Do iron homeostasis biomarkers mediate the associations of liability to type 2 diabetes and glycemic traits in liver steatosis and cirrhosis: a two-step Mendelian randomization study.

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.

Associations of soy product intake with all-cause, cardiovascular disease and cancer mortality: Guangzhou Biobank Cohort Study and updated meta-analyses.

PURPOSE: We examined the associations of soy product intake with all-cause, cardiovascular disease (CVD), and cancer mortality and mediations through CVD risk factors based on the Guangzhou Biobank Cohort Study (GBCS), and conducted updated meta-analyses. METHODS: A total of 29,825 participants aged 50 + years were included. Causes of death were identified through record linkage. Soy product intake was assessed by food frequency questionnaire. Cox proportional hazards regression was used to analyze the associations between soy product intake and mortality, yielding hazard ratios (HRs) and 95% confidence intervals (CIs). Mediation analyses with CVD risk factors as mediators, and updated meta-analyses were conducted. RESULTS: During 454,689 person-years of follow-up, 6899 deaths occurred, including 2694 CVD and 2236 cancer. Participants who consumed soy product of 1-6 portions/week, versus no consumption, had significantly lower risks of all-cause and CVD mortality (adjusted HR (95% CI) 0.91 (0.86, 0.97) and 0.87 (0.79, 0.96), respectively). In participants who consumed soy product of ≥ 7 portions/week, the association of higher intake with lower CVD mortality was modestly mediated by total cholesterol (4.2%, 95% CI 1.0-16.6%). Updated meta-analyses showed that the highest level of soy product intake, versus the lowest, was associated with lower risks of all-cause and CVD mortality (pooled HR (95% CI) 0.92 (0.88, 0.96) and 0.92 (0.87, 0.98), respectively). CONCLUSION: Moderate and high soy product intake were associated with lower risks of all-cause and CVD mortality. Our findings provide support for current dietary guidelines recommending moderate soy product intake, and contribute additional evidence regarding the potential protective effects of high soy product intake.

Assessing the safety of lipid-modifying medications among Chinese adolescents: a drug-target Mendelian randomization study.

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.

Does ACE2 mediate the detrimental effect of exposures related to COVID-19 risk: A Mendelian randomization investigation.

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.

Quantity and Variety in Fruit and Vegetable Consumption and Mortality in Older Chinese: A 15-year Follow-Up of a Prospective Cohort Study.

BACKGROUND: Independent associations of quantity and variety of fruit and vegetables (FVs) with mortality in older people are still unclear. OBJECTIVES: This study aimed to explore the association between the quantity and variety in FV consumption and mortality in older Chinese. METHODS: A total of 19,597 participants of the Guangzhou Biobank Cohort Study aged >50 y were recruited from 2003 to 2006 and followed up until April 2021. The diet was assessed using a 300-item validated FFQ. Variety as a continuous variable was defined as the number of unique FV items (excluding potatoes, legumes, and fruit juices) intake per week over the past week. The associations of quantity and variety of FVs with mortality were analyzed, and analyses by the color of edible parts was performed. Multivariable Cox regression yielded HRs and 95% CIs. RESULTS: During 286,821 person-year of follow-up, 4385 deaths occurred, including 1678 cardiovascular diseases (CVD), 1450 cancer, and 1257 other causes. Compared with the lowest quintile of variety in FV, the highest quintile was associated with lower risks of all-cause (HR: 0.81; 95% CI: 0.73-0.89) and CVD mortality (HR: 0.79; 95% CI 0.67-0.92). A greater variety of green and white FV intake was associated with lower risks of all-cause and CVD morality, and a greater variety of red/purple FV intake was associated with lower risks of all-cause and cancer mortality. However, the quantity of FV intake showed no association with all-cause, CVD, and cancer mortality. CONCLUSION: Our findings have first showed that the variety, rather than quantity, in FV intake was associated with a lower risk of mortality in older Chinese. Dietary guidelines may recommend increasing the variety in FV intake, especially green, red/purple, and white FVs in older people.

Mode of transport, genetic susceptibility, and incidence of coronary heart disease.

BACKGROUND: Car use has been associated with higher risk of coronary heart disease (CHD). However, whether the associations of transport modes with CHD vary by genetic susceptibility to CHD are unknown. This study aims to investigate the associations of genetic susceptibility and modes of transport with incidence of CHD. METHODS: We included 339,588 white British participants from UK Biobank with no history of CHD or stroke at baseline or within two years of follow-up (52.3% in work). Genetic susceptibility to CHD was quantified through weighted polygenic risk scores derived from 300 single-nucleotide polymorphisms related to CHD risk. Categories of transport mode included exclusive car use and alternatives to the car (e.g., walking, cycling and public transport), separately for non-commuting (e.g., getting about [n=339,588] excluding commuting for work), commuting (in the sub-set in work [n=177,370] who responded to the commuting question), and overall transport (transport mode for both commuting and non-commuting [n=177,370]). We used Cox regression with age as the underlying timescale to estimate hazard ratios (HR) of CHD (n=13,730; median 13.8-year follow-up) and tested the interaction between genetic susceptibility and travel modes with adjustment for confounders. RESULTS: Compared to those using alternatives to the car, hazards of CHD were higher for exclusive use of cars for overall transport (HR: 1.16, 95% confidence interval (CI): 1.08-1.25), non-commuting (HR: 1.08, 95% CI: 1.04-1.12) and commuting (HR: 1.16, 95% CI: 1.09-1.23), after adjusting for confounders plus genetic susceptibility. HRs of CHD were 1.45 (95% CI: 1.38-1.52) and 2.04 (95% CI: 1.95-2.12) for the second and third tertile of genetic susceptibility to CHD, respectively, compared to the first. There was, in general, no strong evidence of interactions between genetic susceptibility and categories of overall, non-commuting and commuting transport. Estimated 10-year absolute risk of CHD was lower for the alternatives to the car across strata of genetic susceptibility, compared with exclusive use of cars for overall, non-commuting and commuting transport. CONCLUSION: Exclusive use of cars was associated with a relatively higher risk of CHD across all strata of genetic susceptibility. Using alternatives to the car should be encouraged for prevention of CHD for the general population including individuals at high genetic risk.

The influence of growth and sex hormones on risk of alzheimer's disease: a mendelian randomization study.

Alzheimer's disease is more prevalent in women, possibly due to sex or growth hormones but existing evidence is inconclusive. We investigated whether genetically predicted sex and growth hormones are associated with risk of Alzheimer's disease. Genetic variants strongly and independently predicting insulin-like growth factor 1 (IGF-1), testosterone and sex hormone-binding globulin (SHBG) were obtained from large, published genome wide associations studies (GWAS) and applied to GWAS of Alzheimer's disease based on clinical diagnosis (cases = 21,982, control = 41,944) from the International Genomics of Alzheimer's Project and the UK Biobank parental (maternal cases = 27,696; paternal cases = 14,338) and siblings' diagnosis (cases = 2,171) as proxy cases. Published GWAS summary statistics were used in our analyses. Estimates were obtained from inverse variance weighting with sensitivity analysis (i.e., MR-Egger, weighted median and MR-PRESSO). Multivariable analyses adjusted for pleiotropic effects and possible sources of selection bias were also performed. Genetically predicted higher total testosterone may reduce the risk of paternal Alzheimer's disease (odds ratio (OR) 0.86, 95% confidence interval (CI) 0.76 to 0.97, per SD increase in testosterone) and in meta-analysis for women (OR 0.92, 95% CI 0.87, 0.98) with directionally similar results from other analyses. SHBG were not associated with Alzheimer's disease. IGF-1 in women was inversely associated with risk of clinical Alzheimer's disease in sensitivity analysis but not in the main analysis. These results suggest genetically predicted higher total testosterone may lower risk of Alzheimer's disease. The role of testosterone and the immune system in Alzheimer's disease could be further investigated.

