Mendelian Randomization Analysis Dissects the Relationship between NAFLD, T2D, and Obesity and Provides Implications to Precision Medicine

Abstract

Background:Non-alcoholic fatty liver disease (NAFLD) is epidemiologically correlated with both type 2 diabetes (T2D) and obesity. However, the causal inter-relationships among the three diseases have not been completely investigated. Aim:We aim to explore the causal relationships among the three diseases. Design and methods:We performed a genome-wide association study (GWAS) on fatty liver disease in ~400,000 UK BioBank samples. Using this data as well as the largest-to-date publicly available summarylevel GWAS data, we performed a two-sample bidirectional Mendelian Randomization (MR) analysis. This analysis tested the causal inter-relationship between NAFLD, T2D, and obesity, as well as the association between genetically driven NAFLD (with two well-established SNPs at the PNPLA3 and TM6SF2 loci) and glycemic and lipidemic traits, respectively. Transgenic mice expressing the human PNPLA3 I148I (TghPNPLA3-I148I) and PNPLA3 I148M (TghPNPLA3-I148M) isoforms were used to further validate the causal effects. Results:We found that genetically instrumented hepatic steatosis significantly increased the risk for T2D (OR=1.3, 95% CI: [1.2, 1.4], p=8.3e-14) but not the intermediate glycemic phenotypes at the Bonferroni-adjusted level of significance (p<0.002). There was a moderate, but significant causal association between genetically driven hepatic steatosis and decreased risk for BMI (β=-0.027 SD, 95%CI: [-0.043, -0.01], p=1.3e-4), but an increased risk for WHRadjBMI (Waist-Hip Ratio adjusted for BMI) (β=0.039 SD, 95%CI: [0.023, 0.054], p=8.2e-7), as well as a decreased level for total cholesterol (β=-0.084 SD, 95%CI [-0.13, -0.036], p=6.8e-4), but not triglycerides (β=0.02 SD, 95%CI [-0.023, 0.062], p=0.36). The reverse MR analyses suggested that genetically driven T2D (OR=1.1, 95% CI: [1.0, 1.2], p=1.7e-3), BMI (OR=2.3, 95% CI: [2.0, 2.7], p=1.4e-25) and WHRadjBMI (OR=1.5, 95% CI: [1.3, 1.8], p=1.1e-6) causally increase the NAFLD risk. In the animal study, as compared to the TghPNPLA3-I148I controls, the TghPNPLA3-I148M mice developed higher fasting glucose level and reduced glucose clearance. Meanwhile, the TghPNPLA3-I148M mice demonstrated a reduced body weight, increased central to peripheral fat ratio, decreased circulating total cholesterol as compared to the TghPNPLA3-I148I controls. Conclusion:This large-scale bidirectional MR study suggests that lifelong, genetically driven NAFLD is a causal risk factor for T2D (hence potentially a "NAFLD-driven T2D" subtype) and central obesity (or "NAFLD-driven obesity" subtype), but protects against overall obesity; while genetically driven T2D, obesity, and central obesity also causally increase the risk of NAFLD, hence a "metabolic NAFLD". This causal relationship revealed new insights into disease subtypes and provided novel hypotheses for precision treatment or prevention for the three diseases.

The effect of liver enzymes on body composition: A Mendelian randomization study

“…Reasons for an inverse association of ALT with fat mass are unclear since fat mass is a well-established causal factor for diabetes which is unlikely to be contributing to the positive association of ALT with diabetes seen here. [5,6] But these inverse estimates are consistent with a previous MR study [5] showing ALT negatively associated with BMI using the same genetic variants predicting ALT applied to the 2018 GIANT and UK Biobank meta-analysis. The positive associations of GGT with body composition, in particular with fat mass, might be relevant to the observed associations of GGT with cardiovascular disease risk.…”

“…Recently, MR studies using different data sources have found ALT inversely associated with body mass index (BMI), indicating higher ALT might reduce BMI. [5,6] This finding appears to contradict observational studies that show adiposity associated with poor liver function. [7] However BMI does not distinguish muscle mass from fat mass.…”

A brief history of human disease genetics

“…These phenome-wide association studies (PheWAS) have revealed the extent to which many variants have pleiotropic effects across multiple traits 83 . Some of these relationships are expected, such as the impact of obesity variants on risk of hepatic steatosis and type 2 diabetes 84 or variants that influence multiple autoimmune conditions 85 . Others connect diseases and traits in surprising ways, highlighting shared polygenic, pleiotropic effects and cell-type specificity, and delivering insights into shared biology and overlapping mechanisms 86,87 .…”

The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes: an IMI DIRECT study

“…Physical inactivity may also predispose to non-alcoholic fatty liver disease (NAFLD) [8], which in turn may also adversely affect glucose homeostasis [9][10][11]. Indeed, recent Mendelian randomisation studies hint at bidirectional causal relationships between NAFLD and type 2 diabetes [12,13]. Various mechanisms for these relationships have been proposed [14], with chronic positive energy balance considered a primordial modifiable risk factor [15,16].…”