Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors.
Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors.
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DOI：
10.1161/circgenetics.109.934455
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发表时间：
2010-12
期刊：
影响因子：
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通讯作者：
Coresh J
中科院分区：
文献类型：
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作者：
Yang Q;Köttgen A;Dehghan A;Smith AV;Glazer NL;Chen MH;Chasman DI;Aspelund T;Eiriksdottir G;Harris TB;Launer L;Nalls M;Hernandez D;Arking DE;Boerwinkle E;Grove ML;Li M;Linda Kao WH;Chonchol M;Haritunians T;Li G;Lumley T;Psaty BM;Shlipak M;Hwang SJ;Larson MG;O'Donnell CJ;Upadhyay A;van Duijn CM;Hofman A;Rivadeneira F;Stricker B;Uitterlinden AG;Paré G;Parker AN;Ridker PM;Siscovick DS;Gudnason V;Witteman JC;Fox CS;Coresh J
血清尿酸盐水平升高可导致痛风，并与心血管危险因素有关。我们进行了全基因组关联，以寻找血清尿酸盐和痛风的遗传易感性位点，并调查了血清尿酸盐与痛风和选定的心血管危险因素和冠心病（CHD）之间的因果关系。在CHARGE联盟的5个基于人群的队列中对28，283名白色个体的血清尿酸盐和痛风进行了全基因组关联研究（GWAS）的荟萃分析。在所有全基因组显著基因座上最显著的SNP对血清尿酸盐的影响被添加以创建遗传尿酸盐评分。女性基因组健康研究（WGHS; n= 22，054）中重复了这一发现。8个遗传位点的SNP与血清尿酸水平具有全基因组显著性（p值4×10−8至2×10−242; SLC 22 A11、GCKR、R3 HDM 2-INHBC区域、RREB 1、PDZK 1、SLC 2A 9、ABCG 2、SLC 17 A1）。只有两个位点[SLC 2A 9，ABCG 2]显示全基因组与痛风显著相关。遗传性尿酸盐评分与血清尿酸盐和痛风密切相关（比值比12.4/100 umol/L; p值=3×10−39），但与血压、血糖、eGFR、慢性肾脏疾病或CHD无关。在WGHS中也观察到遗传评分与后者表型之间缺乏关联。遗传尿酸盐评分分析提示血清尿酸盐与痛风之间存在因果关系，但未提供证据证明血清尿酸盐与心血管危险因素和冠心病之间存在因果关系。
Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed genome-wide association 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). Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the CHARGE consortium for serum urate and gout in 28,283 white individuals. The effect of the most significant SNP 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 (WGHS; n=22,054). SNPs at 8 genetic loci achieved genome-wide significance with serum urate levels (p-values 4×10−8 to 2×10−242; SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, SLC17A1). Only two 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 umol/L; p-value=3×10−39), but not with blood pressure, glucose, eGFR, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes was also observed in WGHS. 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.