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Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study.
Lancet. 2008 Dec 06; 372(9654):1953-61.Lct

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<5.0 x 10(-8)) or the Rotterdam cohort (p<1.0 x 10(-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 x 10(-168) and 2.9 x 10(-18) for white and black participants, respectively); missense rs2231142 in ABCG2 (p=2.5 x 10(-60) and 9.8 x 10(-4)), and rs1165205 in SLC17A3 (p=3.3 x 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 x 10(-14)), rs2231142 (1.74, 1.51-1.99, p=3.3 x 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 mumol/L in the Framingham cohort, 269-386 mumol/L in the Rotterdam cohort, and 303-426 mumol/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.

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Authors+Show Affiliations

Dehghan A
Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands.
Köttgen A
No affiliation info available
Yang Q
No affiliation info available
Hwang SJ
No affiliation info available
Kao WL
No affiliation info available
Rivadeneira F
No affiliation info available
Boerwinkle E
No affiliation info available
Levy D
No affiliation info available
Hofman A
No affiliation info available
Astor BC
No affiliation info available
Benjamin EJ
No affiliation info available
van Duijn CM
No affiliation info available
Witteman JC
No affiliation info available
Coresh J
No affiliation info available
Fox CS
No affiliation info available

MeSH

AllelesChromosomes, Human, 4-5Chromosomes, Human, 6-12 and XCohort StudiesFemaleGenetics, PopulationGenome, HumanGenome-Wide Association StudyGenotypeGoutHumansHyperuricemiaMaleMiddle AgedNetherlandsPolymorphism, Single NucleotidePrevalenceRisk FactorsUric Acid

Pub Type(s)

Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18834626

Citation

Dehghan, Abbas, et al. "Association of Three Genetic Loci With Uric Acid Concentration and Risk of Gout: a Genome-wide Association Study." Lancet (London, England), vol. 372, no. 9654, 2008, pp. 1953-61.
Dehghan A, Köttgen A, Yang Q, et al. Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study. Lancet. 2008;372(9654):1953-61.
Dehghan, A., Köttgen, A., Yang, Q., Hwang, S. J., Kao, W. L., Rivadeneira, F., Boerwinkle, E., Levy, D., Hofman, A., Astor, B. C., Benjamin, E. J., van Duijn, C. M., Witteman, J. C., Coresh, J., & Fox, C. S. (2008). Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study. Lancet (London, England), 372(9654), 1953-61. https://doi.org/10.1016/S0140-6736(08)61343-4
Dehghan A, et al. Association of Three Genetic Loci With Uric Acid Concentration and Risk of Gout: a Genome-wide Association Study. Lancet. 2008 Dec 6;372(9654):1953-61. PubMed PMID: 18834626.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Association of three genetic loci with uric acid concentration and risk of gout: 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, Y1 - 2008/10/01/ PY - 2008/10/7/pubmed PY - 2008/12/18/medline PY - 2008/10/7/entrez SP - 1953 EP - 61 JF - Lancet (London, England) JO - Lancet VL - 372 IS - 9654 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<5.0 x 10(-8)) or the Rotterdam cohort (p<1.0 x 10(-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 x 10(-168) and 2.9 x 10(-18) for white and black participants, respectively); missense rs2231142 in ABCG2 (p=2.5 x 10(-60) and 9.8 x 10(-4)), and rs1165205 in SLC17A3 (p=3.3 x 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 x 10(-14)), rs2231142 (1.74, 1.51-1.99, p=3.3 x 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 mumol/L in the Framingham cohort, 269-386 mumol/L in the Rotterdam cohort, and 303-426 mumol/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. SN - 1474-547X UR - https://www.unboundmedicine.com/medline/citation/18834626/Association_of_three_genetic_loci_with_uric_acid_concentration_and_risk_of_gout:_a_genome_wide_association_study_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0140-6736(08)61343-4 DB - PRIME DP - Unbound Medicine ER -