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 alpha-carotene and trans-/cis-beta-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-bcarotene (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. (C) 2018 Elsevier B.V. All rights reserved.