Gout is a common disorder resulting from tissue deposition of monosodium urate crystals as a consequence of hyperuricemia. Patients with gout experience very painful attacks caused by precipitation of urate in joints, which triggers subsequent inflammation. Elevated serum uric ...Gout is a common disorder resulting from tissue deposition of monosodium urate crystals as a consequence of hyperuricemia. Patients with gout experience very painful attacks caused by precipitation of urate in joints, which triggers subsequent inflammation. Elevated serum uric acid concentration is a key risk factor for gout (summary from Matsuo et al., 2009 and Woodward et al., 2011). - Genetic Heterogeneity of Serum Uric Acid Concentration Quantitative Trait Loci See also UAQTL2 (see 612076), conferred by variation in the SLC2A9 gene (606142) on chromosome 4p; UAQTL4 (612671), conferred by variation in the SLC17A3 gene (611034) on chromosome 6p21; UAQTL5 (614746), associated with a SNP on chromosome 19q13; and UAQTL6 (614747), associated with a SNP on chromosome 1
Among 90 Japanese patients with increased serum uric acid levels, Matsuo et al. (2009) identified 6 nonsynonymous changes in the ABCG2 gene. Two polymorphic variants occurred at high frequencies and were studied in more detail: Q126X (603756.0002) and Q141K ...Among 90 Japanese patients with increased serum uric acid levels, Matsuo et al. (2009) identified 6 nonsynonymous changes in the ABCG2 gene. Two polymorphic variants occurred at high frequencies and were studied in more detail: Q126X (603756.0002) and Q141K (603756.0007). In vitro cellular studies showed that ATP-dependent urate transport was reduced by 46.7% in cells expressing a Q141K mutation and was nearly eliminated in cells expressing a Q126X mutation, consistent with a loss of function. Both of these variants showed a significant association with hyperuricemia and with gout in a larger cohort of 228 Japanese men, including 161 with gout, and 871 controls. The Q126X allele was associated with a significantly increased risk of hyperuricemia (odds ratio (OR) of 3.61; p = 2.91 x 10(-7)) and gout (OR of 4.25, p = 3.04 x 10(-8)). The Q141K allele was associated with a significantly increased risk of hyperuricemia (OR of 2.06, p = 1.53 x 10(-11)) and gout (OR of 2.23; p = 5.54 x 10(-11)). These 2 variants were assigned to different risk haplotypes, and combinations of these haplotypes conferred different disease risks (up to an odds ratio of 25.8). Matsuo et al. (2009) concluded that loss-of-function variants in the ABCG2 gene impair urate excretion, resulting in hyperuricemia and gout. - Genomewide Association Studies Kottgen et al. (2013) reported the identification and replication of 28 genomewide-significant urate concentration-associated loci, 18 of which were novel, using genomewide association study (GWAS) (26 loci) and pathway (2 loci) approaches. The study combined data from more than 140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC)