scholarly journals Conventional and Genetic Evidence on the Association between Adiposity and CKD

2020 ◽  
Vol 32 (1) ◽  
pp. 127-137 ◽  
Author(s):  
Pengfei Zhu ◽  
William G. Herrington ◽  
Richard Haynes ◽  
Jonathan Emberson ◽  
Martin J. Landray ◽  
...  
Keyword(s):  
Odds Ratio ◽  
Mendelian Randomization ◽  
Underlying Mechanism ◽  
Uk Biobank ◽  
Genetic Associations ◽  
Genetic Analyses ◽  
Waist To Hip Ratio ◽  
Chi Squared ◽  
General Adiposity

BackgroundThe size of any causal contribution of central and general adiposity to CKD risk and the underlying mechanism of mediation are unknown.MethodsData from 281,228 UK Biobank participants were used to estimate the relevance of waist-to-hip ratio and body mass index (BMI) to CKD prevalence. Conventional approaches used logistic regression. Genetic analyses used Mendelian randomization (MR) and data from 394 waist-to-hip ratio and 773 BMI-associated loci. Models assessed the role of known mediators (diabetes mellitus and BP) by adjusting for measured values (conventional analyses) or genetic associations of the selected loci (multivariable MR).ResultsEvidence of CKD was found in 18,034 (6.4%) participants. Each 0.06 higher measured waist-to-hip ratio and each 5-kg/m2 increase in BMI were associated with 69% (odds ratio, 1.69; 95% CI, 1.64 to 1.74) and 58% (1.58; 1.55 to 1.62) higher odds of CKD, respectively. In analogous MR analyses, each 0.06–genetically-predicted higher waist-to-hip ratio was associated with a 29% (1.29; 1.20 to 1.38) increased odds of CKD, and each 5-kg/m2 genetically-predicted higher BMI was associated with a 49% (1.49; 1.39 to 1.59) increased odds. After adjusting for diabetes and measured BP, chi-squared values for associations for waist-to-hip ratio and BMI fell by 56%. In contrast, mediator adjustment using multivariable MR found 83% and 69% reductions in chi-squared values for genetically-predicted waist-to-hip ratio and BMI models, respectively.ConclusionsGenetic analyses suggest that conventional associations between central and general adiposity with CKD are largely causal. However, conventional approaches underestimate mediating roles of diabetes, BP, and their correlates. Genetic approaches suggest these mediators explain most of adiposity-CKD–associated risk.

scholarly journals Association of genetically predicted serum estradiol with risk of thromboembolism in men: A mendelian randomization study

2021 ◽  
Author(s):  
Maria Nethander ◽  
Johan Quester ◽  
Liesbeth Vandenput ◽  
Claes Ohlsson
Keyword(s):  
Ischemic Stroke ◽  
Odds Ratio ◽  
Mendelian Randomization ◽  
Causal Role ◽  
Gene Region ◽  
Uk Biobank ◽  
Increased Risk ◽  
Self Reports ◽  
The Uk

Abstract Context An association was recently reported between genetic markers related to high testosterone and increased risk of thromboembolism in men but a possible causal role of estradiol for risk of thromboembolism in men remains unknown. Objective To determine whether endogenous estradiol has a causal role in thromboembolism in men. Design Two-sample mendelian randomization study using gene-based genetic instruments Setting UK Biobank Participants We assessed the association between endogenous estradiol genetically predicted by 22 variants in the CYP19A1 gene region and risk of thromboembolism (5815 cases) in 170,593 unrelated men of white ancestry in the UK Biobank. Main Outcome Measure Thromboembolism based on self-reports, hospital episodes, and death. Results Endogenous estradiol genetically predicted by variants in the CYP19A1 gene region was inversely associated with risk of thromboembolism (odds ratio per SD increase in estradiol 0.74, 95% confidence interval 0.62-0.90). In contrast, genetic variants in the JMJD1C gene, used as a predictor of high endogenous testosterone, were associated with an increased risk of thromboembolism (odds ratio per SD increase in testosterone 1.39, 1.12-1.72). Subsequent explorative analyses evaluating potential repercussions of thromboembolism revealed that endogenous estradiol genetically predicted by variants in the CYP19A1 gene region was inversely associated with risk of ischemic stroke (0.68, 0.49-0.95) but not myocardial infarction (0.97, 0.84-1.13). Conclusions Genetically predicted estradiol was inversely associated with risk of thromboembolism and ischemic stroke in men. The ratio between testosterone and estradiol, determined by aromatase (CYP19A1) activity, may contribute to the overall impact of sex steroids on thromboembolism in men.

