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Background : Previous studies, including Mendelian randomization (MR), have demonstrated type 2 diabetes (T2D) and glycemic traits are associated with increased risk of metabolic dysfunction-associated steatotic liver disease (MASLD). However, few studies have explored the underlying pathway, such as the role of iron homeostasis. Methods: We used a two-step MR approach to investigate the associations of genetic liability to T2D, glycemic traits, iron biomarkers, and liver diseases. We analyzed summary statistics from various genome-wide association studies of T2D (n = 933,970), glycemic traits (n ≤ 209,605), iron biomarkers (n ≤ 246,139), MASLD (n ≤ 972,707), and related biomarkers (alanine aminotransferase (ALT) and proton density fat fraction (PDFF)). Our primary analysis was based on inverse-variance weighting, followed by several sensitivity analyses. We also conducted mediation analyses and explored the role of liver iron in post hoc analysis. Results: Genetic liability to T2D and elevated fasting insulin (FI) likely increased risk of liver steatosis (ORliability to T2D: 1.14 per doubling in the prevalence, 95% CI: 1.10, 1.19; ORFI: 3.31 per log pmol/l, 95% CI: 1.92, 5.72) and related biomarkers. Liability to T2D also likely increased the risk of developing liver cirrhosis. Genetically elevated ferritin, serum iron, and liver iron were associated with higher risk of liver steatosis (ORferritin: 1.25 per SD, 95% CI 1.07, 1.46; ORliver iron: 1.15 per SD, 95% CI: 1.05, 1.26) and liver cirrhosis (ORserum iron: 1.31, 95% CI: 1.06, 1.63; ORliver iron: 1.34, 95% CI: 1.07, 1.68). Ferritin partially mediated the association between FI and liver steatosis (proportion mediated: 7%, 95% CI: 2–12%). Conclusions: Our study provides credible evidence on the causal role of T2D and elevated insulin in liver steatosis and cirrhosis risk and indicates ferritin may play a mediating role in this association. Highlights: • Ferritin possibly mediates the association of insulin resistance in liver steatosis. Targeting the reduction of ferritin may mitigate the risk of liver steatosis arising from elevated insulin. • Liver iron is likely to be positively associated with liver steatosis and the irreversible stage, liver cirrhosis, and mediates the association of ferritin and liver steatosis. • Genetically elevated HbA1c is shown to decrease the risk of liver steatosis due to its erythrocytic property. Caution should be applied when using HbA1c values for MASLD management. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: With increasing hypercholesterolemia prevalence in East Asian adolescents, pharmacologic interventions (e.g., HMGCR inhibitors (statins) and PCSK9 inhibitors) may have to be considered although their longer-term safety in the general adolescent population is unclear. This study aims to investigate the longer-term safety of HMGCR inhibitors and PCSK9 inhibitors among East Asian adolescents using genetics. Methods: A drug-target Mendelian randomization study leveraging the Global Lipid Genetics Consortium (East Asian, n = 146,492) and individual-level data from Chinese participants in the Biobank clinical follow-up of Hong Kong's "Children of 1997" birth cohort (n = 3443, aged ~ 17.6 years). Safety outcomes (n = 100) included anthropometric and hematological traits, renal, liver, lung function, and other nuclear magnetic resonance metabolomics. Positive control outcomes were cholesterol markers from the "Children of 1997" birth cohort and coronary artery disease from Biobank Japan. Results: Genetic inhibition of HMGCR and PCSK9 were associated with reduction in cholesterol-related NMR metabolomics, e.g., apolipoprotein B (HMGCR: beta [95% CI], − 1.06 [− 1.52 to − 0.60]; PCSK9: − 0.93 [− 1.56 to − 0.31]) and had the expected effect on the positive control outcomes. After correcting for multiple comparisons (p-value < 0.006), genetic inhibition of HMGCR was associated with lower linoleic acid − 0.79 [− 1.25 to − 0.35]. Genetic inhibition of PCSK9 was not associated with the safety outcomes assessed. Conclusions: Statins and PCSK9 inhibitors in East Asian adolescents appeared to be safe based on the outcomes concerned. Larger studies were warranted to verify these findings. This study serves as a proof of principle study to inform the medication safety among adolescents via genetics. [ABSTRACT FROM AUTHOR]

