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Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele.

Tuesday,2012-11-06 12:25 America/Los_Angeles — eenright
TitleGenome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele.
Publication TypeJournal Article
Year of Publication2011
AuthorsTin, A, Woodward, OM, Kao, WHL, Liu, C-T, Lu, X, Nalls, MA, Shriner, D, Semmo, M, Akylbekova, EL, Wyatt, SB, Hwang, S-J, Yang, Q, Zonderman, AB, Adeyemo, AA, Palmer, C, Meng, Y, Reilly, M, Shlipak, MG, Siscovick, D, Evans, MK, Rotimi, CN, Flessner, MF, Köttgen, M, Cupples, AL, Fox, CS, Köttgen, A
Corporate/Institutional AuthorsCARe and CHARGE Consortia,
JournalHum Mol Genet
Volume20
Issue20
Pagination4056-68
Date Published2011 Oct 15
ISSN1460-2083
KeywordsAdult, African Americans, Aged, Animals, CHO Cells, Cricetinae, European Continental Ancestry Group, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Gout, Humans, Loss of Heterozygosity, Male, Middle Aged, Organic Anion Transporters, Organic Cation Transport Proteins, Polymorphism, Single Nucleotide, Uric Acid, Young Adult
Abstract<p>Serum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies (GWAS) of serum urate in African American (AA) populations are lacking. We conducted a meta-analysis of GWAS of serum urate levels and gout among 5820 AA and a large candidate gene study among 6890 AA and 21 708 participants of European ancestry (EA) within the Candidate Gene Association Resource Consortium. Findings were tested for replication among 1996 independent AA individuals, and evaluated for their association among 28 283 EA participants of the CHARGE Consortium. Functional studies were conducted using (14)C-urate transport assays in mammalian Chinese hamster ovary cells. In the discovery GWAS of serum urate, three loci achieved genome-wide significance (P< 5.0 × 10(-8)): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P= 1.0 × 10(-9)), and two loci previously identified in EA participants, SLC2A9 (P= 3.8 × 10(-32)) and SLC22A12 (P= 2.1 × 10(-10)). A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (minor allele frequency 0.01, G65W), was identified and replicated (beta -1.19 mg/dl, P= 2.7 × 10(-16)). (14)C-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA. In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants.</p>
DOI10.1093/hmg/ddr307
Alternate JournalHum. Mol. Genet.
PubMed ID21768215
PubMed Central IDPMC3177647
Grant ListN01-HB-72992 / HB / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
N01-HB-97068 / HB / NHLBI NIH HHS / United States
N01-HB-97053 / HB / NHLBI NIH HHS / United States
N01-HB-72997 / HB / NHLBI NIH HHS / United States
N01-HB-73003 / HB / NHLBI NIH HHS / United States
N01-HC-45205 / HC / NHLBI NIH HHS / United States
N01-HC-95162 / HC / NHLBI NIH HHS / United States
Z01-AG000513 / AG / NIA NIH HHS / United States
N01-HC-05187 / HC / NHLBI NIH HHS / United States
S06GM008016-380111 / GM / NIGMS NIH HHS / United States
U01 HL053934 / HL / NHLBI NIH HHS / United States
N01-HC-85085 / HC / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
S06GM008016-320107 / GM / NIGMS NIH HHS / United States
N01-HC-48047 / HC / NHLBI NIH HHS / United States
N01-HB-97064 / HB / NHLBI NIH HHS / United States
R01HL092577-01A1 / HL / NHLBI NIH HHS / United States
Z01HG200362 / HG / NHGRI NIH HHS / United States
M01RR00080 / RR / NCRR NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
N01-HC-85081 / HC / NHLBI NIH HHS / United States
N01-HC-95163 / HC / NHLBI NIH HHS / United States
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U01 HL063429 / HL / NHLBI NIH HHS / United States
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N01-HC-95165 / HC / NHLBI NIH HHS / United States
U01 HL077813 / HL / NHLBI NIH HHS / United States
N01-HB-97085 / HB / NHLBI NIH HHS / United States
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N01-HC-85086 / HC / NHLBI NIH HHS / United States
U01 HL064360 / HL / NHLBI NIH HHS / United States
N01-HB-73005 / HB / NHLBI NIH HHS / United States
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R01 AG028321 / AG / NIA NIH HHS / United States
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/ / Intramural NIH HHS / United States
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