Breastfeeding and ApoB in late adolescence: a Hong Kong birth cohort study.

Breastfeeding is widely promoted. Experimental evidence concerning long-term benefits is limited. Observational studies are open to bias from confounding by socio-economic position. We assessed the association of breastfeeding with late adolescent lipid sub-fractions, particularly apolipoprotein B (ApoB) and non-high-density lipoprotein cholesterol (non-HDL-c), overall and by sex. We took advantage of a setting where breastfeeding has little association with higher socio-economic position and where several results from randomized controlled trials of breastfeeding promotion have been replicated. We used the population-representative "Children of 1997" birth cohort comprising 88% of births in Hong Kong in April and May 1997. Associations of breastfeeding in the first 3 months of life (never, mixed, exclusive) with lipid sub-fractions were obtained using linear regression adjusted for potential confounders including parental socio-economic position, maternal place of birth, type of delivery, gestational age, and birth weight. Differences by sex were assessed. Multiple imputation and inverse probability weighting were used to recover the original sample. Of the 3462 participants included, mean age was 17.6 years and 48.8% were girls. Mean ApoB was 0.74 g/L (standard deviation 0.15). Exclusive versus never breastfeeding was associated with lower ApoB (-0.027 g/L, 95% confidence interval (CI)-0.046 to-0.007, p = 0.007) and lower non-HDL-c (-0.143 mmol/L, 95% CI-0.237 to-0.048) with similar estimates by sex. CONCLUSION: Breastfeeding may provide some population-level lifelong protection against cardiovascular disease. This study supports policies promoting breastfeeding as a modifiable exposure that contributes to a healthy start in life as an investment for lifelong cardiovascular disease prevention. WHAT IS KNOWN: • Apolipoprotein B (ApoB) is a recognized risk factor for cardiovascular disease, but whether breastfeeding affects ApoB in later life overall and by sex is unknown. WHAT IS NEW: • Exclusive breastfeeding in the first 3 months of life was associated with lower ApoB in late adolescence, with similar estimates for both sexes. • The inverse association of breastfeeding with ApoB suggests that breastfeeding could reduce cardiovascular disease and overall mortality over the lifespan.

Evaluating the efficacy and mechanism of metformin targets on reducing Alzheimer's disease risk in the general population: a Mendelian randomisation study.

AIMS/HYPOTHESIS: Metformin use has been associated with reduced incidence of dementia in diabetic individuals in observational studies. However, the causality between the two in the general population is unclear. This study uses Mendelian randomisation (MR) to investigate the causal effect of metformin targets on Alzheimer's disease and potential causal mechanisms in the brain linking the two. METHODS: Genetic proxies for the effects of metformin drug targets were identified as variants in the gene for the corresponding target that associated with HbA1c level (N=344,182) and expression level of the corresponding gene (N≤31,684). The cognitive outcomes were derived from genome-wide association studies comprising 527,138 middle-aged Europeans, including 71,880 with Alzheimer's disease or Alzheimer's disease-by-proxy. MR estimates representing lifelong metformin use on Alzheimer's disease and cognitive function in the general population were generated. Effect of expression level of 22 metformin-related genes in brain cortex (N=6601 donors) on Alzheimer's disease was further estimated. RESULTS: Genetically proxied metformin use, equivalent to a 6.75 mmol/mol (1.09%) reduction on HbA1c, was associated with 4% lower odds of Alzheimer's disease (OR 0.96 [95% CI 0.95, 0.98], p=1.06×10-4) in non-diabetic individuals. One metformin target, mitochondrial complex 1 (MCI), showed a robust effect on Alzheimer's disease (OR 0.88, p=4.73×10-4) that was independent of AMP-activated protein kinase. MR of expression in brain cortex tissue showed that decreased MCI-related gene (NDUFA2) expression was associated with lower Alzheimer's disease risk (OR 0.95, p=4.64×10-4) and favourable cognitive function. CONCLUSIONS/INTERPRETATION: Metformin use may cause reduced Alzheimer's disease risk in the general population. Mitochondrial function and the NDUFA2 gene are plausible mechanisms of action in dementia protection.

