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Review
. 2022 Dec;39(12):e14982.
doi: 10.1111/dme.14982. Epub 2022 Oct 31.

Advancing a causal role of type 2 diabetes and its components in developing macro- and microvascular complications via genetic studies

Altayeb Ahmed  1 , Naveed Sattar  2 , Hanieh Yaghootkar  1
Affiliations
Review

Advancing a causal role of type 2 diabetes and its components in developing macro- and microvascular complications via genetic studies

Altayeb Ahmed et al. Diabet Med. 2022 Dec.

Abstract

The role of diabetes in developing microvascular and macrovascular complications has been subject to extensive research. Despite multiple observational and genetic studies, the causal inference of diabetes (and associated risk factors) on those complications remains incomplete. In this review, we focused on type 2 diabetes, as the major form of diabetes, and investigated the evidence of causality provided by observational and genetic studies. We found that genetic studies based on Mendelian randomization provided consistent evidence of causal inference of type 2 diabetes on macrovascular complications; however, the evidence for causal inference on microvascular complications has been somewhat limited. We also noted high BMI could be causal for several diabetes complications, notable given high BMI is commonly upstream of type 2 diabetes and the recent calls to target weight loss more aggressively. We emphasize the need for further studies to identify type 2 diabetes components that mostly drive the risk of those complications. Even so, the genetic evidence summarized broadly concurs with the need for a multifactorial risk reduction approach in type 2 diabetes, including addressing excess adiposity.

Keywords: genetics of type 2 diabetes; macrovascular disease; mendelian randomization; microvascular disease.

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Conflict of interest statement

NS has received grant and personal fees from AstraZeneca, Boehringer Ingelheim and Novartis; grant from Roche Diagnostics; and personal fees from Abbott Laboratories, Afimmune, Amgen, Eli Lilly, Hanmi Pharmaceuticals, Merck Sharp & Dohme, Novo Nordisk, Pfizer and Sanofi outside the submitted work.

Figures

FIGURE 1
FIGURE 1
The analogy between Mendelian randomization and Randomized Controlled Trials (RCT). In an RCT, participants are randomly assigned to either treatment or control group and receive a different treatment or management protocol. Consequently, reverse causation and bias are significantly reduced as randomization and group assignment is done at the start of the study. In Mendelian randomization, participants are grouped according to their genetic risk profile for the exposure of interest. For example, to investigate whether type 2 diabetes is causally associated with vascular complications, individuals are randomized based on their genetically defined type 2 diabetes liability. The random inheritance of genetic variants from each parent independent of the outcome, environment and lifestyle factors, reduces the chance of reverse causation and confounding factors.
FIGURE 2
FIGURE 2
The assumptions of the Mendelian randomization method. First, the relevance assumption implies that instrumental variables must be associated with the exposure of interest. Second, the independence assumption states that there has to be no shared common cause between the instrumental variants and confounding factors. Third, the exclusion restriction assumption implies that the instrument variables do not affect the outcome except through the risk factor of interest.
FIGURE 3
FIGURE 3
Pleiotropy in Mendelian randomization. A ‘vertical pleiotropy’ occurs if the genetic instrument associates with other traits downstream of the exposure of interest. A ‘horizontal pleiotropy’ occurs when the genetic instrument is associated with traits that are on other independent pathways.
FIGURE 4
FIGURE 4
Type 2 diabetes causal effect on micro/macrovascular complications. This forest plot shows the result of several Mendelian randomization studies using genetic variants associated with type 2 diabetes as instrumental variables to investigate whether genetically predicted type 2 diabetes increases the risk of developing microvascular and macrovascular complications. Results shows the corresponding change in risk expressed in odds ratio (OR, 95% CI) on the x‐axis for genetically increased risk of type 2 diabetes, while the y‐axis shows different microvascular and macrovascular complications.
See this image and copyright information in PMC

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