the rest of the genome has risk.  However, the reward could be great: taking a major step along the cutting edge of genomic science and moving the field to a better understanding of HIV pathogenesis.  As with CCR5 and maraviroc, our strategy may identify variant targets whose mechanisms provide for development of new medications or HIV vaccines.

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