Impact of lung function on cardiovascular diseases and cardiovascular risk factors: a two sample bidirectional Mendelian randomisation study.

INTRODUCTION: Observational 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. METHODS: We 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. RESULTS: FEV1 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. CONCLUSION: Higher lung function likely protect against CAD and stroke.

Assessing the linear and non-linear association of HbA1c with cardiovascular disease: a Mendelian randomisation study.

AIMS/HYPOTHESIS: We aimed to evaluate whether genetically predicted HbA1c has an effect on the risk of cardiovascular diseases and investigate the shape of the relationship of genetically predicted HbA1c with cardiovascular diseases. METHODS: We performed linear univariable, multivariable and non-linear Mendelian randomisation analyses in 373,571 white British participants (mean age 56.9) from the UK Biobank. RESULTS: In univariable linear Mendelian randomisation analysis, a 1 mmol/mol increase in genetically predicted HbA1c was associated with higher risk of coronary artery disease (OR 1.03, 95% CI 1.02, 1.05), stroke (OR 1.02, 95% CI 1.00, 1.05) and hypertension (OR 1.02, 95% CI 1.01, 1.03). Multivariable Mendelian randomisation adjusted for the effect of haemoglobin gave a consistent conclusion for coronary artery disease. The associations with stroke and hypertension were directionally similar but with wider CI overlapping the null. Non-linear Mendelian randomisation indicated that the shape of the effect of genetically predicted HbA1c on cardiovascular outcomes was likely linear. CONCLUSIONS/INTERPRETATION: The study suggests a detrimental effect of HbA1c on coronary artery disease in both men and women, and the effect is via a glycaemic characteristic. The shape of the genetic association of HbA1c with these cardiovascular outcomes, in particular coronary artery disease, is likely to be linear.

Mendelian Randomization Focused Analysis of Vitamin D on the Secondary Prevention of Ischemic Stroke.

BACKGROUND AND PURPOSE: Experimental studies showed vitamin D (Vit-D) could promote vascular regeneration and repair. Prior randomized studies had focused mainly on primary prevention. Whether Vit-D protects against ischemic stroke and myocardial infarction recurrence among subjects with prior ischemic insults was unknown. Here, we dissected through Mendelian randomization any effect of Vit-D on the secondary prevention of recurrent ischemic stroke and myocardial infarction. METHODS: Based on a genetic risk score for Vit-D constructed from a derivation cohort sample (n=5331, 45% Vit-D deficient, 89% genotyped) via high-throughput exome-chip screening of 12 prior genome-wide association study-identified genetic variants of Vit-D mechanistic pathways (rs2060793, rs4588, and rs7041; F statistic, 73; P<0.001), we performed a focused analysis on prospective recurrence of myocardial infarction (MI) and ischemic stroke in an independent subsample with established ischemic disease (n=441, all with prior first ischemic event; follow-up duration, 41.6±14.3 years) under a 2-sample, individual-data, prospective Mendelian randomization approach. RESULTS: In the ischemic disease subsample, 11.1% (n=49/441) had developed recurrent ischemic stroke or MI and 13.3% (n=58/441) had developed recurrent or de novo ischemic stroke/MI. Kaplan-Meier analyses showed that genetic risk score predicted improved event-free survival from recurrent ischemic stroke or MI (log-rank, 13.0; P=0.001). Cox regression revealed that genetic risk score independently predicted reduced risk of recurrent ischemic stroke or MI combined (hazards ratio, 0.62 [95% CI, 0.48-0.81]; P<0.001), after adjusted for potential confounders. Mendelian randomization supported that Vit-D is causally protective against the primary end points of recurrent ischemic stroke or MI (Wald estimate: odds ratio, 0.55 [95% CI, 0.35-0.81]) and any recurrent or de novo ischemic stroke/MI (odds ratio, 0.64 [95% CI, 0.42-0.91]) and recurrent MI alone (odds ratio, 0.52 [95% CI, 0.30-0.81]). CONCLUSIONS: Genetically predicted lowering in Vit-D level is causal for the recurrence of ischemic vascular events in persons with prior ischemic stroke or MI.

