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In search of causal pathways in diabetes: a study using proteomics and genotyping data from a cross-sectional study
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
Karolinska Inst, Div Family Med & Primary Care, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.ORCID iD: 0000-0003-2247-8454
Karolinska Inst, Div Family Med & Primary Care, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden;Dalarna Univ, Sch Hlth & Social Sci, Falun, Sweden.
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2019 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, no 11, p. 1998-2006Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis: The pathogenesis of type 2 diabetes is not fully understood. We investigated whether circulating levels of preselected proteins were associated with the outcome 'diabetes' and whether these associations were causal.

Methods: In 2467 individuals of the population-based, cross-sectional EpiHealth study (45-75 years, 50% women), 249 plasma proteins were analysed by the proximity extension assay technique. DNA was genotyped using the Illumina HumanCoreExome-12 v1.0 BeadChip. Diabetes was defined as taking glucose-lowering treatment or having a fasting plasma glucose of >= 7.0 mmol/l. The associations between proteins and diabetes were assessed using logistic regression. To investigate causal relationships between proteins and diabetes, a bidirectional two-sample Mendelian randomisation was performed based on large, genome-wide association studies belonging to the DIAGRAM and MAGIC consortia, and a genome-wide association study in the EpiHealth study.

Results: Twenty-six proteins were positively associated with diabetes, including cathepsin D, retinal dehydrogenase 1, alpha-l-iduronidase, hydroxyacid oxidase 1 and galectin-4 (top five findings). Three proteins, lipoprotein lipase, IGF-binding protein 2 and paraoxonase 3 (PON-3), were inversely associated with diabetes. Fourteen of the proteins are novel discoveries. The Mendelian randomisation study did not disclose any significant causal effects between the proteins and diabetes in either direction that were consistent with the relationships found between the protein levels and diabetes.

Conclusions/interpretation: The 29 proteins associated with diabetes are involved in several physiological pathways, but given the power of the study no causal link was identified for those proteins tested in Mendelian randomisation. Therefore, the identified proteins are likely to be biomarkers for type 2 diabetes, rather than representing causal pathways.

Place, publisher, year, edition, pages
SPRINGER , 2019. Vol. 62, no 11, p. 1998-2006
Keywords [en]
Diabetes, Genotyping, Mendelian randomisation, Proteomics, Type 2 diabetes
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-396951DOI: 10.1007/s00125-019-4960-8ISI: 000491944900005PubMedID: 31446444OAI: oai:DiVA.org:uu-396951DiVA, id: diva2:1370570
Funder
Swedish Research Council, 2015-03477Swedish Heart Lung Foundation, 20150429Göran Gustafsson Foundation for Research in Natural Sciences and Medicine, 1637Available from: 2019-11-15 Created: 2019-11-15 Last updated: 2019-11-15Bibliographically approved

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