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.

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.

Causal Effect of Relative Carbohydrate Intake on Hypertension through Psychological Well-Being and Adiposity: A Mendelian Randomization Study.

Observations of the association between carbohydrate intake and hypertension are inconsistent, with mediating pathways unclear. We aimed to investigate the causal effect of relative carbohydrate intake on hypertension and the mediating roles of psychological well-being and adiposity. Using summary-level statistics of genome-wide association studies of European ancestry, we conducted univariable and multivariable Mendelian randomization (MR) to estimate the bidirectional causal association between relative carbohydrate intake (total energy-adjusted, mean: 42-51%) and hypertension (FinnGen: 42,857 cases/162,837 controls; UK Biobank: 77,723 cases/330,366 controls) and two-step MR to assess the mediating effects of psychological well-being indicators and adiposity traits on the association. MR estimates of hypertension from FinnGen and UK Biobank were meta-analyzed using the fixed-effect model given no heterogeneity. Meta-analyses of multivariable MR estimates from FinnGen and UK Biobank indicated that each one-SD higher relative carbohydrate intake was associated with 71% (odds ratio: 0.29; 95% confidence interval: 0.11-0.79) lower risk of hypertension, independently of other dietary macronutrients. Hypertension showed no reverse effect on carbohydrate intake. Five psychological well-being indicators and four adiposity traits causally mediated the association between relative carbohydrate intake and hypertension, including body mass index (mediation proportion: 51.37%), waist circumference (40.54%), waist-to-hip ratio (35.00%), hip circumference (24.77%), major depressive disorder (23.37%), positive affect (17.08%), depressive symptoms (16.52%), life satisfaction (16.05%), and neuroticism (11.22%). Higher relative carbohydrate intake was causally associated with lower hypertension risk, substantially mediated by better psychological well-being and less adiposity. Our findings inform causal targets and pathways for the prevention and intervention of hypertension.

Causal associations of sarcopenia-related traits with cardiometabolic disease and Alzheimer's disease and the mediating role of insulin resistance: A Mendelian randomization study.

The causal influence of sarcopenia on cardiometabolic disease and Alzheimer's disease and whether and to what extent insulin resistance plays a mediating role therein were unclear. We performed two-step, two-sample Mendelian randomization applying genetic instruments of sarcopenia-related traits based on GWASs from the UK Biobank (up to 461,026 European participants) to examine their causal associations with six cardiometabolic diseases and Alzheimer's disease extracted from large-scale European descent GWASs with adjustment for body fat percentage and physical activity, and to assess proportions of the causal effects mediated by insulin resistance. Genetic instruments of insulin resistance were derived from the GWASs by Meta-Analyses of Glucose and Insulin-related traits Consortium and Global Lipids Genetics Consortium. Each 1-SD lower grip strength, appendicular lean mass (ALM) and whole-body lean mass (WBLM), as well as lower walking pace, were causally associated with higher risks of diabetes (odds ratio [OR] range: 1.20 [95% confidence interval: 1.10-1.32] for ALM to 2.30 [1.14-4.68] for walking pace), nonalcoholic fatty liver disease ([NAFLD], 1.33 [1.08-1.64] for ALM to 2.30 [1.02-5.18] for grip strength), hypertension (1.12 [1.05-1.20] for ALM to 4.43 [2.68-7.33] for walking pace), coronary heart disease ([CHD], 1.20 [1.13-1.27] for ALM to 2.73 [1.84-4.05] for walking pace), myocardial infarction ([MI], 1.18 [1.11-1.25] for ALM to 2.47 [1.63-3.73] for walking pace), small vessel stroke (1.25 [1.15-1.37] for ALM to 1.29 [1.10-1.52] for WBLM), and Alzheimer's disease (1.10 [1.05-1.15] for ALM to 1.28 [1.19-1.38] for WBLM). These causal associations were largely independent of body fat percentage and physical activity. Insulin resistance mediated 16%-34% of the effect of grip strength and 7%-28% of the effect of ALM on diabetes, NAFLD, hypertension, CHD, and MI. The direct effect of WBLM on diabetes diminished toward null with adjustment for insulin resistance. We found no evidence that insulin resistance was on the causal pathways from walking pace to the studied disease outcomes. Causal findings from the inverse-variance weighted method were validated by sensitivity analyses. These findings support improving sarcopenia-related traits as precautions against major cardiometabolic diseases and Alzheimer's disease, with particular emphasis on insulin resistance as a target in the intervention of sarcopenia-related cardiometabolic risk.

Causal impacts of educational attainment on chronic liver diseases and the mediating pathways: Mendelian randomization study.

