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

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) = 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 nevirapine-induced 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.

• Authors: 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
• Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America (Clin Infect Dis) Vol. 53 Issue 4 Pg. 341-8 (Aug 2011) ISSN: 1537-6591 [Electronic] United States
• PMID: 21810746 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents
• CCHCR1 protein, human
• Intracellular Signaling Peptides and Proteins
• stavudine, lamivudine, nevirapine drug combination
• Lamivudine
• Nevirapine
• Stavudine

Topics

• Anti-HIV Agents (adverse effects, therapeutic use)
• Chromosomes, Human, Pair 6
• Drug Eruptions (etiology, genetics)
• Genetic Predisposition to Disease
• Genome-Wide Association Study (methods)
• HIV Infections (drug therapy)
• Humans
• Intracellular Signaling Peptides and Proteins (genetics)
• Lamivudine (therapeutic use)
• Logistic Models
• Nevirapine (adverse effects, therapeutic use)
• Polymorphism, Single Nucleotide
• ROC Curve
• Retrospective Studies
• Risk Factors
• Stavudine (therapeutic use)
• Thailand