New susceptibility locus for coronary artery disease on chromosome 3q22.3

Erdmann, Jeanette; Großhennig, Anika; Braund, Peter S.; König, Inke R.; Hengstenberg, Christian; Hall, Alistair S.; Linsel-Nitschke, Patrick; Kathiresan, Sekar; Wright, Barlow C.; Trégouët, David‐Alexandre; Cambien, François; Bruse, Petra; Aherrahrou, Zouhair; Wagner, Arnika K.; Stark, Klaus; Schwartz, Stephen M.; Salomaa, Veikko; Elosúa, Roberto; Melander, Olle; Voight, Benjamin F.; O’Donnell, Christopher J; Peltonen, Leena; Siscovick, David S.; Altshuler, David; Merlini, Piera Angelica; Peyvandi, Flora; Bernardinelli, Luisa; Ardissino, Diego; Schillert, Arne; Blankenberg, Stefan; Zeller, Tanja; Wild, Philipp S.; Schwarz, Dániel; Tiret, Laurence; Perret, Claire; Schreiber, Stefan; Mokhtari, Nour Eddine El; Schäfer, Arne; März, Winfried; Renner, Wilfried; Bugert, Peter; Klüter, Harald; Schrezenmeir, Jürgen; Rubin, Diana; Ball, Stephen G.; Balmforth, Anthony J.; Wichmann, H‐Erich; Meitinger, Thomas; Fischer, Marcus; Meisinger, Christa; Baumert, Jens; Peters, Annette; Ouwehand, Willem H.; Deloukas, Panos; Thompson, John R.; Ziegler, Andreas; Samani, Nilesh J.; Schunkert, Heribert

doi:10.1038/ng.307

Cited by 429 publications

(257 citation statements)

References 13 publications

(16 reference statements)

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“…In the first years of GWAS discoveries, identification of further loci came from individual genome‐wide association studies (Erdmann et al , 2009; Myocardial Infarction Genetics Consortium et al , 2009; Tregouet et al , 2009; IBC 50K CAD Consortium, 2011; Wang et al , 2011), whereas more recently the formation of large, international consortia has accumulated a sufficient statistical power for new discoveries. The joint forces of the CARDIoGRAM (Schunkert et al , 2011), C4D (Coronary Artery Disease C4D Genetics Consortium, 2011) and finally the CARDIoGRAMplusC4D (CARDIoGRAMplusC4D Consortium et al , 2013; Nikpay et al , 2015) consortium allowed the analysis of up to 180,000 individuals, about half of which had CAD.…”

Section: Genome‐wide Association Studies In Coronary Artery Disease Amentioning

confidence: 99%

“…(B) The number of SNP s detected with genome‐wide significance after replication correlates with the number of individuals included in the discovery studies. Symbols denote the numbers of genotyped SNP s [dots: ≤ 500,000 SNP s (Samani et al , 2007; McPherson et al , 2007; Helgadottir et al , 2007; Myocardial Infarction Genetics Consortium, 2009; Erdmann et al , 2009; Tregouet et al , 2009; IBC 50K CAD Consortium, 2011; Lu et al , 2012); asterisks: 2,500,000 SNP s (Coronary Artery Disease C4D Genetics Consortium, 2011; Schunkert et al , 2011; CARDIoGRAMplusC4D Consortium et al , 2013); arrow: 940,000 SNP s (Nikpay et al , 2015)].…”

Section: Genome‐wide Association Studies In Coronary Artery Disease Amentioning

confidence: 99%

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The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

2016

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Cardiovascular diseases are leading causes for death worldwide. Genetic disposition jointly with traditional risk factors precipitates their manifestation. Whereas the implications of a positive family history for individual risk have been known for a long time, only in the past few years have genome‐wide association studies (GWAS) shed light on the underlying genetic variations. Here, we review these studies designed to increase our understanding of the pathophysiology of cardiovascular diseases, particularly coronary artery disease and myocardial infarction. We focus on the newly established pathways to exemplify the translation from the identification of risk‐related genetic variants to new preventive and therapeutic strategies for cardiovascular disease.

