Introduction:
Both genetic and environmental factors contribute to triglyceride, LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C) levels. While genome-wide association studies test the genetic factors systematically, testing and reporting a few factors may lead to fragmented literature for environmental correlates.
Hypothesis:
We hypothesize that one may systematically screen environmental factors to discover and replicate robust correlations with serum lipid levels. To address this hypothesis, we conduct an environment-wide association study (EWAS) to comprehensively and systematically associate multiple environmental factors with serum lipid levels.
Methods:
We utilized four independent surveys from the National Health and Nutrition Examination Survey (NHANES), collected between 1999 and 2006. 322 urine and blood markers of environmental factors were assayed in 500 to 7000 individuals. We used linear regression to associate each standardized environmental factor (mean subtracted and divided by the standard deviation) to triglycerides, LDL-C, and HDL-C adjusting for age, age-squared, sex, ethnicity, socioeconomic status (SES), and body mass index (BMI). Final estimates were additionally adjusted for waist circumference, diabetes status, blood pressure, and cohort. Multiple comparisons were controlled for the false discovery rate (the estimated ratio of false positives among statistically significant findings). Significant findings were tentatively validated across surveys. Finally, we conducted sensitivity analyses adjusting for 62 questionnaire-based variables in order to assess the degree of bias.
Results:
We identified and validated 22, 8, and 17 environmental factors correlated with triglycerides, LDL-C and HDL-C levels, respectively. Novel associations include markers of air pollution associated with lower HDL-C (p=0.006, 3% lower, N=2000) and vitamin E (-tocopherol) associated with unfavorable lipid levels (triglycerides: p=10
-17
, 17% higher, N=3000; LDL-C: p=3x10
-14
, 6% higher, N=3,000; HDL-C: p=6x10
-6
, 3% lower, N=7000). We also confirmed many known or previously speculated associations, such as lower levels in HDL-C with a marker of nicotine, cotinine, and higher triglycerides and lower HDL-C with levels of persistent fat-soluble contaminants, and lower triglycerides and higher HDL-C levels with nutrient markers such as iron, folate, vitamin C, and vitamin D, and enterolactone.
Conclusions:
EWAS is a way to create hypothesis regarding the association of environmental factors to serum lipids. Due to the cross-sectional nature of the surveys, findings may be biased by confounders or may be reverse causal. Nonetheless, we document a wide array of both known and novel associations, such as nutrients, vitamins, and persistent pollutants, with lipid levels that should be examined in depth in longitudinal studies.
Systematic evaluation of environmental factors: persistent pollutants and nutrients correlated with serum lipid levels