Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout

Abstract

ObjectiveThe first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout.MethodsWe carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia).ResultsThis new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F) and one suggestive locus (rs12980365 of ZNF724) at the genome-wide significance level (p<5.0×10– 8). The present study also identified the loci of ABCG2, ALDH2 and SLC2A9. One of them, rs671 of ALDH2, was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three ‘gout vs AHUA GWAS’-specific loci (CNTN5, MIR302F and ZNF724) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level.ConclusionsThis meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.

High-Protein Diet Induces Hyperuricemia in a New Animal Model for Studying Human Gout

“…ABCG2 is also expressed in intestine, and many patients with hyperuricemia lost the expression of ABCG2 in intestines. The current researches based on genome-wide association study (GWAS) analysis almost focus on the comparison between patients and healthy people, and the results displayed the difference in these genes including ABCG2, SLC2A9, HNF1A, HNF4A, ALDH2, CNTN5, MIR302F and so on [15,16]. The mechanism of developing hyperuricemia and gout and the reasons for disruption or mutation in these genes remain unclear.…”

Pleiotropic effect of the ABCG2 gene in gout: involvement in serum urate levels and progression from hyperuricemia to gout

“…Deficiency in ABCG2 generates dysfunctional mitochondria [25] and reduced copy number of mitochondrial DNA associates with increased risk of gout in NZ Polynesian [26]. The observation that colchicine is able to rescue the 141K trafficking defect [23], the proposal that autophagy machinery and the inflammasome interact in the innate immune response [27], and evidence for association of ABCG2 rs2231142 with gout in the presence of HU in East Asian populations [28][29][30], suggests that ABCG2 may be important in gout beyond its established role in elevating urate levels. This hypothesis is further supported by the observation that the effect size of ABCG2 on urate in Europeans and Japanese is 58% and 73% that of SLC2A9, the most influential urate locus [4,31], respectively, yet the effect size of ABCG2 on gout is consistently larger than that of SLC2A9 [4,5,32].…”

<p>Triglycerides and Total Cholesterol Concentrations in Association with Hyperuricemia in Chinese Adults in Qingdao, China</p>

“…[1][2][3] Classically, HUA is related to nonmodifiable risk factors, such as gender, age, and genetics, and modifiable risk factors, such as dietary factors and lifestyle. [4][5][6][7] HUA is a precursor and one of the main risk factors for gout, and maybe develop all sorts of complications, such as gouty arthritis, 8,9 metabolic syndromes, [10][11][12][13] diabetes, 10,14 and acute and chronic kidney disease. [15][16][17] Those complications affect the life quality of patients and make difficulties to manage HUA.…”