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Type 2 diabetes, glycaemic traits and cardiovascular disease: a Mendelian Randomization study
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.ORCID-id: 0000-0003-2247-8454
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.ORCID-id: 0000-0003-2256-6972
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.ORCID-id: 0000-0003-2071-5866
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

Type 2 diabetes (T2D) and its hallmarks insulin resistance, impaired insulin secretion, and hyperglycaemia affect over 400 million persons worldwide and are associated with raised cardiovascular risk, but their causal role has been difficult to dissect due to overlap between risk factors. We used Mendelian randomization analysis, which utilises genetic polymorphisms associated with a risk factor, to assess causal effects of T2D, insulin resistance, insulin secretion, and fasting glucose on mortality, ischaemic stroke, and coronary artery disease (CAD) risk in 120,091 adults in the UK Biobank and in the CARDIoGRAMplusC4D consortium (63,746 cases of CAD and 130,681 controls). We found evidence for a causal effect of T2D on raised CAD risk (odds ratio (OR) per doubling in the odds of T2D, 1.07, 95% confidence interval (CI) 1.05 – 1.09, P = 1.2 x 10-9) and for a causal effect of impaired insulin secretion on the risk of CAD (OR per SD-unit decrease, 1.14, 95% CI 1.06 – 1.22, P = 0.002). The genetic score for insulin resistance was associated with increased coronary artery disease risk; however, sensitivity analysis indicated that the instrument might not be appropriate to use for robust causal inference testing. Our results support previous reports of a causal role of T2D and impaired insulin secretion in coronary artery disease and point to a complex relationship between variants affecting insulin resistance and cardiovascular outcomes.

Nyckelord [en]
diabetes, insulin resistance, mendelian randomization, uk biobank, heart disease, cardiovascular disease
Nationell ämneskategori
Medicinska och farmaceutiska grundvetenskaper Klinisk medicin
Identifikatorer
URN: urn:nbn:se:uu:diva-316888OAI: oai:DiVA.org:uu-316888DiVA, id: diva2:1079252
Tillgänglig från: 2017-03-08 Skapad: 2017-03-08 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
Ingår i avhandling
1. Insulin Resistance: Causes, biomarkers and consequences
Öppna denna publikation i ny flik eller fönster >>Insulin Resistance: Causes, biomarkers and consequences
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The worldwide increasing number of persons affected by largely preventable diseases like diabetes demands better prevention and treatment. Insulin is required for effective utilisation of circulating nutrients. Impaired responsiveness to insulin (insulin resistance, IR) is a hallmark of type 2 diabetes and independently raises the risk of heart attack and stroke. The pathophysiology of IR is incompletely understood. High-throughput measurement of large numbers of circulating biomarkers may provide new insights beyond established risk factors.

The aims of this thesis were to (i) use proteomics, metabolomics and genomics methods in large community samples to identify biomarkers of IR; (ii) assess biomarkers for risk prediction and insights into aetiology and consequences of IR; and (iii) use Mendelian randomisation analysis to assess causality.

In Study I, analysis of 80 circulating proteins in 70-to-77-year-old Swedes identified cathepsin D as a biomarker for IR and highlighted a tentative causal effect of IR on raised plasma tissue plasminogen activator levels. In Study II, nontargeted fasting plasma metabolomics was used to discover 52 metabolites associated with glycaemic traits in non-diabetic 70-year-old men. Replication in independent samples of several thousand persons provided evidence for a causal effect of IR on reduced plasma oleic acid and palmitoleic acid levels. In Study III, nontargeted metabolomics in plasma samples obtained at three time points during an oral glucose challenge in 70-year-old men identified associations between a physiologic measure of IR and concentration changes in medium-chain acylcarnitines, monounsaturated fatty acids, bile acids and lysophosphatidylethanolamines. Study IV provided evidence in two large longitudinal cohorts for causal effects of type 2 diabetes and impaired insulin secretion on raised coronary artery disease risk.

In conclusion, the Studies in this thesis provide new insights into the pathophysiology and adverse health consequences of IR and illustrate the value of combining traditional epidemiologic designs with recent molecular techniques and bioinformatics methods. The results provide limited evidence for the role of circulating proteins and small molecules in IR and require replication in separate studies and validation in experimental designs.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2017. s. 54
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1316
Nyckelord
insulin resistance, diabetes, insulin secretion, cardiovascular, mendelian randomization, proteomics, metabolomics, genomics, molecular epidemiology, complex disease, risk prediction, coronary heart disease, stroke, hyperglycemia
Nationell ämneskategori
Medicinska och farmaceutiska grundvetenskaper Klinisk medicin Cell- och molekylärbiologi Endokrinologi och diabetes Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi Fysiologi
Identifikatorer
urn:nbn:se:uu:diva-316891 (URN)978-91-554-9856-6 (ISBN)
Disputation
2017-05-22, Room E10:1309 (BMC Navet), Biomedicinskt Centrum (BMC), Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2017-04-28 Skapad: 2017-03-14 Senast uppdaterad: 2018-01-13

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Nowak, ChristophSundstrom, JohanIngelsson, ErikFall, Tove
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Molekylär epidemiologiScience for Life Laboratory, SciLifeLabKardiologi
Medicinska och farmaceutiska grundvetenskaperKlinisk medicin

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