Evaluating the role of non-alcoholic fatty liver disease in cardiovascular diseases and type 2 diabetes: a Mendelian randomization study in Europeans and East Asians

Abstract

Background Whether non-alcoholic fatty liver disease (NAFLD) causes cardiovascular disease (CVD) and type 2 diabetes (T2D) is unclear and possible differences between ethnicities have not been thoroughly explored. We used Mendelian randomization (MR) to assess the role of NAFLD in CVD and T2D risk in Europeans and East Asians. Methods We conducted a MR study using genetic predictors of alanine aminotransferase (ALT), liability to NAFLD, aspartate transaminase (AST), liver magnetic resonance imaging corrected T1 and proton density fat fraction and combined them with genome-wide association studies (GWAS) summary statistics of CVD, T2D and glycaemic traits (sample size ranging from 14 400 to 977 320). Inverse-variance weighted analysis was used to assess the effect of NAFLD in these outcomes, with sensitivity analyses and replication in FinnGen. We conducted analyses in East Asians using ethnicity-specific genetic predictors of ALT and AST, and the respective outcome GWAS summary statistics. Results In Europeans, higher ALT was associated with higher T2D risk (odds ratio: 1.77 per standard deviation, 95% CI 1.5 to 2.08), with similar results for other exposures, across sensitivity analyses and in FinnGen. Although NAFLD proxies were related to higher coronary artery disease (CAD) and stroke risk, sensitivity analyses suggested possible bias by horizontal pleiotropy. In East Asians, higher ALT was possibly associated with higher T2D risk, and ALT and AST were inversely associated with CAD. Conclusions NAFLD likely increases the risk of T2D in Europeans and East Asians. Potential differential effects on CAD between Europeans and East Asians require further investigation.

Associations of non‐alcoholic fatty liver disease and cirrhosis with liver cancer in European and East Asian populations: A Mendelian randomization study

“…40 These MR studies suggested that NAFLD and cirrhosis were risk factors for the diseases/disorders of interest. [30][31][32][33][34][35][36][37][38][39][40] Consistent results were observed in prior observational studies. 41,42 These results implied that NAFLD and cirrhosis may interact with some other factors and then increase liver cancer risk.…”

“…A MR study investigated the potential causal relationship between primary biliary cirrhosis and hypothyroidism 40 . These MR studies suggested that NAFLD and cirrhosis were risk factors for the diseases/disorders of interest 30–40 . Consistent results were observed in prior observational studies 41,42 .…”

“…29 To our knowledge, there were no MR studies being conducted to explore whether NAFLD and cirrhosis were causally related to liver cancer. Existing MR studies assessed the potential causal associations of NAFLD with cardiovascular disease, [30][31][32][33][34] diabetes, 30,35,36 obesity, 36 insulin resistance, 37 psoriasis, 38 and kidney function. 39 A MR study investigated the potential causal relationship between primary biliary cirrhosis and hypothyroidism.…”

Multitrait Genome-Wide Analysis in the UK Biobank Reveals Novel and Distinct Variants Influencing Cardiovascular Traits in Africans and Europeans

“…In conclusion, our findings add to the growing body of literature describing the complexity and diversity of the genetic underpinnings of cardiovascular traits across different populations 81–83 . This work lays a foundation for more precise and personalized approaches to preventing and managing cardiovascular diseases, ultimately aiming to reduce health disparities across different ethnic groups.…”

Potential Causal Association between Elevated Gamma-Glutamyl Transferase Level and Stroke: A Two-Sample Mendelian Randomization Study

“…In the literature we reviewed, we found no MR analysis results about a causal association between GGT level and stroke. We did find studies that used MR analyses to link stroke with another indication of liver function, such as non-alcoholic fatty liver disease or bilirubin level [6,23,[60][61][62]; in those studies non-alcoholic fatty liver disease had a limited effect on stroke and showed controversial results. Although we used two-sample MR as a research method to reduce bias, we deemed alcohol to be a confounding factor because it has a substantial effect on GGT level.…”