Genome-wide association study identifies a new locus for coronary artery disease on chromosome 10p11.23

被引：102

作者：

Erdmann, Jeanette ^{[1
]}

Willenborg, Christina ^{[1
,2
]}

Nahrstaedt, Janja ^{[1
,2
]}

Preuss, Michael ^{[2
]}

Koenig, Inke R. ^{[2
]}

Baumert, Jens ^{[4
]}

Linsel-Nitschke, Patrick ^{[1
]}

Gieger, Christian ^{[4
]}

Tennstedt, Stephanie ^{[1
]}

Belcredi, Petra ^{[4
]}

Aherrahrou, Zouhair ^{[1
]}

Klopp, Norman ^{[4
]}

Loley, Christina ^{[2
]}

Stark, Klaus ^{[3
]}

Hengstenberg, Christian ^{[3
]}

Bruse, Petra ^{[1
]}

Freyer, Jennifer ^{[1
]}

Wagner, Arnika K. ^{[1
,6
]}

Medack, Anja ^{[1
]}

Lieb, Wolfgang ^{[1
,5
]}

Grosshennig, Anika

Sager, Hendrik B. ^{[1
]}

Reinhardt, Adrian ^{[1
]}

Schaefer, Arne ^{[7
]}

Schreiber, Stefan ^{[7
,8
]}

El Mokhtari, Nour Eddine ^{[7
]}

Raaz-Schrauder, Dorette ^{[9
]}

Illig, Thomas ^{[4
]}

Garlichs, Christoph D. ^{[9
]}

Ekici, Arif B. ^{[10
]}

Reis, Andre ^{[10
]}

Schrezenmeir, Juergen ^{[11
]}

Rubin, Diana ^{[11
]}

Ziegler, Andreas ^{[2
]}

Wichmann, H. -E. ^{[4
,12
,13
]}

Doering, Angela ^{[4
]}

Meisinger, Christa ^{[4
]}

Meitinger, Thomas ^{[14
,15
]}

Peters, Annette ^{[4
]}

Schunkert, Heribert ^{[1
]}

机构：

[1] Med Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany

[2] Med Univ Lubeck, Inst Med Biometrie & Stat, D-23538 Lubeck, Germany

[3] Univ Klinikum Regensburg, Klin & Poliklin Innere Med 2, Regensburg, Germany

[4] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol, Neuherberg, Germany

[5] Framingham Heart Dis Epidemiol Study, Framingham, MA USA

[6] Hannover Med Sch, Inst Biometrie, Hannover, Germany

[7] Univ Kiel, Inst Klin Mol Biol, Kiel, Germany

[8] Univ Klinikum Schleswig Holstein, Med Klin 1, Campus Kiel, Germany

[9] Univ Hosp Erlangen, Med Clin 2, Erlangen, Germany

[10] Univ Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany

[11] Max Rubner Inst, Inst Physiol & Biochem Ernahrung, Kiel, Germany

[12] LMU, Inst Med Informat Sci, Munich, Germany

[13] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany

[14] Deutsch Forschungszentrum Umwelt & Gesundheit, Inst Humangenet, Neuherberg, Germany

[15] Tech Univ Munich, Inst Humangenet, Munich, Germany

来源：

EUROPEAN HEART JOURNAL | 2011年 / 32卷 / 02期

关键词：

Genome-wide association study; GWA; Myocardial infarction; Coronary artery disease; Genetics; KIAA1462; Chromosome; 9p21.3; MYOCARDIAL-INFARCTION; GENOTYPE; AUGSBURG; RISK; SUSCEPTIBILITY; POLYMORPHISMS; REPLICATION; ONSET; MEN;

D O I：

10.1093/eurheartj/ehq405

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Aims Recent genome-wide association (GWA) studies identified 10 chromosomal loci for coronary artery disease (CAD) or myocardial infarction (MI). However, these loci explain only a small proportion of the genetic variability of these pertinent diseases. We sought to identify additional CAD/MI loci by applying a three-stage approach. Methods and results We genotyped n = 1157 MI cases and n = 1748 controls from a population-based study population [German MI Family Study (GerMIFS) III (KORA)] with genome-wide SNP arrays. At this first stage, n = 462 SNPs showed association with MI at P < 1 x 10(-3) in two-sided logistic regression. In a second stage, 415 of these SNPs were evaluated in silico in two independent GWA samples, the GerMIFS I (875 cases/1644 controls) and GerMIFS II (1222 cases/1298 controls). Nine SNPs, representing three regions, displayed consistent replication in this in silico analysis (P < 0.05 for each GWA sample): five SNPs at 9p21.3, a well-known CAD/MI locus, two SNPs at 10p11.21, and two SNPs at 2p24.3. Wet-lab replication, i.e. the third stage, of SNP rs3739998 (representing the novel locus at 10p11.21, p. S1002T in the KIAA1462 gene) in additional 5790 cases and 5302 controls confirmed the association (P = 9.54 x 10(-4)), but not for the 2p24.3 locus. The combined P-value across all stages for SNP rs3739998 is P = 1.27 x 10(-11) [ odds ratio (OR) = 1.15 (1.11-1.20)]. Conclusion Analysis of a GWA study followed by in silico and wet-lab replication steps identified the KIAA1462 gene, encoding a yet uncharacterized protein, on chromosome 10p11.23 with genome-wide significant association for CAD/MI. Further studies are needed to characterize the functional role of this locus in the aetiology of these diseases.

引用

页码：158 / 168

页数：11

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