Genome-wide association study implicates PARD3B-based AIDS restriction.

BACKGROUND Host genetic variation influences human immunodeficiency virus (HIV) infection and progression to AIDS. Here we used clinically well-characterized subjects from 5 pretreatment HIV/AIDS cohorts for a genome-wide association study to identify gene associations with rate of AIDS progression. METHODS European American HIV seroconverters (n = 755) were interrogated for single-nucleotide polymorphisms (SNPs) (n = 700,022) associated with progression to AIDS 1987 (Cox proportional hazards regression analysis, co-dominant model). RESULTS Association with slower progression was observed for SNPs in the gene PARD3B. One of these, rs11884476, reached genome-wide significance (relative hazard = 0.3; P =3. 370 × 10(-9)) after statistical correction for 700,022 SNPs and contributes 4.52% of the overall variance in AIDS progression in this study. Nine of the top-ranked SNPs define a PARD3B haplotype that also displays significant association with progression to AIDS (hazard ratio, 0.3; P = 3.220 × 10(-8)). One of these SNPs, rs10185378, is a predicted exonic splicing enhancer; significant alteration in the expression profile of PARD3B splicing transcripts was observed in B cell lines with alternate rs10185378 genotypes. This SNP was typed in European cohorts of rapid progressors and was found to be protective for AIDS 1993 definition (odds ratio, 0.43, P = .025). CONCLUSIONS These observations suggest a potential unsuspected pathway of host genetic influence on the dynamics of AIDS progression.

[1]  O. Delaneau,et al.  Screening Low-Frequency SNPS From Genome-Wide Association Study Reveals a New Risk Allele for Progression to AIDS , 2011, Journal of acquired immune deficiency syndromes.

[2]  O. Delaneau,et al.  Multiple-cohort genetic association study reveals CXCR6 as a new chemokine receptor involved in long-term nonprogression to AIDS. , 2010, The Journal of infectious diseases.

[3]  C. Winkler,et al.  Host genes associated with HIV/AIDS: advances in gene discovery. , 2010, Trends in genetics : TIG.

[4]  J. Goedert,et al.  Multistage genomewide association study identifies a locus at 1q41 associated with rate of HIV-1 disease progression to clinical AIDS. , 2010, The Journal of infectious diseases.

[5]  E. Thiel,et al.  Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. , 2009, The New England journal of medicine.

[6]  Elizabeth T. Cirulli,et al.  Common Genetic Variation and the Control of HIV-1 in Humans , 2009, PLoS genetics.

[7]  O. Delaneau,et al.  Genomewide Association Study of a Rapid Progression Cohort Identifies New Susceptibility Alleles for Aids (anrs Genomewide Association Study 03) , 2022 .

[8]  Philippe Froguel,et al.  Genomewide association study of an AIDS-nonprogression cohort emphasizes the role played by HLA genes (ANRS Genomewide Association Study 02). , 2009, The Journal of infectious diseases.

[9]  H. Schuitemaker,et al.  Association of HLA-C and HCP5 gene regions with the clinical course of HIV-1 infection , 2009, AIDS.

[10]  Donna R. Maglott,et al.  Human immunodeficiency virus type 1, human protein interaction database at NCBI , 2008, Nucleic Acids Res..

[11]  Cyril Dalmasso,et al.  Distinct Genetic Loci Control Plasma HIV-RNA and Cellular HIV-DNA Levels in HIV-1 Infection: The ANRS Genome Wide Association 01 Study , 2008, PloS one.

[12]  D. Vlahov,et al.  MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis , 2008, Nature Genetics.

[13]  C. Hoggart,et al.  Simultaneous Analysis of All SNPs in Genome-Wide and Re-Sequencing Association Studies , 2008, PLoS genetics.

[14]  J. Goedert,et al.  Detecting AIDS restriction genes: from candidate genes to genome-wide association discovery. , 2008, Vaccine.

[15]  M. McCarthy,et al.  Genome-wide association studies for complex traits: consensus, uncertainty and challenges , 2008, Nature Reviews Genetics.

