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Environment-wide association study to identify novel factors associated with peripheral arterial disease: Evidence from the National Health and Nutrition Examination Survey (1999–2004)

  • Author Footnotes
    1 These authors contributed equally to this work.
    Xiaodong Zhuang
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Cardiology Department, First Affiliated Hospital of Sun Yat-Sen University, China

    Key Laboratory on Assisted Circulation, Ministry of Health, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Ao Ni
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Statistical Science, School of Mathematics and Computational Science, Sun Yat-Sen University, China
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  • Lizhen Liao
    Affiliations
    Department of Health, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, China
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  • Yue Guo
    Affiliations
    Cardiology Department, First Affiliated Hospital of Sun Yat-Sen University, China

    Key Laboratory on Assisted Circulation, Ministry of Health, China
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  • Wei Dai
    Affiliations
    Department of Statistical Science, School of Mathematics and Computational Science, Sun Yat-Sen University, China
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  • Yunxi Jiang
    Affiliations
    Department of Statistical Science, School of Mathematics and Computational Science, Sun Yat-Sen University, China
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  • Huimin Zhou
    Affiliations
    Cardiology Department, First Affiliated Hospital of Sun Yat-Sen University, China

    Key Laboratory on Assisted Circulation, Ministry of Health, China
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  • Xun Hu
    Affiliations
    Cardiology Department, First Affiliated Hospital of Sun Yat-Sen University, China

    Key Laboratory on Assisted Circulation, Ministry of Health, China
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  • Zhimin Du
    Affiliations
    Cardiology Department, First Affiliated Hospital of Sun Yat-Sen University, China

    Key Laboratory on Assisted Circulation, Ministry of Health, China
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  • Xueqin Wang
    Correspondence
    Corresponding author. Department of Statistical Science, School of Mathematics and Computational Science, Sun Yat-Sen University, China.
    Affiliations
    Department of Statistical Science, School of Mathematics and Computational Science, Sun Yat-Sen University, China

    Joint Institute of Engineering, Sun Yat-Sen University, Carnegie Mellon University, China
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  • Xinxue Liao
    Correspondence
    Corresponding author. The First Affiliated Hospital of Sun Yat-sen University, China.
    Affiliations
    Cardiology Department, First Affiliated Hospital of Sun Yat-Sen University, China

    Key Laboratory on Assisted Circulation, Ministry of Health, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.

      Highlights

      • Testing associations of single factors with PAD might leading to incomplete understanding of possible factors.
      • Environment-wide association study can prioritize environmental factors for identified novel associations.
      • We provide new knowledge on the complex array of environmental correlates of PAD.

      Abstract

      Background and aims

      An environment-wide association study (EWAS) may be useful to comprehensively test and validate associations between environmental factors and peripheral arterial disease (PAD) in an unbiased manner.

      Methods

      Data from cross-sectional cohorts from the US National Health and Nutrition Examination Survey (1999–2004) were randomly 50:50 split into training set and testing set. A value of ankle-brachial index (ABI) <1.0 or >1.4 defined PAD. We performed multiple linear regression analyses associating each of the 417 environmental and self-reported factors with PAD in the training set (false discovery rate <5%). Significant findings were validated in the testing set (p < 0.05) and entered into a logistic regression model with penalized likelihood based on the Akaike Information Criterion (AIC).

      Results

      Overall, 6819 participants >40 years old were included. The validated factors comprised positive associations with smoking-associated factors (cigarette smoker, family smoker and smoked >100 cigarettes, urinary cotinine), cadmium, urinary albumin, C-reactive protein, blood o-xylene and thyroxine 4, and inverse associations with α-carotene and trans-/cis-β-carotene for PAD. Finally, only 4 of these factors were nominally significant in the AIC-selected model: cadmium (OR 1.27, 95% CI 1.12–1.45), cis-β-carotene (OR 0.81, 95% CI 0.72–0.91), CRP (OR 1.19, 95% CI 1.03–1.38) and urinary albumin (OR 1.20, 95% CI 1.04–1.38).

      Conclusions

      Our systematic evaluation provides new knowledge on the complex array of environmental correlates of PAD. These identified correlates need to be probed in further observational and interventional studies.

      Keywords

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