Uric Acid Concentration, Serum, Quantitative Trait Locus 1

A number sign (#) is used with this entry because of evidence that serum uric acid concentration and susceptibility to gout can be conferred by variation in the ABCG2 gene (603756) on chromosome 4q22.

Description

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.

Mapping

The Pacific Austronesian population, including Taiwanese aborigines, has a remarkably high prevalence of hyperuricemia and gout, suggesting a founder effect across the Pacific region. Cheng et al. (2004) reported a genomewide linkage study of 21 multiplex pedigrees with gout from an aboriginal tribe in Taiwan. From observations of familial clustering, early onset of gout, and clinically severe manifestations, they hypothesized that a major gene plays a role in this trait. A highly significant linkage for gout at marker D4S2623 was found on 4q25. When alcohol consumption was included as a covariate in the model, the lod score increased to 5.66.

By genomewide linkage analysis of 7,699 participants in the Framingham cohort and in 4,148 participants in a Rotterdam cohort, Dehghan et al. (2008) found a significant association between serum uric acid concentration and a gln141-to-lys (Q141K; 603756.0007) substitution (rs2231142) in the ABCG2 gene on chromosome 4q22 (p = 9.0 x 10(-20) and p = 3.3 x 10(-9), respectively). The findings were replicated in the ARIC cohort of 11,024 white and 3,843 black individuals, yielding p values of 9.7 x 10(-30) and 9.8 x 10(-4), respectively. The combined p value for white individuals from all 3 cohorts was 2.5 x 10(-60), and further analysis showed that the SNP was direction-consistent with the development of gout in white participants (OR of 1.74; p = 3.3 x 10(-15)).

Pathogenesis

Martinon et al. (2006) showed that monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD), both crystals found in gout, engage the caspase-1 (CASP1; 147678)-activating NALP3 (606416) inflammasome, resulting in the production of active interleukin (IL1)-1-beta (IL1B; 147720) and IL18 (IL18; 600953). Macrophages from mice deficient in various components of the inflammasome such as CASP1, ASC (606838), and NALP3 are defective in crystal-induced IL1B activation. Moreover, an impaired neutrophil influx was found in an in vivo model of crystal-induced peritonitis in inflammasome-deficient mice or mice deficient in the IL1B receptor (IL1R; 147810). Martinon et al. (2006) concluded that their findings provide insight into the molecular processing underlying the inflammatory conditions of gout and pseudogout, and further support a pivotal role of the inflammasome in several autoinflammatory diseases.

Inheritance

Gout is a disorder in which, as in essential hypertension, diabetes mellitus, and hypercholesterolemia, there is room for debate as to whether polygenic or monomeric inheritance is its genetic basis. Although numerous other genetic and environmental factors influence the level of serum uric acid and although the phenotype gout can probably be produced by nongenetic elevations of serum uric acid, classic familial gout may be a monomeric dominantly inherited disorder. Certainly there is genetic heterogeneity in gout as in the other phenotypes listed above. This heterogeneity is documented by the definition of X-linked forms of gout (e.g., 300323). Evidence for both an increased rate of uric acid synthesis and an impaired net elimination of uric acid by the kidney has been advanced. In some reported families with both parents affected, children have been affected unusually early and severely and may represent homozygotes (Emmerson, 1960).

The view on the polygenic inheritance of gout was stated by Neel et al. (1965) and by Wyngaarden and Kelley (1972). Hyperuricemia in Filipinos has been shown to result from interplay of environmental and genetic factors (Healey et al., 1967). Morton (1979) analyzed the family data of Hauge and Harvald (1955) and of Neel et al. (1965) and concluded that hyperuricemia ascertained through a gouty proband is rarely due to a major gene.

Molecular Genetics

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).

Nomenclature

The locus on chromosome 4q22 identified by Dehghan et al. (2008) was previously designated 'UAQTL3,' but is now believed to represent the same UAQTL1 locus on 4q25 identified by Cheng et al. (2004) (Matsuo et al., 2009).