Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study

Abbas Dehghan, Anna Köttgen, Qiong Yang, Shih Jen Hwang, WH Linda Kao, Fernando Rivadeneira, Eric Boerwinkle, Daniel Levy, Albert Hofman, Brad C. Astor, Emelia J. Benjamin, Cornelia M. van Duijn, Jacqueline C. Witteman, Josef Coresh, Caroline S. Fox

Research output: Contribution to journalArticle

Abstract

Background: Hyperuricaemia, a highly heritable trait, is a key risk factor for gout. We aimed to identify novel genes associated with serum uric acid concentration and gout. Methods: Genome-wide association studies were done for serum uric acid in 7699 participants in the Framingham cohort and in 4148 participants in the Rotterdam cohort. Genome-wide significant single nucleotide polymorphisms (SNPs) were replicated in white (n=11 024) and black (n=3843) individuals who took part in the study of Atherosclerosis Risk in Communities (ARIC). The SNPs that reached genome-wide significant association with uric acid in either the Framingham cohort (p-8) or the Rotterdam cohort (p-7) were evaluated with gout. The results obtained in white participants were combined using meta-analysis. Findings: Three loci in the Framingham cohort and two in the Rotterdam cohort showed genome-wide association with uric acid. Top SNPs in each locus were: missense rs16890979 in SLC2A9 (p=7·0×10-168 and 2·9×10-18 for white and black participants, respectively); missense rs2231142 in ABCG2 (p=2·5×10-60 and 9·8×10-4), and rs1165205 in SLC17A3 (p=3·3×10-26 and 0·33). All SNPs were direction-consistent with gout in white participants: rs16890979 (OR 0·59 per T allele, 95% CI 0·52-0·68, p=7·0×10-14), rs2231142 (1·74, 1·51-1·99, p=3·3×10-15), and rs1165205 (0·85, 0·77-0·94, p=0·002). In black participants of the ARIC study, rs2231142 was direction-consistent with gout (1·71, 1·06-2·77, p=0·028). An additive genetic risk score of high-risk alleles at the three loci showed graded associations with uric acid (272-351 μmol/L in the Framingham cohort, 269-386 μmol/L in the Rotterdam cohort, and 303-426 μmol/L in white participants of the ARIC study) and gout (frequency 2-13% in the Framingham cohort, 2-8% in the Rotterdam cohort, and 1-18% in white participants in the ARIC study). Interpretation: We identified three genetic loci associated with uric acid concentration and gout. A score based on genes with a putative role in renal urate handling showed a substantial risk for gout. Funding: Netherlands Organisation for Scientific Research (NWO); the National Heart, Lung, and Blood Institute.

Original languageEnglish (US)
Pages (from-to)1953-1961
Number of pages9
JournalThe Lancet
Volume372
Issue number9654
DOIs
StatePublished - 2008

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Genetic Loci
Gout
Genome-Wide Association Study
Uric Acid
Single Nucleotide Polymorphism
Atherosclerosis
Genome
Alleles
National Heart, Lung, and Blood Institute (U.S.)
Serum
Netherlands
Genes
Meta-Analysis
Organizations
Kidney
Research

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Dehghan, A., Köttgen, A., Yang, Q., Hwang, S. J., Kao, WH. L., Rivadeneira, F., ... Fox, C. S. (2008). Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study. The Lancet, 372(9654), 1953-1961. https://doi.org/10.1016/S0140-6736(08)61343-4

Association of three genetic loci with uric acid concentration and risk of gout : a genome-wide association study. / Dehghan, Abbas; Köttgen, Anna; Yang, Qiong; Hwang, Shih Jen; Kao, WH Linda; Rivadeneira, Fernando; Boerwinkle, Eric; Levy, Daniel; Hofman, Albert; Astor, Brad C.; Benjamin, Emelia J.; van Duijn, Cornelia M.; Witteman, Jacqueline C.; Coresh, Josef; Fox, Caroline S.

In: The Lancet, Vol. 372, No. 9654, 2008, p. 1953-1961.