[16]  David Reich,et al.  Discerning the Ancestry of European Americans in Genetic Association Studies , 2007, PLoS genetics.

[17]  Ncbi.  National Center for Biotechnology Information , 2008 .

[18]  D. Schaubel,et al.  Fitting Semiparametric Additive Hazards Models using Standard Statistical Software , 2007, Biometrical journal. Biometrische Zeitschrift.

[19]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[20]  Jacques Fellay,et al.  A Whole-Genome Association Study of Major Determinants for Host Control of HIV-1 , 2007, Science.

[21]  Stefano Bonora,et al.  Specific mutations in HIV-1 gp41 are associated with immunological success in HIV-1-infected patients receiving enfuvirtide treatment. , 2006, The Journal of antimicrobial chemotherapy.

[22]  R. Manfredi,et al.  A novel antiretroviral class (fusion inhibitors) in the management of HIV infection. Present features and future perspectives of enfuvirtide (T-20). , 2006, Current medicinal chemistry.

[23]  J. Heeney,et al.  Origins of HIV and the Evolution of Resistance to AIDS , 2006, Science.

[24]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[25]  Stephen J O'Brien,et al.  Using mutual information to measure the impact of multiple genetic factors on AIDS. , 2006, Journal of acquired immune deficiency syndromes.

[26]  Chia-Hung Liu,et al.  FASTSNP: an always up-to-date and extendable service for SNP function analysis and prioritization , 2006, Nucleic Acids Res..

[27]  M. Westby,et al.  CCR5 Antagonists: Host-Targeted Antivirals for the Treatment of HIV Infection , 2005, Antiviral chemistry & chemotherapy.

[28]  S. Fan,et al.  p300 Modulates HIV-1 gp120-Induced Apoptosis in Human Proximal Tubular Cells: Associated with Alteration of TGF-β and Smad Signaling , 2005, Nephron Experimental Nephrology.

[29]  L. Lind,et al.  Erythropoietin Impairs Endothelial Vasodilatory Function in Patients with Renal Anemia and in Healthy Subjects , 2005, Nephron Clinical Practice.

[30]  K. Khalili,et al.  Cooperative interaction of C/EBPβ and Tat modulates MCP-1 gene transcription in astrocytes , 2005, Journal of Neuroimmunology.

[31]  J. Paridaen,et al.  Anti-HIV drug development--an overview. , 2004, Current pharmaceutical design.

[32]  Stephen J O'Brien,et al.  Human genes that limit AIDS , 2004, Nature Genetics.

[33]  Stephen J O'Brien,et al.  The influence of HLA genotype on AIDS. , 2003, Annual review of medicine.

[34]  K. Khalili,et al.  Regulation of MCP-1 gene transcription by Smads and HIV-1 Tat in human glial cells. , 2003, Virology.

[35]  N. Saito,et al.  PAR3beta, a novel homologue of the cell polarity protein PAR3, localizes to tight junctions. , 2002, Biochemical and biophysical research communications.

[36]  K. Khalili,et al.  Interaction between TGFbeta signaling proteins and C/EBP controls basal and Tat-mediated transcription of HIV-1 LTR in astrocytes. , 2002, Virology.

[37]  G. Joberty,et al.  Multiple splice variants of Par3 and of a novel related gene, Par3L, produce proteins with different binding properties. , 2002, Gene.

[38]  M. Schemper,et al.  Predictive Accuracy and Explained Variation in Cox Regression , 2000, Biometrics.

[39]  K. Roeder,et al.  Genomic Control for Association Studies , 1999, Biometrics.

[40]  J J Goedert,et al.  Genetic Restriction of HIV-1 Infection and Progression to AIDS by a Deletion Allele of the CKR5 Structural Gene , 1996, Science.

[41]  N Risch,et al.  The Future of Genetic Studies of Complex Human Diseases , 1996, Science.

[42]  John W. Ward,et al.  1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. , 1993, MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports.

[43]  Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. Council of State and Territorial Epidemiologists; AIDS Program, Center for Infectious Diseases. , 1987, MMWR supplements.