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Title: Genome-wide association study identifies variations in 6p21.3 associated with nevirapine-induced rash
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
Chulalongkorn University
Thailand Ministry of Public Health
Mahidol University
Srinakharinwirot University
Institute of Medical Science The University of Tokyo
Keywords: Medicine
Issue Date: 15-Aug-2011
Citation: Clinical Infectious Diseases. Vol.53, No.4 (2011), 341-348
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. © The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.
ISSN: 15376591
Appears in Collections:Scopus 2011-2015

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