Genome-wide association study identifies variations in 6p21.3 associated with nevirapine-induced rash

Soranun Chantarangsu, Taisei Mushiroda, Surakameth Mahasirimongkol, Sasisopin Kiertiburanakul, Somnuek Sungkanuparph, Weerawat Manosuthi, Woraphot Tantisiriwat, Angkana Charoenyingwattana, Thanyachai Sura, Atsushi Takahashi, Michiaki Kubo, Naoyuki Kamatani, Wasun Chantratita, Yusuke Nakamura

Research output: Contribution to journalReview article

42 Citations (Scopus)

Abstract

Background. We aimed to identify disease-predisposing variations with nevirapine-induced rash using genome-wide single-nucleotide polymorphisms (SNPs) as genetic markers. Methods. A genome-wide association study (GWAS) was performed using-550000 markers in 72 human immunodeficiency virus (HIV)-infected Thai patients with nevirapine-induced rash and 77 nevirapine-tolerant patients, and then candidate SNPs were further evaluated in a replication set (88 patients with nevirapine-induced rash and 145 nevirapine-tolerant patients). Results. The genome-wide association analysis and replication studies of candidate SNPs identified significant associations of nevirapine-induced rash with 2 SNPs (rs1265112 and rs746647) within CCHCR1 on chromosome 6p21.3 (P GWAS = 1.6 × 10 -4; P replication = 2.6 × 10 -5; P combined = 1.2 × 10 -8). The odds ratio (OR) of the risk genotypes under a dominant model was 4.36 (95% confidence interval [CI], 2.58-7.36). The noncoding SNPs rs1265112 and rs746647 were in complete linkage disequilibrium with the nonsynonymous SNP rs1576 (r 2 5 1.00), which has been associated with psoriasis. The logistic regression analysis also indicated genetic variations in CCHCR1 to be significantly associated with rash, with an OR of 2.59 (95% CI, 1.82-3.68; P = .007). The receiver operating characteristic curve showed that the algorithm had an area under the curve of 76.4%, which was developed with 5 factors: rs1576*G status, HLA-B*3505 status, not receiving prescribed lead-in of nevirapine, history of drug allergy, and CD4 cell count prior to the nevirapine treatment. Conclusions. We demonstrated that genetic variations in CCHCR1 are strongly associated with nevirapineinduced rash. A predictive model that includes genetic and clinical risk factors for nevirapine-associated rash might be useful in lowering the incidence of rash associated with nevirapine initiation among HIV-infected patients.

Original languageEnglish
Pages (from-to)341-348
Number of pages8
JournalClinical Infectious Diseases
Volume53
Issue number4
DOIs
Publication statusPublished - 15-08-2011

All Science Journal Classification (ASJC) codes

  • Microbiology (medical)
  • Infectious Diseases

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