Effect of Relative Protein Intake on Hypertension and Mediating Role of Physical Fitness and Circulating Fatty Acids: A Mendelian Randomization Study.

OBJECTIVE: To investigate the causal effect of protein intake on hypertension and the related mediating pathways. PATIENTS AND METHODS: Using genome-wide association study summary statistics of European ancestry, we applied univariable and multivariable Mendelian randomization to estimate the bidirectional associations of relative protein intake and related metabolomic signatures with hypertension (FinnGen: Ncase=42,857/Ncontrol=162,837; UK Biobank: Ncase=77,723/Ncontrol=330,366) and blood pressure (International Consortium of Blood Pressure: N=757,601) and two-step Mendelian randomization to assess the mediating roles of 40 cardiometabolic factors therein. Mendelian randomization estimates of hypertension from FinnGen and UK Biobank were meta-analyzed without heterogeneity. We performed the study from May 15, 2023, to September 15, 2023. RESULTS: Each 1-SD higher relative protein intake was causally associated with 69% (odds ratio, 0.31; 95% CI, 0.11 to 0.89) lower hypertension risk independent of the effects of other macronutrients, and was the only macronutrient associated with 2.21 (95% CI, 0.52 to 3.91) mm Hg lower pulse pressure, in a unidirectional manner. Higher plant protein-related metabolomic signature (glycine) was associated with lower hypertension risk and pulse pressure, whereas higher animal protein-related metabolomic signatures (leucine, isoleucine, valine, and isovalerylcarnitine [only systolic blood pressure]) were associated with higher hypertension risk, pulse pressure, and systolic blood pressure. The effect of relative protein intake on hypertension was causally mediated by frailty index (mediation proportion, 40.28%), monounsaturated fatty acids (13.81%), saturated fatty acids (11.39%), grip strength (5.34%), standing height (3.99%), and sitting height (3.61%). CONCLUSION: Higher relative protein intake causally reduces the risk of hypertension, partly mediated by physical fitness and circulating fatty acids.

Mendelian randomization evidence for the causal effect of mental well-being on healthy aging.

Mental well-being relates to multitudinous lifestyle behaviours and morbidities and underpins healthy aging. Thus far, causal evidence on whether and in what pattern mental well-being impacts healthy aging and the underlying mediating pathways is unknown. Applying genetic instruments of the well-being spectrum and its four dimensions including life satisfaction, positive affect, neuroticism and depressive symptoms (n = 80,852 to 2,370,390), we performed two-sample Mendelian randomization analyses to estimate the causal effect of mental well-being on the genetically independent phenotype of aging (aging-GIP), a robust and representative aging phenotype, and its components including resilience, self-rated health, healthspan, parental lifespan and longevity (n = 36,745 to 1,012,240). Analyses were adjusted for income, education and occupation. All the data were from the largest available genome-wide association studies in populations of European descent. Better mental well-being spectrum (each one Z-score higher) was causally associated with a higher aging-GIP (ß [95% confidence interval (CI)] in different models ranging from 1.00 [0.82-1.18] to 1.07 [0.91-1.24] standard deviations (s.d.)) independent of socioeconomic indicators. Similar association patterns were seen for resilience (ß [95% CI] ranging from 0.97 [0.82-1.12] to 1.04 [0.91-1.17] s.d.), self-rated health (0.61 [0.43-0.79] to 0.76 [0.59-0.93] points), healthspan (odds ratio [95% CI] ranging from 1.23 [1.02-1.48] to 1.35 [1.11-1.65]) and parental lifespan (1.77 [0.010-3.54] to 2.95 [1.13-4.76] years). Two-step Mendelian randomization mediation analyses identified 33 out of 106 candidates as mediators between the well-being spectrum and the aging-GIP: mainly lifestyles (for example, TV watching and smoking), behaviours (for example, medication use) and diseases (for example, heart failure, attention-deficit hyperactivity disorder, stroke, coronary atherosclerosis and ischaemic heart disease), each exhibiting a mediation proportion of >5%. These findings underscore the importance of mental well-being in promoting healthy aging and inform preventive targets for bridging aging disparities attributable to suboptimal mental health.

Divergent age-associated and metabolism-associated gut microbiome signatures modulate cardiovascular disease risk.

