Sarcopenia-related traits and coronary artery disease: a bi-directional Mendelian randomization study

Previous Mendelian randomization (MR) studies have yielded a conflicting causal relationship between sarcopenia and coronary artery disease (CAD), and lack the association of CAD with sarcopenia. We performed a bi-directional MR approach to clarify the causality and causal direction between sarcopenia-related traits and CAD. In stage 1 analysis, estimates of inverse variance weighting (IVW) and several sensitivity analyses were obtained by applying genetic variants that predict sarcopenia-related traits to CAD. Conversely, we also applied genetic variants that predict CAD to sarcopenia-related traits in stage 2 analyses. IVW analysis showed that higher handgrip strength reduces risk for CAD: A 1-kilogram (kg) increase in genetically determined left handgrip strength reduced odds of CAD by 36% [odds ratio (OR) = 0.64, 95% confidence interval (CI) 0.498 - 0.821, p = 4.56E-04], and right handgrip strength reduced odds of CAD by 41.1% (OR = 0.599, 95% CI 0.476 - 0.753, p = 1.10E-05). However, genetically predicted CAD did not show any causal association with handgrip strength, and no significant causal relationship was detected between genetically instrumented body lean mass and CAD. Our results suggest that decreased muscle strength but not decreased muscle mass leads to the increased risk of CAD in sarcopenia.

[1]  Sophie V. Eastwood,et al.  Associations Between Measures of Sarcopenic Obesity and Risk of Cardiovascular Disease and Mortality: A Cohort Study and Mendelian Randomization Analysis Using the UK Biobank , 2019, Journal of the American Heart Association.

[2]  René Rizzoli,et al.  Sarcopenia: revised European consensus on definition and diagnosis , 2018, Age and ageing.

[3]  E. Ingelsson,et al.  Associations of Fitness, Physical Activity, Strength, and Genetic Risk With Cardiovascular Disease: Longitudinal Analyses in the UK Biobank Study , 2018, Circulation.

[4]  B. Neale,et al.  Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases , 2018, Nature Genetics.

[5]  Dylan S. Small,et al.  Statistical inference in two-sample summary-data Mendelian randomization using robust adjusted profile score , 2018, The Annals of Statistics.

[6]  G. Davey Smith,et al.  Orienting the causal relationship between imprecisely measured traits using GWAS summary data , 2017, PLoS genetics.

[7]  G. Sergi,et al.  Measurement of lean body mass using bioelectrical impedance analysis: a consideration of the pros and cons , 2017, Aging Clinical and Experimental Research.

[8]  Stephen C. J. Parker,et al.  Large meta-analysis of genome-wide association studies identifies five loci for lean body mass , 2017, Nature Communications.

[9]  Kyle J. Gaulton,et al.  Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness , 2017, Nature Communications.

[10]  P. Vollenweider,et al.  No association between grip strength and cardiovascular risk: The CoLaus population-based study. , 2017, International journal of cardiology.

[11]  G. Smith,et al.  Mendelian randomization in cardiometabolic disease: challenges in evaluating causality , 2017, Nature Reviews Cardiology.

[12]  Dongfeng Zhang,et al.  Association of Grip Strength With Risk of All-Cause Mortality, Cardiovascular Diseases, and Cancer in Community-Dwelling Populations: A Meta-analysis of Prospective Cohort Studies. , 2017, Journal of the American Medical Directors Association.

[13]  Lin Xu,et al.  Effect of handgrip on coronary artery disease and myocardial infarction: a Mendelian randomization study , 2017, Scientific Reports.

[14]  Kayoung Lee.  Muscle Mass and Body Fat in Relation to Cardiovascular Risk Estimation and Lipid-Lowering Eligibility. , 2017, Journal of clinical densitometry : the official journal of the International Society for Clinical Densitometry.

[15]  Helen E. Parkinson,et al.  The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog) , 2016, Nucleic Acids Res..

[16]  S. Humphries,et al.  Association of Lipid Fractions With Risks for Coronary Artery Disease and Diabetes. , 2016, JAMA cardiology.

[17]  Yoosoo Chang,et al.  Relationship Between Low Relative Muscle Mass and Coronary Artery Calcification in Healthy Adults , 2016, Arteriosclerosis, thrombosis, and vascular biology.

[18]  G. Davey Smith,et al.  Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator , 2016, Genetic epidemiology.

[19]  G. Davey Smith,et al.  Best (but oft-forgotten) practices: the design, analysis, and interpretation of Mendelian randomization studies1 , 2016, The American journal of clinical nutrition.

[20]  Sebastian M. Armasu,et al.  A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease , 2015, Nature Genetics.

[21]  K. Choi,et al.  The Implications of Sarcopenia and Sarcopenic Obesity on Cardiometabolic Disease , 2015, Journal of cellular biochemistry.

[22]  Andrew E Moran,et al.  Demographic and epidemiologic drivers of global cardiovascular mortality. , 2015, The New England journal of medicine.

[23]  Saskia le Cessie,et al.  Mendelian randomization studies: a review of the approaches used and the quality of reporting. , 2015, International journal of epidemiology.

[24]  G. Davey Smith,et al.  Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression , 2015, International journal of epidemiology.

[25]  P. Elliott,et al.  UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Range of Complex Diseases of Middle and Old Age , 2015, PLoS medicine.

[26]  A. Butterworth,et al.  Mendelian Randomization Analysis With Multiple Genetic Variants Using Summarized Data , 2013, Genetic epidemiology.

[27]  J. Danesh,et al.  Large-scale association analysis identifies new risk loci for coronary artery disease , 2012, Nature Genetics.

[28]  George Davey Smith,et al.  Using multiple genetic variants as instrumental variables for modifiable risk factors , 2012, Statistical methods in medical research.

[29]  I. Tabata,et al.  A cross-sectional study of sarcopenia in Japanese men and women: reference values and association with cardiovascular risk factors , 2010, European Journal of Applied Physiology.

[30]  T. Takken,et al.  Is grip strength a predictor for total muscle strength in healthy children, adolescents, and young adults? , 2010, European Journal of Pediatrics.

[31]  George Davey Smith,et al.  Mendelian randomization: Using genes as instruments for making causal inferences in epidemiology , 2008, Statistics in medicine.

[32]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[33]  M. Aubertin-Leheudre,et al.  Effect of Sarcopenia on Cardiovascular Disease Risk Factors in Obese Postmenopausal Women , 2006, Obesity.

[34]  M. B. Katan,et al.  Apolipoprotein E isoforms, serum cholesterol, and cancer , 2004 .

[35]  Sidney C. Smith,et al.  MARKERS OF INFLAMMATION AND CARDIOVASCULAR DISEASE: APPLICATION TO CLINICAL AND PUBLIC HEALTH PRACTICE: A STATEMENT FOR HEALTHCARE PROFESSIONALS FROM THE CENTERS FOR DISEASE CONTROL AND PREVENTION AND THE AMERICAN HEART ASSOCIATION , 2003 .

[36]  M. Visser,et al.  Validity of fan-beam dual-energy X-ray absorptiometry for measuring fat-free mass and leg muscle mass. Health, Aging, and Body Composition Study--Dual-Energy X-ray Absorptiometry and Body Composition Working Group. , 1999, Journal of applied physiology.