Genetic variants primarily associated with type 2 diabetes are related to coronary artery disease risk

Jansen, Henning; Loley, Christina; Lieb, Wolfgang; Pencina, Michael J.; Nelson, Christopher P.; Kathiresan, Sekar; Peloso, Gina M.; Voight, Benjamin F.; Assimes, Themistocles L.; Boerwinkle, Eric; Hengstenberg, Christian; Laaksonen, Reijo; McPherson, Ruth; Roberts, Robert; Þorsteinsdóttir, Unnur; Peters, Annette; Gieger, Christian; Rawal, Rajesh; Thompson, John R.; König, Inke R.; Vasan, Ramachandran S.; Erdmann, Jeanette; Samani, Nilesh J.; Schunkert, Heribert

doi:10.1016/j.atherosclerosis.2015.05.033

Cited by 26 publications

(21 citation statements)

References 50 publications

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“…90,91 The association between high blood glucose and IHD was also demonstrated to start below the threshold required to diagnose diabetes mellitus: compared with lower fasting glucose concentrations, a glucose of ≥6.1 but <7 mmol/L was associated with 17% higher risk of IHD (HR 1.17, 95% CI 1.08-1.26; 1011 deaths). 90 Although initial MR experiments associating genetic risk of type 2 diabetes mellitus to IHD risk were equivocal, 92 more recent studies support causal assertions. Each genetically determined 1% increase in HbA1c is associated with about a 50% increased risk of IHD (odds ratio 1.53, 95% CI 1.14-2.05), similar in size to observational associations (although there is substantial uncertainty in both these estimates).…”

Section: Diabetes Mellitus and Atherosclerosismentioning

confidence: 90%

Epidemiology of Atherosclerosis and the Potential to Reduce the Global Burden of Atherothrombotic Disease

Herrington

Lacey

Sherliker

et al. 2016

Circulation Research

1,145

666

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Atherosclerosis is a leading cause of vascular disease worldwide. Its major clinical manifestations include ischemic heart disease, ischemic stroke, and peripheral arterial disease. In high-income countries, there have been dramatic declines in the incidence and mortality from ischemic heart disease and ischemic stroke since the middle of the 20th century. For example, in the United Kingdom, the probability of death from vascular disease in middle-aged men (35-69 years) has decreased from 22% in 1950 to 6% in 2010. Most low-and middle-income countries have also reported declines in mortality from stroke over the last few decades, but mortality trends from ischemic heart disease have been more varied, with some countries reporting declines and others reporting increases (particularly those in Eastern Europe and Asia). Many major modifiable risk factors for atherosclerosis have been identified, and the causal relevance of several risk factors is now well established (including, but not limited to, smoking, adiposity, blood pressure, blood cholesterol, and diabetes mellitus). Widespread changes in health behaviors and use of treatments for these risk factors are responsible for some of the dramatic declines in vascular mortality in high-income countries. In order that these declines continue and are mirrored in less wealthy nations, increased efforts are needed to tackle these major risk factors, particularly smoking and the emerging obesity epidemic. (Circ Res. 2016;118:535-546.

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Section: Diabetes Mellitus and Atherosclerosismentioning

confidence: 90%

Epidemiology of Atherosclerosis and the Potential to Reduce the Global Burden of Atherothrombotic Disease

Herrington

Lacey

Sherliker

et al. 2016

Circulation Research

1,145

666

View full text Add to dashboard Cite

show abstract

“…In this issue of Atherosclerosis, Jansen and colleagues used genetic markers as proxies for diabetes status to investigate whether T2DM e associated SNPs are also associated with increased risk of CAD in Caucasians, using the CARDIoGRAM Consortium dataset comprising~22,000 CAD cases and~65,000 controls [2,6,7]. They argued that if T2DM is a causal risk factor for CAD, then genetic variants associated with T2DM would consequently be expected to be associated with CAD.…”

Section: Commentarymentioning

confidence: 97%

“…The T2DM SNPs associated with CAD were deduced to cause T2DM through a number of distinct metabolic processes, influencing beta cell function, insulin secretion, insulin sensitivity, obesity or acting through as yet unknown mechanisms (Fig. 1) [6]. Therefore, analysis of the underlying datasets may identify significant enrichment of genes and their predicted proteins in key metabolic pathways and protein e protein interaction networks pertinent to the pathogenesis of CAD, including CAD in the setting of T2DM and preclinical diabetes.…”