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Section: Genome‐wide Association Studies In Coronary Artery Disease Amentioning

confidence: 99%

Section: Genome‐wide Association Studies In Coronary Artery Disease Amentioning

confidence: 99%

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

2016

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“…9 Indeed, it has been reported that a score of six SNPs enables to discriminate FH patients from healthy controls. 57 We calculated the score as described by Futema et al for the patients with high LDLC levels but without a rare disease-causing variant and compared the score with the controls of the German MI Family Study II 58 (n = 1298). Not all SNPs were covered by exome sequencing, so we calculated the score based on GeneChip Human Mapping 500 K Array Set (Affymetrix) available for 234 of the 255 CAD patients.…”

Section: Apob Gene Variantsmentioning

confidence: 99%

Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction

et al. 2015

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Familial hypercholesterolemia (FH) is an oligogenic disorder characterized by markedly elevated low-density lipoprotein cholesterol (LDLC) levels. Variants in four genes have been reported to cause the classical autosomal-dominant form of the disease. FH is largely under-diagnosed in European countries. As FH increases the risk for coronary artery disease (CAD) and myocardial infarction (MI), it might be specifically overlooked in the large number of such patients. Here, we systematically examined the frequency of potential FH-causing variants by exome sequencing in 255 German patients with premature MI and a positive family history for CAD. We further performed co-segregation analyses in an average of 5.5 family members per MI patient. In total, we identified 11 potential disease-causing variants that co-segregate within the families, that is, 5% of patients with premature MI and positive CAD family history had FH. Eight variants were previously reported as disease-causing and three are novel (LDLR.c.811G4A p.(V271I)), PCSK9.c.610G4A (p. (D204N)) and STAP1.c.139A4G (p. (T47A))). Co-segregation analyses identified multiple additional family members carrying one of these FH variants and the clinical phenotype of either FH (n = 2) or FH and premature CAD (n = 15). However, exome sequencing also revealed that some variants in FH genes, which have been reported to cause FH, do not co-segregate with FH. The data reveal that a large proportion of FH patients escape the diagnosis, even when they have premature MI. Hence, systematic molecular-genetic screening for FH in such patients may reveal a substantial number of cases and thereby allow a timely LDLC-lowering in both FH/MI patients as well as their variantcarrying family members.

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“…3 Several large-scale association studies using a large number of genetic variations, including single nucleotide polymorphisms (SNPs), have recently identified the susceptibility genes and loci for CAD. [4][5][6][7][8][9][10][11][12] However, not all of the reported associations could be replicated in other studies even if middle-to large-sized samples were investigated in the original reports, suggesting that the contribution of genetic factors was not large enough to be replicated in some cases. 13 Validation studies for the association in other populations are, therefore, crucial to establish the role of diseaserelated genes.…”

Section: Introductionmentioning

confidence: 99%

Validation of eight genetic risk factors in East Asian populations replicated the association of BRAP with coronary artery disease

et al. 2009

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Coronary artery disease (CAD) is caused by a thrombotic occlusion or spasm of the coronary artery. Association of genetic variants with susceptibility to CAD has been reported in various populations, but the association should be replicated in other populations to establish the role of genetic variants in CAD. We conducted a case-control study with a total of 1480 CAD cases and 2115 controls from two East Asian populations, Japanese and Korean, to validate the associations of CAD with eight single nucleotide polymorphisms (SNPs) in eight loci, which were identified from large-scale whole-genome association studies in Europeans or East Asians. Among the tested SNPs, one SNP in BRAP (rs11066001) showed a significant association in allele frequency distribution with CAD in both the Japanese (Odds ratio (OR)¼1.63, 95% confidence interval (CI); 1.41-1.89, P¼5.0Â10 À11 , corrected P (Pc)¼4.0Â10 À10 ) and Korean populations (OR¼1.68, 95% CI; 1.41-2.00, P¼6.5Â10 À9 , Pc¼5.2Â10 À9 ), and a meta-analysis showed a significant association in the East Asian populations (OR¼1.65, 95% CI; 1.48-1.85, P¼1.8Â10 À18 , Pc¼1.4Â10 À17 ), whereas no evidence of association was found for the other SNPs. In addition, a combined analysis of BRAP and another CAD locus on 9p21 suggested that these loci had a synergistic role in the susceptibility. Failure to replicate the association with the other SNPs, which were reported in the European populations, suggested that their contributions to CAD were not large enough to be readily captured in the East Asian populations.

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New susceptibility locus for coronary artery disease on chromosome 3q22.3

Cited by 429 publications

References 13 publications

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction

Validation of eight genetic risk factors in East Asian populations replicated the association of BRAP with coronary artery disease

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