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Population-Level Protection Attributable to Host Genetic Markers Conferring Resistance to AIDS Progression A. MUNOZ*, M. SMITH, R. SKOLASKY, J. MARGOLICK, J. GIORGI, C. RINALDO, J. PHAIR, C. KEEBERGER, R. KASLOW, and S. O'BRIEN.
Johns Hopkins Univ., Baltimore, MD Objectives: To characterize combined effects of CCR5, CCR2, CCR5 promoter base pair 59029, SDF1 3' untranslated region and ILIO-592 variants on AIDS progression, and to quantify the protection they conferred at population level.
Methods: Study population comprised 404 seroconverters (346 caucasian) with 181 (45%) clinical AIDS cases diagnosed prior to the HAART era. Complete data, listed from resistant to susceptible for each marker, were available on CCR5(+/D32,+/+), CCR2(64I/64I,+/64I, +/+), CCR5 promoter (G/G,G/A,A/A), SDF1 (3'A/3'A,+/3'A,+/+), and ILIO-592 (+/+,+/5'A,5'A/5'A). Inferences were achieved by regression tree methods (recursive partitioning using Cox regression) and multivariate extensions of measures of population attributable protection (PAP).
Results: Of 162 possible genotype combinations, 52 were present (most common: +/+ for all and G/A for promoter; n= 51). Regression tree methods summarized the information on AIDS progression into five nodes with N(AIDS): 141 (84), 134 (49), 82 (32), 34 (14), and 13 (2) individuals, whose significantly (p<0.01) different relative hazards were 1, 0.62, 0.53, 0.38 and 0.13 (defined by SDF1= 3'A/3'A) respectively. Resistance of G/A promoter was modified by IL10 whose protection, in turn, varied by infection duration. The overall PAP was 44% (95% CI: 22%, 64%). Using 3, 5, 7, 9 and 11 years as cut off values for infection duration, the PAPs were 19%, 47%, 47%, 53% and 96%, respectively.
Conclusion: Had the protective host genetic polymorphisms in CCR5, CCR2, CCR5 promoter, SDF1 and IL10 not been present in our cohort, the AIDS incidence would have been 44% higher. HLA could further enhance the PAP.
Key Words: chemokines, epidemiologic methods, genetics
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