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

Abstract

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. 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. 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 (pdif < .001). 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.