scholarly journals Coffee Consumption and Cardiovascular Diseases: A Mendelian Randomization Study

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2218
Author(s):  
Shuai Yuan ◽  
Paul Carter ◽  
Amy M. Mason ◽  
Stephen Burgess ◽  
Susanna C. Larsson
Keyword(s):  
Cardiovascular Disease ◽  
Cardiovascular Diseases ◽  
Intracerebral Hemorrhage ◽  
Genetic Variants ◽  
Odds Ratio ◽  
Observational Studies ◽  
Mendelian Randomization ◽  
Coffee Consumption ◽  
Uk Biobank ◽  
The Uk

Coffee consumption has been linked to a lower risk of cardiovascular disease in observational studies, but whether the associations are causal is not known. We conducted a Mendelian randomization investigation to assess the potential causal role of coffee consumption in cardiovascular disease. Twelve independent genetic variants were used to proxy coffee consumption. Summary-level data for the relations between the 12 genetic variants and cardiovascular diseases were taken from the UK Biobank with up to 35,979 cases and the FinnGen consortium with up to 17,325 cases. Genetic predisposition to higher coffee consumption was not associated with any of the 15 studied cardiovascular outcomes in univariable MR analysis. The odds ratio per 50% increase in genetically predicted coffee consumption ranged from 0.97 (95% confidence interval (CI), 0.63, 1.50) for intracerebral hemorrhage to 1.26 (95% CI, 1.00, 1.58) for deep vein thrombosis in the UK Biobank and from 0.86 (95% CI, 0.50, 1.49) for subarachnoid hemorrhage to 1.34 (95% CI, 0.81, 2.22) for intracerebral hemorrhage in FinnGen. The null findings remained in multivariable Mendelian randomization analyses adjusted for genetically predicted body mass index and smoking initiation, except for a suggestive positive association for intracerebral hemorrhage (odds ratio 1.91; 95% CI, 1.03, 3.54) in FinnGen. This Mendelian randomization study showed limited evidence that coffee consumption affects the risk of developing cardiovascular disease, suggesting that previous observational studies may have been confounded.

scholarly journals Body mass index and mortality in UK Biobank: revised estimates using Mendelian randomization

2018 ◽  
Author(s):  
Kaitlin H Wade ◽  
David Carslake ◽  
Naveed Sattar ◽  
George Davey Smith ◽  
Nicholas J Timpson
Keyword(s):  
Body Mass Index ◽  
Body Mass ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Genotypic Variation ◽  
Lung Cancer Mortality ◽  
Causal Role ◽  
Uk Biobank ◽  
All Cause Mortality

AbstractObjectiveObtain estimates of the causal relationship between different levels of body mass index (BMI) and mortality.MethodsMendelian randomization (MR) was conducted using genotypic variation reliably associated with BMI to test the causal effect of increasing BMI on all-cause and cause-specific mortality in participants of White British ancestry in UK Biobank.ResultsMR analyses supported existing evidence for a causal association between higher levels of BMI and greater risk of all-cause mortality (hazard ratio (HR) per 1kg/m2: 1.02; 95% CI: 0.97,1.06) and mortality from cardiovascular diseases (HR: 1.12; 95% CI: 1.02, 1.23), specifically coronary heart disease (HR: 1.19; 95% CI: 1.05, 1.35) and those other than stroke/aortic aneurysm (HR: 1.13; 95% CI: 0.93, 1.38), stomach cancer (HR: 1.30; 95% CI: 0.91, 1.86) and oesophageal cancer (HR: 1.08; 95% CI: 0.84, 1.38), and with decreased risk of lung cancer mortality (HR: 0.97; 95% CI: 0.84, 1.11). Sex-stratified analyses supported a causal role of higher BMI in increasing the risk of mortality from bladder cancer in males and other causes in females, but in decreasing the risk of respiratory disease mortality in males. The characteristic J-shaped observational association between BMI and mortality was visible with MR analyses but with a smaller value of BMI at which mortality risk was lowest and apparently flatter over a larger range of BMI.ConclusionResults support a causal role of higher BMI in increasing the risk of all-cause mortality and mortality from other causes. However, studies with greater numbers of deaths are needed to confirm the current findings.

