Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels.
Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels.
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DOI：
10.1161/circulationaha.110.948570
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发表时间：
2011-02-22
期刊：
影响因子：
37.8
通讯作者：
Chasman DI
中科院分区：
文献类型：
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作者：
Dehghan A;Dupuis J;Barbalic M;Bis JC;Eiriksdottir G;Lu C;Pellikka N;Wallaschofski H;Kettunen J;Henneman P;Baumert J;Strachan DP;Fuchsberger C;Vitart V;Wilson JF;Paré G;Naitza S;Rudock ME;Surakka I;de Geus EJ;Alizadeh BZ;Guralnik J;Shuldiner A;Tanaka T;Zee RY;Schnabel RB;Nambi V;Kavousi M;Ripatti S;Nauck M;Smith NL;Smith AV;Sundvall J;Scheet P;Liu Y;Ruokonen A;Rose LM;Larson MG;Hoogeveen RC;Freimer NB;Teumer A;Tracy RP;Launer LJ;Buring JE;Yamamoto JF;Folsom AR;Sijbrands EJ;Pankow J;Elliott P;Keaney JF;Sun W;Sarin AP;Fontes JD;Badola S;Astor BC;Hofman A;Pouta A;Werdan K;Greiser KH;Kuss O;Meyer zu Schwabedissen HE;Thiery J;Jamshidi Y;Nolte IM;Soranzo N;Spector TD;Völzke H;Parker AN;Aspelund T;Bates D;Young L;Tsui K;Siscovick DS;Guo X;Rotter JI;Uda M;Schlessinger D;Rudan I;Hicks AA;Penninx BW;Thorand B;Gieger C;Coresh J;Willemsen G;Harris TB;Uitterlinden AG;Järvelin MR;Rice K;Radke D;Salomaa V;Willems van Dijk K;Boerwinkle E;Vasan RS;Ferrucci L;Gibson QD;Bandinelli S;Snieder H;Boomsma DI;Xiao X;Campbell H;Hayward C;Pramstaller PP;van Duijn CM;Peltonen L;Psaty BM;Gudnason V;Ridker PM;Homuth G;Koenig W;Ballantyne CM;Witteman JC;Benjamin EJ;Perola M;Chasman DI
C反应蛋白（CRP）是一种慢性炎症的遗传标志物，与心血管疾病密切相关。我们的目的是确定与CRP水平相关的遗传变异。我们对来自15项基于人群的研究的66，185名参与者进行了CRP的全基因组关联（GWA）分析。我们在一个由来自10项独立研究的16,540名个体组成的复制组中寻找全基因组显著和提示性基因座的复制。我们发现了18个全基因组显著位点，并为其中8个提供了复制证据。我们的研究结果证实了7个以前已知的基因座，并介绍了11个新的基因座，这些基因座与代谢综合征相关的途径有关（APOC 1、HNF 1A、LEPR、GCKR、HNF 4A和PTPN 2），免疫系统（CRP、IL 6 R、NLRP 3、IL 1F 10和IRF 1），或存在于以前不知道在慢性炎症中起作用的区域（PPP1R3B、SALL1、PABPC 4、ASCL1、RORA和BCL 7B）。我们发现体重指数（BMI）与LEPR有显著的相互作用（p<2.9×10−6）。用于总结风险等位基因影响的加权遗传风险评分与CRP水平密切相关，并解释了约5%的性状方差;然而，没有证据表明这些遗传变异解释了CRP与冠心病的相关性。我们确定了18个与CRP水平相关的位点。我们的研究强调了参与慢性炎症调节的免疫应答和代谢调节途径。
C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We aimed to identify genetic variants that are associated with CRP levels. We performed a genome wide association (GWA) analysis of CRP in 66,185 participants from 15 population-based studies. We sought replication for the genome wide significant and suggestive loci in a replication panel comprising 16,540 individuals from ten independent studies. We found 18 genome-wide significant loci and we provided evidence of replication for eight of them. Our results confirm seven previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2), immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1), or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found significant interaction of body mass index (BMI) with LEPR (p<2.9×10−6). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained approximately 5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease. We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.