Evaluation of glycemic traits in susceptibility to COVID-19 risk: a Mendelian randomization study.

BACKGROUND: Observational studies suggest poorer glycemic traits and type 2 diabetes associated with coronavirus disease 2019 (COVID-19) risk although these findings could be confounded by socioeconomic position. We conducted a two-sample Mendelian randomization to clarify their role in COVID-19 risk and specific COVID-19 phenotypes (hospitalized and severe cases). METHOD: We identified genetic instruments for fasting glucose (n = 133,010), 2 h glucose (n = 42,854), glycated hemoglobin (n = 123,665), and type 2 diabetes (74,124 cases and 824,006 controls) from genome wide association studies and applied them to COVID-19 Host Genetics Initiative summary statistics (17,965 COVID-19 cases and 1,370,547 population controls). We used inverse variance weighting to obtain the causal estimates of glycemic traits and genetic predisposition to type 2 diabetes in COVID-19 risk. Sensitivity analyses included MR-Egger and weighted median method. RESULTS: We found genetic predisposition to type 2 diabetes was not associated with any COVID-19 phenotype (OR: 1.00 per unit increase in log odds of having diabetes, 95%CI 0.97 to 1.04 for overall COVID-19; OR: 1.02, 95%CI 0.95 to 1.09 for hospitalized COVID-19; and OR: 1.00, 95%CI 0.93 to 1.08 for severe COVID-19). There were no strong evidence for an association of glycemic traits in COVID-19 phenotypes, apart from a potential inverse association for fasting glucose albeit with wide confidence interval. CONCLUSION: We provide some genetic evidence that poorer glycemic traits and predisposition to type 2 diabetes unlikely increase the risk of COVID-19. Although our study did not indicate glycemic traits increase severity of COVID-19, additional studies are needed to verify our findings.

Amyloid, tau and risk of Alzheimer's disease: a Mendelian randomization study.

This study was carried out to assess the effect of amyloid and tau on Alzheimer's disease using two-sample Mendelian randomization design. Genetic associations with plasma amyloid species (amyloid precursor protein, amyloid-like protein 2, serum amyloid P-component, amyloid beta peptide), cerebrospinal fluid (CSF) amyloid beta, total tau, and phosphorylated tau181 were extracted from the largest genome-wide association study (GWAS) available. Genetic associations with Alzheimer's disease were obtained from a GWAS of proxy-cases based on family history of Alzheimer's disease with 314,278 participants from the UK Biobank and a GWAS with clinically diagnosed Alzheimer's disease from the International Genomics of Alzheimer's Project (IGAP) with 21,982 cases and 41,944 controls. Estimates were obtained using inverse variance weighting with sensitivity analyses including MR-Egger, weighted median and MR-PRESSO. Presence of bias due to selective survival and competing risk was also considered. Plasma amyloid species, CSF total tau and phosphorylated tau181 were not associated with Alzheimer's disease. For CSF Aß42, no association was found using the proxy-cases but an inverse association was found after removing outliers with MR-PRESSO using IGAP. Higher genetically predicted (p < 1 × 10-5) plasma amyloid species, CSF total tau and phosphorylated tau181 (based on sample sizes ~ 3300) were not associated with Alzheimer's disease using family history or clinically diagnosed cases while effects of CSF Aß42 were inconsistent between the family history and IGAP GWAS.

