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Canadian Journal of Cardiology

The Genetic Link Between Diabetes and Atherosclerosis

  • Stephanie Ross
    Affiliations
    Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada
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  • Hertzel Gerstein
    Affiliations
    Department of Medicine and Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada
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  • Guillaume Paré
    Correspondence
    Corresponding author: Dr Guillaume Paré, Population Health Research Institute, McMaster University, Hamilton General Hospital Campus, DB-CVSRI, 237 Barton Street East, Rm. C3103, Hamilton, Ontario L8L2X2, Canada. Tel.: +1-905-527-4322, ext. 40377; fax: +1-905-296-5806.
    Affiliations
    Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada

    Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada

    Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada

    Thrombosis and Atherosclerosis Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Canada
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Published:January 21, 2018DOI:https://doi.org/10.1016/j.cjca.2018.01.016

      Abstract

      Epidemiological studies have indicated that the risk of atherothrombotic coronary artery disease (CAD) is higher in patients with diabetes, but these results have not been consistently observed across clinical trials. To address this apparent discrepancy, we can apply the results of genome-wide association studies (GWAS) to provide a better understanding of the shared genetic architecture of diabetes and atherothrombotic CAD. For instance, a large GWAS has identified 16 novel loci that are associated with both diabetes and atherothrombotic CAD. These genetic variants may also be used to assess potential causal relationships reported in observational studies and clinical trials through Mendelian randomization analyses. For example, several Mendelian randomization analyses have shown that diabetes is associated with CAD independent of other risk factors (odds ratio [OR]: 1.63, 95% confidence interval [CI]: 1.23–2.07; P = 0.002). Furthermore, Mendelian randomization analyses can provide more insight into the perceived risk of diabetes among patients without diabetes receiving statin therapy. Here, genetically lower activity of HMG-CoA reductase (HMGCR) was associated with a modest increase in diabetes (OR per allele: 1.02, 95% CI: 1.00–1.05). These results highlight the biological mechanisms that link diabetes with the use of statins. In addition, this work illustrates the great potential value of genetic studies to clarify the mechanistic relationships among atherosclerotic vascular disease, dysglycemia, and diabetes. More research is needed to delineate and subsequently better understand the genetic links between diabetes and atherosclerosis.

      Résumé

      Des études épidémiologiques ont indiqué que le risque de coronaropathie athérothrombotique était plus élevé chez les patients diabétiques, mais ces résultats n’ont pas été observés constamment lors des essais cliniques. Afin d’expliquer cette divergence apparente, nous pouvons appliquer les résultats d’études d’association pangénomique (GWAS ou Genome-Wide Association Studies) afin de mieux cerner l’architecture génétique commune entre le diabète et les coronaropathies athérothrombotiques. Par exemple, une vaste étude GWAS a permis de repérer 16 nouveaux loci associés au diabète et aux coronaropathies athérothrombotiques. Ces variantes génétiques peuvent aussi servir à évaluer les liens de causalité possibles rapportés lors des études observationnelles et des essais cliniques au moyen d’analyses avec répartition aléatoire mendélienne. Par exemple, plusieurs analyses avec répartition aléatoire mendélienne ont montré que le diabète est associé aux coronaropathies indépendamment d’autres facteurs de risque (rapport de cotes [RC]: 1,63; intervalle de confiance [IC] à 95 %: 1,23-2,07; p = 0,002). De plus, les analyses avec répartition aléatoire mendélienne peuvent nous permettre de mieux cerner le risque perçu de diabète parmi les patients non diabétiques suivant un traitement par une statine. Ici, l’architecture génétique à l’origine de l’activité inférieure de l’enzyme HMGCR (3-hydroxy-3-méthylglutaryl-CoA réductase) a été associée à une légère augmentation du diabète (RC par allèle: 1,02; IC à 95 %: 1,00-1,05). Ces résultats mettent en évidence les mécanismes biologiques liant le diabète à l’utilisation de statines. De plus, ce travail illustre le rôle potentiellement important des études génétiques dans la compréhension des liens mécanistiques entre les maladies vasculaires athéroscléreuses, la dysglycémie et le diabète. D’autres recherches sont nécessaires afin de décrire puis de mieux comprendre les liens génétiques entre le diabète et l’athérosclérose.
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