Gout Clinical Updates, July 20, 2011

The age-standardized serum uric acid (sUA) gout relationship demonstrated a differential impact of sUA level on gout incidence between men and women, according to a recent study by researchers in the School of Medicine at the China Medical University in Taichung, Taiwan.

Previous reports have suggested that gout incidence increased with (sUA) level. “In addition to sUA, we aimed to examine the gender-specific risk factors for incident gout,” the researchers wrote in the study, which was published in Clinical Rheumatology.

The prospective study was conducted using data of the MJ Health Screening Center and outcome database from Taiwan’s National Health Insurance. The Cox proportional hazard model was used for risk analysis of incident gout. During a mean follow-up of 7.31 years for 132,556 individuals aged ≥18 years, 1,606 subjects (1,341 men and 265 women) with clinical gout were defined.

“Hyperuricemia (sUA ≥7.7 mg/dL for men or ≥6.6 mg/dL for women) was the most important risk factor for gout development with a respective hazard ratio of 9.65 (95% confidence level, 8.53-10.9) for men and 9.28 (7.00-12.3) for women,” the researchers wrote.

The age-standardized sUA-gout relationship demonstrated a differential impact of sUA level on gout incidence between men and women. Metabolic comorbidities of hypertension, obesity, and hyperlipidemia were significantly associated with gout, with respective HR of 1.32 (1.17-1.48), 1.30 (1.15-1.47), and 1.12 (0.99-1.26) for men and 1.34 (1.02-1.77), 2.15 (1.67-2.76), and 1.70 (1.32-2.19) for women.

“However, the relationship between diabetes and incident gout was not as prominent. The sex difference of sUA-gout relationship and the association between metabolic comorbidities and incident gout were demonstrated. Generalizability of these findings to other ethnic population needs further investigation,” the authors concluded.

Genome Study for Serum Urate and Gout Among African Americans

Data published in a recent study supports the importance of multi-ethnic genome-wide association studies (GWAS) in the identification of novel risk loci as well as functional variants.

“Serum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies of serum urate in African American (AA) populations are lacking,” researchers from the Johns Hopkins Bloomberg School of Public Health wrote in the study, which was published in Human Molecular Genetics.

The researchers conducted a meta-analysis of GWAS of serum urate levels and gout among 5,820 AA and a large candidate gene study among 6,890 AA and 21,708 European Americans (EA) within the Candidate Gene Association Resource (CARe) Consortium. Findings were tested for replication among 1,996 independent AA individuals, and evaluated for their association among 28,283 EA participants of the CHARGE

Consortium.

Functional studies were conducted using (14)C-urate transport assays in mammalian CHO cells. In the GWAS of serum urate, three loci achieved genome-wide significance (p<5.0×10(-8)): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, p=1.0×10(-9)), and two loci previously identified in EA, SLC2A9 (p= 3.8×10(-32)) and SLC22A12 (p=2.1×10(-10)).

A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (MAF 0.01, G65W), was identified and replicated (beta -1.19 mg/dl, p= 2.7E-16). (14)C-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead SNPs showed direction-consistent association with urate among AA.

“In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants,” the researchers wrote.

SourcesGender-Specific Risk Factors For Incident Gout: A Prospective Cohort Study [Clinical Rheumatology]

Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele [Human Molecular Genetics]