A Genome-wide Association Study Identifies Common Variants Influencing Serum Uric Acid Concentrations in a Chinese Population

Overview

Journal BMC Med Genomics

Publisher Biomed Central

Specialty Genetics

Date 2014 Feb 12

PMID 24513273

Citations 37

Authors

Binyao Yang

Zengnan Mo

Chen Wu

Handong Yang

Xiaobo Yang

Yunfeng He

Lixuan Gui

Li Zhou

Huan Guo

Xiaomin Zhang

Jing Yuan

Xiayun Dai

Jun Li

Gaokun Qiu

Suli Huang

Qifei Deng

Yingying Feng

Lei Guan

Die Hu

Xiao Zhang

Tian Wang

Jiang Zhu

Xinwen Min

Mingjian Lang

Dongfeng Li

Frank B Hu

Dongxin Lin

Tangchun Wu

Meian He

Affiliations

Soon will be listed here.

Abstract

Background: Uric acid (UA) is a complex phenotype influenced by both genetic and environmental factors as well as their interactions. Current genome-wide association studies (GWASs) have identified a variety of genetic determinants of UA in Europeans; however, such studies in Asians, especially in Chinese populations remain limited.

Methods: A two-stage GWAS was performed to identify single nucleotide polymorphisms (SNPs) that were associated with serum uric acid (UA) in a Chinese population of 12,281 participants (GWAS discovery stage included 1452 participants from the Dongfeng-Tongji cohort (DFTJ-cohort) and 1999 participants from the Fangchenggang Area Male Health and Examination Survey (FAMHES). The validation stage included another independent 8830 individuals from the DFTJ-cohort). Affymetrix Genome-Wide Human SNP Array 6.0 chips and Illumina Omni-Express platform were used for genotyping for DFTJ-cohort and FAMHES, respectively. Gene-environment interactions on serum UA levels were further explored in 10,282 participants from the DFTJ-cohort.

Results: Briefly, we identified two previously reported UA loci of SLC2A9 (rs11722228, combined P = 8.98 × 10-31) and ABCG2 (rs2231142, combined P = 3.34 × 10-42). The two independent SNPs rs11722228 and rs2231142 explained 1.03% and 1.09% of the total variation of UA levels, respectively. Heterogeneity was observed across different populations. More importantly, both independent SNPs rs11722228 and rs2231142 were nominally significantly interacted with gender on serum UA levels (P for interaction = 4.0 × 10-2 and 2.0 × 10-2, respectively). The minor allele (T) for rs11722228 in SLC2A9 has greater influence in elevating serum UA levels in females compared to males and the minor allele (T) of rs2231142 in ABCG2 had stronger effects on serum UA levels in males than that in females.

Conclusions: Two genetic loci (SLC2A9 and ABCG2) were confirmed to be associated with serum UA concentration. These findings strongly support the evidence that SLC2A9 and ABCG2 function in UA metabolism across human populations. Furthermore, we observed these associations are modified by gender.

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References

McCarroll S, Kuruvilla F, Korn J, Cawley S, Nemesh J, Wysoker A . Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet. 2008; 40(10):1166-74. DOI: 10.1038/ng.238. View

Caulfield M, Munroe P, ONeill D, Witkowska K, Charchar F, Doblado M . SLC2A9 is a high-capacity urate transporter in humans. PLoS Med. 2008; 5(10):e197. PMC: 2561076. DOI: 10.1371/journal.pmed.0050197. View

Vitart V, Rudan I, Hayward C, Gray N, Floyd J, Palmer C . SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet. 2008; 40(4):437-42. DOI: 10.1038/ng.106. View

Johnson R, Rideout B . Uric acid and diet--insights into the epidemic of cardiovascular disease. N Engl J Med. 2004; 350(11):1071-3. DOI: 10.1056/NEJMp048015. View

Guan M, Zhou D, Ma W, Chen Y, Zhang J, Zou H . Association of an intronic SNP of SLC2A9 gene with serum uric acid levels in the Chinese male Han population by high-resolution melting method. Clin Rheumatol. 2010; 30(1):29-35. DOI: 10.1007/s10067-010-1597-x. View

