Genome-wide association study of peripheral neuropathy with D-drug-containing regimens in AIDS Clinical Trials Group protocol 384.

TitleGenome-wide association study of peripheral neuropathy with D-drug-containing regimens in AIDS Clinical Trials Group protocol 384.
Publication TypeJournal Article
Year of Publication2014
AuthorsLeger PD, Johnson DH, Robbins GK, Shafer RW, Clifford DB, Li J, McLaren PJ, Haas DW
JournalJ Neurovirol
Volume20
Issue3
Pagination304-8
Date Published2014 Jun
ISSN1538-2443
KeywordsAcquired Immunodeficiency Syndrome, Anti-HIV Agents, Case-Control Studies, Drug Combinations, Drug Therapy, Combination, Genome-Wide Association Study, Genotype, Humans, Lamivudine, Multicenter Studies as Topic, Peripheral Nervous System Diseases, Polymorphism, Genetic, Principal Component Analysis, Randomized Controlled Trials as Topic, Retrospective Studies, Stavudine, Treatment Outcome, Zidovudine
Abstract

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.

DOI10.1007/s13365-014-0235-9
Alternate JournalJ. Neurovirol.
PubMed ID24554482
PubMed Central IDPMC4114519
Grant ListAI-038855 / AI / NIAID NIH HHS / United States
AI-038858 / AI / NIAID NIH HHS / United States
AI-062435 / AI / NIAID NIH HHS / United States
AI-068634 / AI / NIAID NIH HHS / United States
AI-069415 / AI / NIAID NIH HHS / United States
AI-069419 / AI / NIAID NIH HHS / United States
AI-069423 / AI / NIAID NIH HHS / United States
AI-069424 / AI / NIAID NIH HHS / United States
AI-069428 / AI / NIAID NIH HHS / United States
AI-069432 / AI / NIAID NIH HHS / United States
AI-069434 / AI / NIAID NIH HHS / United States
AI-069450 / AI / NIAID NIH HHS / United States
AI-069452 / AI / NIAID NIH HHS / United States
AI-069465 / AI / NIAID NIH HHS / United States
AI-069471 / AI / NIAID NIH HHS / United States
AI-069472 / AI / NIAID NIH HHS / United States
AI-069474 / AI / NIAID NIH HHS / United States
AI-069477 / AI / NIAID NIH HHS / United States
AI-069484 / AI / NIAID NIH HHS / United States
AI-069495 / AI / NIAID NIH HHS / United States
AI-069501 / AI / NIAID NIH HHS / United States
AI-069502 / AI / NIAID NIH HHS / United States
AI-069511 / AI / NIAID NIH HHS / United States
AI-069513 / AI / NIAID NIH HHS / United States
AI-069532 / AI / NIAID NIH HHS / United States
AI-069556 / AI / NIAID NIH HHS / United States
AI-077505 / AI / NIAID NIH HHS / United States
AI-25859 / AI / NIAID NIH HHS / United States
AI-27661 / AI / NIAID NIH HHS / United States
AI-34835 / AI / NIAID NIH HHS / United States
AI-34853 / AI / NIAID NIH HHS / United States
AI-38844 / AI / NIAID NIH HHS / United States
AI-46370 / AI / NIAID NIH HHS / United States
AI-54999 / AI / NIAID NIH HHS / United States
AI-69467 / AI / NIAID NIH HHS / United States
AI-69495 / AI / NIAID NIH HHS / United States
AL-32782 / / PHS HHS / United States
GM-80178 / GM / NIGMS NIH HHS / United States
HL-087726 / HL / NHLBI NIH HHS / United States
K01 AI062435 / AI / NIAID NIH HHS / United States
NS-059330 / NS / NINDS NIH HHS / United States
P30 AI054999 / AI / NIAID NIH HHS / United States
R01 AI077505 / AI / NIAID NIH HHS / United States
R21 HL087726 / HL / NHLBI NIH HHS / United States
R21 NS059330 / NS / NINDS NIH HHS / United States
T32 GM080178 / GM / NIGMS NIH HHS / United States
TR-000445 / TR / NCATS NIH HHS / United States
U01 AI-068636 / AI / NIAID NIH HHS / United States
U01 AI025859 / AI / NIAID NIH HHS / United States
U01 AI027661 / AI / NIAID NIH HHS / United States
U01 AI032782 / AI / NIAID NIH HHS / United States
U01 AI034835 / AI / NIAID NIH HHS / United States
U01 AI034853 / AI / NIAID NIH HHS / United States
U01 AI038844 / AI / NIAID NIH HHS / United States
U01 AI038855 / AI / NIAID NIH HHS / United States
U01 AI038858 / AI / NIAID NIH HHS / United States
U01 AI046370 / AI / NIAID NIH HHS / United States
U01 AI068636 / AI / NIAID NIH HHS / United States
UL1 TR000445 / TR / NCATS NIH HHS / United States
UM1 AI068634 / AI / NIAID NIH HHS / United States
UM1 AI068636 / AI / NIAID NIH HHS / United States
UM1 AI069415 / AI / NIAID NIH HHS / United States
UM1 AI069419 / AI / NIAID NIH HHS / United States
UM1 AI069423 / AI / NIAID NIH HHS / United States
UM1 AI069424 / AI / NIAID NIH HHS / United States
UM1 AI069428 / AI / NIAID NIH HHS / United States
UM1 AI069432 / AI / NIAID NIH HHS / United States
UM1 AI069434 / AI / NIAID NIH HHS / United States
UM1 AI069439 / AI / NIAID NIH HHS / United States
UM1 AI069450 / AI / NIAID NIH HHS / United States
UM1 AI069452 / AI / NIAID NIH HHS / United States
UM1 AI069465 / AI / NIAID NIH HHS / United States
UM1 AI069467 / AI / NIAID NIH HHS / United States
UM1 AI069471 / AI / NIAID NIH HHS / United States
UM1 AI069472 / AI / NIAID NIH HHS / United States
UM1 AI069474 / AI / NIAID NIH HHS / United States
UM1 AI069477 / AI / NIAID NIH HHS / United States
UM1 AI069484 / AI / NIAID NIH HHS / United States
UM1 AI069495 / AI / NIAID NIH HHS / United States
UM1 AI069501 / AI / NIAID NIH HHS / United States
UM1 AI069502 / AI / NIAID NIH HHS / United States
UM1 AI069511 / AI / NIAID NIH HHS / United States
UM1 AI069513 / AI / NIAID NIH HHS / United States
UM1 AI069532 / AI / NIAID NIH HHS / United States
UM1 AI069556 / AI / NIAID NIH HHS / United States
UM1 AI106701 / AI / NIAID NIH HHS / United States