Insight into associations between the gut microbiome with metabolism and aging is crucial for tailoring interventions to promote healthy longevity. In a discovery cohort of 10,207 individuals aged 40-93 years, we used 21 metabolic parameters to classify individuals into five clusters, termed metabolic multimorbidity clusters (MCs), that represent different metabolic subphenotypes. Compared to the cluster classified as metabolically healthy (MC1), clusters classified as 'obesity-related mixed' (MC4) and 'hyperglycemia' (MC5) exhibited an increased 11.1-year cardiovascular disease (CVD) risk by 75% (multivariable-adjusted hazard ratio (HR): 1.75, 95% confidence interval (CI): 1.43-2.14) and by 117% (2.17, 1.72-2.74), respectively. These associations were replicated in a second cohort of 9,061 individuals with a 10.0-year follow-up. Based on analysis of 4,491 shotgun fecal metagenomes from the discovery cohort, we found that gut microbial composition was associated with both MCs and age. Next, using 55 age-specific microbial species to capture biological age, we developed a gut microbial age (MA) metric, which was validated in four external cohorts comprising 4,425 metagenomic samples. Among individuals aged 60 years or older, the increased CVD risk associated with MC4 or MC5, as compared to MC1, MC2 or MC3, was exacerbated in individuals with high MA but diminished in individuals with low MA, independent of age, sex and other lifestyle and dietary factors. This pattern, in which younger MA appears to counteract the CVD risk attributable to metabolic dysfunction, implies a modulating role of MA in cardiovascular health for metabolically unhealthy older people.

Association between triglyceride glucose index and breast cancer in 142,184 Chinese adults: findings from the REACTION study.

Background: The triglyceride glucose (TyG) index has been associated with an increased risk in breast cancer. However, this association remains unclear among the Chinese population. This study aimed to investigate whether the TyG index is associated with the risk of prevalent breast cancer in Chinese women. Methods: This cross-sectional study included 142,184 women from the REACTION (Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal) Study, which recruited adults aged 40 years or older from 25 centers across mainland China between 2011 and 2012. The TyG index was calculated according to the formula: Ln (fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2). Multivariable-adjusted logistic regression models were used to evaluate odds ratios (ORs) and 95% confidence intervals (CIs) regarding the associations between the TyG index and breast cancer. Results: Multivariable-adjusted logistic regression analysis showed that compared with the lowest quartile of the TyG index, the highest quartile of the TyG index was significantly associated with an increased risk of prevalent breast cancer, with an OR (95% CI) of 1.61 (1.19-2.17). In the stratified analysis, the association of each 1 SD increase in the TyG index with risk of prevalent breast cancer was more dominant in individuals with menarche at age 13-17, those who were postmenopausal, those with a history of breastfeeding, and those who had two to four children, with the ORs (95% CIs) of 1.35 (1.09-1.68), 1.27 (1.05-1.54), 1.26 (1.05-1.52), and 1.32 (1.08-1.62), respectively. Moreover, among those without discernible insulin resistance (homeostatic model assessment-insulin resistance [HOMA-IR] ≥2.5), hyperglycemia and dyslipidemia, each 1 SD increase in the TyG index was associated with a 1.36-fold increase in breast cancer risk, with an OR (95% CI) of 2.36 (1.44-3.87). Conclusion: The TyG index is significantly associated with the prevalent breast cancer risk among middle-aged and elderly Chinese women.

Association of circulating long-chain free fatty acids and incident diabetes risk among normoglycemic Chinese adults: a prospective nested case-control study.

