Author + information
- Xiaodong Zhuang1,2,
- Yanbo Shen3,4,
- Yue Guo1,2,
- Ao Ni3,4,
- Yunxi Jiang3,4,
- Xueqin Wang3,4 and
- Xinxue Liao1,2
- 1Cardiology department, first affiliated hospital of Sun Yat-Sen University
- 2Key Laboratory on Assisted Circulation, Ministry of Health
- 3Joint Institute of Engineering, Sun Yat-Sen University, Carnegie Mellon University
- 4Department of Statistical Science, School of Mathematics and Computational Science, Sun Yat-Sen University
Lower extremity peripheral arterial diseases (PAD) are caused by a complex combination of many genetic and environmental factors. Few methods are available to comprehensively associate specific physical environmental factors with disease. We conducted a pilot Environmental-Wide Association Study (EWAS), in which epidemiological data are comprehensively and systematically interpreted in a manner analogous to a Genome Wide Association Study.
We utilized available Centers for Disease Control (CDC) National Health and Nutrition Examination Survey (NHANES) cohorts from years 1999 to 2004, which evaluated a total of 6819 participants to prioritize environmental factors associated with PAD. We performed multiple cross-sectional analyses associating 258 unique environmental factors with clinical status for PAD defined by ankle-brachial index (ABI) <1.00 or >1.4. Logistic regression models were adjusted for age, sex, body mass index, poverty index, and ethnicity; we estimated the false discovery rate to adjust for multiple hypotheses.
After correlating 258 variables with ABI, we found 10 variables significantly associated with ABI (<1.00 or >1.4) consistently showed a false discovery rate <0.05 after adjustment for multiple hypotheses. Of these variables, 7 were positively associated with PAD, including biomarkers of blood cadmium, 2-isopropoxyphenol, o-Xylene, urine tungsten, urine mercury, tar content and smoking. Three variables inversely associated with PAD, including biomarkers of urine thallium, total mercury and physical activity.
Despite difficulty in ascertaining causality, the potential for novel factors of large effect associated with PAD justify the use of EWAS to create hypotheses regarding the broad contribution of the environment to disease.