1. Evaluating the Impact of Functional Genetic Variation on HIV-1 Control
- Author
-
Paul J McLaren, Sara L Pulit, Deepti Gurdasani, Istvan Bartha, Patrick R Shea, Cristina Pomilla, Namrata Gupta, Effrossyni Gkrania-Klotsas, Elizabeth H Young, Norbert Bannert, Julia Del Amo, M John Gill, Jill Gilmour, Paul Kellam, Anthony D Kelleher, Anders Sönnerborg, Steven M Wolinsky, Robert Zangerle, Frank A Post, Martin Fisher, David W Haas, Bruce D Walker, Kholoud Porter, David B Goldstein, Manjinder S Sandhu, Paul I W de Bakker, Jacques Fellay, Gkrania-Klotsas, Effrossyni [0000-0002-0930-8330], Sandhu, Manjinder [0000-0002-2725-142X], Apollo - University of Cambridge Repository, United States Agency for International Development (USAID), Swiss National Science Foundation, Swiss HIV Cohort Study, Harvard University (Estados Unidos), University of California, San Francisco (Estados Unidos), Unión Europea. Comisión Europea. 7 Programa Marco, Red de Investigación Cooperativa en Investigación en Sida, NIH - National Institute of Allergy and Infectious Diseases (NIAID), NIH - National Cancer Institute (NCI), NIH - National Institute on Drug Abuse (NIDA), NIH - National Institute of Mental Health (NIMH), NIH - National Heart, Lung, and Blood Institute (NHLBI), NIH - National Institute on Deafness and Communication Disorders (NIDCD), Red de Investigación Cooperativa en Investigación en Sida (España), NIH - National Institute of Allergy and Infectious Diseases (NIAID) (Estados Unidos), NIH - National Cancer Institute (NCI) (Estados Unidos), NIH - National Institute on Drug Abuse (NIDA) (Estados Unidos), NIH - National Institute of Mental Health (NIMH) (Estados Unidos), NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos), and NIH - National Institute on Deafness and Communication Disorders (NIDCD) (Estados Unidos)
- Subjects
Exome sequencing ,Male ,0301 basic medicine ,AUTISM SPECTRUM DISORDERS ,HIV Infections ,DETERMINANTS ,Human genetic variation ,WHOLE-GENOME ASSOCIATION ,Whole Exome Sequencing ,0302 clinical medicine ,INFECTION ,Genotype ,WIDE ASSOCIATION ,host genetics of infection ,Immunology and Allergy ,POPULATION ,11 Medical and Health Sciences ,Genetics ,virus diseases ,Middle Aged ,Viral Load ,3. Good health ,Infectious Diseases ,RARE VARIANTS ,Host-Pathogen Interactions ,HIV/AIDS ,Female ,Life Sciences & Biomedicine ,Viral load ,Adult ,Immunology ,HOST CONTROL ,HIV host dependency factors ,Biology ,Microbiology ,Polymorphism, Single Nucleotide ,Host genetics of infection ,Major Articles and Brief Reports ,03 medical and health sciences ,Acquired immunodeficiency syndrome (AIDS) ,Genetic variation ,LINKAGE ,medicine ,Humans ,Genetic Predisposition to Disease ,Genotyping ,HIV-1 control ,Genetic association ,Science & Technology ,Genetic Variation ,06 Biological Sciences ,medicine.disease ,HIV-1 progression ,030104 developmental biology ,HIV-1 ,exome sequencing ,030217 neurology & neurosurgery - Abstract
We evaluated the impact of coding variation on HIV control by exome sequencing with emphasis on known HIV host dependency factors. Outside of the MHC region, exonic variants with large effect sizes are not a major contributor to HIV control., Background Previous genetic association studies of human immunodeficiency virus-1 (HIV-1) progression have focused on common human genetic variation ascertained through genome-wide genotyping. Methods We sought to systematically assess the full spectrum of functional variation in protein coding gene regions on HIV-1 progression through exome sequencing of 1327 individuals. Genetic variants were tested individually and in aggregate across genes and gene sets for an influence on HIV-1 viral load. Results Multiple single variants within the major histocompatibility complex (MHC) region were observed to be strongly associated with HIV-1 outcome, consistent with the known impact of classical HLA alleles. However, no single variant or gene located outside of the MHC region was significantly associated with HIV progression. Set-based association testing focusing on genes identified as being essential for HIV replication in genome-wide small interfering RNA (siRNA) and clustered regularly interspaced short palindromic repeats (CRISPR) studies did not reveal any novel associations. Conclusions These results suggest that exonic variants with large effect sizes are unlikely to have a major contribution to host control of HIV infection.