BACKGROUND: Long-chain free fatty acids (FFAs) are associated with risk of incident diabetes. However, a comprehensive assessment of the associations in normoglycemic populations is lacking. OBJECTIVES: Our study aimed to comprehensively investigate the prospective associations and patterns of FFA profiles with diabetes risk among normoglycemic Chinese adults. METHODS: This is a prospective nested case-control study from the China Cardiometabolic Disease and Cancer Cohort (4C) study. We quantitatively measured 53 serum FFAs using a targeted metabolomics approach in 1707 incident diabetes subjects and 1707 propensity score-matched normoglycemic controls. Conditional logistic regression models were employed to estimate odds ratios (ORs) for associations. Least Absolute Shrinkage and Selection Operator (LASSO) penalty regression and quantile g-computation (qg-comp) analyses were implemented to estimate the association between multi-FFA exposures and incident diabetes. RESULTS: The majority of odd-chain FFAs exhibited an inverse association with incident diabetes, wherein the ORs per SD increment of all 7 saturated fatty acids (SFAs), monounsaturated fatty acid (MUFA) 15:1, and polyunsaturated fatty acid (PUFA) 25:2 were ranging from 0.79 to 0.88 (95% CIs ranging between 0.71 and 0.97). Even-chain FFAs comprised 99.3% of total FFAs and displayed heterogeneity with incident diabetes. SFAs with 18-26 carbon atoms are inversely linked to incident diabetes, with ORs ranging from 0.81 to 0.86 (95% CIs ranging between 0.73 and 0.94). MUFAs 26:1 (OR: 0.85; 95% CI: 0.76, 0.94), PUFAs 20:4 (OR: 0.84; 95% CI: 0.75, 0.94), and 24:2 (OR: 0.87; 95% CI: 0.78, 0.97) demonstrated significant associations. In multi-FFA exposure model, 24 FFAs were significantly associated with incident diabetes, most of which were consistent with univariate results. The mixture OR was 0.78 (95% CI: 0.61, 0.99; P = 0.04159). Differential correlation network analysis revealed pre-existing perturbations in intraclass and interclass FFA coregulation before diabetes onset. CONCLUSIONS: These findings underscore the variations in diabetes risk associated with FFAs across chain length and unsaturation degree, highlighting the importance of recognizing FFA subtypes in the pathogenesis of diabetes.

Effect of 5:2 Regimens: Energy-Restricted Diet or Low-Volume High-Intensity Interval Training Combined With Resistance Exercise on Glycemic Control and Cardiometabolic Health in Adults With Overweight/Obesity and Type 2 Diabetes: A Three-Arm Randomized Controlled Trial.

OBJECTIVE: We aimed to examine the effects of a 5:2 diet (2 days per week of energy restriction by formula diet) or an exercise (2 days per week of high-intensity interval training and resistance training) intervention compared with routine lifestyle education (control) on glycemic control and cardiometabolic health among adults with overweight/obesity and type 2 diabetes. RESEARCH DESIGN AND METHODS: This two-center, open-label, three-arm, parallel-group, randomized controlled trial recruited 326 participants with overweight/obesity and type 2 diabetes and randomized them into 12 weeks of diet intervention (n = 109), exercise intervention (n = 108), or lifestyle education (control) (n = 109). The primary outcome was the change of glycemic control measured as glycated hemoglobin (HbA1c) between the diet or exercise intervention groups and the control group after the 12-week intervention. RESULTS: The diet intervention significantly reduced HbA1c level (%) after the 12-week intervention (-0.72, 95% CI -0.95 to -0.48) compared with the control group (-0.37, 95% CI -0.60 to -0.15) (diet vs. control -0.34, 95% CI -0.58 to -0.11, P = 0.007). The reduction in HbA1c level in the exercise intervention group (-0.46, 95% CI -0.70 to -0.23) did not significantly differ from the control group (exercise vs. control -0.09, 95% CI -0.32 to 0.15, P = 0.47). The exercise intervention group was superior in maintaining lean body mass. Both diet and exercise interventions induced improvements in adiposity and hepatic steatosis. CONCLUSIONS: These findings suggest that the medically supervised 5:2 energy-restricted diet could provide an alternative strategy for improving glycemic control and that the exercise regimen could improve body composition, although it inadequately improved glycemic control.

Body size, insulin sensitivity, metabolic health and risk of cardiovascular disease in Chinese adults: Insights from the China Cardiometabolic Disease and Cancer Cohort (4C) study.

