Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies

Reilly, Muredach P.; Li, Mingyao; He, Jing; Ferguson, Jane F.; Stylianou, Ioannis M.; Mehta, Nehal N.; Burnett, Mary Susan; Devaney, Joseph M.; Knouff, Christopher W.; Thompson, John R.; Horne, Benjamin D.; Stewart, Alexandre F.R.; Assimes, Themistocles L.; Wild, Philipp S.; Allayee, Hooman; Nitschke, Patrick Linsel; Patel, Riyaz; Martinelli, Nicola; Girelli, Domenico; Quyyumi, Arshed A.; Anderson, Jeffrey L.; Erdmann, Jeanette; Hall, Alistair S.; Schunkert, Heribert; Quertermous, Thomas; Blankenberg, Stefan; Hazen, Stanley L.; Roberts, Robert; Kathiresan, Sekar; Samani, Nilesh J.; Epstein, Stephen E.; Rader, Daniel J.

doi:10.1016/s0140-6736(10)61996-4

Cited by 473 publications

(375 citation statements)

References 39 publications

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“…Although not directly proven by our study, this suggestion is in line with the results from a recent GWAS showing associations between the individual SNPs of the score and CAD, but not MI on top of CAD [38]. Thus it is possible that clinical use of known anti-atherosclerotic therapy is warranted to reduce the speed of development of the intermediate phenotypes of atherosclerosis in the form of increased IMT and carotid plaques, and in turn ultimately to minimize the development of atherosclerosis and the increased risk of MI in subjects with a high genetic risk score.…”

Section: Possible Clinical Implicationssupporting

confidence: 91%

A myocardial infarction genetic risk score is associated with markers of carotid atherosclerosis

Hamrefors

Hedblad

Engström

et al. 2011

Journal of Internal Medicine

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Abstract. Hamrefors V, Hedblad B, Engström G, Almgren P, Sjögren M, Melander O (Lund University, Malmö, Sweden). A myocardial infarction genetic risk score is associated with markers of carotid atherosclerosis. J Intern Med 2012;271: 271-281.Objective. To assess whether or not a genetic risk score that was previously shown to be associated with myocardial infarction (MI) and coronary artery disease (CAD) is also associated with markers of carotid atherosclerosis.Design. A total of 4022 middle-aged subjects from the general Swedish population were genotyped and individually assigned a genetic risk score based on 13 single-nucleotide polymorphisms (SNPs), previously associated with MI and CAD. The genetic score (Score-MI) was then related to carotid bulb intimamedia thickness (IMT), common carotid artery (CCA) IMT and to the occurrence of carotid plaques in the study population.Results. Score-MI was associated with IMT of the bulb (P < 0.001) and the CCA (P < 0.001) in unadjusted analyses, and with IMT of the bulb after adjustment for cardiovascular risk factors (P = 0.003). The effect size of Score-MI on IMT of the bulb was similar to that of LDL cholesterol. After adjustment for cardiovascular risk factors, Score-MI was also associated with the occurrence of carotid plaques (odds ratio per quintile of Score-MI = 1.11; 95% confidence interval 1.04-1.18; P = 0.001). In addition to SNPs with known effects on LDL levels, Score-MI showed nominal associations with increasing systolic blood pressure and decreasing C-reactive protein levels.Conclusions. This genetic risk score was independently associated with carotid bulb IMT and carotid plaques, providing evidence of an association with early markers of atherosclerosis. This might imply that the genetic MI risk conferred by the score is related to early atherosclerosis and that the risk score may identify at an early stage candidates at risk of developing intermediate phenotypes of atherosclerosis. Further studies should test whether or not assessing the genetic score could be valuable for early treatment decisions in these subjects.

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Section: Possible Clinical Implicationssupporting

confidence: 91%

A myocardial infarction genetic risk score is associated with markers of carotid atherosclerosis

Hamrefors

Hedblad

Engström

et al. 2011

Journal of Internal Medicine

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“…In this context, it has been hypothesized that different genetic risk factors may contribute to either CAD or MI given the complex nature of transition from a normal coronary artery to MI. Indeed, a recent GWA metaanalysis 33 has addressed this issue and has indicated the presence of genetic predispositions leading to MI (in the presence of coronary atherosclerosis) as well as those shared between CAD and MI (promoting coronary atherosclerosis). The present findings of SNPtrait associations can support this notion; that is, the strength of association is prominent for MI at BRAP/ALDH2 on 12q24, whereas it is comparable between the disease entities at CDKN2A/B on 9q21 (Supplementary Table IX).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study of coronary artery disease in the Japanese

et al. 2011

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A new understanding of the genetic basis of coronary artery disease (CAD) has recently emerged from genome-wide association (GWA) studies of common single-nucleotide polymorphisms (SNPs), thus far performed mostly in European-descent populations. To identify novel susceptibility gene variants for CAD and confirm those previously identified mostly in populations of European descent, a multistage GWA study was performed in the Japanese. In the discovery phase, we first genotyped 806 cases and 1337 controls with 451 382 SNP markers and subsequently assessed 34 selected SNPs with direct genotyping (541 additional cases) and in silico comparison (964 healthy controls). In the replication phase, involving 3052 cases and 6335 controls, 12 SNPs were tested; CAD association was replicated and/or verified for 4 (of 12) SNPs from 3 loci: near BRAP and ALDH2 on 12q24 (P¼1.6Â10 À34 ), HLA-DQB1 on 6p21 (P¼4.7Â10 À7 ), and CDKN2A/B on 9p21 (P¼6.1Â10 À16 ). On 12q24, we identified the strongest association signal with the strength of association substantially pronounced for a subgroup of myocardial infarction cases (P¼1.4Â10 À40 ). On 6p21, an HLA allele, DQB1*0604, could show one of the most prominent association signals in an B8-Mb interval that encompasses the LTA gene, where an association with myocardial infarction had been reported in another Japanese study. CAD association was also identified at CDKN2A/B, as previously reported in different populations of European descent and Asians. Thus, three loci confirmed in the Japanese GWA study highlight the likely presence of risk alleles with two types of genetic effects -population specific and common -on susceptibility to CAD.

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“…A novel mechanism linking these observations might involve ADAMTS‐7, an extracellular matrix (ECM) protease. Variants in ADAMTS7 have been identified to be associated with CAD (Coronary Artery Disease C4D Genetics Consortium, 2011; Reilly et al , 2011; Schunkert et al , 2011). ADAMTS7 was more strongly associated with CAD rather than MI, suggesting a major role in plaque formation and not in plaque rupture (Reilly et al , 2011).…”

Section: Vascular Remodellingmentioning

confidence: 99%

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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Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies

Cited by 473 publications

References 39 publications

A myocardial infarction genetic risk score is associated with markers of carotid atherosclerosis

A myocardial infarction genetic risk score is associated with markers of carotid atherosclerosis

Genome-wide association study of coronary artery disease in the Japanese

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

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