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Susanna C. Larsson - One of the best experts on this subject based on the ideXlab platform.

  • Sleep Duration and Stroke: Prospective Cohort Study and Mendelian Randomization Analysis.
    Stroke, 2020
    Co-Authors: Olga E. Titova, Karl Michaëlsson, Susanna C. Larsson
    Abstract:

    Background and Purpose: Studies of sleep duration in relation to specific types of stroke are scarce. Moreover, the results are inconclusive and causality remains unclear. Our objective was to inve...

  • Homocysteine and small vessel stroke : A Mendelian Randomization Analysis
    Annals of neurology, 2019
    Co-Authors: Susanna C. Larsson, Matthew Traylor, Hugh S. Markus
    Abstract:

    Objective Trials of B vitamin therapy to lower blood total homocysteine (tHcy) levels for prevention of stroke are inconclusive. Secondary analyses of trial data and epidemiological studies suggest that tHcy levels may be particularly associated with small vessel stroke (SVS). We assessed whether circulating tHcy and B vitamin levels are selectively associated with SVS, but not other stroke subtypes, using Mendelian Randomization. Methods We used summary statistics data for single-nucleotide polymorphisms (SNPs) associated with tHcy (n = 18), folate (n = 3), vitamin B6 (n = 1), and vitamin B12 (n = 14) levels, and the corresponding data for stroke from the MEGASTROKE consortium (n = 16,952 subtyped ischemic stroke cases and 404,630 noncases). Results Genetically predicted tHcy was associated with SVS, with an odds ratio of 1.34 (95% confidence interval [CI], 1.13-1.58; p = 6.7 × 10-4 ) per 1 standard deviation (SD) increase in genetically predicted tHcy levels, but was not associated with large artery or cardioembolic stroke. The association was mainly driven by SNPs at or near the MTHFR and MUT genes. The odds ratios of SVS per 1 SD increase in genetically predicted folate and vitamin B6 levels were 0.49 (95% CI, 0.34-0.71; p = 1.3 × 10-4 ) and 0.70 (95% CI, 0.52-0.94; p = 0.02), respectively. Genetically higher vitamin B12 levels were not associated with any stroke subtype. Interpretation These findings suggest that any effect of homocysteine-lowering treatment in preventing stroke will be confined to the SVS subtype. Whether genetic variants at or near the MTHFR and MUT genes influence SVS risk through pathways other than homocysteine levels and downstream effects require further investigation. Ann Neurol 2019;85:495-501.

  • Branched-chain amino acids and Alzheimer's disease: a Mendelian Randomization Analysis.
    Scientific reports, 2017
    Co-Authors: Susanna C. Larsson, Hugh S. Markus
    Abstract:

    We conducted a two-sample Mendelian Randomization study to test the hypothesis that raised plasma levels of the branched-chain amino acids isoleucine, leucine, and valine are associated with Alzheimer's disease (AD). From a genome-wide association study of 16,596 individuals of European ancestry, we obtained summary statistics for four independent single nucleotide polymorphisms (SNPs) associated with isoleucine levels and one SNP associated with both leucine and valine levels at genome-wide significance. Summary statistics of the associations of the five SNPs with AD were obtained from the International Genomics of Alzheimer's Project (17,008 AD cases and 37,154 controls). Based on four SNPs, the odds ratio of AD per genetically predicted one standard deviation higher isoleucine levels was 1.35 (95% CI, 1.08-1.69; p = 0.007). The leucine- and valine-raising allele was not associated with AD (p = 0.46). These data suggest that a genetic predisposition to raised plasma isoleucine levels is positively associated with AD.

Hugh S. Markus - One of the best experts on this subject based on the ideXlab platform.

  • Modifiable Lifestyle Factors and Risk of Stroke: A Mendelian Randomization Analysis.
    Stroke, 2021
    Co-Authors: Eric L Harshfield, Marios K. Georgakis, Rainer Malik, M Dichgans, Hugh S. Markus
    Abstract:

    Background and Purpose: Assessing whether modifiable risk factors are causally associated with stroke risk is important in planning public health measures, but determining causality can be difficul...