Evaluating the impact of AMPK activation, a target of metformin, on risk of cardiovascular diseases and cancer in the UK Biobank: a Mendelian randomisation study.

AIMS/HYPOTHESIS: Whether metformin reduces cardiovascular or cancer risk is unclear owing to concerns over immortal time bias and confounding in observational studies. This study evaluated the effect of AMP-activated protein kinase (AMPK), the target of metformin, on risk of cardiovascular disease and cancer. METHODS: This is a Mendelian randomisation design, using AMPK, the pharmacological target of metformin, to infer the AMPK pathway-dependent effects of metformin on risk of cardiovascular disease and cancer in participants of white British ancestry in the UK Biobank. RESULTS: A total of 391,199 participants were included (mean age 56.9 years; 54.1% women), including 26,690 cases of type 2 diabetes, 38,098 cases of coronary artery disease and 80,941 cases of overall cancer. Genetically predicted reduction in HbA1c (%) instrumented by AMPK variants was associated with a 61% reduction in risk of type 2 diabetes (OR 0.39; 95% CI 0.20, 0.78; p = 7.69 × 10-3), a 53% decrease in the risk of coronary artery disease (OR 0.47; 95% CI 0.26, 0.84; p = 0.01) and a 44% decrease in the risk of overall cancer (OR 0.56; 95% CI 0.36, 0.85; p = 7.23 × 10-3). Results were similar using median or quartiles of AMPK score, with dose-response effects (p for trend = 4.18 × 10-3 for type 2 diabetes, 4.37 × 10-3 for coronary artery disease and 4.04 × 10-3 for overall cancer). CONCLUSIONS/INTERPRETATION: This study provides some genetic evidence that AMPK activation by metformin may protect against cardiovascular disease and cancer, which needs to be confirmed by randomised controlled trials.

Association between prenatal depressive symptoms and eczema in infants: The Born in Guangzhou Cohort Study.

BACKGROUND: Eczema is a growing threat on infants' health, and the role of maternal depression in the risk of eczema's early onset is unclear. This study aimed to examine the associations of different exposure timing of prenatal depressive symptoms with offspring's eczema in infancy. METHODS: The study was part of the ongoing prospective Born in Guangzhou Cohort Study. Maternal depressive symptoms were assessed at both early (<20th week of gestation) and late pregnancy (≥33rd week of gestation to delivery) using the Self-Rating Depression Scale. Information on the diagnosis of eczema was collected when the children were 1 year old. Multivariable logistic regression was used to examine the association between prenatal depressive symptoms and infants' eczema and test for moderation by parental history of allergic diseases. RESULTS: In this population, 7.7% (447/5825) of mothers experienced persistent depressive symptoms during pregnancy, 10.1% (590/5825) had depressive symptoms only at early pregnancy, and 8.4% (489/5825) of women experienced depressive symptoms only at late pregnancy. After adjusting for potential confounders, higher risks of eczema were observed in infants of mothers with persistent prenatal depressive symptoms when compared to those children without maternal depressive symptoms throughout pregnancy (OR: 1.55, 95% CI 1.19-2.03). These associations were marginally more pronounced among children in families without parents affected by allergic diseases than in other families (P for interaction = .064 for courses of prenatal depressive symptoms). CONCLUSION: Persistent maternal depressive symptoms during pregnancy increased the risk of infants' eczema, especially in children without family history of allergic diseases. These associations, if proved to be causal, could be an intervention target not only to improve women's health but also to prevent offspring's eczema.

The impact of GDF-15, a biomarker for metformin, on the risk of coronary artery disease, breast and colorectal cancer, and type 2 diabetes and metabolic traits: a Mendelian randomisation study.

