RT Journal Article SR Electronic T1 Using genetics to detangle the relationships between red cell distribution width and cardiovascular diseases: a unique role for body mass index JF Open Heart JO Open Heart FD British Cardiovascular Society SP e001713 DO 10.1136/openhrt-2021-001713 VO 8 IS 2 A1 Timothy E Thayer A1 Shi Huang A1 Eric Farber-Eger A1 Joshua A Beckman A1 Evan L Brittain A1 Jonathan D Mosley A1 Quinn S Wells YR 2021 UL http://openheart.bmj.com/content/8/2/e001713.abstract AB Objective Red cell distribution width (RDW) is an enigmatic biomarker associated with the presence and severity of multiple cardiovascular diseases (CVDs). It is unclear whether elevated RDW contributes to, results from, or is pleiotropically related to CVDs. We used contemporary genetic techniques to probe for evidence of aetiological associations between RDW, CVDs, and CVD risk factors.Methods Using an electronic health record (EHR)-based cohort, we built and deployed a genetic risk score (GRS) for RDW to test for shared genetic architecture between RDW and the cardiovascular phenome. We also created GRSs for common CVDs (coronary artery disease, heart failure, atrial fibrillation, peripheral arterial disease, venous thromboembolism) and CVD risk factors (body mass index (BMI), low-density lipoprotein, high-density lipoprotein, systolic blood pressure, diastolic blood pressure, serum triglycerides, estimated glomerular filtration rate, diabetes mellitus) to test each for association with RDW. Significant GRS associations were further interrogated by two-sample Mendelian randomisation (MR). In a separate EHR-based cohort, RDW values from 1-year pre-gastric bypass surgery and 1–2 years post-gastric bypass surgery were compared.Results In a cohort of 17 937 subjects, there were no significant associations between the RDW GRS and CVDs. Of the CVDs and CVD risk factors, only genetically predicted BMI was associated with RDW. In subsequent analyses, BMI was associated with RDW by multiple MR methods. In subjects undergoing bariatric surgery, RDW decreased postsurgery and followed a linear relationship with BMI change.Conclusions RDW is unlikely to be aetiologically upstream or downstream of CVDs or CVD risk factors except for BMI. Genetic and clinical association analyses support an aetiological relationship between BMI and RDW.Data are available on reasonable request. All data were derived from Vanderbilt University Medical Center’s (VUMC) deidentified electronic health record, as such, the individual-level data are not available on request unless approved by VUMC.