title: Population-Specific Resequencing Associates the ATP-Binding Cassette Subfamily C Member 4 Gene With Gout in New Zealand Māori and Pacific Men.
abstract: There is no evidence for a genetic association between organic anion transporters 1-3 (SLC22A6, SLC22A7, and SLC22A8) and multidrug resistance protein 4 (MRP4; encoded by ABCC4) with the levels of serum urate or gout. The Māori and Pacific (Polynesian) population of New Zealand has the highest prevalence of gout worldwide. The aim of this study was to determine whether any Polynesian population-specific genetic variants in SLC22A6-8 and ABCC4 are associated with gout.
  
  
  
  All participants had ≥3 self-reported Māori and/or Pacific grandparents. Among the total sample set of 1,808 participants, 191 hyperuricemic and 202 normouricemic individuals were resequenced over the 4 genes, and the remaining 1,415 individuals were used for replication. Regression analyses were performed, adjusting for age, sex, and Polynesian ancestry. To study the functional effect of nonsynonymous variants of ABCC4, transport assays were performed in Xenopus laevis oocytes.
  
  
  
  A total of 39 common variants were detected, with an ABCC4 variant (rs4148500) significantly associated with hyperuricemia and gout. This variant was monomorphic for the urate-lowering allele in Europeans. There was evidence for an association of rs4148500 with gout in the resequenced samples (odds ratio [OR] 1.62 [P = 0.012]) that was replicated (OR 1.25 [P = 0.033]) and restricted to men (OR 1.43 [P = 0.001] versus OR 0.98 [P = 0.89] in women). The gout risk allele was associated with fractional excretion of uric acid in male individuals (β = -0.570 [P = 0.01]). A rare population-specific allele (P1036L) with predicted strong functional consequence reduced the uric acid transport activity of ABCC4 by 30%.
  
  
  
  An association between ABCC4 and gout and fractional excretion of uric acid is consistent with the established role of MRP4 as a unidirectional renal uric acid efflux pump.
authors.affiliation: University of Otago, Dunedin, New Zealand.
authors.forename: Callum
authors.initials: C
authors.lastname: Tanner
authors.affiliation: University of Otago, Dunedin, New Zealand.
authors.forename: James
authors.initials: J
authors.lastname: Boocock
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Eli A
authors.initials: EA
authors.lastname: Stahl
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Amanda
authors.initials: A
authors.lastname: Dobbyn
authors.affiliation: Brigham and Women's Hospital and VA Boston Healthcare System, Harvard Medical School, Boston, Massachusetts.
authors.forename: Asim K
authors.initials: AK
authors.lastname: Mandal
authors.affiliation: University of Otago, Dunedin, New Zealand.
authors.forename: Murray
authors.initials: M
authors.lastname: Cadzow
authors.affiliation: University of Otago, Dunedin, New Zealand.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Phipps-Green
authors.affiliation: University of Otago, Dunedin, New Zealand.
authors.forename: Ruth K
authors.initials: RK
authors.lastname: Topless
authors.affiliation: Ngati Porou Hauora Charitable Trust, Te Puia Springs, New Zealand.
authors.forename: Jennie Harré
authors.initials: JH
authors.lastname: Hindmarsh
authors.affiliation: University of Otago Christchurch, Christchurch, New Zealand.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Stamp
authors.affiliation: University of Auckland, Auckland, New Zealand.
authors.forename: Nicola
authors.initials: N
authors.lastname: Dalbeth
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Hyon K
authors.initials: HK
authors.lastname: Choi
authors.affiliation: Brigham and Women's Hospital and VA Boston Healthcare System, Harvard Medical School, Boston, Massachusetts.
authors.forename: David B
authors.initials: DB
authors.lastname: Mount
authors.affiliation: University of Otago, Dunedin, New Zealand.
authors.forename: Tony R
authors.initials: TR
authors.lastname: Merriman
mesh_terms: D000328:Adult; D000818:Animals; D015153:Blotting, Western; D016022:Case-Control Studies; D005260:Female; D006073:Gout / Q000235:genetics*; D006801:Humans; D033461:Hyperuricemia / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D009520:New Zealand; D009865:Oocytes / Q000378:metabolism; D027362:Organic Anion Transport Protein 1 / Q000235:genetics; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D014527:Uric Acid / Q000378:metabolism / Q000652:urine; D014982:Xenopus laevis
chemical_list: D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D014527:Uric Acid; C073492:ABCC4 protein, human; C490280:SLC22A7 protein, human; C114338:organic anion transport protein 3