title: Human Leukocyte Antigen Class I Genes Associated With Stevens-Johnson Syndrome and Severe Ocular Complications Following Use of Cold Medicine in a Brazilian Population.
abstract: Describing the association with human leukocyte antigen (HLA) alleles could facilitate the understanding of increased risk factors for development of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in patients with severe ocular complications (SOCs).
  
  
  
  To investigate the association between HLA class I genes and cold medicine (CM)-associated SJS/TEN with SOCs.
  
  
  
  This case-control study was conducted between February 8, 2013, and August 29, 2014. Thirty-nine Brazilian patients with CM-SJS/TEN of 74 patients with SJS/TEN with SOCs and 133 healthy Brazilian volunteers were enrolled. Human leukocyte antigen class I genes (HLA-A, HLA-B, and HLA-C) were examined to determine whether there was a genetic predisposition for CM-SJS/TEN with SOC. Patients were interviewed to identify possible etiologic factors. Data analysis was performed from April 14, 2013, to August 29, 2014.
  
  
  
  Genetic predisposition for CM-SJS/TEN with SOCs by analysis of HLA class I genes.
  
  
  
  Of 74 patients included in the analysis, 32 (43%) were male; mean (SD) age was 36.01 [15.42] years. HLA-A*66:01 (odds ratio [OR], 24.0; 95% CI, 2.79-206.0; P < .001), HLA-B*44:03 (OR, 2.71; 95% CI, 1.11-6.65; P = .04), and HLA-C*12:03 (OR, 5.6; 95% CI, 1.67-18.80; P = .006) were associated with Brazilian CM-SJS/TEN with SOCs, and HLA-A*11:01 (OR, 0.074; 95% CI, 0.004-1.26; P = .008), HLA-B*08:01 (OR, 0.15; 95% CI, 0.02-1.15; P = .048), and HLA-B*51:01 (OR, 0.23; 95% CI, 0.05-1.03; P = .045) were inversely associated with Brazilian CM-SJS/TEN with SOCs (39 cases: 19 Pardo and 16 European ancestry; 14 males and 25 females; age, 35.2 [14.4] years; and 133 controls: 66 Pardo and 61 European ancestry; 55 males and 78 females; age, 41.2 [12.9] years). When multiple test correction within the HLA locus, HLA-A*66:01 and HLA-C*12:03 demonstrated associations. When participants were segregated into Pardo and locus is considered, HLA-A*66:01 was associated with CM-SJS/TEN with SOC among individuals of both ethnic groups (Pardo: OR, 12.2; 95% CI, 1.19-125.0; P = .03; and European: OR, 21.2; 95% CI, 0.97-465.0; P = .04). An association was observed only in the European cohort for HLA-B*44:03 (OR, 5.50; 95% CI, 1.47-20.50; P = .01) and HLA-C*12:03 (OR, 8.79; 95% CI, 1.83-42.20; P = .008).
  
  
  
  This study suggests that HLA-A*66:01 might be a marker for CM-SJS/TEN with SOCs in Brazilian individuals of Pardo and European ancestry and that HLA-B*44:03 and HLA-C*12:03 might be markers only in those of European ancestry. Moreover, HLA-A*11:01 might be a marker of resistance to CM-SJS/TEN with SOCs.
authors.affiliation: Department of Ophthalmology, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Tais H
authors.initials: TH
authors.lastname: Wakamatsu
authors.affiliation: Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto, Prefectural University of Medicine, Kyoto, Japan3Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ueta
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Katsushi
authors.initials: K
authors.lastname: Tokunaga
authors.affiliation: Department of Statistical Genetics, Osaka University, Osaka, Japan5Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Department of Ophthalmology, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Renata R
authors.initials: RR
authors.lastname: Loureiro
authors.affiliation: Department of Ophthalmology, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Karita A
authors.initials: KA
authors.lastname: Costa
authors.affiliation: Department of Ophthalmology, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Juliana Maria F
authors.initials: JMF
authors.lastname: Sallum
authors.affiliation: Department of Ophthalmology, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: José Arthur
authors.initials: JA
authors.lastname: Milhomens
authors.affiliation: Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto, Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Chikara
authors.initials: C
authors.lastname: Inoue
authors.affiliation: Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Sotozono
authors.affiliation: Department of Ophthalmology, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: José Álvaro P
authors.initials: JÁP
authors.lastname: Gomes
authors.affiliation: Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto, Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kinoshita
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001938:Brazil; D016022:Case-Control Studies; D002648:Child; D015352:Dry Eye Syndromes / Q000139:chemically induced / Q000235:genetics*; D005260:Female; D005819:Genetic Markers; D060005:Genotyping Techniques; D015234:HLA-A Antigens / Q000235:genetics*; D015235:HLA-B Antigens / Q000235:genetics*; D015236:HLA-C Antigens / Q000235:genetics*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D057985:Multi-Ingredient Cold, Flu, and Allergy Medications / Q000009:adverse effects*; D016133:Polymerase Chain Reaction; D013262:Stevens-Johnson Syndrome / Q000209:etiology / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens; D057985:Multi-Ingredient Cold, Flu, and Allergy Medications