title: The Pharmacogenomic Association of Fcγ Receptors and Cytochrome P450 Enzymes With Response to Rituximab or Cyclophosphamide Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.
abstract: The Rituximab in ANCA-Associated Vasculitis (RAVE) trial compared rituximab to cyclophosphamide as induction therapy for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We undertook the current study to determine whether known single-nucleotide polymorphisms (SNPs) for Fcγ receptors (FcγR) or cytochrome P450 (CYP) enzymes were associated with the response to treatment with rituximab and cyclophosphamide, respectively.
  
  
  
  Functional SNPs for FcγR (FcγRIIa 519G>A, FcγRIIb 695T>C, FcγRIIIa 559T>G) and CYP enzymes (CYP2B6 1459C>T, CYP2C19 681G>A) were analyzed by direct sequencing of polymerase chain reaction-amplified genomic DNA. Each SNP was tested as a predictor of complete remission at 6 months or remission with continued prednisone administration using logistic regression and including the covariates of baseline Birmingham Vasculitis Activity Score for Wegener's Granulomatosis, ANCA type, and new versus relapsing disease. The associations of these SNPs with the secondary outcomes of time to complete remission, time to relapse, or time to B cell reconstitution were analyzed by Cox proportional hazard tests.
  
  
  
  No significant associations were identified between complete remission and any FcγR genotype in the rituximab group or any CYP genotype in the cyclophosphamide group. However, when the treatment groups were combined, an association was found between the 519AA genotype of FcγRIIa and complete remission (P = 0.01). The 519AA genotype predicted complete remission (P = 0.006) and a shorter time to complete remission (P < 0.001).
  
  
  
  The finding that the homozygous FcγRIIa 519AA variant was associated with complete response and a shorter time to complete response in the RAVE trial, independent of treatment type, implies that FcγRIIa may be broadly involved in disease pathogenesis and response to therapy.
authors.affiliation: Mayo Clinic and Foundation, Rochester, Minnesota, and Scottsdale, Arizona.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Cartin-Ceba
authors.affiliation: Ohio State University, Columbus.
authors.forename: Divya
authors.initials: D
authors.lastname: Indrakanti
authors.affiliation: Mayo Clinic and Foundation, Rochester, Minnesota, and Scottsdale, Arizona.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Specks
authors.affiliation: Massachusetts General Hospital, Boston.
authors.forename: John H
authors.initials: JH
authors.lastname: Stone
authors.affiliation: Cleveland Clinic, Cleveland, Ohio.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Hoffman
authors.affiliation: University of Groningen, Groningen, The Netherlands.
authors.forename: Cees G M
authors.initials: CG
authors.lastname: Kallenberg
authors.affiliation: Cleveland Clinic, Cleveland, Ohio.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Langford
authors.affiliation: University of Pennsylvania, Philadelphia.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Merkel
authors.affiliation: Hospital for Special Surgery, New York, New York.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Spiera
authors.affiliation: Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Monach
authors.affiliation: Duke University Medical Center, Durham, North Carolina.
authors.forename: E William
authors.initials: EW
authors.lastname: St Clair
authors.affiliation: Johns Hopkins University, Baltimore, Maryland.
authors.forename: Philip
authors.initials: P
authors.lastname: Seo
authors.affiliation: Immune Tolerance Network, San Francisco, California.
authors.forename: Nadia K
authors.initials: NK
authors.lastname: Tchao
authors.affiliation: Mayo Clinic and Foundation, Rochester, Minnesota, and Scottsdale, Arizona.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Ytterberg
authors.affiliation: Genentech, South San Francisco, California.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Brunetta
authors.affiliation: Ohio State University, Columbus.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Song
authors.affiliation: Ohio State University, Columbus.
authors.forename: Dan
authors.initials: D
authors.lastname: Birmingham
authors.affiliation: Ohio State University, Columbus.
authors.forename: Brad H
authors.initials: BH
authors.lastname: Rovin
mesh_terms: D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D019268:Antibodies, Antineutrophil Cytoplasmic; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000627:therapeutic use*; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D017452:Receptors, IgG / Q000502:physiology*; D012074:Remission Induction; D000069283:Rituximab / Q000627:therapeutic use*
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D017452:Receptors, IgG; D000069283:Rituximab; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System