Aulchenko Y, Struchalin M, Van Duijn C . ProbABEL package for genome-wide association analysis of imputed data. BMC Bioinformatics. 2010; 11:134. PMC: 2846909. DOI: 10.1186/1471-2105-11-134. View

Kolz M, Johnson T, Sanna S, Teumer A, Vitart V, Perola M . Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations. PLoS Genet. 2009; 5(6):e1000504. PMC: 2683940. DOI: 10.1371/journal.pgen.1000504. View

Barrett J, Fry B, Maller J, Daly M . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2004; 21(2):263-5. DOI: 10.1093/bioinformatics/bth457. View

Doring A, Gieger C, Mehta D, Gohlke H, Prokisch H, Coassin S . SLC2A9 influences uric acid concentrations with pronounced sex-specific effects. Nat Genet. 2008; 40(4):430-6. DOI: 10.1038/ng.107. View

10.

Brandstatter A, Kiechl S, Kollerits B, Hunt S, Heid I, Coassin S . Sex-specific association of the putative fructose transporter SLC2A9 variants with uric acid levels is modified by BMI. Diabetes Care. 2008; 31(8):1662-7. PMC: 2494626. DOI: 10.2337/dc08-0349. View

11.

Yamagishi K, Tanigawa T, Kitamura A, Kottgen A, Folsom A, Iso H . The rs2231142 variant of the ABCG2 gene is associated with uric acid levels and gout among Japanese people. Rheumatology (Oxford). 2010; 49(8):1461-5. DOI: 10.1093/rheumatology/keq096. View

12.

Oda M, Satta Y, Takenaka O, Takahata N . Loss of urate oxidase activity in hominoids and its evolutionary implications. Mol Biol Evol. 2002; 19(5):640-53. DOI: 10.1093/oxfordjournals.molbev.a004123. View

13.

Wilk J, Djousse L, Borecki I, Atwood L, Hunt S, Rich S . Segregation analysis of serum uric acid in the NHLBI Family Heart Study. Hum Genet. 2000; 106(3):355-9. DOI: 10.1007/s004390000243. View

14.

Tan A, Gao Y, Yang X, Zhang H, Qin X, Mo L . Low serum osteocalcin level is a potential marker for metabolic syndrome: results from a Chinese male population survey. Metabolism. 2011; 60(8):1186-92. DOI: 10.1016/j.metabol.2011.01.002. View

15.

Wallace C, Newhouse S, Braund P, Zhang F, Tobin M, Falchi M . Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia. Am J Hum Genet. 2008; 82(1):139-49. PMC: 2253977. DOI: 10.1016/j.ajhg.2007.11.001. View

16.

Matsuo H, Takada T, Ichida K, Nakamura T, Nakayama A, Takada Y . Identification of ABCG2 dysfunction as a major factor contributing to gout. Nucleosides Nucleotides Nucleic Acids. 2011; 30(12):1098-104. DOI: 10.1080/15257770.2011.627902. View

17.

Wang F, Zhu J, Yao P, Li X, He M, Liu Y . Cohort Profile: the Dongfeng-Tongji cohort study of retired workers. Int J Epidemiol. 2012; 42(3):731-40. DOI: 10.1093/ije/dys053. View

18.

Johnson R, Titte S, Cade J, Rideout B, Oliver W . Uric acid, evolution and primitive cultures. Semin Nephrol. 2005; 25(1):3-8. DOI: 10.1016/j.semnephrol.2004.09.002. View

19.

Karns R, Zhang G, Sun G, Indugula S, Cheng H, Havas-Augustin D . Genome-wide association of serum uric acid concentration: replication of sequence variants in an island population of the Adriatic coast of Croatia. Ann Hum Genet. 2012; 76(2):121-7. PMC: 3302578. DOI: 10.1111/j.1469-1809.2011.00698.x. View

20.

Johnson A, Handsaker R, Pulit S, Nizzari M, ODonnell C, de Bakker P . SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics. 2008; 24(24):2938-9. PMC: 2720775. DOI: 10.1093/bioinformatics/btn564. View