Uric acid is the, biochemically active, final breakdown product of purine oxidation in humans. Hyperuricemia, elevated levels of serum urate, can cause gout, the most prevalent inflammatory arthritis in developed countries. Furthermore, increased levels of serum urate are associated with components of the metabolic syndrome, such as obesity, high blood pressure and insulin resistance, type 2 diabetes and with cardiovascular disease. The heritability of serum urate concentrations is estimated at 50%-70%. Eleven loci identified by previous genome-wide association studies (GWAS) explain 5-6% of serum urate variance, suggesting that additional loci remain to be identified. We performed a meta-analysis of GWAS on serum urate concentrations among 48 studies with more than 140,000 participants of European ancestry, and on gout among >70,000 individuals (2,125 cases) in the Global Urate Genetics Consortium (GUGC). Secondary analyses included, among others, stratification by sex, pathway analyses, and look-ups of the associated loci in individuals of other ancestries as well as with urate-correlated traits. Replication was performed in 32,813 independent samples. Altogether, we identified and replicated 28 genome-wide significant SNPs associated with serum urate concentrations, including 18 new loci. Nominal association with gout and fractional excretion of urate was found for 17 and 10 of the urate GWAS SNPs respectively, with consistent directions of effect. Effect sizes on serum urate levels were similar among individuals of Indian ancestry, African Americans and Japanese individuals. The genes implicated highlight new biological pathways offering novel avenues into the treatment and prevention of gout.
GWAS META-ANALYSIS OF SERUM URATE CONCENTRATIONS AND GOUT IN DIVERSE POPULATIONS
Ciullo M;
2012
Abstract
Uric acid is the, biochemically active, final breakdown product of purine oxidation in humans. Hyperuricemia, elevated levels of serum urate, can cause gout, the most prevalent inflammatory arthritis in developed countries. Furthermore, increased levels of serum urate are associated with components of the metabolic syndrome, such as obesity, high blood pressure and insulin resistance, type 2 diabetes and with cardiovascular disease. The heritability of serum urate concentrations is estimated at 50%-70%. Eleven loci identified by previous genome-wide association studies (GWAS) explain 5-6% of serum urate variance, suggesting that additional loci remain to be identified. We performed a meta-analysis of GWAS on serum urate concentrations among 48 studies with more than 140,000 participants of European ancestry, and on gout among >70,000 individuals (2,125 cases) in the Global Urate Genetics Consortium (GUGC). Secondary analyses included, among others, stratification by sex, pathway analyses, and look-ups of the associated loci in individuals of other ancestries as well as with urate-correlated traits. Replication was performed in 32,813 independent samples. Altogether, we identified and replicated 28 genome-wide significant SNPs associated with serum urate concentrations, including 18 new loci. Nominal association with gout and fractional excretion of urate was found for 17 and 10 of the urate GWAS SNPs respectively, with consistent directions of effect. Effect sizes on serum urate levels were similar among individuals of Indian ancestry, African Americans and Japanese individuals. The genes implicated highlight new biological pathways offering novel avenues into the treatment and prevention of gout.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
