Frequency of CYP2C9 polymorphisms in Polynesian people and potential relevance to management of gout with benzbromarone.
OBJECTIVE
Gout is a major health problem in Polynesians and allopurinol, the drug of choice for the management gout, appears to be less effective in Polynesian patients. The uricosuric drug benzbromarone is an alternative treatment but CYP2C9 poor metabolisers (PMs) may be at a heightened risk of benzbromarone-induced hepatotoxicity. The objectives of this study were to determine the frequency of the PM alleles CYP2C9*2 and CYP2C9*3 in New Zealand (NZ) Caucasian and Polynesian gout cohorts; and then to test for novel CYP2C9 polymorphisms in Polynesians.


METHODS
Eight hundred and fifty-two Caucasians (537 controls, 315 gout patients) and 1072 Māori and Pacific Island (Polynesian) people (620 controls, 452 gout patients) were genotyped for CYP2C9*2 and CYP2C9*3. Forty Polynesians were screened for novel CYP2C9 polymorphisms using whole genome sequencing.


RESULTS
Frequency of CYP2C9 PM alleles was significantly higher in Caucasians compared to Polynesians (CYP2C9*2: 13.5% versus 3.1%; CYP2C9*3: 5.5% versus 1.6%, P<1.2E-11). Within Polynesians, CYP2C9 PM alleles were rarer in Western Polynesians (Samoa, Tonga) than Eastern Polynesians (NZ and Cook Island Maori; CYP2C9*2: 0.6% versus 2.5%; CYP2C9*3: 0.4% versus 2.0%; P<0.03). A total of 152 SNPs were found by sequencing. None of these variants were predicted by in silico analysis to significantly impact on CYP2C9 expression or activity.


CONCLUSIONS
Prospective CYP2C9 genotyping of Caucasian gout patients may be warranted for benzbromarone, whereas the low frequencies of CYP2C9 PM alleles in Polynesians suggests that the CYP2C9 polymorphism may be of little or no relevance to benzbromarone prescribing in this population.
Department of Surgical Sciences, University of Otago, Dunedin School of Medicine, PO Box 913, 9054 Dunedin, New Zealand. Electronic address: rebecca.roberts@otago.ac.nz.
Rebecca L
RL
Roberts
Department of Surgical Sciences, University of Otago, Dunedin School of Medicine, PO Box 913, 9054 Dunedin, New Zealand.
Mary C
MC
Wallace
Department of Pharmacy, University of Otago, Dunedin, New Zealand.
Daniel F B
DF
Wright
Department of Biochemistry, University of Otago, Dunedin, New Zealand.
Murray
M
Cadzow
Department of Medicine, University of Auckland, Auckland, New Zealand.
Nicola
N
Dalbeth
Department of Medicine, University of Auckland, Auckland, New Zealand.
Peter B
PB
Jones
Department of Medicine, University of Otago, Christchurch, New Zealand.
Lisa K
LK
Stamp
Department of Medicine, University of Otago, Wellington, New Zealand.
Andrew A
AA
Harrison
Department of Biochemistry, University of Otago, Dunedin, New Zealand.
Michael A
MA
Black
Department of Biochemistry, University of Otago, Dunedin, New Zealand.
Tony R
TR
Merriman
D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001553:Benzbromarone / Q000627:therapeutic use*; D065729:Cytochrome P-450 CYP2C9; D006073:Gout / Q000188:drug therapy* / Q000235:genetics*; D006074:Gout Suppressants / Q000627:therapeutic use*; D006801:Humans; D009520:New Zealand / Q000208:ethnology; D020641:Polymorphism, Single Nucleotide; D011114:Polynesia / Q000208:ethnology; D044465:White People
D006074:Gout Suppressants; D001553:Benzbromarone; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases
CYP2C9 poor metabolizer allele; Hepatotoxicity; Uricosuric agent