  • Modifiable lifestyle factors and risk of stroke: a Mendelian Randomization Analysis
    2020
    Co-Authors: Eric L Harshfield, Marios K. Georgakis, Rainer Malik, M Dichgans, Hugh S. Markus
    Abstract:

    ABSTRACT Aims Assessing whether modifiable risk factors are causally associated with reduced stroke risk is important in planning public health measures, but determining causality can be difficult in epidemiological data. Leveraging large-scale genetic data in a technique known as Mendelian randomisation, we aimed to determine whether modifiable lifestyle factors including educational attainment, smoking, and body mass index are causal risk factors for ischaemic stroke and its different subtypes and haemorrhagic stroke. Methods and Results We performed two-sample and multivariable Mendelian Randomization to assess the causal effect of twelve lifestyle factors on risk of stroke and whether these effects are independent. We found genetic predisposition to increased number of years of education to be inversely associated with ischaemic, large-artery, and small-vessel stroke, as well as with intracerebral haemorrhage. Genetic predisposition to ever smoking regularly, higher body mass index (BMI), and higher waist-hip ratio are also associated with ischaemic and large-artery stroke. Additionally, we found that the effects of education, BMI, and smoking on ischaemic stroke to be independent of each other. Conclusion Genetic predisposition to higher educational attainment can reduce the risk of ischaemic, large-artery, and small-vessel stroke, while genetic predisposition to smoking and higher anthropometry measures can increase the risk of these stroke subtypes. This suggests that lifestyle modification addressing these risk factors will reduce stroke risk.

  • Homocysteine and small vessel stroke : A Mendelian Randomization Analysis
    Annals of neurology, 2019
    Co-Authors: Susanna C. Larsson, Matthew Traylor, Hugh S. Markus
    Abstract:

    Objective Trials of B vitamin therapy to lower blood total homocysteine (tHcy) levels for prevention of stroke are inconclusive. Secondary analyses of trial data and epidemiological studies suggest that tHcy levels may be particularly associated with small vessel stroke (SVS). We assessed whether circulating tHcy and B vitamin levels are selectively associated with SVS, but not other stroke subtypes, using Mendelian Randomization. Methods We used summary statistics data for single-nucleotide polymorphisms (SNPs) associated with tHcy (n = 18), folate (n = 3), vitamin B6 (n = 1), and vitamin B12 (n = 14) levels, and the corresponding data for stroke from the MEGASTROKE consortium (n = 16,952 subtyped ischemic stroke cases and 404,630 noncases). Results Genetically predicted tHcy was associated with SVS, with an odds ratio of 1.34 (95% confidence interval [CI], 1.13-1.58; p = 6.7 × 10-4 ) per 1 standard deviation (SD) increase in genetically predicted tHcy levels, but was not associated with large artery or cardioembolic stroke. The association was mainly driven by SNPs at or near the MTHFR and MUT genes. The odds ratios of SVS per 1 SD increase in genetically predicted folate and vitamin B6 levels were 0.49 (95% CI, 0.34-0.71; p = 1.3 × 10-4 ) and 0.70 (95% CI, 0.52-0.94; p = 0.02), respectively. Genetically higher vitamin B12 levels were not associated with any stroke subtype. Interpretation These findings suggest that any effect of homocysteine-lowering treatment in preventing stroke will be confined to the SVS subtype. Whether genetic variants at or near the MTHFR and MUT genes influence SVS risk through pathways other than homocysteine levels and downstream effects require further investigation. Ann Neurol 2019;85:495-501.

