Editor's choice: Association of Functional Polymorphism rs2231142 (Q141K) in the ABCG2 Gene With Serum Uric Acid and Gout in 4 US Populations: The PAGE Study

Gout is one of the most common forms of inflammatory arthritis (1). The prevalence and incidence of gout have increased in recent decades (2, 3), and it now accounts for almost 4 million outpatient visits every year in the United States (4). An elevated concentration of serum uric acid, or hyperuricemia, is a key risk factor for gout and may also be a risk factor for cardiovascular disease incidence and mortality, hypertension, and chronic kidney disease (5–7). Most epidemiologic and genetic research on gout and hyperuricemia has been conducted in populations of European or Asian ancestry. In the United States, there have been 2 studies in African Americans (8, 9) but none in Mexican Americans or American Indians, despite epidemiologic evidence suggesting that the prevalence of gout in African Americans (830.4 per 100,000 persons) is higher than that in European Americans (752.9 per 100,000 persons) (3, 10). Both environmental and genetic factors play important roles in the etiology of hyperuricemia and gout. Epidemiologic studies suggest that men are more likely to develop gout than women, and the prevalence increases with age in both sexes, especially among women after menopause (9). Other known environmental risk factors for hyperuricemia and gout include obesity, hypertension, type 2 diabetes, use of diuretics, and alcohol consumption (1). Genetic studies have demonstrated that serum uric acid levels are highly heritable (10). Several genomic loci influencing serum uric acid levels and the prevalence of gout have been identified in recent genome-wide association studies, mostly in populations of European descent (11–16). A single-nucleotide polymorphism (SNP) consistently associated with both uric acid and gout is rs2231142, located on the ATP-binding cassette, subfamily G, member 2 gene (ABCG2; OMIM (Online Mendelian Inheritance in Man) number 603756). More specifically, the T allele at rs2231142 has been shown to be associated with increased serum uric acid levels and odds of gout in persons of European (14, 15, 17, 18), African (14), Japanese (19, 20), and New Zealand Pacific Island (21) ancestry. More importantly, the resultant missense polymorphism at codon 141 (glutamine to lysine, Q141K) has been shown to be a loss-of-function mutation in 2 independent functional studies (22, 23). Previous studies have shown that the association between rs2231142 and uric acid and gout is stronger in men than in women, suggesting that sex modifies this association (14, 15); however, the evidence has been inconsistent (18). In addition, few studies have had sufficiently large sample sizes to systematically examine potential interactions with other major risk factors for gout, including age, diabetes, menopausal status, hormone therapy, obesity, alcohol consumption, hypertension, and antihypertensive treatment (14, 18). Lastly, the association between rs2231142 and serum uric acid and gout has not been established in Mexican-American or American Indian populations. Therefore, we conducted a study within the Population Architecture using Genomics and Epidemiology (PAGE) Study (24) to determine the association between rs2231142 and serum uric acid and gout in 4 general US populations and to specifically examine the potential heterogeneity of these associations across major gout risk factors.