Research output: Contribution to journalArticle

Dehghan, A, Köttgen, A, Yang, Q, Hwang, SJ, Kao, WHL, Rivadeneira, F, Boerwinkle, E, Levy, D, Hofman, A, Astor, BC, Benjamin, EJ, van Duijn, CM, Witteman, JC, Coresh, J & Fox, CS 2008, 'Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study', The Lancet, vol. 372, no. 9654, pp. 1953-1961. https://doi.org/10.1016/S0140-6736(08)61343-4
Dehghan, Abbas ; Köttgen, Anna ; Yang, Qiong ; Hwang, Shih Jen ; Kao, WH Linda ; Rivadeneira, Fernando ; Boerwinkle, Eric ; Levy, Daniel ; Hofman, Albert ; Astor, Brad C. ; Benjamin, Emelia J. ; van Duijn, Cornelia M. ; Witteman, Jacqueline C. ; Coresh, Josef ; Fox, Caroline S. / Association of three genetic loci with uric acid concentration and risk of gout : a genome-wide association study. In: The Lancet. 2008 ; Vol. 372, No. 9654. pp. 1953-1961.
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title = "Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study",
abstract = "Background: Hyperuricaemia, a highly heritable trait, is a key risk factor for gout. We aimed to identify novel genes associated with serum uric acid concentration and gout. Methods: Genome-wide association studies were done for serum uric acid in 7699 participants in the Framingham cohort and in 4148 participants in the Rotterdam cohort. Genome-wide significant single nucleotide polymorphisms (SNPs) were replicated in white (n=11 024) and black (n=3843) individuals who took part in the study of Atherosclerosis Risk in Communities (ARIC). The SNPs that reached genome-wide significant association with uric acid in either the Framingham cohort (p-8) or the Rotterdam cohort (p-7) were evaluated with gout. The results obtained in white participants were combined using meta-analysis. Findings: Three loci in the Framingham cohort and two in the Rotterdam cohort showed genome-wide association with uric acid. Top SNPs in each locus were: missense rs16890979 in SLC2A9 (p=7·0×10-168 and 2·9×10-18 for white and black participants, respectively); missense rs2231142 in ABCG2 (p=2·5×10-60 and 9·8×10-4), and rs1165205 in SLC17A3 (p=3·3×10-26 and 0·33). All SNPs were direction-consistent with gout in white participants: rs16890979 (OR 0·59 per T allele, 95{\%} CI 0·52-0·68, p=7·0×10-14), rs2231142 (1·74, 1·51-1·99, p=3·3×10-15), and rs1165205 (0·85, 0·77-0·94, p=0·002). In black participants of the ARIC study, rs2231142 was direction-consistent with gout (1·71, 1·06-2·77, p=0·028). An additive genetic risk score of high-risk alleles at the three loci showed graded associations with uric acid (272-351 μmol/L in the Framingham cohort, 269-386 μmol/L in the Rotterdam cohort, and 303-426 μmol/L in white participants of the ARIC study) and gout (frequency 2-13{\%} in the Framingham cohort, 2-8{\%} in the Rotterdam cohort, and 1-18{\%} in white participants in the ARIC study). Interpretation: We identified three genetic loci associated with uric acid concentration and gout. A score based on genes with a putative role in renal urate handling showed a substantial risk for gout. Funding: Netherlands Organisation for Scientific Research (NWO); the National Heart, Lung, and Blood Institute.",
author = "Abbas Dehghan and Anna K{\"o}ttgen and Qiong Yang and Hwang, {Shih Jen} and Kao, {WH Linda} and Fernando Rivadeneira and Eric Boerwinkle and Daniel Levy and Albert Hofman and Astor, {Brad C.} and Benjamin, {Emelia J.} and {van Duijn}, {Cornelia M.} and Witteman, {Jacqueline C.} and Josef Coresh and Fox, {Caroline S.}",
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TY - JOUR

T1 - Association of three genetic loci with uric acid concentration and risk of gout

T2 - a genome-wide association study

AU - Dehghan, Abbas

AU - Köttgen, Anna

AU - Yang, Qiong

AU - Hwang, Shih Jen

AU - Kao, WH Linda

AU - Rivadeneira, Fernando

AU - Boerwinkle, Eric

AU - Levy, Daniel

AU - Hofman, Albert

AU - Astor, Brad C.

AU - Benjamin, Emelia J.

AU - van Duijn, Cornelia M.

AU - Witteman, Jacqueline C.

AU - Coresh, Josef

AU - Fox, Caroline S.