  • Branched-chain amino acids and Alzheimer's disease: a Mendelian Randomization Analysis.
    Scientific reports, 2017
    Co-Authors: Susanna C. Larsson, Hugh S. Markus
    Abstract:

    We conducted a two-sample Mendelian Randomization study to test the hypothesis that raised plasma levels of the branched-chain amino acids isoleucine, leucine, and valine are associated with Alzheimer's disease (AD). From a genome-wide association study of 16,596 individuals of European ancestry, we obtained summary statistics for four independent single nucleotide polymorphisms (SNPs) associated with isoleucine levels and one SNP associated with both leucine and valine levels at genome-wide significance. Summary statistics of the associations of the five SNPs with AD were obtained from the International Genomics of Alzheimer's Project (17,008 AD cases and 37,154 controls). Based on four SNPs, the odds ratio of AD per genetically predicted one standard deviation higher isoleucine levels was 1.35 (95% CI, 1.08-1.69; p = 0.007). The leucine- and valine-raising allele was not associated with AD (p = 0.46). These data suggest that a genetic predisposition to raised plasma isoleucine levels is positively associated with AD.

George Davey Smith - One of the best experts on this subject based on the ideXlab platform.

  • Prescription Opioid Use and Risk for Major Depressive Disorder and Anxiety and Stress-Related Disorders: A Multivariable Mendelian Randomization Analysis.
    JAMA psychiatry, 2021
    Co-Authors: Daniel B. Rosoff, George Davey Smith, Falk W. Lohoff
    Abstract:

    Importance Growing evidence suggests that prescription opioid use affects depression and anxiety disorders; however, observational studies are subject to confounding, making causal inference and determining the direction of these associations difficult. Objective To investigate the potential bidirectional associations between the genetic liability for prescription opioid and other nonopioid pain medications and both major depressive disorder (MDD) and anxiety and stress-related disorders (ASRD) using genetically based methods. Design, Setting, and Participants We performed 2-sample Mendelian Randomization (MR) using summary statistics from genome-wide association studies (GWAS) to assess potential associations of self-reported prescription opioid and nonopioid analgesics, including nonsteroidal anti-inflammatories (NSAIDs) and acetaminophen-like derivatives use with MDD and ASRD. The GWAS data were derived from participants of predominantly European ancestry included in observational cohorts. Data were analyzed February 20, 2020, to May 4, 2020. Main Outcomes and Measures Major depressive disorder, ASRD, and self-reported pain medications (opioids, NSAIDs, anilides, and salicylic acid). Results The GWAS data were derived from participants of predominantly European ancestry included in the population-based UK Biobank and Lundbeck Foundation Initiative for Integrative Psychiatric Research studies: approximately 54% of the initial UK Biobank sample and 55.6% of the Lundbeck Foundation Initiative for Integrative Psychiatric Research sample selected for the ASRD GWAS were women. In a combined sample size of 737 473 study participants, single-variable MR showed that genetic liability for increased prescription opioid use was associated with increased risk of both MDD (odds ratio [OR] per unit increase in log odds opioid use, 1.14; 95% CI, 1.06-1.22;P  Conclusions and Relevance The findings of this Mendelian Randomization Analysis suggest evidence for potential causal associations between the genetic liability for increased prescription opioid use and the risk for MDD and ASRD. While replication studies are necessary, these findings may inform prevention and intervention strategies directed toward the opioid epidemic and depression.

  • Mendelian Randomization Analysis of the causal effect of adiposity on hospital costs.
    Journal of health economics, 2020
    Co-Authors: Padraig Dixon, Neil M Davies, William Hollingworth, Sean Harrison, George Davey Smith
    Abstract:

    Estimates of the marginal effect of measures of adiposity such as body mass index (BMI) on healthcare costs are important for the formulation and evaluation of policies targeting adverse weight profiles. Most estimates of this association are affected by endogeneity bias. We use a novel identification strategy exploiting Mendelian Randomization - random germline genetic variation modelled using instrumental variables - to identify the causal effect of BMI on inpatient hospital costs. Using data on over 300,000 individuals, the effect size per person per marginal unit of BMI per year varied according to specification, including £21.22 (95% confidence interval (CI): £14.35-£28.07) for conventional inverse variance weighted models to £18.85 (95% CI: £9.05-£28.65) for penalized weighted median models. Effect sizes from Mendelian Randomization models were larger in most cases than non-instrumental variable multivariable adjusted estimates (£13.47, 95% CI: £12.51-£14.43). There was little evidence of non-linearity. Within-family estimates, intended to address dynastic biases, were imprecise.