AIMS/HYPOTHESIS: Growth differentiation factor 15 (GDF-15), a suggested biomarker for metformin use, may explain the potential cardioprotective and anti-cancer properties of metformin. We conducted a Mendelian randomisation study to examine the role of GDF-15 in risk of coronary artery disease (CAD) and breast and colorectal cancer. Secondary analyses included examination of the association of GDF-15 with type 2 diabetes, glycaemic traits, BP, lipids and BMI. METHODS: We obtained SNPs strongly (p value <5 × 10-8) predicting GDF-15 from a genome-wide association study (GWAS) (n = 5440) and applied them to genetic studies of CAD (CARDIoGRAMplusC4D 1000 Genomes-based GWAS [n = 184,305]), type 2 diabetes (DIAGRAM [DIAbetes Genetics Replication And Meta-analysis; n = 898,130]), glycaemic traits (MAGIC [the Meta-Analyses of Glucose and Insulin-related traits Consortium; HbA1c: n = 123,665; fasting glucose: n = 46,186]), BP, breast cancer and colorectal cancer (UK Biobank [n ≤ 401,447]), lipids (GLGC [Global Lipids Genetic Consortium; n ≤ 92,820]) and adiposity (GIANT [Genetic Investigation of ANthropometric Traits Consortium; n = 681,275]). Causal estimates were obtained using inverse variance weighting, taking into account correlations between SNPs. Sensitivity analyses included focusing on the lead SNP (rs888663) and validation for CAD in the UK Biobank and for breast cancer in the Breast Cancer Association Consortium. RESULTS: Using 5 SNPs, increased GDF-15 was associated with lower CAD (OR 0.93 per SD increase, 95% CI 0.87, 0.99) and breast cancer (OR 0.89 per SD increase, 95% CI 0.82, 0.96), with similar results from lead SNP analysis. However, the associations with CAD (OR 0.99 per SD increase, 95% CI 0.93, 1.04) and breast cancer (OR 0.97 per SD increase, 95% CI 0.94, 1.01) in the validation studies were not as apparent. GDF-15 was not associated with type 2 diabetes, glycaemic traits, CAD risk factors or colorectal cancer. CONCLUSIONS/INTERPRETATION: There is no convincing evidence that GDF-15 reduces risk of CAD or breast or colorectal cancer. Whether the observed inverse association of metformin use with cancer risk is via other unexplored mechanistic pathways warrants further investigation.

Lean mass, grip strength and risk of type 2 diabetes: a bi-directional Mendelian randomisation study.

AIMS/HYPOTHESIS: Muscle mass and strength may protect against type 2 diabetes as a sink for glucose disposal. In randomised controlled trials, resistance training improves glucose metabolism in people with the metabolic syndrome. Whether increasing muscle mass and strength protects against diabetes in the general population is unknown. We assessed the effect of markers of muscle mass and strength on diabetes and glycaemic traits using bi-directional Mendelian randomisation. METHODS: Inverse variance weighting estimates were obtained by applying genetic variants that predict male lean mass, female lean mass and grip strength, obtained from the UK Biobank GWAS, to the largest available case-control study of diabetes (DIAbetes Genetics Replication And Meta-analysis [DIAGRAM]; n = 74,124 cases and 824,006 controls) and to a study of glycaemic traits (Meta-Analyses of Glucose and Insulin-related traits Consortium [MAGIC]). Conversely, we also applied genetic variants that predict diabetes, HbA1c, fasting glucose, fasting insulin and HOMA-B to UK Biobank summary statistics for genetic association with lean mass and grip strength. As sensitivity analyses we used weighted median, Mendelian randomisation (MR)-Egger and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) and removed pleiotropic SNPs. RESULTS: Grip strength was not significantly associated with diabetes using inverse variance weighting (OR 0.72 per SD increase in grip strength, 95% CI 0.51, 1.01, p = 0.06) and including pleiotropic SNPs but was significantly associated with diabetes using MR-PRESSO (OR 0.77, 95% CI 0.62, 0.95, p = 0.02) after removing pleiotropic SNPs. Female lean mass was significantly associated with diabetes (OR 0.91, 95% CI 0.84, 0.99, p = 0.02) while male lean mass was not significant but directionally similar (OR 0.94, 95% CI 0.88, 1.01, p = 0.09). Conversely, diabetes was inversely and significantly associated with male lean mass (ß -0.02 SD change in lean mass, 95% CI -0.04, -0.00, p = 0.04) and grip strength (ß -0.01, 95% CI -0.02, -0.00, p = 0.01). CONCLUSIONS/INTERPRETATION: Increased muscle mass and strength may be related to lower diabetes risk. Diabetes may also be associated with grip strength and lean mass. Muscle strength could warrant further investigation as a possible target of intervention for diabetes prevention.

