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Background:Increasing childhood obesity is a global issue requiring potentially local solutions to ensure it does not continue into adulthood. We systematically identified potentially modifiable targets of obesity at the onset and end of puberty in Hong Kong, the most economically developed major Chinese city.Methods:We conducted an environment-wide association study (EWAS) and an epigenome-wide association study of obesity to systematically assess associations with body mass index (BMI) and waist–hip ratio (WHR) in Hong Kong’s population-representative ‘Children of 1997’ birth cohort. Univariable linear regression was used to select exposures related to obesity at ~11.5 years (BMI and obesity risk n ≤ 7119, WHR n = 5691) and ~17.6 years (n = 3618) at Bonferroni-corrected significance, and multivariable regression to adjust for potential confounders followed by replicated multivariable regression (n = 308) and CpG by CpG analysis (n = 286) at ~23 years. Findings were compared with evidence from published randomized controlled trials (RCTs) and Mendelian randomization (MR) studies.Results:At ~11.5 and~17.6 years the EWAS identified 14 and 37 exposures associated with BMI, as well as 7 and 12 associated with WHR, respectively. Most exposures had directionally consistent associations at ~23 years. Maternal second-hand smoking, maternal weight, and birth weight were consistently associated with obesity. Diet (including dairy intake and artificially sweetened beverages), physical activity, snoring, binge eating, and earlier puberty were positively associated with BMI at ~17.6 years, while eating before sleep was inversely associated with BMI at ~17.6 years. Findings for birth weight, dairy intake, and binge eating are consistent with available evidence from RCTs or MR studies. We found 17 CpGs related to BMI and 17 to WHR.Conclusions:These novel insights into potentially modifiable factors associated with obesity at the outset and the end of puberty could, if causal, inform future interventions to improve population health in Hong Kong and similar Chinese settings.Funding:This study including the follow-up survey and epigenetics testing was supported by the Health and Medical Research Fund Research Fellowship, Food and Health Bureau, Hong Kong SAR Government (#04180097). The DNA extraction of the samples used for epigenetic testing was supported by CFS-HKU1.

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.

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.

IntroductionObservational studies suggested lung function is inversely associated with cardiovascular disease (CVD) although these studies could be confounded. We conducted a two sample Mendelian randomisation study using summary statistics from genome-wide association studies (GWAS) to clarify the role of lung function in CVD and its risk factors, and conversely the role of CVD in lung function.MethodsWe obtained genetic instruments for forced expiratory volume in 1 s (FEV1: 260) and forced vital capacity (FVC: 320) from publicly available UK Biobank summary statistics (n=421 986) and applied to GWAS summary statistics for coronary artery disease (CAD) (n=184 305), stroke (n=446 696), atrial fibrillation (n=1 030 836) and heart failure (n=977 320) and cardiovascular risk factors. Inverse variance weighting was used to assess the impact of lung function on these outcomes, with various sensitivity analyses. Bidirectional Mendelian randomisation was used to assess reverse causation.ResultsFEV1 and FVC were inversely associated with CAD (OR per SD increase, 0.72 (95% CI 0.63 to 0.82) and 0.70 (95%CI 0.62 to 0.78)), overall stroke (0.87 (95%CI 0.77 to 0.97), 0.90 (95% CI 0.82 to 1.00)) and some stroke subtypes. FEV1 and FVC were inversely associated with type 2 diabetes and systolic blood pressure. Sensitivity analyses produced similar findings although the association with CAD was attenuated after adjusting for height (eg, OR for 1SD FEV10.95 (0.75 to 1.19), but not for stroke or type 2 diabetes. There was no strong evidence for reverse causation.ConclusionHigher lung function likely protect against CAD and stroke.

Background Observational studies and small intervention studies suggest alcohol raises gamma-glutamyltransferase (GGT). We used Mendelian randomization to assess the causal effect of alcohol use on GGT in older Chinese people. Methods An instrumental variable (IV) analysis in 2,321 men and 2,757 women aged 50+ years from phase 3 of the Guangzhou Biobank Cohort Study with ALDH2 (rs671) genotyped, alcohol use and GGT available was used to assess the causal effect of alcohol use on GGT. Rs671 was used as an IV and F-statistics was used to test for weak instrument hypothesis. An F-statistic of ≥10 indicates the IV is not weak. Results In men, the F-statistic for rs671 on alcohol use was 70. Using IV analysis alcohol use increased GGT by 10.60 U/L per alcohol unit (10 gram ethanol) per day (95% confidence interval (CI) 6.58 to 14.62). The estimate was lower in observational multivariate regression: 3.48 U/L GGT per alcohol unit per day (95% CI 2.84 to 4.11) adjusted for age, education, physical activity and smoking. In women, rs671 was not associated with alcohol or GGT and the F-statistic was 7 precluding IV analysis. Conclusion In Mendelian randomization, we found confirmative evidence that alcohol use increases GGT among Southern Chinese men. Moreover, we found that the ALDH2 variant rs671 was not associated with GGT among Southern Chinese women who generally consume very low levels of alcohol. Taken together our findings strongly suggest that alcohol increases GGT, although we cannot rule out the possibility that other unknown factors may cause a different relation between alcohol and GGT in other populations.