  • Circulating selenium and prostate cancer risk: A Mendelian Randomization Analysis
    Journal of the National Cancer Institute, 2018
    Co-Authors: James Yarmolinsky, Carolina Bonilla, Philip C Haycock, Ryan Langdon, Luca A. Lotta, Claudia Langenberg, Caroline L Relton, Sarah J Lewis, David M. Evans, George Davey Smith
    Abstract:

    In the Selenium and Vitamin E Cancer Prevention Trial (SELECT), selenium supplementation (causing a median 114 μg/L increase in circulating selenium) did not lower overall prostate cancer risk, but increased risk of high-grade prostate cancer and type 2 diabetes. Mendelian Randomization Analysis uses genetic variants to proxy modifiable risk factors and can strengthen causal inference in observational studies. We constructed a genetic instrument comprising 11 single nucleotide polymorphisms robustly (P < 5 × 10-8) associated with circulating selenium in genome-wide association studies. In a Mendelian Randomization Analysis of 72 729 men in the PRACTICAL Consortium (44 825 case subjects, 27 904 control subjects), 114 μg/L higher genetically elevated circulating selenium was not associated with prostate cancer (odds ratio [OR] = 1.01, 95% confidence interval [CI] = 0.89 to 1.13). In concordance with findings from SELECT, selenium was weakly associated with advanced (including high-grade) prostate cancer (OR = 1.21, 95% CI = 0.98 to 1.49) and type 2 diabetes (OR = 1.18, 95% CI = 0.97 to 1.43; in a type 2 diabetes genome-wide association study meta-Analysis with up to 49 266 case subjects and 249 906 control subjects). Our Mendelian Randomization analyses do not support a role for selenium supplementation in prostate cancer prevention and suggest that supplementation could have adverse effects on risks of advanced prostate cancer and type 2 diabetes.

  • Circulating selenium and prostate cancer risk: a Mendelian Randomization Analysis
    2017
    Co-Authors: James Yarmolinsky, Carolina Bonilla, Philip C Haycock, Ryan Langdon, Luca A. Lotta, Claudia Langenberg, Caroline L Relton, Sarah J Lewis, David M. Evans, George Davey Smith
    Abstract:

    In the Selenium and Vitamin E Cancer Prevention Trial (SELECT), selenium supplementation (causing a median 114 μg/L increase in circulating selenium) did not lower overall prostate cancer risk, but increased risk of high-grade prostate cancer and type 2 diabetes. Mendelian Randomization Analysis uses genetic variants to proxy modifiable risk factors and can strengthen causal inference in observational studies. We constructed a genetic risk score comprising eleven single-nucleotide polymorphisms robustly ( P -8 ) associated with circulating selenium in genome-wide association studies. In a Mendelian Randomization Analysis of 72,729 men in the PRACTICAL Consortium (44,825 cases, 27,904 controls), 114 μg/L higher genetically-elevated circulating selenium was not associated with prostate cancer (OR: 1.01; 95% CI: 0.89-1.13). Concordant with findings from SELECT, selenium was weakly associated with advanced (including high-grade) prostate cancer (OR: 1.21; 95% CI: 0.98-1.49) and type 2 diabetes (OR: 1.18; 95% CI: 0.97-1.43; in a type 2 diabetes GWAS meta-Analysis with up to 49,266 cases, 249,906 controls). Mendelian Randomization mirrored the outcome of selenium supplementation in SELECT and may offer an approach for the prioritization of interventions for follow-up in large-scale randomized controlled trials.

