Causal factors underlying diabetes risk informed by Mendelian randomisation analysis: evidence, opportunities and challenges

Abstract

Diabetes and its complications cause a heavy disease burden globally. Identifying exposures, risk factors and molecular processes causally associated with the development of diabetes can provide important evidence bases for disease prevention and spur novel therapeutic strategies. Mendelian randomisation (MR), an epidemiological approach that uses genetic instruments to infer causal associations between an exposure and an outcome, can be leveraged to complement evidence from observational and clinical studies. This narrative review aims to summarise the evidence on potential causal risk factors for diabetes by integrating published MR studies on type 1 and 2 diabetes, and to reflect on future perspectives of MR studies on diabetes. Despite the genetic influence on type 1 diabetes, few MR studies have been conducted to identify causal exposures or molecular processes leading to increased disease risk. In type 2 diabetes, MR analyses support causal associations of somatic, mental and lifestyle factors with development of the disease. These studies have also identified biomarkers, some of them derived from the gut microbiota, and molecular processes leading to increased disease risk. These studies provide valuable data to better understand disease pathophysiology and explore potential therapeutic targets. Because genetic association studies have mostly been restricted to participants of European descent, multi-ancestry cohorts are needed to examine the role of different types of physical activity, dietary components, metabolites, protein biomarkers and gut microbiome in diabetes development. Graphical abstract

The causal relationship between bacterial pneumonia and diabetes: a two-sample mendelian randomization study

“…The existing body of evidence linking diabetes and bacteria primarily focuses on intestinal flora. 35 Previous observational studies have revealed a higher incidence of bacterial pneumonia among hospitalized individuals with diabetes. 36 Additionally, patients with inadequate blood glucose control exhibit an elevated susceptibility to diabetes-related pneumonia necessitating hospitalization.…”

Diabetes, glycaemic profile and risk of vitiligo: a Mendelian randomisation study

“…Because of the complex pathogenesis of diabetes and its tendency to be complicated by other disease complications, we believe that the association between type T2DM and vitiligo mentioned in observational studies may be related to confounding factors. Two MR Analyses(21, 22) suggested a significant causal association between T2DM and depression, and one meta-analysis(23) concluded that vitiligo induces varying degrees of psychological problems. This finding may be an important reason why vitiligo is associated with T2DM in several observational studies.…”

Novel genetic loci, lifestyle factors, and inflammatory markers identified as risk factors for sarcoidosis

“…26 The design has been widely used in medical research due to two major merits. 27,28 First, the method can minimize confounding because genetic variants are randomly assorted at conception and thus not associated with confounder (e.g., environmental and self-adopted factors). This process at the population level resembles the randomization process in the randomized controlled trials.…”