title: Pyrexia in dabrafenib-treated melanoma patients is not associated with common genetic variation or HLA polymorphisms.
abstract: OBJECTIVE
  Pyrexia is a common adverse event (AE) on dabrafenib treatment (monotherapy or combination with trametinib). Since germline SNPs and HLA alleles are implicated in drug-induced AEs, this study investigated their association with pyrexia.
  
  
  METHODS
  1006 melanoma subjects from five dabrafenib-trametinib clinical studies underwent genotyping for genome-wide SNPs, which enabled imputation of 150 HLA alleles. SNP/HLA allele frequencies were compared between pyrexia cases (n = 218) and controls (n = 361) out of the 1006 subjects by meta-analysis.
  
  
  RESULTS
  This analysis had adequate power to detect association of common SNPs or HLA alleles with moderate to large effects on pyrexia (odds ratio >6), but no significant association was found.
  
  
  CONCLUSIONS
  The study suggests that common genetic variation or HLA polymorphisms do not contribute substantially to dabrafenib-induced pyrexia.
authors.affiliation: GlaxoSmithKline Research & Development, Philadelphia, PA, USA.
authors.forename: Diptee
authors.initials: D
authors.lastname: Kulkarni
authors.affiliation: GlaxoSmithKline Research & Development, Philadelphia, PA, USA.
authors.forename: Kijoung
authors.initials: K
authors.lastname: Song
authors.affiliation: PAREXEL International, Durham, NC, USA (previously employed by GSK, Durham, NC, USA; work performed on this publication done while employed by GSK).
authors.forename: Linda
authors.initials: L
authors.lastname: Briley
authors.affiliation: PAREXEL International, Durham, NC, USA (previously employed by GSK, Durham, NC, USA; work performed on this publication done while employed by GSK).
authors.forename: Karen
authors.initials: K
authors.lastname: King
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA (previously employed by GSK, Philadelphia, USA; work performed on this publication done while employed by GSK).
authors.forename: Christine
authors.initials: C
authors.lastname: Dabrowski
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA (previously employed by GSK, Philadelphia, USA; work performed on this publication done while employed by GSK).
authors.forename: Bijoyesh
authors.initials: B
authors.lastname: Mookerjee
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA (previously employed by GSK, Philadelphia, USA; work performed on this publication done while employed by GSK).
authors.forename: Jeff
authors.initials: J
authors.lastname: Legos
authors.affiliation: GlaxoSmithKline Research & Development, Stevenage, Hertfordshire, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Spraggs
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects*; D016022:Case-Control Studies; D005334:Fever / Q000139:chemically induced* / Q000235:genetics; D056726:Genetic Association Studies; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D010091:Oximes / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D006680:HLA Antigens; D007093:Imidazoles; D010091:Oximes; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib
keywords: HLA alleles; SNPs; dabrafenib; pyrexia; trametinib