  • Exploring causal associations of alcohol with cardiovascular and metabolic risk factors in a Chinese population using Mendelian Randomization Analysis.
    Scientific reports, 2015
    Co-Authors: Amy E Taylor, David Carslake, Yun Qian, Sijun Liu, Jiaping Chen, Hongbing Shen, George Davey Smith
    Abstract:

    Observational studies suggest that moderate alcohol consumption may be protective for cardiovascular disease, but results may be biased by confounding and reverse causality. Mendelian Randomization, which uses genetic variants as proxies for exposures, can minimise these biases and therefore strengthen causal inference. Using a genetic variant in the ALDH2 gene associated with alcohol consumption, rs671, we performed a Mendelian Randomization Analysis in 1,712 diabetes cases and 2,076 controls from Nantong, China. Analyses were performed using linear and logistic regression, stratified by sex and diabetes status. The A allele of rs671 was strongly associated with reduced odds of being an alcohol drinker in all groups, but prevalence of alcohol consumption amongst females was very low. The A allele was associated with reduced systolic and diastolic blood pressure and decreased total and HDL cholesterol in males. The A allele was also associated with decreased triglyceride levels, but only robustly in diabetic males. There was no strong evidence for associations between rs671 and any outcomes in females. Our results suggest that associations of alcohol consumption with blood pressure and HDL-cholesterol are causal. Alcohol also appeared to have adverse effects on triglyceride levels, although this may be restricted to diabetics.

Tao Huang - One of the best experts on this subject based on the ideXlab platform.

  • Abstract P656: Cardioembolic Risk Factors and Ischemic Stroke a Mendelian Randomization Analysis
    Stroke, 2021
    Co-Authors: Danyang Tian, Tao Huang, Linjing Zhang, Zhenhuang Zhuang, Dongsheng Fan
    Abstract:

    Background: Cardioembolic stroke accounts for a large proportion of ischemic stroke. Observational studies have shown that several risk factors are associated with cardioembolic stroke. However, whether such associations reflect causality remains unknown. Objectives: We aimed to determine whether established and provisional cardioembolic risk factors are causally associated cardioembolic stroke, and whether they have pathways of causal influence on other ischemic stroke subtypes. Methods: Genetic instruments for atrial fibrillation (AF), myocardial infarction (MI), some electrocardiogram (ECG) indices and NT-pro BNP were obtained from large genetic consortiums. Summarized data of ischemic stroke and its subtypes were extracted from the MEGASTROKE consortium. Causal estimates were calculated by applying inverse variance-weighted Analysis and other methods. Results: Genetically predicted AF was significantly associated with higher odds of ischemic stroke (OR 1.20, 95% CI 1.16-1.24, P=6.53х10 -30 ) and cardioembolic stroke (OR 1.95, 95% CI 1.85-2.06, P=8.81х10 -125 ). Genetically predicted MI was significantly associated with higher odds of large artery stroke (OR 1.487, 95% CI 1.25-1.77, P=9.53х10 -6 ). Suggestive associations were found between genetically determined resting heart rate and higher odds of ischemic stroke (OR 1.01, 95% CI 1.00-1.02, P=0.005), large artery stroke (OR 1.02, 95% CI 1.00-1.04, P=0.026) and cardioembolic stroke (OR 1.02, 95% CI 1.00-1.04, P=0.028). There was no causal association of P-wave terminal force in the precordial lead V1 (PTFVI), P-wave duration (PWD), N-terminal-pro-brain Natriuretic Peptide (NT-pro BNP) or PR interval with ischemic stroke or any subtypes. Conclusion: Genetic predisposition to AF and heart rate are associated with cardioembolic stroke. No evidence of causality relationship of MI, PTFVI, PWD, NT-pro BNP and PR interval on cardioembolic stroke is found.

  • Genetic and Causal Relationship Between Coffee Intake and Cardiometabolic Risks: Cross-Phenotype Association And Mendelian Randomization Analysis
    2020
    Co-Authors: Xinpei Wang, Jinzhu Jia, Tao Huang
    Abstract:

