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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Article info
Publication history
Published online: January 21, 2018
Accepted:
January 4,
2018
Received:
October 2,
2017
Footnotes
See page 571 for disclosure information.
Identification
Copyright
© 2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