AIMS: To assess the excess risk of cardiovascular disease (CVD) associated with different criteria for metabolic health, and the interplay of body size, insulin sensitivity and metabolic health with CVD risk. MATERIALS AND METHODS: We conducted a prospective study involving 115 638 participants from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. Metabolic health was defined using three different definitions: (1) insulin sensitivity defined by homeostatic model assessment of insulin resistance index; (2) absence of metabolic syndrome according to the National Cholesterol Education Program Adult Treatment Panel III criteria; and (3) simultaneous absence of metabolic abnormalities (diabetes, hypertension, dyslipidaemia). The primary endpoint was a composite of incident CVD events comprising the first occurrence of myocardial infarction, stroke, heart failure, or cardiovascular death. RESULTS: During a mean 3.61-year follow-up period, obese individuals with insulin sensitivity (multivariable-adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.37-2.08), or without metabolic syndrome (HR 1.46, 95% CI 1.13-1.89) still exhibited increased CVD risks, when compared to their normal-weight counterparts. Otherwise, those with obesity but simultaneous absence of metabolic abnormalities demonstrated similar CVD risk compared to normal-weight individuals (HR 0.91, 95% CI 0.53-1.59). CVD risk increased with the number of abnormalities across body mass index categories, regardless of insulin sensitivity. CONCLUSIONS: This study emphasizes the need for refined definitions of metabolic health and advocates for meticulous screening for metabolic abnormalities to reduce cardiovascular risks, even in individuals with normal weight and insulin sensitivity.

The Association between Educational Attainment and the Risk of Nonalcoholic Fatty Liver Disease among Chinese Adults: Findings from the REACTION Study.

Background/Aims: : Low educational attainment is a well-established risk factor for nonalcoholic fatty liver disease (NAFLD) in developed areas. However, the association between educational attainment and the risk of NAFLD is less clear in China. Methods: : A cross-sectional study including over 200,000 Chinese adults across mainland China was conducted. Information on education level and lifestyle factors were obtained through standard questionnaires, while NAFLD and advanced fibrosis were diagnosed using validated formulas. Outcomes included the risk of NAFLD in the general population and high probability of fibrosis among patients with NAFLD. Logistic regression analysis was employed to estimate the risk of NAFLD and fibrosis across education levels. A causal mediation model was used to explore the potential mediators. Results: : Comparing with those receiving primary school education, the multi-adjusted odds ratios (95% confidence intervals) for NAFLD were 1.28 (1.16 to 1.41) for men and 0.94 (0.89 to 0.99) for women with college education after accounting for body mass index. When considering waist circumference, the odds ratios (95% CIs) were 0.94 (0.86 to 1.04) for men and 0.88 (0.80 to 0.97) for women, respectively. The proportions mediated by general and central obesity were 51.00% and 68.04% for men, while for women the proportions were 48.58% and 32.58%, respectively. Furthermore, NAFLD patients with lower educational attainment showed an incremental increased risk of advanced fibrosis in both genders. Conclusions: : In China, a low education level was associated with a higher risk of prevalent NAFLD in women, as well as high probability of fibrosis in both genders.

Brain tissue- and cell type-specific eQTL Mendelian randomization reveals efficacy of FADS1 and FADS2 on cognitive function.

Epidemiological studies suggested an association between omega-3 fatty acids and cognitive function. However, the causal role of the fatty acid desaturase (FADS) gene, which play a key role in regulating omega-3 fatty acids biosynthesis, on cognitive function is unclear. Hence, we used two-sample Mendelian randomization (MR) to estimate the gene-specific causal effect of omega-3 fatty acids (N = 114,999) on cognitive function (N = 300,486). Tissue- and cell type-specific effects of FADS1/FADS2 expression on cognitive function were estimated using brain tissue cis-expression quantitative trait loci (cis-eQTL) datasets (GTEx, N ≤ 209; MetaBrain, N ≤ 8,613) and single cell cis-eQTL data (N = 373), respectively. These causal effects were further evaluated in whole blood cis-eQTL data (N ≤ 31,684). A series of sensitivity analyses were conducted to validate MR assumptions. Leave-one-out MR showed a FADS gene-specific effect of omega-3 fatty acids on cognitive function [ß = -1.3 × 10-2, 95% confidence interval (CI) (-2.2 × 10-2, -5 × 10-3), P = 2 × 10-3]. Tissue-specific MR showed an effect of increased FADS1 expression in cerebellar hemisphere and FADS2 expression in nucleus accumbens basal ganglia on maintaining cognitive function, while decreased FADS1 expression in nine brain tissues on maintaining cognitive function [colocalization probability (PP.H4) ranged from 71.7% to 100.0%]. Cell type-specific MR showed decreased FADS1/FADS2 expression in oligodendrocyte was associated with maintaining cognitive function (PP.H4 = 82.3%, respectively). Increased FADS1/FADS2 expression in whole blood showed an effect on cognitive function maintenance (PP.H4 = 86.6% and 88.4%, respectively). This study revealed putative causal effect of FADS1/FADS2 expression in brain tissues and blood on cognitive function. These findings provided evidence to prioritize FADS gene as potential target gene for maintenance of cognitive function.