Background Rapid growth is related to adverse respiratory outcomes although possibly confounded or limited by growth modelling methods. We investigated the association of infant and pubertal growth with lung function, wheezing and asthma in a non-Western setting. Methods In Hong Kong's 'Children of 1997' Chinese birth cohort (n  = 8327), weight during infancy and weight, height and body mass index (BMI) during puberty were modelled using a super-imposition by translation and rotation model to identify (larger or smaller) size, (earlier or later) tempo and (slower or faster) velocity. Sex-specific associations with forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), FEV1/FVC (Global Lung function Initiative z-score) and self-reported wheezing and asthma at ∼17.5 years were assessed. Results For each fraction higher than average weight growth velocity during infancy, FVC was higher in boys (0.90 SD, 95% CI 0.35; 1.44) and girls (0.77 SD, 95% CI 0.24; 1.30), FEV1/FVC was lower (–0.74 SD, 95% CI –1.38; –0.10) and wheezing was higher (odds ratio 6.92, 95% CI 1.60; 29.99) in boys and an inverse association with FVC was observed for tempo but not for size. Associations for weight growth velocity in puberty were similar but weaker. Greater size and higher velocity of BMI growth was associated with higher FVC, lower FEV1/FVC and higher asthma and wheezing risk. Conclusion Accelerated infant and pubertal weight growth were associated with disproportionate lung size and airway growth, and higher risk of asthma; optimizing early-life growth patterns could be important. [ABSTRACT FROM AUTHOR]

Objectives: Adiposity, smoking, and lower socioeconomic position (SEP) increase COVID‐19 risk while the association of vitamin D, blood pressure, and glycemic traits in COVID‐19 risk were less clear. Whether angiotensin‐converting enzyme 2 (ACE2), the key receptor for SARS‐CoV‐2, mediates these associations has not been investigated. We conducted a Mendelian randomization study to assess the role of these exposures in COVID‐19 and mediation by ACE2. Methods: We extracted genetic variants strongly related to various exposures (vitamin D, blood pressure, glycemic traits, smoking, adiposity, and educational attainment [SEP proxy]), and ACE2 cis‐variants from genome‐wide association studies (GWAS, n ranged from 28 204 to 3 037 499) and applied them to GWAS summary statistics of ACE2 (n = 28 204) and COVID‐19 (severe, hospitalized, and susceptibility, n ≤ 2 942 817). We used inverse variance weighted as the main analyses, with MR‐Egger and weighted median as sensitivity analyses. Mediation analyses were performed based on product of coefficient method. Results: Higher adiposity, lifetime smoking index, and lower educational attainment were consistently associated with higher risk of COVID‐19 phenotypes while there was no strong evidence for an association of other exposures in COVID‐19 risk. ACE2 partially mediates the detrimental effects of body mass index (ranged from 4.3% to 8.2%), waist‐to‐hip ratio (ranged from 11.2% to 16.8%), and lower educational attainment (ranged from 4.0% to 7.5%) in COVID‐19 phenotypes while ACE2 did not mediate the detrimental effect of smoking. Conclusions: We provided genetic evidence that reducing ACE2 could partly lower COVID‐19 risk amongst people who were overweight/obese or of lower SEP. [ABSTRACT FROM AUTHOR]

Background and Aims: Smoking increases the risk of severe COVID‐19, but whether lung function or chronic obstructive pulmonary disease (COPD) mediate the underlying associations is unclear. We conducted the largest Mendelian randomization study to date, to our knowledge, to address these questions. Design Mendelian randomization study using summary statistics from genome‐wide association studies (GWAS), FinnGen and UK Biobank. The main analysis was the inverse variance weighted method, and we included a range of sensitivity analyses to assess the robustness of the findings. Setting: GWAS which included international consortia, FinnGen and UK Biobank. Participants: The sample size ranged from 193 638 to 2 586 691. Measurements Genetic determinants of life‐time smoking index, lung function [e.g. forced expiratory volume in 1 sec (FEV1)], chronic obstructive pulmonary disease (COPD) and different severities of COID‐19. Results: Smoking increased the risk of COVID‐19 compared with population controls for overall COVID‐19 [odds ratio (OR) = 1.19 per standard deviation (SD) of life‐time smoking index, 95% confidence interval (CI) = 1.11–1.27], hospitalized COVID‐19 (OR = 1.67, 95% CI = 1.42–1.97) or severe COVID‐19 (OR = 1.48, 95% CI = 1.10–1.98), with directionally consistent effects from sensitivity analyses. Lung function and COPD liability did not appear to mediate these associations. Conclusion: There is genetic evidence that smoking probably increases the risk of severe COVID‐19 and possibly also milder forms of COVID‐19. Decreased lung function and increased risk of chronic obstructive pulmonary disease do not seem to mediate the effect of smoking on COVID‐19 risk. [ABSTRACT FROM AUTHOR]

