title: Obesity and peripheral arterial disease: A Mendelian Randomization analysis.
abstract: OBJECTIVE
  Observational studies showed that obesity is a major risk factor for peripheral arterial disease (PAD). However, conventional epidemiology studies are vulnerable to residual bias from confounding factors. We aimed to explore the causality of obesity in development of PAD using Mendelian Randomization (MR) approach.
  
  
  METHODS
  A MR analysis was performed in 11,477 community-dwelling adults aged 40 years and above recruited from two nearby communities during 2011-2013 in Shanghai, China. We genotyped 14 body mass index (BMI) associated common variants identified and validated in East Asians. PAD was defined as ankle-to-brachial index (ABI) <0.90 or >1.40. Weighted BMI genetic risk score (GRS) was used as the Instrumental Variable (IV).
  
  
  RESULTS
  After adjusted for confounding factors, we found that each standard deviation (SD, 2.76 points) increase in BMI-GRS was associated with 0.43 (95% confidence interval [CI]: 0.36-0.49) kg/m(2) increase in BMI (P < 0.0001) and an odds ratio (OR) for PAD of 1.17 (95% CI: 1.07-1.27; P = 0.0004). Compared with the lowest quartile of BMI-GRS, the second, third and highest quartile associated with 9%, 19% and 45% increment of PAD risk, respectively (P for trend = 0.002). In the MR analysis, we demonstrated a causal relationship between obesity and PAD (OR = 1.44 per BMI-unit, 95% CI: 1.18-1.75; P = 0.0003).
  
  
  CONCLUSIONS
  This study suggested that obesity may be causally associated with PAD after controlling for the potential intermediate factors like hypertension, dyslipidemia and hyperglycemia.
authors.affiliation: State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine and Shanghai Clinical Center for Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, China; Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine and Shanghai Clinical Center for Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, China; Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Medical Systems Biology Research Center, Tsinghua University School of Medicine, Beijing, 100084, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine and Shanghai Clinical Center for Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, China; Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Tiange
authors.initials: T
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine and Shanghai Clinical Center for Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, China; Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine and Shanghai Clinical Center for Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, China; Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Lv
authors.affiliation: State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine and Shanghai Clinical Center for Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, China; Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine and Shanghai Clinical Center for Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, China; Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine and Shanghai Clinical Center for Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, China; Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine and Shanghai Clinical Center for Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, China; Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Weiqing
authors.initials: W
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine and Shanghai Clinical Center for Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, China; Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Yufang
authors.initials: Y
authors.lastname: Bi
authors.affiliation: Medical Systems Biology Research Center, Tsinghua University School of Medicine, Beijing, 100084, China; National Engineering Research Center for Beijing Biochip Technology, Beijing, 102206, China. Electronic address: ymsun@capitalbio.com.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine and Shanghai Clinical Center for Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, China; Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: feifei-a@163.com.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medical Genomics, Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, National Clinical Research Center for Metabolic Diseases, Collaborative Innovation Center of Systems Biomedicine and Shanghai Clinical Center for Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, China; Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Ning
mesh_terms: D000328:Adult; D015992:Body Mass Index; D016009:Chi-Square Distribution; D002681:China / Q000453:epidemiology; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D016014:Linear Models; D016015:Logistic Models; D057182:Mendelian Randomization Analysis; D015999:Multivariate Analysis; D009765:Obesity / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D016017:Odds Ratio; D058729:Peripheral Arterial Disease / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D010641:Phenotype; D063177:Pulse Wave Analysis; D018570:Risk Assessment; D012307:Risk Factors; D059289:Vascular Stiffness
keywords: Body mass index; Genetic risk score; Mendelian Randomization; Peripheral arterial disease