Dataset Information

Genome-Wide Association Study of Human Immunodeficiency Virus (HIV)-1 Coreceptor Usage in Treatment-Naive Patients from An AIDS Clinical Trials Group Study.

ABSTRACT: OBJECTIVES:We conducted a genome-wide association study to explore whether common host genetic variants (>5% frequency) were associated with presence of virus able to use CXCR4 for entry. METHODS:Phenotypic determination of human immunodeficiency virus (HIV)-1 coreceptor usage was performed on pretreatment plasma HIV-1 samples from treatment-naive participants in AIDS Clinical Trials Group A5095, a study of initial antiretroviral regimens. Associations between genome-wide single-nucleotide polymorphisms (SNPs), CCR5 ?32 genotype, and human leukocyte antigen (HLA) class I alleles and viral coreceptor usage were explored. RESULTS:Viral phenotypes were obtained from 593 patients with available genome-wide SNP data. Forty-four percent of subjects had virus capable of using CXCR4 for entry as determined by phenotyping. Overall, no associations, including those between polymorphisms in genes encoding viral coreceptors and their promoter regions or in HLA genes previously associated with HIV-1 disease progression, passed the statistical threshold for genome-wide significance (P < 5.0 × 10(-8)) in any comparison. However, the presence of viruses able to use CXCR4 for entry was marginally associated with the CCR5 ?32 genotype in the nongenome-wide analysis. CONCLUSIONS:No human genetic variants were significantly associated with virus able to use CXCR4 for entry at the genome-wide level. Although the sample size had limited power to definitively exclude genetic associations, these results suggest that host genetic factors, including those that influence coreceptor expression or the immune pressures leading to viral envelope diversity, are either rare or have only modest effects in determining HIV-1 coreceptor usage.

SUBMITTER: Henrich TJ

PROVIDER: S-EPMC4324186 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Genome-Wide Association Study of Human Immunodeficiency Virus (HIV)-1 Coreceptor Usage in Treatment-Naive Patients from An AIDS Clinical Trials Group Study.

Henrich Timothy J TJ McLaren Paul J PJ Rao Suhas S P SS Lin Nina H NH Hanhauser Emily E Giguel Francoise F Gulick Roy M RM Ribaudo Heather H de Bakker Paul I W PI Kuritzkes Daniel R DR

Open forum infectious diseases 20140301 1

<h4>Objectives</h4>We conducted a genome-wide association study to explore whether common host genetic variants (>5% frequency) were associated with presence of virus able to use CXCR4 for entry.<h4>Methods</h4>Phenotypic determination of human immunodeficiency virus (HIV)-1 coreceptor usage was performed on pretreatment plasma HIV-1 samples from treatment-naive participants in AIDS Clinical Trials Group A5095, a study of initial antiretroviral regimens. Associations between genome-wide single-n ...[more]

PMID: 25734091

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Project description:Association studies have shown and continue to show a substantial amount of success in identifying links between multiple single nucleotide polymorphisms (SNPs) and phenotypes. These studies are also believed to provide insights toward identification of new drug targets and therapies. Albeit of all the success, challenges still remain for applying and prioritizing these associations based on available biological knowledge. Along with single variant association analysis, genetic interactions also play an important role in uncovering the etiology and progression of complex traits. For gene-gene interaction analysis, selection of the variants to test for associations still poses a challenge in identifying epistatic interactions among the large list of variants available in high-throughput, genome-wide datasets. Therefore in this study, we propose a pipeline to identify interactions among genetic variants that are associated with multiple phenotypes by prioritizing previously published results from main effect association analysis (genome-wide and phenome-wide association analysis) based on a-priori biological knowledge in AIDS Clinical Trials Group (ACTG) data. We approached the prioritization and filtration of variants by using the results of a previously published single variant PheWAS and then utilizing biological information from the Roadmap Epigenome project. We removed variants in low functional activity regions based on chromatin states annotation and then conducted an exhaustive pairwise interaction search using linear regression analysis. We performed this analysis in two independent pre-treatment clinical trial datasets from ACTG to allow for both discovery and replication. Using a regression framework, we observed 50,798 associations that replicate at p-value 0.01 for 26 phenotypes, among which 2,176 associations for 212 unique SNPs for fasting blood glucose phenotype reach Bonferroni significance and an additional 9,970 interactions for high-density lipoprotein (HDL) phenotype and fasting blood glucose (total of 12,146 associations) reach FDR significance. We conclude that this method of prioritizing variants to look for epistatic interactions can be used extensively for generating hypotheses for genomewide and phenome-wide interaction analyses. This original Phenome-wide Interaction study (PheWIS) can be applied further to patients enrolled in randomized clinical trials to establish the relationship between patient's response to a particular drug therapy and non-linear combination of variants that might be affecting the outcome.

Dataset Information

Genome-Wide Association Study of Human Immunodeficiency Virus (HIV)-1 Coreceptor Usage in Treatment-Naive Patients from An AIDS Clinical Trials Group Study.

Publications

Genome-Wide Association Study of Human Immunodeficiency Virus (HIV)-1 Coreceptor Usage in Treatment-Naive Patients from An AIDS Clinical Trials Group Study.

Similar Datasets

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