Background: Observationally, poorer maternal respiratory health is associated with poorer birth outcomes, possibly confounded by socioeconomic position and other maternal attributes. We used multivariable Mendelian randomization (MR) to obtain unconfounded estimates of effect of maternal lung function on birthweight, independent of maternal height.Methods: Single nucleotide polymorphisms (SNPs) for forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) in women were obtained from publicly available summary statistics from the UK Biobank. SNPs for asthma were obtained from the Trans-National Asthma Genetic consortium. SNPs for height in women were obtained from the Genetic Investigation of Anthropometric Traits consortium and the genetic estimates were obtained the UK Biobank. The genetic associations with maternally-driven birthweight were obtained from the Early Growth Genetics consortium. Multivariable MR estimates were obtained using inverse variance weighting with multivariable MR-Egger as sensitivity analysis.Results: Maternal lung capacity, as indicated by FVC, was positively associated with maternally-driven birthweight (0.08 per standard deviation, 95% confidence interval 0.01 to 0.15) independent of maternal height, whereas no clear such associations were shown for maternal airway function, indicated by FEV1 and peak expiratory flow, or for asthma, on maternally-driven birthweight. Similar findings were shown using MR-Egger.Conclusions: These findings suggest that maternal lung function, especially lung capacity independent of maternal height, is directly associated with maternally-driven birthweight, and highlights the importance of maternal respiratory health in fetal growth. [ABSTRACT FROM AUTHOR]

We aimed to determine if prematurity and lower birth weight are associated with poorer lung function in a non-western developed setting with less marked confounding by socioeconomic position. Using multivariable linear regression in Hong Kong's "Children of 1997" birth cohort, adjusted associations of prematurity and birth weight with forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and forced expiratory flow at 25–75% of the pulmonary volume (FEF25–75%) at ~17.5 years were assessed. Associations for birth weight were stronger in boys for FEV1 (boys: 0.31 L, 95% confidence interval (CI) 0.24 to 0.38, girls: 0.18 L, 95% CI 0.12 to 0.25), FVC (boys: 0.36 L, 95% CI 0.27 to 0.44, girls: 0.22 L, 95% CI 0.15 to 0.28) and FEF25–75% (boys: 0.35 L, 95% CI 0.21 to 0.49, girls: 0.22 L, 95% CI 0.09 to 0.34) adjusted for age, socioeconomic position and infant and maternal characteristics. Similarly adjusted, preterm birth (compared to full-term birth) was associated with lower FEV1/FVC and FEF25–75%. Thus, associations of lower birth weight, especially in boys, and prematurity with poorer lung function at 17.5 years were found. Identifying underlying mechanism might contribute to the improvement of pulmonary health and the prevention of adult respiratory illness. [ABSTRACT FROM AUTHOR]

