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

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.