Meta-Analysis of 28,141 Individuals Identifies Common Variants within Five New Loci That Influence Uric Acid Concentrations
نویسندگان
چکیده
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 = 5.2x10(-201)), ABCG2 (p = 3.1x10(-26)), SLC17A1 (p = 3.0x10(-14)), SLC22A11 (p = 6.7x10(-14)), SLC22A12 (p = 2.0x10(-9)), SLC16A9 (p = 1.1x10(-8)), GCKR (p = 1.4x10(-9)), LRRC16A (p = 8.5x10(-9)), and near PDZK1 (p = 2.7x10(-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 = 4.0x10(-26)) and propionyl-L-carnitine (p = 5.0x10(-8)) concentrations, which in turn were associated with serum UA levels (p = 1.4x10(-57) and p = 8.1x10(-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.
منابع مشابه
Replication of the five novel loci for uric acid concentrations and potential mediating mechanisms.
Uric acid (UA) is the final catabolic product of purine metabolism and elevated levels are associated with diabetes and cardiovascular disease. A recent meta-analysis of genome-wide association studies totalling 28,141 participants identified five novel loci associated with serum UA levels. In our population-based cohort of 7795 subjects, we replicated four of these five loci; PDZK1 (rs12129861...
متن کاملGenome-wide meta-analysis identifies new susceptibility loci for migraine
Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls. We identified 12 loci associated with migraine susceptibility ...
متن کاملCommon Variants in LRP2 and COMT Genes Affect the Susceptibility of Gout in a Chinese Population
Gout is a common inflammation disease resulting from an increase in serum uric acid. Nearly 70% of uric acid is excreted via the kidneys. To date, evidence for an association between genetic loci and gout is absent, equivocal or not replicated. Our study aims to test variants in two genes abundantly expressed in the kidney, LRP2 and COMT, for their association with uric acid and gout. In total,...
متن کاملApplication of a New Method for GWAS in a Related Case/Control Sample with Known Pedigree Structure: Identification of New Loci for Nephrolithiasis
In contrast to large GWA studies based on thousands of individuals and large meta-analyses combining GWAS results, we analyzed a small case/control sample for uric acid nephrolithiasis. Our cohort of closely related individuals is derived from a small, genetically isolated village in Sardinia, with well-characterized genealogical data linking the extant population up to the 16(th) century. It i...
متن کاملGenome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer
Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ~ 4% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of GWAS, comprising 5,748 breast cancer cases and 8,084 controls together with 46,785 cases and 42,892 controls from 4 studies ge...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- PLoS Genetics
دوره 5 شماره
صفحات -
تاریخ انتشار 2009