PY - 2008

Y1 - 2008

N2 - Background: Hyperuricaemia, a highly heritable trait, is a key risk factor for gout. We aimed to identify novel genes associated with serum uric acid concentration and gout. Methods: Genome-wide association studies were done for serum uric acid in 7699 participants in the Framingham cohort and in 4148 participants in the Rotterdam cohort. Genome-wide significant single nucleotide polymorphisms (SNPs) were replicated in white (n=11 024) and black (n=3843) individuals who took part in the study of Atherosclerosis Risk in Communities (ARIC). The SNPs that reached genome-wide significant association with uric acid in either the Framingham cohort (p-8) or the Rotterdam cohort (p-7) were evaluated with gout. The results obtained in white participants were combined using meta-analysis. Findings: Three loci in the Framingham cohort and two in the Rotterdam cohort showed genome-wide association with uric acid. Top SNPs in each locus were: missense rs16890979 in SLC2A9 (p=7·0×10-168 and 2·9×10-18 for white and black participants, respectively); missense rs2231142 in ABCG2 (p=2·5×10-60 and 9·8×10-4), and rs1165205 in SLC17A3 (p=3·3×10-26 and 0·33). All SNPs were direction-consistent with gout in white participants: rs16890979 (OR 0·59 per T allele, 95% CI 0·52-0·68, p=7·0×10-14), rs2231142 (1·74, 1·51-1·99, p=3·3×10-15), and rs1165205 (0·85, 0·77-0·94, p=0·002). In black participants of the ARIC study, rs2231142 was direction-consistent with gout (1·71, 1·06-2·77, p=0·028). An additive genetic risk score of high-risk alleles at the three loci showed graded associations with uric acid (272-351 μmol/L in the Framingham cohort, 269-386 μmol/L in the Rotterdam cohort, and 303-426 μmol/L in white participants of the ARIC study) and gout (frequency 2-13% in the Framingham cohort, 2-8% in the Rotterdam cohort, and 1-18% in white participants in the ARIC study). Interpretation: We identified three genetic loci associated with uric acid concentration and gout. A score based on genes with a putative role in renal urate handling showed a substantial risk for gout. Funding: Netherlands Organisation for Scientific Research (NWO); the National Heart, Lung, and Blood Institute.

AB - Background: Hyperuricaemia, a highly heritable trait, is a key risk factor for gout. We aimed to identify novel genes associated with serum uric acid concentration and gout. Methods: Genome-wide association studies were done for serum uric acid in 7699 participants in the Framingham cohort and in 4148 participants in the Rotterdam cohort. Genome-wide significant single nucleotide polymorphisms (SNPs) were replicated in white (n=11 024) and black (n=3843) individuals who took part in the study of Atherosclerosis Risk in Communities (ARIC). The SNPs that reached genome-wide significant association with uric acid in either the Framingham cohort (p-8) or the Rotterdam cohort (p-7) were evaluated with gout. The results obtained in white participants were combined using meta-analysis. Findings: Three loci in the Framingham cohort and two in the Rotterdam cohort showed genome-wide association with uric acid. Top SNPs in each locus were: missense rs16890979 in SLC2A9 (p=7·0×10-168 and 2·9×10-18 for white and black participants, respectively); missense rs2231142 in ABCG2 (p=2·5×10-60 and 9·8×10-4), and rs1165205 in SLC17A3 (p=3·3×10-26 and 0·33). All SNPs were direction-consistent with gout in white participants: rs16890979 (OR 0·59 per T allele, 95% CI 0·52-0·68, p=7·0×10-14), rs2231142 (1·74, 1·51-1·99, p=3·3×10-15), and rs1165205 (0·85, 0·77-0·94, p=0·002). In black participants of the ARIC study, rs2231142 was direction-consistent with gout (1·71, 1·06-2·77, p=0·028). An additive genetic risk score of high-risk alleles at the three loci showed graded associations with uric acid (272-351 μmol/L in the Framingham cohort, 269-386 μmol/L in the Rotterdam cohort, and 303-426 μmol/L in white participants of the ARIC study) and gout (frequency 2-13% in the Framingham cohort, 2-8% in the Rotterdam cohort, and 1-18% in white participants in the ARIC study). Interpretation: We identified three genetic loci associated with uric acid concentration and gout. A score based on genes with a putative role in renal urate handling showed a substantial risk for gout. Funding: Netherlands Organisation for Scientific Research (NWO); the National Heart, Lung, and Blood Institute.

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