Genetic Predisposition to Diabetes and Abdominal Aortic Aneurysm: A Two Stage Mendelian Randomisation Study

Dylan R Morris; Gregory T Jones; Michael V Holmes; Matthew J Bown; Richard Bulbulia; Tejas P Singh; Jonathan Golledge

doi:10.1016/j.ejvs.2021.10.038

Genetic Predisposition to Diabetes and Abdominal Aortic Aneurysm: A Two Stage Mendelian Randomisation Study

Eur J Vasc Endovasc Surg. 2022 Mar;63(3):512-519. doi: 10.1016/j.ejvs.2021.10.038. Epub 2021 Dec 13.

Authors

Dylan R Morris¹, Gregory T Jones², Michael V Holmes³, Matthew J Bown⁴, Richard Bulbulia³, Tejas P Singh¹, Jonathan Golledge⁵

Affiliations

¹ Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia; The Department of Vascular and Endovascular Surgery, Townsville University Hospital, Townsville, Queensland, Australia.
² Department of Surgical Sciences, University of Otago, Dunedin, New Zealand.
³ Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK; Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁴ Department of Cardiovascular Sciences and National Institute of Health Research Leicester Biomedical Research Centre, University of Leicester, Leicester, UK.
⁵ Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia; The Department of Vascular and Endovascular Surgery, Townsville University Hospital, Townsville, Queensland, Australia. Electronic address: Jonathan.Golledge@jcu.edu.au.

PMID: 34916110
DOI: 10.1016/j.ejvs.2021.10.038

Abstract

Objective: Observational studies demonstrate an inverse association between type II diabetes and abdominal aortic aneurysm (AAA) for reasons that are unclear. The aim of this study was to clarify the causal association between type II diabetes predisposition and AAA using Mendelian randomisation.

Methods: Effect estimates for single nucleotide polymorphisms (SNPs) associated with diabetes were obtained from the DIAbetes Meta-ANalysis of Trans-Ethnic association studies (DIAMANTE) consortium to construct a genetic instrumental variable. Corresponding effect estimates for associations of these SNPs with AAA were obtained from the International Aneurysm Consortium comprising six separate AAA genomewide association studies (4 972 cases and 99 858 controls). Mendelian randomisation estimates were calculated using inverse variance, weighted median, and MR-Egger methods, and compared against recently published observational estimates.

Results: A genetic risk score was constructed from 206 SNPs associated with diabetes. All three Mendelian randomisation models showed no effect of genetic liability to diabetes and risk of AAA (inverse variance: odds ratio 1.04 per unit higher log odds, 95% 0.98 - 1.11, p = .19; MR-Egger slope p = .33; weighted median p = .50). Results were similar after excluding the TCF7L2 locus (inverse variance p = .075). Findings from the Mendelian randomisation analysis differed from previous observational reports of an inverse association (p_dif < .001).

Conclusion: Lifelong genetic predisposition to diabetes does not appear to protect against AAA. These findings differ from traditional epidemiological studies showing an inverse association between diabetes and AAA, for reasons that remain unclear.

Keywords: Abdominal aortic aneurysm; Diabetes; Mendelian randomisation.

Publication types

Meta-Analysis

MeSH terms

Aortic Aneurysm, Abdominal* / epidemiology
Aortic Aneurysm, Abdominal* / genetics
Diabetes Mellitus, Type 2* / diagnosis
Diabetes Mellitus, Type 2* / epidemiology
Diabetes Mellitus, Type 2* / genetics
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Mendelian Randomization Analysis / methods
Polymorphism, Single Nucleotide

Abstract

Publication types

MeSH terms

Grants and funding