Meta-Analysis of 28,141 Individuals Identifies Common Variants within Five New Loci That Influence Uric Acid Concentrations
By M. Kolz, T. Johnson, Serena Sanna, A. Teumer, V. Vitart, M. Perola, M. Mangino, E. Albrecht, Chris Wallace, Martin Farrall and 46 more. PLoS Genetics, 2009
658 citations recorded by the source corpus.
Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (p = 5.2×10−201), ABCG2 (p = 3.1×10−26), SLC17A1 (p = 3.0×10−14), SLC22A11 (p = 6.7×10−14), SLC22A12 (p = 2.0×10−9), SLC16A9 (p = 1.1×10−8), GCKR (p = 1.4×10−9), LRRC16A (p = 8.5×10−9), and near PDZK1 (p = 2.7×10−9). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (p = 4.0×10−26) and propionyl-L-carnitine (p = 5.0×10−8) concentrations, which in turn were associated with serum UA levels (p = 1.4×10−57 and p = 8.1×10−54, respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels.
Subfields: Epidemiology, Nephrology, Pathology and Forensic Medicine
View Paper: https://www.semanticscholar.org/paper/0142166f257954b9dd78830f63a4631f4463e6c2
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Citations in the corpus
- Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data (2013, neutral): “3 and 8 ).”
- Gout. Epidemiology of gout (2010, background): “Two recent meta-analyses of genomewide association studies have confi rmed these associations, although except for SCL2A9, which may account for up to 5% of variance of uric acid levels, the other genetic associations each appear to account for less than 1% of variance [46,47].”
- Modulation of Genetic Associations with Serum Urate Levels by Body-Mass-Index in Humans (2015, background): “The top two loci, which account for about half of the genetic variance explained so far, have been noted to display marked gender differences in their effect [3– 6], while other urate loci not [2,7].”