BACKGROUND AND AIMS: Educational attainment is an essential socio-economic indicator with broad implications for lifestyle behaviour and metabolic health. We aimed to investigate the causal effect of education on chronic liver diseases and the potential mediating pathways. METHODS: We applied univariable Mendelian randomization (MR) to assess the causal associations between educational attainment and non-alcoholic fatty liver disease (NAFLD) (cases/controls: 1578/307 576 in FinnGen; 1664/400 055 in UK Biobank), viral hepatitis (1772/307 382; 1215/403 316), hepatomegaly (199/222 728; 297/400 055), chronic hepatitis (699/301 014; 277/403 316), cirrhosis (1362/301 014; 114/400 055) and liver cancer (518/308 636; 344/393 372) using summary statistics of genome-wide association studies from the FinnGen Study and the UK Biobank, respectively. We used two-step MR to evaluate potential mediators and their mediation proportions in the association. RESULTS: Meta-analysis of inverse variance weighted MR estimates from FinnGen and UK Biobank showed that genetically predicted 1-SD (4.2 years) higher education was causally associated with decreased risks of NAFLD (OR: 0.48; 95%CI: 0.37-0.62), viral hepatitis (0.54; 0.42-0.69) and chronic hepatitis (0.50; 0.32-0.79), but not hepatomegaly, cirrhosis and liver cancer. Nine, two and three out of 34 modifiable factors were identified as causal mediators in the associations of education with NAFLD, viral hepatitis and chronic hepatitis, respectively, including six adiposity traits (mediation proportion: 16.5%-32.0%), major depression (16.9%), two glucose metabolism-related traits (2.2%-15.8%) and two lipids (9.9%-12.1%). CONCLUSIONS: Our findings supported the causal protective effects of education on chronic liver diseases and outlined mediating pathways to inform prevention and intervention strategies to reduce the burden of liver diseases, especially for individuals with lower education.

Hypertriglyceridemic hyperapoB and the development and resolution of nonalcoholic fatty liver disease: a cohort study.

Hypertriglyceridemic hyperapoB is an adverse lipoprotein phenotype characterized by low high density lipoprotein (HDL) cholesterol, high triglycerides, high apolipoprotein B (ApoB), and low low density lipoprotein (LDL) cholesterol to ApoB ratio. We investigated whether and to what extent hypertriglyceridemic hyperapoB associates with the incidence and resolution of nonalcoholic fatty liver disease (NAFLD). This prospective cohort study included 9,019 Chinese participants 40 years or older, from 2010 to 2015. Logistic regression models were used to examine the odds ratios (ORs) for the incidence and resolution of NAFLD associated with the hypertriglyceridemic hyperapoB lipoprotein phenotype and individual lipid and lipoprotein parameters. During a median 4.3 years of follow-up, compared with participants with optimal phenotype, the fully adjusted ORs (95% CIs) for participants with hypertriglyceridemic hyperapoB were 2.75 (1.91, 3.95) and 0.57 (0.33, 1.00) for incidence and resolution of NAFLD, respectively. These associations were consistent across subgroup participants with varied demographic, lifestyle, and metabolic status. Individually, each unit increase in HDL cholesterol (OR: 0.98; 95% CI: 0.97, 0.99), natural logarithm-transformed triglycerides (1.89; 1.52, 2.36), and ApoB (1.006; 1.002, 1.011) was independently associated with NAFLD incidence, and only triglycerides (0.77; 0.60, 0.99) was independently associated with NAFLD resolution. Our findings suggest that Chinese adults with hypertriglyceridemic hyperapoB have a higher risk of NAFLD incidence and a lower likelihood of NAFLD resolution. These associations were stable among adults with different demographic, lifestyle, and metabolic status, supporting hypertriglyceridemic hyperapoB as a valuable clinical marker for the prevention and control of NAFLD.

Mendelian randomization evidence for the causal effects of socio-economic inequality on human longevity among Europeans.

