title: Identification of MHC Haplotypes Associated with Drug-induced Hypersensitivity Reactions in Cynomolgus Monkeys.
abstract: Drug-induced hypersensitivity reactions can significantly impact drug development and use. Studies to understand risk factors for drug-induced hypersensitivity reactions have identified genetic association with specific human leukocyte antigen (HLA) alleles. Interestingly, drug-induced hypersensitivity reactions can occur in nonhuman primates; however, association between drug-induced hypersensitivity reactions and major histocompatibility complex (MHC) alleles has not been described. In this study, tissue samples were collected from 62 cynomolgus monkeys from preclinical studies in which 9 animals had evidence of drug-induced hypersensitivity reactions. Microsatellite analysis was used to determine MHC haplotypes for each animal. A total of 7 haplotypes and recombinant MHC haplotypes were observed, with distribution frequency comparable to known MHC I allele frequency in cynomolgus monkeys. Genetic association analysis identified alleles from the M3 haplotype of the MHC I B region (B*011:01, B*075:01, B*079:01, B*070:02, B*098:05, and B*165:01) to be significantly associated (χ2test for trend, p < 0.05) with occurrence of drug-induced hypersensitivity reactions. Sequence similarity from alignment of alleles in the M3 haplotype B region and HLA alleles associated with drug-induced hypersensitivity reactions in humans was 86% to 93%. These data demonstrate that MHC alleles in cynomolgus monkeys are associated with drug-induced hypersensitivity reactions, similar to HLA alleles in humans.
authors.affiliation: 1 Pfizer, Drug Safety Research and Development, Groton, Connecticut, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: 1 Pfizer, Drug Safety Research and Development, Groton, Connecticut, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Whritenour
authors.affiliation: 1 Pfizer, Drug Safety Research and Development, Groton, Connecticut, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Sanford
authors.affiliation: 1 Pfizer, Drug Safety Research and Development, Groton, Connecticut, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Houle
authors.affiliation: 1 Pfizer, Drug Safety Research and Development, Groton, Connecticut, USA.
authors.forename: Karissa K
authors.initials: KK
authors.lastname: Adkins
mesh_terms: D000483:Alleles; D000818:Animals; D004353:Drug Evaluation, Preclinical; D004342:Drug Hypersensitivity / Q000235:genetics*; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D008252:Macaca fascicularis / Q000235:genetics*; D008285:Major Histocompatibility Complex / Q000235:genetics*; D018895:Microsatellite Repeats; D017422:Sequence Analysis, DNA
chemical_list: D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II
keywords: MHC; cynomolgus monkey; drug-induced hypersensitivity reaction; haplotype