Section: Commentarymentioning

confidence: 98%

Double trouble: T2DM genetic risk factors play a causal role in CAD

Hamad

Beaney²,

Buxton³

et al. 2015

Atherosclerosis

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Type 2 diabetes mellitus T2D T2DM Single nucleotide polymorphism SNP Genetic risk score Pathogenesis CommentaryCoronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide [1]. A major risk factor for CAD that has long been recognised is type 2 diabetes mellitus (T2DM). In addition, obesity, sedentary lifestyle and stress are common shared risk factors that contribute to the close association between T2DM and CAD. It is not yet obvious whether and to what degree this close association between the two conditions can be attributed to shared genetic risk factors. In contrast to other risk factors shared between T2DM and CAD, genetic risk factors offer the advantage of being unaffected by the various confounders affecting the association between these two conditions. T2DM and CAD both have polygenic inheritance and genetic studies have identified numerous distinct loci for both diseases. For CAD, over 50 single nucleotide polymorphisms (SNPs) have been identified in genome-wide association studies (GWAS), but only a few of these also associated with traditional CAD risk factors (lipid and blood pressure traits) and none of these were associated with glyco-metabolic traits at a genome-wide significant level (p < 5 Â 10 À8 ) [2e4]. In the setting of T2DM, some components of the genetic predisposition to CAD appear to differ from those found in the general population. A variant related to the g-glutamyl cycle of amino acid transport that had not been previously identified in the general population was found to be associated with CAD at a genome wide-level of significance in T2DM, representing a novel genetic risk factor for CAD in T2DM [5].In this issue of Atherosclerosis, Jansen and colleagues used genetic markers as proxies for diabetes status to investigate whether T2DM e associated SNPs are also associated with increased risk of CAD in Caucasians, using the CARDIoGRAM Consortium dataset comprising~22,000 CAD cases and~65,000 controls [2,6,7]. They argued that if T2DM is a causal risk factor for CAD, then genetic variants associated with T2DM would consequently be expected to be associated with CAD. They investigated whether the risk alleles of T2DM -associated SNPs previously identified in GWAS also increase the risk of CAD. A systematic literature search identified 48 variants currently known to be robustly associated with T2DM, of which 4 were excluded (on technical grounds or because of statistically e defined pleiotropy) and the remaining 44 were included in the study. For 29 of these variants, the T2DM risk allele gave an effect in the expected direction, (i.e. increased risk of CAD) and for ten SNPs this was statistically significant (p < 0.05). Of these, only the T2DM SNP at the chromosome 2q36.3 locus, which contains the insulin receptor substrate 1 (IRS1) and LOC64673 genes, remained significantly associated with CAD after correcting for multiple testing (p ¼ 3.4 Â 10 À5 , Bonferroni corrected threshold p value 0.0011). Interestingly, for two of the remaining 15 variants (CILP2 and ...

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“…Evidence from genetic studies suggests that this relationship is causal [2, 3]. As such, there is growing interest in factors which may promote a “pro-atherogenic” environment in diabetes.…”

Section: Introductionmentioning

confidence: 99%

Variant rs10911021 that associates with coronary heart disease in type 2 diabetes, is associated with lower concentrations of circulating HDL cholesterol and large HDL particles but not with amino acids

Beaney

McLachlan

Wannamethee

et al. 2016

Cardiovasc Diabetol

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AimsAn intergenic locus on chromosome 1 (lead SNP rs10911021) was previously associated with coronary heart disease (CHD) in type 2 diabetes (T2D). Using data from the UCLEB consortium we investigated the relationship between rs10911021 and CHD in T2D, whether rs10911021 was associated with levels of amino acids involved in the γ-glutamyl cycle or any conventional risk factors (CRFs) for CHD in the T2D participants.MethodsFour UCLEB studies (n = 6531) had rs10911021 imputation, CHD in T2D, CRF and metabolomics data determined using a nuclear magnetic resonance based platform.ResultsThe expected direction of effect between rs10911021 and CHD in T2D was observed (1377 no CHD/160 CHD; minor allele OR 0.80, 95 % CI 0.60–1.06) although this was not statistically significant (p = 0.13). No association between rs10911021 and CHD was seen in non-T2D participants (11218 no CHD/1274 CHD; minor allele OR 1.00 95 % CIs 0.92–1.10). In T2D participants, while no associations were observed between rs10911021 and the nine amino acids measured, rs10911021 was associated with HDL-cholesterol (p = 0.0005) but the minor “protective” allele was associated with lower levels (−0.034 mmol/l per allele). Focusing more closely on the HDL-cholesterol subclasses measured, we observed that rs10911021 was associated with six large HDL particle measures in T2D (all p < 0.001). No significant associations were seen in non-T2D subjects.ConclusionsOur findings are consistent with a true association between rs10911021 and CHD in T2D. The protective minor allele was associated with lower HDL-cholesterol and reductions in HDL particle traits. Our results indicate a complex relationship between rs10911021 and CHD in T2D.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0435-0) contains supplementary material, which is available to authorized users.

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Genetic variants primarily associated with type 2 diabetes are related to coronary artery disease risk

Cited by 26 publications

References 50 publications

Epidemiology of Atherosclerosis and the Potential to Reduce the Global Burden of Atherothrombotic Disease

Epidemiology of Atherosclerosis and the Potential to Reduce the Global Burden of Atherothrombotic Disease

Double trouble: T2DM genetic risk factors play a causal role in CAD

Variant rs10911021 that associates with coronary heart disease in type 2 diabetes, is associated with lower concentrations of circulating HDL cholesterol and large HDL particles but not with amino acids

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