Human longevity correlates with socio-economic status, and there is evidence that educational attainment increases human lifespan. However, to inform meaningful health policies, we need fine-grained causal evidence on which dimensions of socio-economic status affect longevity and the mediating roles of modifiable factors such as lifestyle and disease. Here we performed two-sample Mendelian randomization analyses applying genetic instruments of education, income and occupation (n = 248,847 to 1,131,881) to estimate their causal effects and consequences on parental lifespan and self-longevity (n = 28,967 to 1,012,240) from the largest available genome-wide association studies in populations of European ancestry. Each 4.20 years of additional educational attainment were causally associated with a 3.23-year-longer parental lifespan independently of income and occupation and were causally associated with 30-59% higher odds of self-longevity, suggesting that education was the primary determinant. By contrast, each one-standard-deviation-higher income and one-point-higher occupation was causally associated with 3.06-year-longer and 1.29-year-longer parental lifespans, respectively, but not independently of the other socio-economic indicators. We found no evidence for causal effects of income or occupation on self-longevity. Mediation analyses conducted in predominantly European-descent individuals through two-step Mendelian randomization suggested that among 59 candidates, cigarettes per day, body mass index, waist-to-hip ratio, hypertension, coronary heart disease, myocardial infarction, stroke, Alzheimer's disease, type 2 diabetes, heart failure and lung cancer individually played substantial mediating roles (proportion mediated, >10%) in the effect of education on specific longevity outcomes. These findings inform interventions for remediating longevity disparities attributable to socio-economic inequality.

Genetic Evidence for Causal Effects of Socioeconomic, Lifestyle, and Cardiometabolic Factors on Epigenetic-Age Acceleration.

GrimAge acceleration (GrimAgeAccel) and PhenoAge acceleration (PhenoAgeAccel) are DNA methylation-based markers of accelerated biological aging, standing out in predicting mortality and age-related cardiometabolic morbidities. Causal risk factors for GrimAgeAccel and PhenoAgeAccel are unclear. In this study, we performed 2-sample univariable and multivariable Mendelian randomization (MR) to investigate causal associations of 19 modifiable socioeconomic, lifestyle, and cardiometabolic factors with GrimAgeAccel and PhenoAgeAccel. Instrument variants representing 19 modifiable factors were extracted from genome-wide association studies (GWASs) with up to 1 million Europeans. Summary statistics for GrimAgeAccel and PhenoAgeAccel were derived from a GWAS of 34 710 Europeans. We identified 12 and 8 factors causally associated with GrimAgeAccel and PhenoAgeAccel, respectively. Smoking was the strongest risk factor (ß [standard error {SE}]: 1.299 [0.107] year) for GrimAgeAccel, followed by higher alcohol intake, higher waist circumference, daytime napping, higher body fat percentage, higher body mass index, higher C-reactive protein, higher triglycerides, childhood obesity, and type 2 diabetes; whereas education was the strongest protective factor (ß [SE]: -1.143 [0.121] year), followed by household income. Furthermore, higher waist circumference (ß [SE]: 0.850 [0.269] year) and education (ß [SE]: -0.718 [0.151] year) were the leading causal risk and protective factors for PhenoAgeAccel, respectively. Sensitivity analyses strengthened the robustness of these causal associations. Multivariable MR analyses further demonstrated independent effects of the strongest risk and protective factors on GrimAgeAccel and PhenoAgeAccel, respectively. In conclusion, our findings provide novel quantitative evidence on modifiable causal risk factors for accelerated epigenetic aging, suggesting promising intervention targets against age-related morbidity and improving healthy longevity.

Causal effect of lower birthweight on non-alcoholic fatty liver disease and mediating roles of insulin resistance and metabolites.

BACKGROUND & AIMS: The causal association of lower birthweight with non-alcoholic fatty liver disease (NAFLD) and the mediating pathways remain unclear. We aimed to investigate the causal, independent association of lower birthweight with NAFLD and identify potential metabolic mediators and their mediation effects in this association. METHODS: We performed two-step, two-sample Mendelian randomization (MR) using genome-wide association study (GWAS) summary statistics for birthweight from the Early Growth Genetics Consortium of 298 142 Europeans, NAFLD from a GWAS meta-analysis of 8434 NAFLD cases and 770 180 controls of Europeans, and 25 candidate mediators from corresponding reliable GWASs. RESULTS: Genetically determined each 1-SD lower birthweight was associated with a 45% (95% CI: 1.25-1.69) increased risk of NAFLD, and this causal association persisted after adjusting for childhood obesity or adult adiposity traits in multivariable MR. Two-step MR identified 6 of 25 candidate mediators partially mediate the effect of lower birthweight on NAFLD, including fasting insulin (proportion mediated: 22.05%), leucine (17.29%), isoleucine (13.55%), valine (11.37%), alanine (10.01%) and monounsaturated fatty acids (MUFA; 7.23%). Bidirectional MR suggested a unidirectional effect of insulin resistance on isoleucine, leucine and valine and a unidirectional effect of alanine on insulin resistance. CONCLUSIONS: This MR study elucidated the causal impact of lower birthweight on subsequent risk of NAFLD, independently of later-life adiposity and identified mediators including insulin resistance, branched-chain amino acids, alanine and MUFA in this association pathway. Our findings shed light on the pathogenesis of NAFLD and imply additional targets for prevention and intervention of NAFLD attributed to low birthweight.

