Using genetics to detangle the relationships between red cell distribution width and cardiovascular diseases: a unique role for body mass index

Abstract

ObjectiveRed 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.MethodsUsing 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.ResultsIn 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.ConclusionsRDW 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.

Red cell distribution width and its polygenic score in relation to mortality and cardiometabolic outcomes

“…The authors suggested that relationship between RDW and cardiovascular outcomes may partly be related to aging ( 43 ). Another previous study ( 18 ) showed non-significant relationships between genetically-increased-RDW and CVDs. In accordance with the previous studies, we did not find any significant relationship between PGS-RDW and CVDs in this study with individual follow-up data.…”

“…Several potential mechanisms were proposed to contribute to these associations, such as inflammation ( 6 ) and oxidative stress ( 7 ), which could affect red blood cell (RBC) production and erythropoiesis, and thereby RDW. There are also some previous studies of genetically predicted-RDW in relation to CVDs ( 12 , 18 , 43 , 44 ). A study from the UK Biobank reported that genetically increased RDW was not predictive for incident cardiovascular disease.…”

“…PGS is becoming popular in predicting complex diseases such as type-2 diabetes, coronary artery disease and inflammatory bowel disease ( 17 ). Association between PGS for RDW and cardiovascular diseases has also been examined in an interesting cross-sectional study suggesting the possibility of using genetic susceptibility to infer causal relationships ( 18 ).…”

Exploring regression dilution bias using repeat measurements of 2858 variables in ≤49 000 UK Biobank participants

“… 22–30 Of these, previous studies using Mendelian randomization suggest a causal effect of higher CRP on schizophrenia, though not cardiovascular disease, cancers or several other chronic diseases, and of 25(OH)D on all-cause and cancer mortality. 31–34 Furthermore, all may be accurate predictors for premature mortality and correction for random error is important whether the multivariable regression analysis is exploring causality or just association.…”

Metabolomic markers mediate erythrocyte anisocytosis in older adults: Results from three independent aging cohorts

“…Anisocytosis can be assessed clinically using the metric of red blood cell distribution width (RDW), which provides information on the degree of heterogeneity or variation of erythrocyte volume and size. RDW over 14% is considered abnormal, and high RDW has been consistently associated with adverse outcomes, such as cardiovascular disease, metabolic syndrome, and mortality [2][3][4][5][6][7][8]. RDW has also been proposed as an inflammatory marker because it is associated with tumor necrosis factor-alpha and interleukin 6.…”