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Background: Mendelian randomization (MR) studies show iron positively associated with type 2 diabetes (T2D) but included potentially biasing hereditary haemochromatosis variants and did not assess reverse causality., Methods: We assessed the relation of iron homeostasis with T2D and glycaemic traits bidirectionally, using genome-wide association studies (GWAS) of iron homeostasis biomarkers [ferritin, serum iron, total iron-binding capacity (TIBC), transferrin saturation (TSAT) (n ≤ 246 139)], T2D (DIAMANTE n = 933 970 and FinnGen n = 300 483), and glycaemic traits [fasting glucose (FG), 2-h glucose, glycated haemoglobin (HbA1c) and fasting insulin (FI) (n ≤ 209 605)]. Inverse variance weighting (IVW) was the main analysis, supplemented with sensitivity analyses and assessment of mediation by hepcidin., Results: Iron homeostasis biomarkers were largely unrelated to T2D, although serum iron was potentially associated with higher T2D [odds ratio: 1.07 per standard deviation; 95% confidence interval (CI): 0.99 to 1.16; P-value: 0.078) in DIAMANTE only. Higher ferritin, serum iron, TSAT and lower TIBC likely decreased HbA1c, but were not associated with other glycaemic traits. Liability to T2D likely increased TIBC (0.03 per log odds; 95% CI: 0.01 to 0.05; P-value: 0.005), FI likely increased ferritin (0.29 per log pmol/L; 95% CI: 0.12 to 0.47; P-value: 8.72 x 10-4). FG likely increased serum iron (0.06 per mmol/L; 95% CI: 0.001 to 0.12; P-value: 0.046). Hepcidin did not mediate these associations., Conclusion: It is unlikely that ferritin, TSAT and TIBC cause T2D although an association for serum iron could not be excluded. Glycaemic traits and liability to T2D may affect iron homeostasis, but mediation by hepcidin is unlikely. Corresponding mechanistic studies are warranted., (© The Author(s) 2023; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

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., (© The Author(s) 2022; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: To summarize modifiable factors for coronavirus disease 2019 (COVID-19) suggested by Mendelian randomization studies., Methods: In this systematic review, we searched PubMed, EMBASE and MEDLINE, from inception to 15 November 2021, for Mendelian randomization studies in English. We selected studies that assessed associations of genetically predicted exposures with COVID-19-related outcomes (severity, hospitalization and susceptibility). Risk of bias of the included studies was evaluated based on the consideration of the three main assumptions for instrumental variable analyses., Results: We identified 700 studies through systematic search, of which 50 Mendelian randomization studies were included. Included studies have explored a wide range of socio-demographic factors, lifestyle attributes, anthropometrics and biomarkers, predisposition to diseases and druggable targets in COVID-19 risk. Mendelian randomization studies suggested that increases in smoking, obesity and inflammatory factors were associated with higher risk of COVID-19. Predisposition to ischaemic stroke, combined bipolar disorder and schizophrenia, attention-deficit and hyperactivity disorder, chronic kidney disease and idiopathic pulmonary fibrosis was potentially associated with higher COVID-19 risk. Druggable targets, such as higher protein expression of histo-blood group ABO system transferase (ABO), interleukin (IL)-6 and lower protein expression of 2'-5' oligoadenylate synthetase 1 (OAS1) were associated with higher risk of COVID-19. There was no strong genetic evidence supporting the role of vitamin D, glycaemic traits and predisposition to cardiometabolic diseases in COVID-19 risk., Conclusion: This review summarizes modifiable factors for intervention (e.g. smoking, obesity and inflammatory factors) and proteomic signatures (e.g. OAS1 and IL-6) that could help identify drugs for treating COVID-19., (© The Author(s) 2022; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)