Sex-stratified genome-wide association and transcriptome-wide Mendelian randomization studies reveal drug targets of heart failure.

The prevalence of heart failure (HF) subtypes, which are classified by left ventricular ejection fraction (LVEF), demonstrate significant sex differences. Here, we perform sex-stratified genome-wide association studies (GWASs) on LVEF and transcriptome-wide Mendelian randomization (MR) on LVEF, all-cause HF, HF with reduced ejection fraction (HFrEF), and HF with preserved ejection fraction (HFpEF). The sex-stratified GWASs of LVEF identified three sex-specific loci that were exclusively detected in the sex-stratified GWASs. Three drug target genes show sex-differential effects on HF/HFrEF via influencing LVEF, with NPR2 as the target gene for the HF drug Cenderitide under phase 2 clinical trial. Our study highlights the importance of considering sex-differential genetic effects in sex-balanced diseases such as HF and emphasizes the value of sex-stratified GWASs and MR in identifying putative genetic variants, causal genes, and candidate drug targets for HF, which is not identifiable using a sex-combined strategy.

Diabesity phenotype in relation to the incidence and resolution of nonalcoholic fatty liver disease: A prospective cohort study.

BACKGROUND: Diabesity is a term used to emphasize the dual epidemic and the combined detrimental effects of diabetes and obesity. We aimed to investigate the associations of diabesity with the incidence and resolution of nonalcoholic fatty liver disease (NAFLD). METHODS: This prospective cohort study included 5549 participants with a median follow-up of 4.3 years (2010-2015). Diabesity was defined as six categories by the combinations of glucose tolerance status (normal glucose tolerance [NGT], prediabetes, and diabetes) diagnosed by fasting and oral glucose tolerance test 2-h glucose and hemoglobin A1c and general or abdominal obesity status. We examined the odds ratios (ORs) for the incidence and resolution of NAFLD associated with diabesity categories, respectively. RESULTS: For NAFLD incidence, compared with the diabesity category of NGT with nonobesity, the categories of either glucose intolerance or general obesity were associated with higher risks of NAFLD, of which the categories with obesity, regardless of glucose intolerance status, exhibited greater risks (ORs ranged from 3.19 to 4.49) than the categories of nonobesity. For NAFLD resolution, the categories of prediabetes or diabetes with obesity were associated with decreased likelihoods of a resolution of NAFLD (ORs ranged from 0.40 to 0.58). These association patterns were consistent across various definitions of diabesity by glucose tolerance status diagnosed by different combinations of glycemic parameters and general or abdominal obesity. CONCLUSIONS: The diabesity association pattern with NAFLD incidence was mainly determined by obesity, while that with NAFLD resolution was driven by the combined phenotype of glucose intolerance and obesity.

Age-specific difference in the temporal relationships between updated cardiovascular health construct and arterial stiffness in middle-aged and older adults.

Previous studies have found that the association between modifiable risk factors and arterial stiffness varied with age. We aimed to explore the age-specific difference in the relationship between new cardiovascular health (CVH) score and arterial stiffness and further detected the age-specific temporal relationships in a prospective cohort study. During a median 4.3 years follow-up, 3757 participants were recruited in this study. A modified AHA "Life's Essential 8" construct (mLE8 with lacking information on diet habits) was used to evaluate CVH. Branchial-ankle pulse wave velocity (baPWV) was measured to assess arterial stiffness. Data were analyzed with logistic regression models, restricted cubic splines (RCS), and cross-lagged path analysis (age < 60 vs. age ≥ 60). In age-stratified analysis, moderate (OR = 2.21, 95% CI 1.11-4.43) and low (OR = 3.37, 95% CI 1.63-7.00) CVH were related with a higher incidence of elevated baPWV compared to high CVH in middle-aged adults, while this association was not detected in older adults. RCS curve showed a steeper linear association between CVH score and elevated baPWV in middle-aged adults than older individuals. In the cross-lagged path analysis, the decline in CVH score preceded the increment in arterial stiffness in middle-aged adults, but they appeared to alter simultaneously in older adults. Our study detected an age-specific difference in the relationship between mLE8 CVH score and elevated baPWV and showed that low CVH preceded alterations of baPWV in middle-aged adults, suggesting the importance of improvement in CVH during the early stage of the lifespan.

