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A Single Nucleotide Polymorphism in the Resistin Gene Is Associated with Adverse Metabolic Changes on HAART: An Exploratory Pharmacogenetic Association Study of A5005s, the Metabolic Sub-study of ACTG 384
Koustubh Ranade*1, R Parker1, L Ploughman1, R Parker2, P Tebas3, W Powderly4, S Grinspoon5, K Mulligan6, M Noor1,7, and M Dubé8
1Bristol-Myers Squibb, Princeton, NJ, US; 2Statistical and Data Analysis Ctr, Boston, MA, US; 3Univ of Pennsylvania, Philadelphia, US; 4Univ Coll Dublin, Ireland; 5Harvard Sch of Publ Hlth, Boston, MA, US; 6Univ of California, San Francisco, US; 7Bristol-Myers Squibb, Plainsboro, NJ, US; and 8Indiana Univ, Indianapolis, US
Background: Dyslipidemia and insulin resistance can be
associated with HAART, but the incidence and severity vary widely suggesting a
genetic component. We sought single nucleotide polymorphisms in select candidate
genes associated with higher risk for adverse metabolic changes after
initiating HAART.
Methods: We genotyped 189 HIV+ subjects (mean
age 38 years, 88% male, 56% Caucasian, 28% black, and 14% Hispanic) from ACTG
5005s for whom DNA samples and biochemical profiles prior to HAART and on
therapy were available with 285 single nucleotide polymorphisms in 137
candidate genes. Principal components and cluster analyses of metabolic
variables at week 32 were employed to identify a sub-group of patients at risk
for developing adverse metabolic changes. Single nucleotide polymorphisms
association with group membership was analyzed by Fisher’s exact test and differences
in metabolic variables between groups was analyzed by Kruskal-Wallis test.
Results: Multivariate analysis revealed a high-risk
and a low-risk subgroup of patients. At baseline, lipids and insulin resistance
by HOMA-IR were comparable between the 2 groups. At 32 weeks, the low-risk subgroup
(n = 141) had lower mean body mass index
(25±5
kg/m2), normal mean total cholesterol (180±29 mg/dL), LDL (110±28
mg/dL), triglycerides (143±77 mg/dL), and HOMA-IR (1.6±1.2). Relative to this
subgroup, the high-risk group (n = 47)
had higher body mass index (29±7 kg/m2, p
<0.001), higher total cholesterol (258±47 mg/dL, p <0.001), LDL (175±32
mg/dL, p <0.001), triglycerides
(305±236
mg/dL, p <0.001), and HOMA-IR (4±5.6, p <0.001). Race (p = 0.2) and sex (p =
0.3) were not significantly associated with risk of adverse metabolic changes. C®T single
nucleotide polymorphism in the second intron of the resistin gene was
associated with significantly increased risk for developing adverse metabolic
changes on HAART (p = 0.001). Heterozygotes
(n = 65; odds ratio=2.8; 95%CI 1.4 to
5.7) and homozygotes (n = 5; odds
ratio = 19.4; 95%CI 2 to 182) were at increased risk relative to wild type (n = 117) of being in this high-risk
group. This polymorphism consistently increased risk of adverse metabolic
changes on HAART in all races.
Conclusions: In this exploratory pharmacogenetic study, a
single nucleotide polymorphism in the resistin gene was significantly
associated with risk of developing adverse metabolic changes on HAART. Confirmation
in other cohorts and relationship to individual ART agents is required.
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