Sleep duration and risk of diabetes: Observational and Mendelian randomization studies.

Inadequate sleep could contribute to type 2 diabetes, but observational studies are inconsistent and open to biases, particularly from confounding. We used Mendelian randomization (MR) to obtain an unconfounded estimate of the effect of sleep duration on diabetes, fasting glucose (FG) and hemoglobin A1c (HbA1c), and an observation study to assess differences by sex. Using MR, we assessed the effects of genetically instrumented sleep on diabetes, based on 68 single nucleotide polymorphisms (SNPs), applied to the DIAbetes Genetics Replication and meta-analysis case (n = 26,676)-control (n = 132,532) study and on FG and HbA1c, based on 55 SNPs, applied to the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) study of FG (n = 122,743) and HbA1c (n = 123,665). In the population-representative Hong Kong Chinese "Children of 1997" birth cohort we assessed whether associations of sleep duration at ~17.5 years with FG and HbA1c differed by sex. Using inverse variance weighting with multiplicative random effects, sleep duration was not associated with diabetes (odds ratio (OR) 0.85 per hour of sleep, 95% confidence interval (CI) 0.64 to 1.13), FG (-0.032 mmol/l per hour of sleep, 95% CI -0.126 to 0.063) or HbA1c (-0.022% per hour of sleep, 95% CI -0.069 to 0.024). In "Children of 1997", the associations of sleep duration with FG differed by sex (p for interaction 0.05) but not with HbA1c. Overall sleep duration does not appear to be related to diabetes, FG or HbA1c, but the possibility of sex differences merits investigation.

Associations of growth from birth to puberty with glycemic indicators at ~17.5 years: Evidence from Hong Kong's "Children of 1997" birth cohort.

BACKGROUND: From an evolutionary biology perspective, where growth and reproduction trade-off against longevity, we assessed the associations of growth from birth to puberty by phase with later glycemic indicators and any differences by sex. METHODS: In the population-representative Hong Kong Chinese "Children of 1997" birth cohort (n = 8327), the relation of initial size (weight-for-age z score (WAZ) at birth, length/height-for-age z score (LAZ) at 3 months or body-mass-index-for-age z score (BAZ) at 3 months based on the World Health Organization growth standards/references) and growth at different phases (WAZ gains from 0 to 2 and 2 to 8 years, LAZ or BAZ gains from 3 months to 3 years, 3 to 8 years and 8 to 14 years) with fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) at ~17.5 years, was assessed using adjusted partial least squares regression. Additional analyses further considered growth in late and early infancy. RESULTS: This study included 3276 of the cohort participants. Higher WAZ gain from 2 to 8 years, LAZ and BAZ gains from 3 to 8 years were consistently associated with higher FPG, adjusted for maternal and infant characteristics, family history of diabetes and household income. Also, higher BAZ gain from 3 to 8 years was associated with higher HbA1c. These associations did not differ by sex. CONCLUSIONS: Our findings suggest different mechanisms could underlie the pathogenesis of glucose intolerance. Factors that drive specific growth at different phases need to be evaluated to better inform child growth management for long-term health outcomes.