Association between updated cardiovascular health construct and risks of non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: The American Heart Association (AHA) updated the construct and algorithm of cardiovascular health (CVH) recently. We aimed to explore the relationship between the new CVH score and the development of non-alcoholic fatty liver disease (NAFLD). METHODS AND RESULTS: 3266 adults free of NAFLD identified via ultrasound were recruited in this prospective study. A modified AHA "Life's Essential 8" (mLE8, i.e., physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure) were collected to evaluate the CVH score. Then participants were categorized into low, moderate, and high CVH subgroups based on overall mLE8 CVH score. According to modified Life's Simple 7 (mLS7) CVH construct, participants were also subdivided into poor, intermediate, and ideal CVH subgroups. During a median 4.3 years follow-up, 623 incident cases of NAFLD were recorded. Compared to those with high CVH, participants with low CVH (adjusted OR = 2.56, 95% CI 1.55-4.24) and moderate CVH (adjusted OR = 1.83, 95% CI 1.17-2.85) had a significantly increased risk of incident NAFLD. Participants with poor CVH (mLS7) but without low CVH (mLE8) did not show a significant elevated risk of incident NAFLD (P = 0.1053). A significant trend was found between increased changes in mLE8 score and a lower risk of NAFLD occurrence. CONCLUSION: Our findings suggested high mLE8 CVH score was associated with a lower risk of NAFLD incidence. The new CVH construct showed a more reasonable classification of CVH status and was more robust in association with NAFLD risks compared with the original one.

Early-life famine exposure, adulthood obesity patterns, and risk of low-energy fracture.

Malnutrition in early life increases the risk of osteoporosis, but the association of early-life undernutrition combined with adulthood obesity patterns with low-energy fracture remains unknown. This study included 5323 community-dwelling subjects aged ⩾40 years from China. Early-life famine exposure was identified based on the participants' birth dates. General obesity was assessed using the body mass index (BMI), and abdominal obesity was evaluated with the waist-to-hip ratio (WHR). Low-energy fracture was defined as fracture occurring after the age of ⩾40 typically caused by falls from standing height or lower. Compared to the nonexposed group, the group with fetal, childhood, and adolescence famine exposure was associated with an increased risk of fracture in women with odds ratios (ORs) and 95% confidence intervals (CIs) of 3.55 (1.57-8.05), 3.90 (1.57-9.71), and 3.53 (1.05-11.88), respectively, but not in men. Significant interactions were observed between fetal famine exposure and general obesity with fracture among women (P for interaction = 0.0008). Furthermore, compared with the groups with normal BMI and WHR, the group of women who underwent fetal famine exposure and had both general and abdominal obesity had the highest risk of fracture (OR, 95% CI: 3.32, 1.17-9.40). These results indicate that early-life famine exposure interacts with adulthood general obesity and significantly increases the risk of low-energy fracture later in life in women.

Sex-specific causality of MRI-derived body compositions on glycaemic traits: Mendelian randomization and observational study.