Background: Lower birth weight is associated with diabetes although the underlying mechanisms are unclear. Muscle mass could be a modifiable link and hence a target of intervention. We assessed the associations of birth weight with muscle and fat mass observationally in a population with little socio-economic patterning of birth weight and using Mendelian randomization (MR) for validation. Methods: In the population-representative “Children of 1997” birth cohort (n = 8,327), we used multivariable linear regression to assess the adjusted associations of birth weight (kg) with muscle mass (kg) and body fat (%) at ~17.5 years. Genetically predicted birth weight (effect size) was applied to summary genetic associations with fat-free mass and fat mass (kg) from the UK Biobank (n = ~331,000) to obtain unconfounded estimates using inverse-variance weighting. Results: Observationally, birth weight was positively associated with muscle mass (3.29 kg per kg birth weight, 95% confidence interval (CI) 2.83 to 3.75) and body fat (1.09% per kg birth weight, 95% CI 0.54 to 1.65). Stronger associations with muscle mass were observed in boys than in girls (p for interaction 0.004). Using MR, birth weight was positively associated with fat-free mass (0.77 kg per birth weight z-score, 95% CI 0.22 to 1.33) and fat mass (0.58, 95% CI 0.01 to 1.15). No difference by sex was evident. Conclusion: Higher birth weight increasing muscle mass may be relevant to lower birth weight increasing the risk of diabetes and suggests post-natal muscle mass as a potential target of intervention. [ABSTRACT FROM AUTHOR]

Background: Information on the relationship between sleep duration and obesity among children in urban Guangzhou, China is limited. This study aims to examine the relationship between sleep duration and obesity in children aged 6-18 years.Methods: The sample consisted of 11,830 children aged 6-18 years. The children were randomly selected from 13 schools in three urban districts of Guangzhou. The study was conducted from September to November 2013. The height and weight of the children were measured. Adiposity status was estimated using body mass index and according to the cut point in China criteria. In the structured questionnaire, children reported daily sleep hours (less than 7 h, 7-9 h and more than 9 h), weekly food intake amount (including vegetables, fruit, sugar beverages and meat), physical activity and sedentary time. A caretaker would answer the questionnaire on behalf of a child aged below nine.Results: A total of 8,760 children (49.0 % boys) completed the study. The prevalence of obesity was 8.4 % (9.8 % in boys and 5.7 % in girls). Adjusted for age, diet and physical activity/sedentary behaviour, the odds ratio (OR) for obesity comparing sleeping <7 h (short sleep duration, SSD) with ≥9 h (long sleep duration, LSD) was 0.70 (95 % CI: 0.69-0.72) among boys and 1.73 (95 % CI: 1.71-1.74) among girls. Stratified by age, OR for boys aged 6-12 years comparing SSD with LSD was 0.60 (95 % CI: 0.55-0.66); by contrast, OR was 1.33 (95 % CI: 1.30-1.37) for boys aged 13-18 years.Conclusion: Short sleep duration is associated with increased chances of obesity among girls and 13- to 18-year-old boys, but the chances of obesity are decreased among 6- to 12-year-old boys. Age and gender should be regarded as specific characteristics for the effects of short sleep on obesity. [ABSTRACT FROM AUTHOR]

Background: Information on the association between iron metabolism and dyslipidaemia in children is limited. Thus, this study aims to evaluate the iron metabolic status of children with different body mass index (BMI) and to examine the association between iron metabolism and dyslipidaemia risk. Method: In total, 1866 children and adolescents aged 7–18 were enrolled in this study, including 912 boys and 954 girls. In this cross-sectional study, parameters for anthropometry, lipids and iron metabolism including transferrin, soluble transferrin receptor (sTfR), ferritin and serum iron (SF) were evaluated. Data regarding demographic characteristics, diet, and physical activity were collected by self-reported questionnaires. Results: The prevalence of dyslipidaemia and iron deficiency in children and adolescents increased based on BMI categories (both P < 0.05) and were 58.3 and 8.9% in subjects with obesity, respectively. The lowest SF and the highest ferritin levels were observed in subjects who were obese (both P < 0.001). Subjects with dyslipidaemia had lower SF, transferrin and sTfR levels by different BMI categories, and those who were obese had higher ferritin levels (all P < 0.05). Most importantly, higher concentrations of transferrin and sTfR were related to lower dyslipidaemia risk (OR for transferrin: 0.49, 95% CI: 0.33–0.71; OR for sTfR: 0.68, 95% CI: 0.46–0.99). Conclusions: A downward trend in SF level by BMI categories and the highest ferritin level in subjects with obesity suggested that iron storage was associated with BMI in children and adolescents. Moreover, an inverse relationship was observed between transferrin and sTfR concentrations and dyslipidaemia risk in children with different BMI. [ABSTRACT FROM AUTHOR]