Causal Associations Between Age at Diagnosis of Diabetes and Cardiovascular Outcomes: A Mendelian Randomization Study.

CONTEXT: Whether diabetes diagnosed at different age groups is causally associated with cardiovascular diseases (CVDs) is unknown. OBJECTIVE: We conducted 2-sample Mendelian randomization analyses to investigate the causal associations of diabetes by age at diagnosis with 5 type-specific CVDs and 11 cardiometabolic traits. METHODS: We selected 208 single nucleotide polymorphisms (SNPs) for diabetes and 3, 21, 57, and 14 SNPs for diabetes diagnosed at <50, 50-60, 60-70, and >70 years, respectively, based on the genome-wide association study (GWASs) (24 986 cases/187 130 controls) in the UK Biobank, and extracted genetic associations with stroke, myocardial infarction, heart failure, atrial fibrillation, and CVD mortality, as well as blood pressures, adiposity measurements, and lipids and apolipoproteins from corresponding European-descent GWASs. The inverse variance-weighted method was used as the main analysis with several sensitivity analyses. RESULTS: Diabetes diagnosed at all 4 age groups was causally associated with increased risks of stroke (5-8%) and myocardial infarction (8-10%), higher systolic blood pressure (0.56-0.94 mmHg) and waist to hip ratio (0.003-0.004), and lower body mass index (0.31-0.42 kg/m2), waist circumference (0.68-0.99 cm), and hip circumference (0.57-0.80 cm). Diabetes diagnosed at specific age groups was causally associated with increased risks of heart failure (4%) and CVD mortality (8%), higher diastolic blood pressure (0.20 mmHg) and triglycerides (0.06 SD), and lower high-density lipoprotein cholesterol (0.02 mmol/L). The effect sizes of genetically determined diabetes on CVD subtypes and cardiometabolic traits were comparable and the corresponding 95% confidence intervals largely overlapped across the 4 age groups. CONCLUSION: Our findings provide novel evidence that genetically determined diabetes subgroups by age at diagnosis have similar causal effects on CVD and cardiometabolic risks.

Independent Associations of Education, Intelligence, and Cognition With Hypertension and the Mediating Effects of Cardiometabolic Risk Factors: A Mendelian Randomization Study.

BACKGROUND: Education, intelligence, and cognition are associated with hypertension, but which one plays the most prominent role in the pathogenesis of hypertension and which modifiable risk factors mediate the causal effects remains unknown. METHODS: Using summary statistics of genome-wide association studies of predominantly European ancestry, we conducted 2-sample multivariable Mendelian randomization to estimate the independent effects of education, intelligence, or cognition on hypertension (FinnGen study, 70 651 cases/223 663 controls; UK Biobank, 77 723 cases/330 366 controls) and blood pressure (International Consortium of Blood Pressure, 757 601 participants), and used 2-step Mendelian randomization to evaluate 25 potential mediators of the association and calculate the mediated proportions. RESULTS: Meta-analysis of inverse variance weighted Mendelian randomization results from FinnGen and UK Biobank showed that genetically predicted 1-SD (4.2 years) higher education was associated with 44% (95% CI: 0.40-0.79) decreased hypertension risk and 1.682 mm Hg lower systolic and 0.898 mm Hg lower diastolic blood pressure, independently of intelligence and cognition. While the causal effects of intelligence and cognition on hypertension were not independent of education; 6 out of 25 cardiometabolic risk factors were identified as mediators of the association between education and hypertension, ranked by mediated proportions, including body mass index (mediated proportion: 30.1%), waist-to-hip ratio (22.8%), body fat percentage (14.1%), major depression (7.0%), high-density lipoprotein cholesterol (4.7%), and triglycerides (3.4%). These results were robust to sensitivity analyses. CONCLUSIONS: Our findings illustrated the causal, independent impact of education on hypertension and blood pressure and outlined cardiometabolic mediators as priority targets for prevention of hypertension attributable to low education.

Diabesity phenotype and the risks of cardiovascular disease and subclinical atherosclerosis: A prospective cohort study.

