Multiple Genetic Loci Influence Serum Urate Levels and Their Relationship With Gout and Cardiovascular Disease Risk Factors

被引：290

作者：

Yang, Qiong ^{[1
,2
]}

Koettgen, Anna ^{[3
]}

Dehghan, Abbas ^{[4
]}

Smith, Albert V. ^{[5
]}

Glazer, Nicole L. ^{[6
,7
]}

Chen, Ming-Huei ^{[2
,19
]}

Chasman, Daniel I. ^{[28
]}

Aspelund, Thor ^{[5
,8
]}

Eiriksdottir, Gudny ^{[5
]}

Harris, Tamara B. ^{[9
]}

Launer, Lenore ^{[9
]}

Nalls, Michael ^{[29
]}

Hernandez, Dena ^{[29
]}

Arking, Dan E. ^{[12
]}

Boerwinkle, Eric ^{[10
,11
]}

Grove, Megan L. ^{[10
]}

Li, Man ^{[3
]}

Kao, W. H. Linda ^{[3
,13
]}

Chonchol, Michel ^{[14
]}

Haritunians, Talin ^{[15
]}

Li, Guo ^{[6
,7
]}

Lumley, Thomas ^{[16
]}

Psaty, Bruce M. ^{[7
,17
]}

Shlipak, Michael ^{[18
]}

Hwang, Shih-Jen ^{[2
,21
]}

Larson, Martin G. ^{[2
,20
]}

O'Donnell, Christopher J. ^{[2
,22
]}

Upadhyay, Ashish ^{[23
]}

van Duijn, Cornelia M. ^{[4
]}

Hofman, Albert ^{[4
]}

Rivadeneira, Fernando ^{[24
]}

Stricker, Bruno ^{[4
]}

Uitterlinden, Andre G. ^{[24
]}

Pare, Guillaume ^{[28
]}

Parker, Alex N. ^{[30
]}

Ridker, Paul M. ^{[28
]}

Siscovick, David S. ^{[17
,25
]}

Gudnason, Vilmundur ^{[5
,8
]}

Witteman, Jacqueline C. ^{[4
]}

Fox, Caroline S. ^{[2
,21
,26
]}

Coresh, Josef ^{[3
,13
,27
]}

机构：

[1] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[2] NHLBI, Framingham Heart Study, Framingham, MA USA

[3] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21287 USA

[4] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[5] Iceland Heart Assoc, Kopavogur, Iceland

[6] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[7] Univ Washington, Dept Med, Seattle, WA USA

[8] Univ Iceland, Reykjavik, Iceland

[9] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA

[10] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA

[11] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol, Houston, TX USA

[12] Johns Hopkins Med Inst, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA

[13] Johns Hopkins Univ, Dept Med, Baltimore, MD 21287 USA

[14] Univ Colorado Denver & Hlth Sci Ctr, Div Renal Dis & Hypertens, Aurora, CO USA

[15] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA

[16] Univ Washington, Dept Biostat, Seattle, WA 98195 USA

[17] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[18] Univ Calif San Francisco, Div Gen Internal Med, San Francisco VA Med Ctr, San Francisco, CA 94143 USA

[19] Boston Univ, Dept Neurol, Boston, MA 02215 USA

[20] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA

[21] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA

[22] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA

[23] Boston Med Ctr, Renal Sect, Boston, MA USA

[24] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[25] Univ Washington, Dept Med & Epidemiol, Seattle, WA 98195 USA

[26] Brigham & Womens Hosp, Div Endocrinol Hypertens & Metab, Boston, MA 02115 USA

[27] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA

[28] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA

[29] NIA, Neurogenet Lab, Intramural Res Program, Bethesda, MD 20892 USA

[30] Amgen Inc, Cambridge, MA USA

来源：

CIRCULATION-CARDIOVASCULAR GENETICS | 2010年 / 3卷 / 06期

基金：

美国国家卫生研究院;

关键词：

uric acid; gout; cardiovascular diseases; risk factors; genome-wide association study; Mendelian randomization analysis; GENOME-WIDE ASSOCIATION; BLOOD-PRESSURE; URIC-ACID; TRANSPORTER; PROTEIN; VARIANT; ABCG2;

D O I：

10.1161/CIRCGENETICS.109.934455

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background-Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed a genome-wide association study to search for genetic susceptibility loci for serum urate and gout and investigated the causal nature of the associations of serum urate with gout and selected cardiovascular risk factors and coronary heart disease (CHD). Methods and Results-Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology consortium for serum urate and gout in 28 283 white participants. The effect of the most significant single-nucleotide polymorphism at all genome-wide significant loci on serum urate was added to create a genetic urate score. Findings were replicated in the Women's Genome Health Study (n=22 054). Single-nucleotide polymorphisms at 8 genetic loci achieved genome-wide significance with serum urate levels (P=4x10(-8) to 2x10(-242) in SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, and SLC17A1). Only 2 loci (SLC2A9, ABCG2) showed genome-wide significant association with gout. The genetic urate score was strongly associated with serum urate and gout (odds ratio, 12.4 per 100 mu mol/L; P=3x10(-39)) but not with blood pressure, glucose, estimated glomerular filtration rate, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes also was observed in the Women's Genome Health Study. Conclusions-The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum urate and cardiovascular risk factors and CHD. (Circ Cardiovasc Genet. 2010;3:523-530.)

引用

页码：523 / 530

页数：8

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