    Abstract Background: Many epidemiological studies have shown that there is a significant association between coffee intake and cardiometabolic diseases, which may be due to the common genetic structure or causal relationship. Methods: We used linkage disequilibrium score regression Analysis to calculate the genetic correlation between coffee intake and 23 cardiometabolic traits (diseases), and then used cross-phenotype association Analysis to identify the shared genetic loci for the trait pairs with significant genetic correlation. Besides, a bi-directional Mendelian Randomization Analysis was used to explore the causal relationship between coffee intake and 23 cardiometabolic traits (diseases).Results: Coffee intake has a significant genetic correlation (after Bonferroni correction) with body mass index (BMI) (Rg = 0.3713, P-value = 4.13ⅹ10-64), body fat percentage (BF%) (Rg = 0.2810, P-value = 1.81ⅹ10-13), type 2 diabetes (T2D) (unadjusted for BMI) (Rg = 0.1189, P-value = 8.80ⅹ10-6), heart failure (HF) (Rg = 0.2626, P-value = 6.00ⅹ10-9), atrial fibrillation (AF) (Rg = 0.1007, P-value = 4.30ⅹ10-5). There are 203, 18, 86, 13, 38 independent shared loci between coffee intake and BMI, BF%, T2D, HF, AF, respectively, among which 22, 2, 23, 4,13 loci do not achieve genome-wide significance in single trait GWAS. Coffee intake has significant causal effect on BMI (b = 0.0717, P-value = 2.33ⅹ10-5), T2D (unadjusted for BMI, OR = 1.27, P-value = 1.46ⅹ10-7), and intracerebral haemorrhage (ICH) (all types ICH: OR = 1.86, P-value = 3.37ⅹ10-4; deep ICH: OR = 2.12, P-value = 2.93ⅹ10-4 ). And BMI (b = 0.3694, P-value=3.64ⅹ10-154), BF% (b = 0.5500, P-value = 1.68ⅹ10-4), T2D (adjusted for BMI, b = -0.0252, P-value = 4.83ⅹ10-6) and triglycerides (TG) (b = -0.1209, P-value = 4.56ⅹ10-15) have significant causal effect on coffee intake.Conclusions: Our study identified the shared genetic structure and causal relationship between coffee intake and several cardiometabolic traits (diseases), providing a new insight into the mechanism of coffee intake and cardiometabolic traits (diseases).

  • Circulating vitamin E and cardiometabolic measures: a Mendelian Randomization Analysis.
    Journal of clinical biochemistry and nutrition, 2019
    Co-Authors: Chuan-long Fan, Tao Huang, Xuejun Kong, Xiaohong Zhang, Zuquan Zou, Jing Xiao
    Abstract:

    Although a large body of literature reported that high intake of vitamin E played a possible role in reducing risk of cardiometabolic diseases, conflicting results were also found in some observational studies due to confounding factors. Hence, we used a Mendelian Randomization study as an alternative way to examine the causality between circulating vitamin E and cardiometabolic diseases. Summary-level data were extracted from consortia and three single nucleotide polymorphisms were used as instrumental variables. Our study showed that a one-SD increase in circulating vitamin E levels was causally associated with an increased risk of coronary artery disease [odds ratio (OR) 3.16 (95%CI 1.74, 5.73); p = 1.91 × 10-3] at the Bonferroni-adjusted level of significance (p

  • circulating vitamin e and cardiometabolic measures a Mendelian Randomization Analysis
    Journal of Clinical Biochemistry and Nutrition, 2019
    Co-Authors: Chuan-long Fan, Tao Huang, Xuejun Kong, Xiaohong Zhang, Zuquan Zou, Jing Xiao
    Abstract:

    Although a large body of literature reported that high intake of vitamin E played a possible role in reducing risk of cardiometabolic diseases, conflicting results were also found in some observational studies due to confounding factors. Hence, we used a Mendelian Randomization study as an alternative way to examine the causality between circulating vitamin E and cardiometabolic diseases. Summary-level data were extracted from consortia and three single nucleotide polymorphisms were used as instrumental variables. Our study showed that a one-SD increase in circulating vitamin E levels was causally associated with an increased risk of coronary artery disease [odds ratio (OR) 3.16 (95%CI 1.74, 5.73); p = 1.91 × 10-3] at the Bonferroni-adjusted level of significance (p<0.005). Moreover, a one-SD increase in circulating vitamin E levels was associated with a 0.572-SD increase in low density lipoprotein cholesterol (mg/dl), a 0.693-SD increase in total cholesterol (mg/dl), and a 1.45-SD increase in triglyceride (mg/dl), but a 0.502-SD decrease in high density lipoprotein cholesterol (mg/dl) at the Bonferroni-adjusted level of significance (p<0.0028). Our findings indicated that genetically elevated vitamin E was associated with increased risk of coronary artery disease, suggesting an adverse causality between circulating vitamin E and coronary artery disease.

