Genome-wide association study of peripheral neuropathy with D-drug-containing regimens in AIDS clinical trials group protocol 384

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 x 10^-8) and focused on 46 neuropathy-associated genes (threshold, P<3.5 x 10^-5). In the latter analyses, the lowest P values were in KIF1A among Whites (rs10199388, P=8.4 x 10 ^-4), in LITAF among Blacks (rs13333308, P=6.0 x 10^-6), and in NEFL among Hispanics (rs17763685, P=5.6 x 10^-6). Susceptibility to d4T/ddI-associated neuropathy is not explained by a single genetic variant with a marked effect.