Genome-wide association study of peripheral neuropathy with D-drug-containing regimens in AIDS Clinical Trials Group protocol 384
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Stavudine (d4T) was, until recently, one of the most widely prescribed antiretroviral drugs worldwide. While there has been a major shift away from d4T use in resource-limited countries, a large number of patients have previously received (or continue to receive) d4T, and many have developed peripheral neuropathy. The identification of genetic predictors of increased risk might suggest novel therapeutic targets for such patients. In AIDS Clinical Trials Group protocol 384, antiretroviral-naïve patients were randomized to d4T/didanosine (ddI)- or zidovudine/lamivudine-containing regimens. Data from d4T/ddI recipients were analyzed for genome-wide associations (approximately 1 million genetic loci) with new onset distal sensory peripheral neuropathy. Analyses involved 254 patients (49 % White, 34 % Black, 17 % Hispanic), comprising 90 peripheral neuropathy cases (32 grade 1, 35 grade 2, 23 grade 3) and 164 controls. After correcting for multiple comparisons, no polymorphism was consistently associated with neuropathy among all patients, among White, Black, and Hispanic patients analyzed separately, both in genome-wide analyses (threshold, P < 5.0 × 10−8) and focused on 46 neuropathy-associated genes (threshold, P < 3.5 × 10−5). In the latter analyses, the lowest P values were in KIF1A among Whites (rs10199388, P = 8.4 × 10−4), in LITAF among Blacks (rs13333308, P = 6.0 × 10−6), and in NEFL among Hispanics (rs17763685, P = 5.6 × 10−6). Susceptibility to d4T/ddI-associated neuropathy is not explained by a single genetic variant with a marked effect.
KeywordsPeripheral neuropathy HIV-1 Stavudine Didanosine Genomics
The authors are grateful to the many persons with HIV infection who volunteered for ACTG 384 and A5128. In addition, they acknowledge the contributions of study teams and site staff for protocols ACTG 384 and A5128. This project was supported by grant AI-077505 (DWH). The project described was also supported by award number U01 AI-068636 from the National Institute of Allergy and Infectious Diseases (NIAID) and supported by National Institute of Mental Health (NIMH) and National Institute of Dental and Craniofacial Research (NIDCR). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. Additional grant support included AI-038858, AI-068634, AI-038855, GM-80178, AI-062435, AI-069415, AI-069419, AI-069423, AI-069424, AI-069428, AI-069432, AI-069434, AI-069450, AI-069452, AI-069465, AI-069471, AI-069472, AI-069474, AI-069477, AI-069484, AI-069495, AI-069501, AI-069502, AI-069511, AI-069513, AI-069532, AI-069556, AI-25859, AI-27661, AI-34835, AI-34853, AI-38844, AI-46370, AI-54999, AI-69467, AI-69495, AL-32782, HL-087726, NS-059330, and TR-000445.
Conflict of interest
David W. Haas has been the principal investigator on research grants to Vanderbilt University from Boehringer Ingelheim, Merck, and Gilead Sciences and has been a consultant to Merck. Gregory K. Robbins received research support from Gilead Sciences and Schering-Plough and received royalties from Wolters Kluwer. David B. Clifford has served on Data Safety Boards for Millennium, Pfizer, Genzyme, and Amgen and has been a consultant to Biogen Idec, Millennium, Bristol Myers Squibb, Pfizer, Genzyme, Amgen, and Quintiles. For the remaining authors, none were declared.
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