scholarly journals Mendelian Randomization Analysis of Hemostatic Factors and Their Contribution to Peripheral Artery Disease

2020 ◽  
Author(s):  
Aeron M. Small ◽  
Jennifer E. Huffman ◽  
Derek Klarin ◽  
Maria Sabater-Lleal ◽  
Julie A. Lynch ◽  
...  
Keyword(s):  
Peripheral Artery Disease ◽  
Odds Ratio ◽  
Mendelian Randomization ◽  
Factor Vii ◽  
Peripheral Artery ◽  
Protein Variant ◽  
Factor V Leiden Mutation ◽  
Hemostatic Factors ◽  
Artery Disease

Background: Peripheral artery disease (PAD) is the third most common form of atherosclerotic vascular disease and is characterized by significant functional disability and increased cardiovascular mortality. Recent genetic data support a role for a procoagulation protein variant, the factor V Leiden mutation, in PAD. The role of other hemostatic factors in PAD remains unknown. Objective: To evaluate the role of hemostatic factors in PAD using Mendelian randomization. Approach and Results: Two-sample Mendelian randomization to evaluate the roles of FVII (factor VII), FVIII (factor VIII), FXI (factor XI), VWF (von Willebrand factor), and fibrinogen in PAD was performed using summary statistics from GWAS for hemostatic factors performed within the Cohorts for Heart and Aging Research in the Genome Epidemiology Consortium and from GWAS performed for PAD within the Million Veteran Program. Genetically determined FVIII and VWF, but not FVII, FXI, or fibrinogen, were associated with PAD in Mendelian randomization experiments (FVIII: odds ratio, 1.41 [95% CI, 1.23–1.62], P =6.0×10 −7 , VWF: odds ratio, 1.28 [95% CI, 1.07–1.52], P =0.0073). In single variant sensitivity analysis, the ABO locus was the strongest genetic instrument for both FVIII and VWF. Conclusions: Our results suggest a role for hemostasis, and by extension, thrombosis in PAD. Further study is warranted to determine whether VWF and FVIII independently affect the biology of PAD.

scholarly journals Mendelian randomization provides evidence for a causal effect of higher serum IGF-1 concentration on risk of hip and knee osteoarthritis

Rheumatology ◽  
2020 ◽  
Author(s):  
April Hartley ◽  
Eleanor Sanderson ◽  
Lavinia Paternoster ◽  
Alexander Teumer ◽  
Robert C Kaplan ◽  
...  
Keyword(s):  
Risk Score ◽  
Genetic Risk ◽  
Odds Ratio ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Genetic Risk Score ◽  
Uk Biobank ◽  
Knee Oa ◽  
Increased Risk

Abstract Objectives How insulin-like growth factor-1 (IGF-1) is related to OA is not well understood. We determined relationships between IGF-1 and hospital-diagnosed hand, hip and knee OA in UK Biobank, using Mendelian randomization (MR) to determine causality. Methods Serum IGF-1 was assessed by chemiluminescent immunoassay. OA was determined using Hospital Episode Statistics. One-sample MR (1SMR) was performed using two-stage least-squares regression, with an unweighted IGF-1 genetic risk score as an instrument. Multivariable MR included BMI as an additional exposure (instrumented by BMI genetic risk score). MR analyses were adjusted for sex, genotyping chip and principal components. We then performed two-sample MR (2SMR) using summary statistics from Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) (IGF-1, N = 30 884) and the recent genome-wide association study meta-analysis (N = 455 221) of UK Biobank and Arthritis Research UK OA Genetics (arcOGEN). Results A total of 332 092 adults in UK Biobank had complete data. Their mean (s.d.) age was 56.5 (8.0) years and 54% were female. IGF-1 was observationally related to a reduced odds of hand OA [odds ratio per doubling = 0.87 (95% CI 0.82, 0.93)], and an increased odds of hip OA [1.04 (1.01, 1.07)], but was unrelated to knee OA [0.99 (0.96, 1.01)]. Using 1SMR, we found strong evidence for an increased risk of hip [odds ratio per s.d. increase = 1.57 (1.21, 2.01)] and knee [1.30 (1.07, 1.58)] OA with increasing IGF-1 concentration. By contrast, we found no evidence for a causal effect of IGF-1 concentration on hand OA [0.98 (0.57, 1.70)]. Results were consistent when estimated using 2SMR and in multivariable MR analyses accounting for BMI. Conclusion We have found evidence that increased serum IGF-1 is causally related to higher risk of hip and knee OA.