AIM: To investigate the sex-specific causality of body compositions in type 2 diabetes and related glycaemic traits using Mendelian randomization (MR). MATERIALS AND METHODS: We leveraged sex-specific summary-level statistics from genome-wide association studies for three adipose deposits adjusted for body mass index and height, including abdominal subcutaneous adipose tissue, visceral adipose tissue (VATadj) and gluteofemoral adipose tissue (GFATadj), measured by MRI (20 038 women; 19 038 men), and fat mass-adjusted appendicular lean mass (ALMadj) (244 730 women; 205 513 men) in the UK Biobank. Sex-specific statistics of type 2 diabetes were from the Diabetes Genetics Replication and Meta-analysis Consortium and those for fasting glucose and insulin were from the Meta-analyses of Glucose and Insulin-related Traits Consortium. Univariable and multivariable MR (MVMR) were performed. We also performed MR analyses of anthropometric traits and genetic association analyses using individual-level data of body composition as validation. RESULTS: Univariable MR analysis showed that, in women, higher GFATadj and ALMadj exerted a causally protective effect on type 2 diabetes (GFATadj: odds ratio [OR] 0.59, 95% confidence interval [CI; 0.50, 0.69]; ALMadj: OR 0.84, 95% CI [0.77, 0.91]) and VATadj to be riskier in glycaemic traits. MVMR showed that GFATadj retained a robust effect on type 2 diabetes (OR 0.57, 95% CI [0.42, 0.77]; P = 2.6 × 10-4 ) in women, while it was nominally significant in men (OR 0.58, 95% CI [0.35, 0.96]; P = 3.3 × 10-2 ), after adjustment for ASATadj and VATadj. MR analyses of anthropometric measures and genetic association analyses of glycaemic traits confirmed the results. CONCLUSIONS: Body composition has a sex-specific effect on type 2 diabetes, and higher GFATadj has an independent protective effect on type 2 diabetes in both sexes.

The effect of metformin on urate metabolism: Findings from observational and Mendelian randomization analyses.

AIM: To evaluate the effect of metformin on urate metabolism. MATERIALS AND METHODS: Using the UK Biobank, we first performed association analyses of metformin use with urate levels, risk of hyperuricaemia and incident gout in patients with diabetes. To explore the causal effect of metformin on urate and gout, we identified genetic variants proxying the glycated haemoglobin (HbA1c)-lowering effect of metformin targets and conducted a two-sample Mendelian randomization (MR) utilizing the urate and gout genetic summary-level data from the CKDGen (n = 288 649) and the FinnGen cohort. We conducted two-step MR to explore the mediation effect of body mass index and systolic blood pressure. We also performed non-linear MR in the UK Biobank (n = 414 055) to show the results across HbA1c levels. RESULTS: In 18 776 patients with type 2 diabetes in UK Biobank, metformin use was associated with decreased urate [ß = -4.3 µmol/L, 95% confidence interval (CI) -7.0, -1.7, p = .001] and reduced hyperuricaemia risk (odds ratio = 0.87, 95% CI 0.79, 0.96, p = .004), but not gout. Genetically proxied averaged HbA1c-lowering effects of metformin targets, equivalent to a 0.62% reduction in HbA1c, was associated with reduced urate (ß = -12.5 µmol/L, 95% CI -21.4, -4.2, p = .004). Body mass index significantly mediated this association (proportion mediated = 33.0%, p = .002). Non-linear MR results suggest a linear trend of the effect of metformin on urate reduction across various HbA1c levels. CONCLUSIONS: The effect of metformin may reduce urate levels but not incident gout in the general population.

Opposite causal effects of birthweight on myocardial infarction and atrial fibrillation and the distinct mediating pathways: a Mendelian randomization study.

BACKGROUND: Previous observational studies have documented an inverse association of birthweight with myocardial infarction (MI) but a positive association with atrial fibrillation (AF). However, the causality of these associations and the underlying mediating pathways remain unclear. We aimed to investigate the causal effects of birthweight, incorporating both fetal and maternal genetic effects, on MI and AF, and identify potential mediators in their respective pathways. METHODS: We performed Mendelian randomization (MR) analyses using genome-wide association study summary statistics for birthweight (N = 297,356 for own birthweight and 210,248 for offspring birthweight), MI (Ncase=61,000, Ncontrol=577,000), AF (Ncase=60,620, Ncontrol=970,216), and 52 candidate mediators (N = 13,848-1,295,946). Two-step MR was employed to identify and assess the mediation proportion of potential mediators in the associations of birthweight with MI and AF, respectively. As a complement, we replicated analyses for fetal-specific birthweight and maternal-specific birthweight. RESULTS: Genetically determined each 1-SD lower birthweight was associated with a 40% (95% CI: 1.22-1.60) higher risk of MI, whereas each 1-SD higher birthweight was causally associated with a 29% (95% CI: 1.16-1.44) higher risk of AF. Cardiometabolic factors, including lipids and lipoproteins, glucose and insulin, blood pressure, and fatty acids, each mediated 4.09-23.71% of the total effect of birthweight on MI, followed by body composition and strength traits (i.e., appendicular lean mass, height, and grip strength) and socioeconomic indicators (i.e., education and household income), with the mediation proportion for each factor ranging from 8.08 to 16.80%. By contrast, appendicular lean mass, height, waist circumference, childhood obesity, and body mass index each mediated 15.03-45.12% of the total effect of birthweight on AF. Both fetal-specific birthweight and maternal-specific birthweight were inversely associated with MI, while only fetal-specific birthweight was positively associated with AF. Psychological well-being and lifestyle factors conferred no mediating effect in either association. CONCLUSIONS: Cardiometabolic factors mainly mediated the association between lower birthweight and MI, while body composition and strength traits mediated the association between higher birthweight and AF. These findings provide novel evidence for the distinct pathogenesis of MI and AF and advocate adopting a life-course approach to improving fetal development and subsequent causal mediators to mitigate the prevalence and burden of cardiovascular diseases.

