Journal Article

Fraction of Cases of Acquired Immunodeficiency Syndrome Prevented by the Interactions of Identified Restriction Gene Variants

M. J. Silverberg, M. W. Smith, J. S. Chmiel, R. Detels, J. B. Margolick, C. R. Rinaldo, S. J. O’Brien and A. Muñoz

in American Journal of Epidemiology

Published on behalf of Johns Hopkins Bloomberg School of Public Health

Volume 159, issue 3, pages 232-241
Published in print February 2004 | ISSN: 0002-9262
Published online February 2004 | e-ISSN: 1476-6256 | DOI: http://dx.doi.org/10.1093/aje/kwh036
Fraction of Cases of Acquired Immunodeficiency Syndrome Prevented by the Interactions of Identified Restriction Gene Variants

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Previous research has demonstrated isolated effects of host genetic factors on the progression of human immunodeficiency virus type 1 (HIV-1) infection. In this paper, the authors present a novel use of multivariable methods for estimating the prevented fraction of acquired immunodeficiency syndrome (AIDS) cases attributable to six restriction genes after accounting for their epidemiologic interactions. The methods presented will never yield a prevented fraction above 1. The study population consisted of a well-characterized cohort of 525 US men with HIV-1 seroconversion documented during follow-up (1984–1996). On the basis of a regression tree approach using a Cox proportional hazards model for times to clinical AIDS, the combinations of genes associated with the greatest protection, relative to the lack of a protective genotype, consisted of: 1) C-C chemokine receptor 5 (CCR5)-Δ32 and C-C chemokine receptor 2 (CCR2)-64I (relative hazard = 0.44); 2) interleukin 10 (IL10)-+/+ in combination with CCR5-Δ32 or CCR2-64I (relative hazard = 0.45); and 3) IL10-+/+ in combination with stromal-derived factor (SDF1)-3 A and CCR5 promoter P1/~P1 (relative hazard = 0.37). Overall, 30% of potential AIDS cases were prevented by the observed combinations of restriction genes (95% confidence interval: 7, 47). However, the combined effect was confined to the first 4 years following HIV-1 seroconversion. Additional research is needed to identify AIDS restriction genes with stronger and long-lasting protection to better characterize the genetic epidemiology of HIV-1.

Keywords: acquired immunodeficiency syndrome; chemokines; cytokines; epidemiologic methods; HIV-1; HLA antigens; receptors, chemokine; Abbreviations: AIDS, acquired immunodeficiency syndrome; CCR2, C-C chemokine receptor 2; CCR5, C-C chemokine receptor 5; CCR5P, C-C chemokine receptor 5 promoter; CI, confidence interval; HIV-1, human immunodeficiency virus type 1; HLA, human leukocyte antigen; IL10, interleukin 10; MACS, Multicenter AIDS Cohort Study; PF, prevented fraction; RH, relative hazard; SDF1, stromal-derived factor.

Journal Article.  5778 words.  Illustrated.

Subjects: Public Health and Epidemiology

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