Authors:
Abbas Dehghan MD, Anna Köttgen MD, Qiong Yang PhD, Shih-Jen Hwang PhD, WH Linda Kao PhD, Fernando Rivadeneira MD, Eric Boerwinkle PhD, Daniel Levy MD, Albert Hofman MD, Brad C Astor PhD, Emelia J Benjamin MD, Cornelia M van Duijn PhD, Jacqueline C Witteman PhD, Josef Coresh MD, Dr Caroline S Fox MD
Summary:
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•0×10−8) or the Rotterdam cohort (p<1•0×10−7) 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•0×10−168 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.
Source:
The Lancet; (10/01/08)