title: 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.affiliation: Department of Oral Pathology, Research Unit of Herbs and Natural Products for Dental Application, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Soranun
authors.initials: S
authors.lastname: Chantarangsu
authors.forename: Taisei
authors.initials: T
authors.lastname: Mushiroda
authors.forename: Surakameth
authors.initials: S
authors.lastname: Mahasirimongkol
authors.forename: Sasisopin
authors.initials: S
authors.lastname: Kiertiburanakul
authors.forename: Somnuek
authors.initials: S
authors.lastname: Sungkanuparph
authors.forename: Weerawat
authors.initials: W
authors.lastname: Manosuthi
authors.forename: Woraphot
authors.initials: W
authors.lastname: Tantisiriwat
authors.forename: Angkana
authors.initials: A
authors.lastname: Charoenyingwattana
authors.forename: Thanyachai
authors.initials: T
authors.lastname: Sura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Wasun
authors.initials: W
authors.lastname: Chantratita
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
mesh_terms: D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002896:Chromosomes, Human, Pair 6; D003875:Drug Eruptions / Q000209:etiology / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D019259:Lamivudine / Q000627:therapeutic use; D016015:Logistic Models; D019829:Nevirapine / Q000009:adverse effects* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D012372:ROC Curve; D012189:Retrospective Studies; D012307:Risk Factors; D018119:Stavudine / Q000627:therapeutic use; D013785:Thailand
chemical_list: D019380:Anti-HIV Agents; C412616:CCHCR1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C516355:stavudine, lamivudine, nevirapine drug combination; D019259:Lamivudine; D019829:Nevirapine; D018119:Stavudine