OBJECTIVE: The aim of this study was to investigate the associations of diabesity with incident cardiovascular disease (CVD) and subclinical atherosclerosis. METHODS: The prospective cohort study included 8,006 participants without baseline CVD. Diabesity was categorized as (i) normal glucose tolerance (NGT) with nonobesity; (ii) NGT with obesity; (iii) prediabetes with nonobesity; (iv) prediabetes with obesity; (v) diabetes with nonobesity; and (vi) diabetes with obesity. The hazard ratios (HRs) for incident CVD and odds ratios (ORs) for subclinical atherosclerosis associated with diabesity categories were examined. RESULTS: Compared with the category of NGT with nonobesity, the categories of NGT with obesity (HR 1.68; 95% CI: 1.10-2.57), diabetes with nonobesity (HR 1.42; 95% CI: 1.08-1.88), and diabetes with obesity (HR 1.78; 95% CI: 1.24-2.55) were associated with higher risks of CVD. Prediabetes with or without obesity conferred no excess risk for CVD but higher risks for subclinical atherosclerosis. The diabetes with obesity category was associated with the highest risk for elevated pulse pressure (OR 3.07; 95% CI: 2.06-4.58) and albuminuria (OR 3.39; 95% CI: 2.31-4.99), and diabetes with or without obesity showed comparable ORs for elevated brachial-ankle pulse wave velocity. CONCLUSIONS: The association patterns between diabesity and CVD risks support the value of diabesity as a prevention target for CVD.

Comprehensive risk profiles of family history and lifestyle and metabolic risk factors in relation to diabetes: A prospective cohort study.

BACKGROUND: Family history of diabetes, unhealthy lifestyles, and metabolic disorders are individually associated with higher risk of diabetes, but how different combinations of the three risk categories are associated with incident diabetes remains unclear. We aimed to estimate the associations of comprehensive risk profiles of family history and lifestyle and metabolic risk factors with diabetes risk. METHODS: This study included 5290 participants without diabetes at baseline with a mean follow-up of 4.4 years. Five unhealthy lifestyles and five metabolic disorders were each allocated a score, resulting in an aggregated lifestyle and metabolic risk score ranging from 0 to 5. Eight risk profiles were constructed from combinations of three risk categories: family history of diabetes (yes, no), lifestyle risk (high, low), and metabolic risk (high, low). RESULTS: Compared with the profile without any risk category, other profiles exhibited incrementally higher risks of diabetes with increasing numbers of categories: the hazard ratio (HR, 95% confidence interval [CI]) for diabetes ranged from 1.34 (1.01-1.79) to 2.33 (1.60-3.39) for profiles with one risk category, ranged from 2.42 (1.45-4.04) to 4.18 (2.42-7.21) for profiles with two risk categories, and was 4.59 (2.85-7.39) for the profile with three risk categories. The associations between the numbers of risk categories and diabetes risk were more prominent in women (pinteraction  = .025) and slightly more prominent in adults <55 years (pinteraction  = .052). CONCLUSIONS: This study delineated associations between comprehensive risk profiles with diabetes risk, with stronger associations observed in women and slightly stronger associations in adults younger than 55 years.

Causal Associations of Obesity With Chronic Kidney Disease and Arterial Stiffness: A Mendelian Randomization Study.

CONTEXT: Observational studies have been associated obesity with chronic kidney disease (CKD) and arterial stiffness, but the causality remains unclear. OBJECTIVE: We aimed to investigate the causality of obesity with CKD and arterial stiffness using mendelian randomization (MR) analysis. METHODS: We genotyped 14 body mass index (BMI)-associated variants validated in East Asians in 11 384 Chinese adults. A genetic risk score based on the 14 variants and the 14 individual single-nucleotide variations (SNVs, formerly single-nucleotide polymorphisms [SNPs]) were respectively used as instrumental variables (IVs). CKD was defined as estimated glomerular filtration rate less than 60 mL/min/1.73 m2. Arterial stiffness was defined as brachial-ankle pulse wave velocity greater than 1550 cm/s. RESULTS: Using the genetic risk score as the IV, we demonstrated causal relations of each 1-SD increment in BMI with CKD (odds ratio [OR]: 2.36; 95% CI, 1.11-5.00) and arterial stiffness (OR: 1.71; 95% CI, 1.22-2.39). Using the 14 SNVs individually as IVs, each 1-SD increment in BMI was casually associated with CKD (OR: 2.58; 95% CI, 1.39-4.79) and arterial stiffness (OR: 1.87; 95% CI, 1.24-2.81) in the inverse-variance weighted analysis, and MR-Egger regression revealed no evidence of horizontal pleiotropy (both P for intercept ≥ .34). The causality between obesity and CKD was validated in 2-sample MR analysis among Europeans (681 275 of Genetic Investigation of ANthropometric Traits and 133 413 of CKD Genetics). CONCLUSION: This study provided novel insights into the causality of obesity with CKD and arterial stiffness, highlighting the importance of weight management for primary prevention and control of subclinical vascular diseases.