Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load

McLaren Paul J.; Coulonges Cedric; Bartha IstvanLenz Tobias L.Deutsch Aaron J.Bashirova ArmanBuchbinder SusanCarrington Mary N.Cossarizza AndreaDalmau JudithDe Luca AndreaGoedert James J.Gurdasani DeeptiHaas David W.Herbeck Joshua T.Johnson Eric O.Kirk Gregory D.Lambotte OlivierLuo MaMallal Simonvan Manen DanieleMartinez-Picado JavierMeyer LaurenceMiro JoseM.Mullins James I.Obel NielsPoli GuidoSandhu Manjinder S.Schuitemaker HannekeShea Patrick R.Theodorou IoannisWalker Bruce D.Weintrob Amy C.Winkler Cheryl A.Wolinsky Steven M.Raychaudhuri SoumyaGoldstein David B.Telenti Amaliode Bakker Paul I. W.Zagury Jean-FrancoisFellay Jacques

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Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load

机译：Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load

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Previous genome-wide association studies (GWAS) of HIV-1-infected populations have been underpowered to detect common variants with moderate impact on disease outcome and have not assessed the phenotypic variance explained by genome-wide additive effects. By combining the majority of available genome-wide genotyping data in HIV-infected populations, we tested for association between similar to 8 million variants and viral load (HIV RNA copies per milliliter of plasma) in 6,315 individuals of European ancestry. The strongest signal of association was observed in the HLA class I region that was fully explained by independent effects mapping to five variable amino acid positions in the peptide binding grooves of the HLA-B and HLA-A proteins. We observed a second genome-wide significant association signal in the chemokine (C-C motif) receptor (CCR) gene cluster on chromosome 3. Conditional analysis showed that this signal could not be fully attributed to the known protective CCR5 Delta 32 allele and the risk P1 haplotype, suggesting further causal variants in this region. Heritability analysis demonstrated that common human genetic variation-mostly in the HLA and CCR5 regions-explains 25 of the variability in viral load. This study suggests that analyses in non-European populations and of variant classes not assessed by GWAS should be priorities for the field going forward.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2015年第47期|14658-14663|共6页
作者
McLaren Paul J.; Coulonges Cedric; Bartha IstvanLenz Tobias L.Deutsch Aaron J.Bashirova ArmanBuchbinder SusanCarrington Mary N.Cossarizza AndreaDalmau JudithDe Luca AndreaGoedert James J.Gurdasani DeeptiHaas David W.Herbeck Joshua T.Johnson Eric O.Kirk Gregory D.Lambotte OlivierLuo MaMallal Simonvan Manen DanieleMartinez-Picado JavierMeyer LaurenceMiro JoseM.Mullins James I.Obel NielsPoli GuidoSandhu Manjinder S.Schuitemaker HannekeShea Patrick R.Theodorou IoannisWalker Bruce D.Weintrob Amy C.Winkler Cheryl A.Wolinsky Steven M.Raychaudhuri SoumyaGoldstein David B.Telenti Amaliode Bakker Paul I. W.Zagury Jean-FrancoisFellay Jacques;
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作者单位

Columbia Univ, Inst Genom Med, New York, NY 10032 USA;

NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA;

Ist Sci San Raffaele, Div Immunol Transplantat & Infect Dis, I-20132 Milan, ItalyWellcome Trust Sanger Inst, Human Genet, Hinxton CB10 1SA, EnglandUniv Amsterdam, Acad Med Ctr, Ctr Infect Dis & Immun Amsterdam, NL-1105 AZ Amsterdam, NetherlandsFrench Agcy Res AIDS & Hepatitis, ANRS Genom Grp, F-75013 Paris, FranceMIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02129 USAUniformed Serv Univ Hlth Sci, Infect Dis Clin Res Program, Bethesda, MD 20814 USALeidos Biomed Res Inc, Bas Res Lab, Mol Genet Epidemiol Sect, Ctr Canc Res,NCI,Frederick Natl Lab, Frederick, MD 21702 USANorthwestern Univ, Feinberg Sch Med, Div Infect Dis, Chicago, IL 60611 USABrigham & Womens Hosp, Dept Med, Div Genet & Rheumatol, Boston, MA 02115 USAJ Craig Venter Inst, La Jolla, CA 92037 USAUniv Med Ctr Utrecht, Dept Med Genet, NL-3584 CX Utrecht, NetherlandsConservatoire Natl Arts & Metiers, Chaire Bioinformat, EA4627, Lab Genom Bioinformat & Applicat, F-75003 Paris, FranceEcole Polytech Fed Lausanne, Sch Life Sci, Global Hlth Inst, CH-1015 Lausanne, SwitzerlandMax Planck Inst Evolutionary Biol, Dept Evolutionary Ecol, Evolutionary Immunogen, D-24306 Plon, GermanyHarvard Univ, Harvard MIT Div Hlth Sci & Technol, Boston, MA 02115 USASan Francisco Dept Publ Hlth, Bridge HIV 1, San Francisco, CA 94102 USAUniv Modena & Reggio Emilia, Sch Med, Dept Surg Med Dent & Morphol Sci, I-41121 Modena, ItalyUniv Autonoma Barcelona, AIDS Res Inst IrsiCaixa, Inst Invest Ciencies Salut Germans Trias & Pujol, Badalona 08916, SpainSiena Univ Hosp, Univ Div Infect Dis, I-53100 Siena, ItalyVanderbilt Univ, Sch Med, Nashville, TN 37212 USAUniv Washington, Dept Global Hlth, Seattle, WA 98195 USARTI Int, Behav Hlth Epidemiol, Res Triangle Pk, NC 27709 USAJohns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21205 USAINSERM, U1012, F-94270 Le Kremlin Bicetre, FranceUniv Manitoba, Dept Med Microbiol, Winnipeg, MB R3E 0J6, CanadaMurdoch Univ, Inst Immunol & Infect Dis, Perth, WA 6150, AustraliaUniv Barcelona, Hosp Clin, Inst Invest Biomed August Pi & Sunyer, Infect Dis Serv, E-08036 Barcelona, SpainUniv Washington, Dept Microbiol, Seattle, WA 98195 USACopenhagen Univ Hosp, Rigshosp, Dept Infect Dis, DK-2100 Copenhagen, Denmark;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
HIV-1 control; GWAS; heritability; infectious disease; genomics;

Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load

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