  • Dairy intake and body composition and cardiometabolic traits among adults: Mendelian Randomization Analysis of 182041 individuals from 18 studies
    Clinical chemistry, 2019
    Co-Authors: Tao Huang, Mika Kähönen, Vera Mikkilä, Aki S. Havulinna, Jorma Viikari, Olli T. Raitakari, Terho Lehtimäki, Mika Helminen, Noora Kanerva
    Abstract:

    Associations between dairy intake and body composition and cardiometabolic traits have been inconsistently observed in epidemiological studies, and the causal relationship remains ill-defined. We performed Mendelian Randomization Analysis using an established genetic variant located upstream of the lactase gene (LCT-13910 C/T, rs4988235) associated with dairy intake as an instrumental variable (IV). The causal effects of dairy intake on body composition and cardiometabolic traits (lipids, glycemic traits, and inflammatory factors) were quantified by IV estimators among 182041 participants from 18 studies. Each 1 serving/day higher dairy intake was associated with higher lean mass [β (SE) = 0.117 kg (0.035); P = 0.001], higher hemoglobin A1c [0.009% (0.002); P < 0.001], lower LDL [-0.014 mmol/L (0.006); P = 0.013], total cholesterol (TC) [-0.012 mmol/L (0.005); P = 0.023], and non-HDL [-0.012 mmol/L (0.005); P = 0.028]. The LCT-13910 C/T CT + TT genotype was associated with 0.214 more dairy servings/day (SE = 0.047; P < 0.001), 0.284 cm higher waist circumference (SE = 0.118; P = 0.017), 0.112 kg higher lean mass (SE = 0.027; P = 3.8 × 10-5), 0.032 mmol/L lower LDL (SE = 0.009; P = 0.001), and 0.032 mmol/L lower TC (SE = 0.010; P = 0.001). Genetically higher dairy intake was associated with increased lean mass [0.523 kg per serving/day (0.170); P = 0.002] after correction for multiple testing (0.05/18). However, we find that genetically higher dairy intake was not associated with lipids and glycemic traits. The present study provides evidence to support a potential causal effect of higher dairy intake on increased lean mass among adults. Our findings suggest that the observational associations of dairy intake with lipids and glycemic traits may be the result of confounding. © 2019 American Association for Clinical Chemistry.

Stephen Burgess - One of the best experts on this subject based on the ideXlab platform.

  • Association of LPA Variants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies: A Mendelian Randomization Analysis
    JAMA cardiology, 2018
    Co-Authors: Stephen Burgess, Brian A Ference, James R Staley, Daniel F. Freitag, Amy M. Mason, Sune F. Nielsen, Peter Willeit, Robin Young, Praveen Surendran, Savita Karthikeyan
    Abstract:

    Importance: Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk. Objective: To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD. Design, Setting, and Participants: A Mendelian Randomization Analysis was conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018. Exposures: Genetic LPA score and plasma Lp(a) mass concentration. Main Outcomes and Measures: Coronary heart disease. Results: Of the included study participants, 53% were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95% CI, 0.933-0.951; P = 3 × 10−37), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (OR, 0.855; 95% CI, 0.818-0.893; P = 2 × 10−12). Thus, a 101.5-mg/dL change (95% CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk. Conclusions and Relevance: The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (ie, 1 mmol/L).

