Environment-Wide Association Studies of Anemia in the National Health and Nutrition Examination Surveys

Background: Anemia is a global health problem that can lead to chronic illness in adults and may be fatal in children and the elderly. While some dietary factors and heavy metals are known risk factors for anemia, there are no environment-wide studies of anemia. Objectives: Our goal was to identify environment-wide risk factors for anemia. Methods: We evaluated general anemia in children and adults and further classified anemia as a) iron, vitamin B12, or folate deficiency anemia; b) anemia in general chronic diseases; and c) anemia in chronic kidney disease. As well as quantitative measures including level of hemoglobin, serum vitamin B12, red blood cell (RBC) folate, and serum iron. Environment-wide association studies (EWAS) were performed to identify novel environmental risk factors of anemia in discovery and replication subsets of the National Health and Nutrition Examination Surveys (NHANES). Results: We identified and replicated 106 potential environmental risk factors for anemia. As expected, serum iron was the top exposure associated with general anemia for adults. Cadmium was associated with adult hemoglobin levels, as were vitamin Bs, micronutrients, smoking, and alcohol consumption. Further, decreased levels of multiple vitamins, including vitamin A, vitamin Es and multiple vitamin Bs, were associated with general anemia in adults. Use of tobacco and alcohol was also found to be associated with red blood cell folate and serum iron levels. In children, serum iron level was associated with folic acid supplements and vitamin A supplements. Discussion: This is the first EWAS of anemia, providing insights into the environmental etiology of anemia risk in children and adults. These results may lead to the development of public health recommendations to mitigate anemia risk factors. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The authors sincerely acknowledge the financial support from the USDA National Institute of Food and Agriculture and Hatch Appropriations under Project #PEN04275 and Accession #1018544 to Molly A. Hall. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Only existing public dataset was used. The NHANES is a public dataset published by the Centers for Disease Control and Prevention (CDC). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes For replication of our study, we provide links in the Supplementary file to all the raw data files, the R codes in R Markdown format (.Rmd), and corresponding reports (.nb.html), and all the results that were generated by using the R codes.