scholarly journals Cardiometabolic risk factors for COVID-19 susceptibility and severity: A Mendelian randomization analysis

PLoS Medicine ◽  
2021 ◽  
Vol 18 (3) ◽  
pp. e1003553
Author(s):  
Aaron Leong ◽  
Joanne B. Cole ◽  
Laura N. Brenner ◽  
James B. Meigs ◽  
Jose C. Florez ◽  
...  
Keyword(s):  
Odds Ratio ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Statistical Significance ◽  
Epidemiological Studies ◽  
Population Based ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
The Uk

Background Epidemiological studies report associations of diverse cardiometabolic conditions including obesity with COVID-19 illness, but causality has not been established. We sought to evaluate the associations of 17 cardiometabolic traits with COVID-19 susceptibility and severity using 2-sample Mendelian randomization (MR) analyses. Methods and findings We selected genetic variants associated with each exposure, including body mass index (BMI), at p < 5 × 10−8 from genome-wide association studies (GWASs). We then calculated inverse-variance-weighted averages of variant-specific estimates using summary statistics for susceptibility and severity from the COVID-19 Host Genetics Initiative GWAS meta-analyses of population-based cohorts and hospital registries comprising individuals with self-reported or genetically inferred European ancestry. Susceptibility was defined as testing positive for COVID-19 and severity was defined as hospitalization with COVID-19 versus population controls (anyone not a case in contributing cohorts). We repeated the analysis for BMI with effect estimates from the UK Biobank and performed pairwise multivariable MR to estimate the direct effects and indirect effects of BMI through obesity-related cardiometabolic diseases. Using p < 0.05/34 tests = 0.0015 to declare statistical significance, we found a nonsignificant association of genetically higher BMI with testing positive for COVID-19 (14,134 COVID-19 cases/1,284,876 controls, p = 0.002; UK Biobank: odds ratio 1.06 [95% CI 1.02, 1.10] per kg/m2; p = 0.004]) and a statistically significant association with higher risk of COVID-19 hospitalization (6,406 hospitalized COVID-19 cases/902,088 controls, p = 4.3 × 10−5; UK Biobank: odds ratio 1.14 [95% CI 1.07, 1.21] per kg/m2, p = 2.1 × 10−5). The implied direct effect of BMI was abolished upon conditioning on the effect on type 2 diabetes, coronary artery disease, stroke, and chronic kidney disease. No other cardiometabolic exposures tested were associated with a higher risk of poorer COVID-19 outcomes. Small study samples and weak genetic instruments could have limited the detection of modest associations, and pleiotropy may have biased effect estimates away from the null. Conclusions In this study, we found genetic evidence to support higher BMI as a causal risk factor for COVID-19 susceptibility and severity. These results raise the possibility that obesity could amplify COVID-19 disease burden independently or through its cardiometabolic consequences and suggest that targeting obesity may be a strategy to reduce the risk of severe COVID-19 outcomes.

scholarly journals Predicting the effect of statins on cancer risk using genetic variants: a Mendelian randomization study in UK Biobank

2020 ◽  
Author(s):  
Paul Carter ◽  
Mathew Vithayathil ◽  
Siddhartha Kar ◽  
Rahul Potluri ◽  
Amy M. Mason ◽  
...  
Keyword(s):  
Cancer Risk ◽  
Ldl Cholesterol ◽  
Mendelian Randomization ◽  
Statin Treatment ◽  
Potential Effect ◽  
Lipid Lowering ◽  
Uk Biobank ◽  
Genetic Associations ◽  
Standard Deviation Increase ◽  
Alternative Lipid

