A new genetic risk score for gout, based on three recently identified genes believed to be involved in renal urate transportation, could help physicians identify patients with asymptomatic hyperuricemia and guide therapy, according to a study reported online in the Lancet on the Oct. 1.
“Our genetic risk score was associated with up to 40-fold increased risk of developing gout, which is substantially higher than for environmental risk factors, suggesting that knowledge of genotype could help identify individuals at risk of developing gout long before the onset of clinical features of the disease,” wrote Dr. Abbas Dehghan of the Erasmus Medical Center in Rotterdam, the Netherlands, and coauthors from both the United States and the Netherlands (Lancet 2008 Oct. 1[doi:10.1016/S0140-6736(08)613-4]).
The researchers used phenotype and genotype results from a cohort of the Framingham Heart Study and a Rotterdam cohort to identify genetic loci associated with uric acid concentration and then replicated the findings in a third population-based study, the Atherosclerosis Risk in Communities (ARIC) study. The single nucleotide polymorphisms (SNPs) they identified as being associated with uric acid concentration were tested next for association with gout. These results were then replicated using genetic samples from the ARIC study. Finally, they developed the additive gout risk score of high-risk alleles at the three loci identified.
The researchers identified two new loci, ABCG2 and SLC17A3, that show an association with uric acid concentration and risk of gout. In addition, they confirmed the previously reported association of SLC2A9 with uric acid and gout in white individuals and extended the findings to black individuals.
The Framingham cohort study involved three generations of participants, who underwent examinations every 2 years to identify cardiovascular diseases and their risk factors. Almost all were self-identified as white. The Rotterdam cohort study is a prospective, population-based study of determinants of several chronic diseases in individuals older than 5 years. All participants were residents of the Ommoord district of Rotterdam and underwent periodic examination. ARIC is an ongoing population-based study in four U.S. communities. White and black participants aged 45–64 years were recruited and underwent examination roughly every 3 years.
In the Framingham cohort, uric acid concentration was measured at the first examination cycle. Gout was self-reported in the offspring and third-generation cohorts. In the Rotterdam cohort, uric acid concentration was measured at baseline. Individuals treated with drugs exclusively prescribed for gout were regarded as gout patients, based on pharmacy records. In the ARIC study, uric acid concentration was measured at visit one. Gout was identified by self-report at visit 4.
Genotyping of the Framingham cohort was performed for 9,274 participants, and the final sample size was 7,699. Genotyping for the Rotterdam cohort was done for 6,680 participants, with a final sample size was 5,974.
In the ARIC study, the central DNA laboratory genotyped SNPs rs16890979, rs2231142, and rs1165205 individually for 11,024 white participants and 3,843 black participants.
SNPs in SLC2A9 have previously been identified as having an association with uric acid concentration and were connected with low renal fractional excretion of uric acid (the most common cause of hyperuricemia). Three loci had SNPs that reached genome-wide significance in the Framingham cohort. For each locus, the most significant SNPs were rs16890979 (a missense SNP in SLC2A9), rs2231142 (a missense SNP in ABCG2), and rs1165205 (intron 1 of SLC17A3). Similarly, two loci showed genome-wide significance in the Rotterdam cohort: rs6449213 (intron 4 of SLC2A9) and rs2231142.
Both rs6449213 and rs2231142 were strongly associated with uric acid concentration in white and black participants; rs1165205 was strongly associated with uric acid in white participants only. The missense SNP rs16890979 in SLC2A9 has the strongest association with uric acid concentration and gout. In addition, rs16890979 explained the largest variation in uric acid concentration, ranging from 2.8% to 5.3% in white participants across studies; rs16890979 was associated with gout in white individuals from all three studies. Results showing significance were also seen for rs2231142, rs1165205, and rs6449213. In black individuals, only rs2231142 showed a marginal association with gout.
In the Framingham cohort, only rs2231142 remained associated with gout after adjusting for uric acid (odds ratio 1.57, P = .0053). No SNPs in the Rotterdam cohort were significant after adjustment for uric acid. Substantial attenuation of the genotypic effect for all three loci on gout risk was seen after adjustment for uric acid in the ARIC group.
A genetic risk score was generated for every individual by counting the number of alleles associated with high uric acid concentration (rs16890979 C, rs2231142 T, and rs1165205 A; range 0–6). Mean uric acid concentration increased linearly with the number of risk alleles. For individuals with no risk alleles, the crude prevalence of gout was 1%–2% across studies and increased to 8%–18% with six risk alleles. “Although individual common genetic variants confer a modest risk of gout, their combination resulted in a large association with uric acid and gout,” they wrote.