  • Body mass index and breast cancer survival: a Mendelian Randomization Analysis
    International journal of epidemiology, 2017
    Co-Authors: Qi Guo, Stephen Burgess, Manjeet K. Bolla, Qin Wang, Constance Turman, Michael Lush, Jean Abraham, Kristiina Aittomäki, Irene L. Andrulis, Carmel Apicella
    Abstract:

    The COGS project was funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 - HEALTH-F2-2009-223175). The Breast Cancer Association Consortium (BCAC) is funded by Cancer Research-UK (C1287/A10118 and C1287/A12014). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). ELAN Program of the University Hospital Erlangen (BBCC). Funds from Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects “5x1000” ). D.F.E is a Principal Research Fellow of Cancer Research UK. J.L.H is a National Health and Medical Research Council (NHMRC) Australia Fellow. S.B is supported by a fellowship from the Wellcome Trust (100114). M.C.S. is a NHMRC Senior Research Fellow. G.C.T is an NHMRC Senior Principal Research Fellow. D.L is supported by the FWO and the KULPFV/10/016-SymBioSysII. J.L is a UNESCO-L'Oreal International Fellow. I.L.A. holds the Anne and Max Tanenbaum Chair in Molecular Medicine at Mount Sinai Hospital and the University of Toronto. K.A.P. is an Australian National Breast Cancer Foundation Practitioner Fellow. Further funding details are in the attached Supporting information.

  • Corrigendum: Associations of triglyceride levels with longevity and frailty: A Mendelian Randomization Analysis.
    Scientific reports, 2017
    Co-Authors: Zuyun Liu, Stephen Burgess, Zhengdong Wang, Wan Deng, Xuefeng Chu, Jian Cai, Yinsheng Zhu, Jianming Shi, Xuejuan Xie, Yong Wang
    Abstract:

    Corrigendum: Associations of triglyceride levels with longevity and frailty: A Mendelian Randomization Analysis

  • Associations of triglyceride levels with longevity and frailty: A Mendelian Randomization Analysis.
    Scientific reports, 2017
    Co-Authors: Zuyun Liu, Stephen Burgess, Zhengdong Wang, Wan Deng, Xuefeng Chu, Jian Cai, Yinsheng Zhu, Jianming Shi, Xuejuan Xie, Yong Wang
    Abstract:

    Observational studies suggest associations of triglyceride levels with longevity and frailty. This study aimed to test whether the associations are causal. We used data from the Rugao Longevity and Ageing Study, a population-based cohort study performed in Rugao, China. A variant in the APOA5 gene region (rs662799) was used as the genetic instrument. Mendelian Randomization (MR) analyses were performed to examine the associations of genetically predicted triglycerides with two ageing phenotypes – longevity ( ≥95 years) and frailty (modified Fried frailty phenotype and Rockwood frailty index). C allele of rs662799 was robustly associated with higher triglyceride levels in the comparison group (β = 0.301 mmol/L per allele, p 

  • sensitivity analyses for robust causal inference from Mendelian Randomization analyses with multiple genetic variants
    Epidemiology, 2017
    Co-Authors: Tove Fall, Erik Ingelsson, Jack Bowden, Stephen Burgess, Simon G Thompson
    Abstract:

    Mendelian Randomization investigations are becoming more powerful and simpler to perform, due to the increasing size and coverage of genome-wide association studies and the increasing availability of summarized data on genetic associations with risk factors and disease outcomes. However, when using multiple genetic variants from different gene regions in a Mendelian Randomization Analysis, it is highly implausible that all the genetic variants satisfy the instrumental variable assumptions. This means that a simple instrumental variable Analysis alone should not be relied on to give a causal conclusion. In this article, we discuss a range of sensitivity analyses that will either support or question the validity of causal inference from a Mendelian Randomization Analysis with multiple genetic variants. We focus on sensitivity analyses of greatest practical relevance for ensuring robust causal inferences, and those that can be undertaken using summarized data. Aside from cases in which the justification of the instrumental variable assumptions is supported by strong biological understanding, a Mendelian Randomization Analysis in which no assessment of the robustness of the findings to violations of the instrumental variable assumptions has been made should be viewed as speculative and incomplete. In particular, Mendelian Randomization investigations with large numbers of genetic variants without such sensitivity analyses should be treated with skepticism.