Genome-wide association study implicates PARD3B-based AIDS restriction

Jennifer L. Troyer, George W. Nelson, James A. Lautenberger, Leslie Chinn, Carl McIntosh, Randall C. Johnson, Efe Sezgin, Bailey Kessing, Michael Malasky, Sher L. Hendrickson, Guan Li, Joan Pontius, Minzhong Tang, Ping An, Cheryl A. Winkler, Sophie Limou, Sigrid Le Clerc, Olivier Delaneau, Jean Francxois Zagury, Hanneke SchuitemakerDaniëlle Van Manen, Jay Bream, Edward D. Gomperts, Susan Buchbinder, James J. Goedert, Gregory D Kirk, Stephen J. O'Brien

Research output: Contribution to journalArticle

Abstract

Background. Host genetic variation influences human immunodeficiency virus (HIV) infection and progression to AIDS. Here we used clinically well-characterized subjects from=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.

Original languageEnglish (US)
Pages (from-to)1491-1502
Number of pages12
JournalJournal of Infectious Diseases
Volume203
Issue number10
DOIs
StatePublished - May 15 2011
Externally publishedYes

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Genome-Wide Association Study
Acquired Immunodeficiency Syndrome
Single Nucleotide Polymorphism
HIV
Virus Diseases
Haplotypes
Genes
B-Lymphocytes
Odds Ratio
Genotype
Regression Analysis
Genome
Cell Line

ASJC Scopus subject areas

  • Infectious Diseases
  • Immunology and Allergy

Cite this

Troyer, J. L., Nelson, G. W., Lautenberger, J. A., Chinn, L., McIntosh, C., Johnson, R. C., ... O'Brien, S. J. (2011). Genome-wide association study implicates PARD3B-based AIDS restriction. Journal of Infectious Diseases, 203(10), 1491-1502. https://doi.org/10.1093/infdis/jir046

Genome-wide association study implicates PARD3B-based AIDS restriction. / Troyer, Jennifer L.; Nelson, George W.; Lautenberger, James A.; Chinn, Leslie; McIntosh, Carl; Johnson, Randall C.; Sezgin, Efe; Kessing, Bailey; Malasky, Michael; Hendrickson, Sher L.; Li, Guan; Pontius, Joan; Tang, Minzhong; An, Ping; Winkler, Cheryl A.; Limou, Sophie; Le Clerc, Sigrid; Delaneau, Olivier; Zagury, Jean Francxois; Schuitemaker, Hanneke; Van Manen, Daniëlle; Bream, Jay; Gomperts, Edward D.; Buchbinder, Susan; Goedert, James J.; Kirk, Gregory D; O'Brien, Stephen J.

In: Journal of Infectious Diseases, Vol. 203, No. 10, 15.05.2011, p. 1491-1502.

Research output: Contribution to journalArticle

Troyer, JL, Nelson, GW, Lautenberger, JA, Chinn, L, McIntosh, C, Johnson, RC, Sezgin, E, Kessing, B, Malasky, M, Hendrickson, SL, Li, G, Pontius, J, Tang, M, An, P, Winkler, CA, Limou, S, Le Clerc, S, Delaneau, O, Zagury, JF, Schuitemaker, H, Van Manen, D, Bream, J, Gomperts, ED, Buchbinder, S, Goedert, JJ, Kirk, GD & O'Brien, SJ 2011, 'Genome-wide association study implicates PARD3B-based AIDS restriction', Journal of Infectious Diseases, vol. 203, no. 10, pp. 1491-1502. https://doi.org/10.1093/infdis/jir046
Troyer JL, Nelson GW, Lautenberger JA, Chinn L, McIntosh C, Johnson RC et al. Genome-wide association study implicates PARD3B-based AIDS restriction. Journal of Infectious Diseases. 2011 May 15;203(10):1491-1502. https://doi.org/10.1093/infdis/jir046
Troyer, Jennifer L. ; Nelson, George W. ; Lautenberger, James A. ; Chinn, Leslie ; McIntosh, Carl ; Johnson, Randall C. ; Sezgin, Efe ; Kessing, Bailey ; Malasky, Michael ; Hendrickson, Sher L. ; Li, Guan ; Pontius, Joan ; Tang, Minzhong ; An, Ping ; Winkler, Cheryl A. ; Limou, Sophie ; Le Clerc, Sigrid ; Delaneau, Olivier ; Zagury, Jean Francxois ; Schuitemaker, Hanneke ; Van Manen, Daniëlle ; Bream, Jay ; Gomperts, Edward D. ; Buchbinder, Susan ; Goedert, James J. ; Kirk, Gregory D ; O'Brien, Stephen J. / Genome-wide association study implicates PARD3B-based AIDS restriction. In: Journal of Infectious Diseases. 2011 ; Vol. 203, No. 10. pp. 1491-1502.
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abstract = "Background. Host genetic variation influences human immunodeficiency virus (HIV) infection and progression to AIDS. Here we used clinically well-characterized subjects from=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.",
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AU - Troyer, Jennifer L.

AU - Nelson, George W.

AU - Lautenberger, James A.

AU - Chinn, Leslie

AU - McIntosh, Carl

AU - Johnson, Randall C.

AU - Sezgin, Efe

AU - Kessing, Bailey

AU - Malasky, Michael

AU - Hendrickson, Sher L.

AU - Li, Guan

AU - Pontius, Joan

AU - Tang, Minzhong

AU - An, Ping

AU - Winkler, Cheryl A.

AU - Limou, Sophie

AU - Le Clerc, Sigrid

AU - Delaneau, Olivier

AU - Zagury, Jean Francxois

AU - Schuitemaker, Hanneke

AU - Van Manen, Daniëlle

AU - Bream, Jay

AU - Gomperts, Edward D.

AU - Buchbinder, Susan

AU - Goedert, James J.

AU - Kirk, Gregory D

AU - O'Brien, Stephen J.

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N2 - Background. Host genetic variation influences human immunodeficiency virus (HIV) infection and progression to AIDS. Here we used clinically well-characterized subjects from=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.

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