Associations of sleeping patterns and isotemporal substitution of other behavior with the prevalence of CKD in Chinese adults.

Studies have found a U-shaped relationship between sleep duration and chronic kidney disease (CKD) risk, but limited research evaluated the association of reallocating excessive sleep to other behavior with CKD. We included 104 538 participants from the nationwide cohort of the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal Study, with self-reported time of daily-life behavior. Using isotemporal substitution models, we found that substituting 1 h of sleeping with sitting, walking, or moderate-to-vigorous physical activity was associated with a lower CKD prevalence. Leisure-time physical activity displacement was associated with a greater prevalence reduction than occupational physical activity in working population. In stratified analysis, a lower CKD prevalence related to substitution toward physical activity was found in long sleepers. More pronounced correlations were observed in long sleepers with diabetes than in those with prediabetes, and they benefited from other behavior substitutions toward a more active way. The U-shaped association between sleep duration and CKD prevalence implied the potential effects of insufficient and excessive sleep on the kidneys, in which the pernicious link with oversleep could be reversed by time reallocation to physical activity. The divergence in the predicted effect on CKD following time reallocation to behavior of different domains and intensities and in subpopulations with diverse metabolic statuses underlined the importance of optimizing sleeping patterns and adjusting integral behavioral composition.

Interactive Association Between Gut Microbiota and Thyroid Cancer.

CONTEXT: The association between the gut microbiota and thyroid cancer remains controversial. OBJECTIVE: We aimed to systematically investigate the interactive causal relationships between the abundance and metabolism pathways of gut microbiota and thyroid cancer. METHODS: We leveraged genome-wide association studies for the abundance of 211 microbiota taxa from the MiBioGen study (N = 18 340), 205 microbiota metabolism pathways from the Dutch Microbiome Project (N = 7738), and thyroid cancer from the Global Biobank Meta-analysis Initiative (N cases = 6699 and N participants = 1 620 354). We performed a bidirectional Mendelian randomization (MR) to investigate the causality from microbiota taxa and metabolism pathways to thyroid cancer and vice versa. We performed a systematic review of previous observational studies and compared MR results with observational findings. RESULTS: Eight taxa and 12 metabolism pathways had causal effects on thyroid cancer, where RuminococcaceaeUCG004 genus (P = .001), Streptococcaceae family (P = .016), Olsenella genus (P = .029), ketogluconate metabolism pathway (P = .003), pentose phosphate pathway (P = .016), and L-arginine degradation II in the AST pathway (P = .0007) were supported by sensitivity analyses. Conversely, thyroid cancer had causal effects on 3 taxa and 2 metabolism pathways, where the Holdemanella genus (P = .015) was supported by sensitivity analyses. The Proteobacteria phylum, Streptococcaceae family, Ruminococcus2 genus, and Holdemanella genus were significantly associated with thyroid cancer in both the systematic review and MR, whereas the other 121 significant taxa in observational results were not supported by MR. DISCUSSIONS: These findings implicated the potential role of host-microbiota crosstalk in thyroid cancer, while the discrepancy among observational studies calls for further investigations.