Laboratory studies have suggested oncogenic roles of lipids, as well as anticarcinogenic effects of statins. We here assess the potential effect of statin therapy on cancer risk in Mendelian randomization analyses. We obtained genetic associations with the risk of overall and 22 site-specific cancers for 367,703 individuals in UK Biobank. In total, 75,037 individuals had a cancer event. Variants in the HMGCR gene region, which represent proxies for statin treatment, were associated with overall cancer risk (OR per 1 standard deviation increase in LDL-cholesterol 1.32, 95% CI 1.13-1.53, p=0.0003), but variants in gene regions representing alternative lipid-lowering treatment targets (PCSK9, LDLR, NPC1L1, APOC3, LPL) were not. Genetically-predicted LDL-cholesterol was not associated with overall cancer risk (OR 1.01, 95% CI 0.98-1.05, p=0.50). Our results predict that statins reduce cancer risk, but other lipid-lowering treatments do not. This suggests that statins reduce cancer risk through a cholesterol independent pathway.

scholarly journals Age-varying genetic associations and implications for bias in Mendelian randomization analyses

2021 ◽  
Author(s):  
Jeremy A Labrecque ◽  
Sonja A Swanson
Keyword(s):  
Body Mass Index ◽  
Alcohol Consumption ◽  
Body Mass ◽  
Genetic Variants ◽  
Ldl Cholesterol ◽  
Mendelian Randomization ◽  
Uk Biobank ◽  
Genetic Associations ◽  
C Reactive Protein ◽  
Reactive Protein

Estimates from conventional Mendelian randomization (MR) analyses can be biased when the genetic variants proposed as instruments vary over age in their relationship with the exposure. For four exposures commonly studied using MR, we assessed the degree to which their relationship with genetic variants commonly used as instruments varies by age using flexible, spline-based models in UK Biobank data. Using these models, we then estimated how biased MR estimates would be due to age-varying relationships using plasmode simulations. We found that most genetic variants had age-varying relationships with the exposure for which they are a proposed instrument. Body mass index and LDL cholesterol had the most variation while alcohol consumption had very little. This variation over age led to small potential biases in some cases (e.g. alcohol consumption and C-reactive protein) and large potential biases for many proposed instruments for BMI and LDL.

scholarly journals Cross-sectional associations between central and general adiposity with albuminuria: observations from 400,000 people in UK Biobank

2020 ◽  
Vol 44 (11) ◽  
pp. 2256-2266
Author(s):  
Pengfei Zhu ◽  
Sarah Lewington ◽  
Richard Haynes ◽  
Jonathan Emberson ◽  
Martin J. Landray ◽  
...  
Keyword(s):  
Measurement Error ◽  
Urinary Albumin ◽  
Glycosylated Haemoglobin ◽  
Creatinine Ratio ◽  
Central Adiposity ◽  
Uk Biobank ◽  
Cross Sectional ◽  
Waist To Hip Ratio ◽  
Baseline Bmi ◽  
General Adiposity

Abstract Background Whether measures of central adiposity are more or less strongly associated with risk of albuminuria than body mass index (BMI), and by how much diabetes/levels of glycosylated haemoglobin (HbA1c) explain or modify these associations, is uncertain. Methods Ordinal logistic regression was used to estimate associations between values of central adiposity (waist-to-hip ratio) and, separately, general adiposity (BMI) with categories of urinary albumin-to-creatinine ratio (uACR) in 408,527 UK Biobank participants. Separate central and general adiposity-based models were initially adjusted for potential confounders and measurement error, then sequentially, models were mutually adjusted (e.g. waist-to-hip ratio adjusted for BMI, and vice versa), and finally they were adjusted for potential mediators. Results Levels of albuminuria were generally low: 20,425 (5%) had a uACR ≥3 mg/mmol. After adjustment for confounders and measurement error, each 0.06 higher waist-to-hip ratio was associated with a 55% (95%CI 53–57%) increase in the odds of being in a higher uACR category. After adjustment for baseline BMI, this association was reduced to 32% (30–34%). Each 5 kg/m2 higher BMI was associated with a 47% (46–49%) increase in the odds of being in a higher uACR category. Adjustment for baseline waist-to-hip ratio reduced this association to 35% (33–37%). Those with higher HbA1c were at progressively higher odds of albuminuria, but positive associations between both waist-to-hip ratio and BMI were apparent irrespective of HbA1c. Altogether, about 40% of central adiposity associations appeared to be mediated by diabetes, vascular disease and blood pressure. Conclusions Conventional epidemiological approaches suggest that higher waist-to-hip ratio and BMI are independently positively associated with albuminuria. Adiposity–albuminuria associations appear strong among people with normal HbA1c, as well as people with pre-diabetes or diabetes.

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