16 - Obesity and Adipose Distribution Impact Genetically Determined Blood Traits

Poster Number: 16
Publication Number: 16.110

Christopher S. Thom, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Madison B. Wilken, Childrens Hospital of Philadelphia, Philadelphia, PA, United States; Stella T. Chou, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States; Benjamin F. Voight, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States

Background: Obesity afflicts a growing number of children and adults. Related comorbidities are incompletely understood. For example, clinical observations link obesity (body mass index, BMI, >30 kg/m2) with anemia, but it is unclear if these 1) reflect direct causal effects and/or 2) extend to other blood cell traits. We hypothesized that adipose tissue type and location may explain these findings. Increased BMI or truncal adiposity (waist-hip ratio, WHR) raise cardiovascular disease risk (Fig).

Objective: Here, we aimed to define causal genetic effects of BMI and WHR on blood traits and reveal related mechanisms.

Design/Methods: Mendelian randomization (MR), akin to a “genetic randomized controlled trial”, uses variants linked to an exposure trait to estimate causal effects on a given outcome. Random variant allocation at meiosis enables MR to address confounding and reverse causality that otherwise preclude causal inference from observational studies. Multivariable MR and mediation analyses can reveal traits using common genetic mechanisms. Our study used gender- and age-adjusted genome wide association study summary statistics from European individuals

Results: We hypothesized that increased BMI would decrease HGB. Indeed, we found that per 5 kg/m2 increased BMI, HGB decreased by 0.06±0.01 g/dL (p=1x10-5, Fig). Increased BMI also decreased erythrocyte, platelet and white blood cell counts (all with p< 5x10-3). Coordinate effects across lineages suggested BMI effects on hematopoietic progenitor cells (HPCs) that spawn mature blood cells (Fig).
 
We thought altered adipose distribution (WHR) may help explain BMI-related effects. Certain adipose tissues (e.g., bone marrow adipocytes) regulate HPCs and hematopoiesis. In surprising contrast to BMI, increased WHR increased HGB (0.08±0.02 g/dL, p=9x10-6) as well as erythrocyte, platelet, and white cell counts (all with p< 4x10-3, Fig). Multivariable experiments confirmed that WHR effects functioned through common pathways with BMI, and helped identify putatively responsible genes (e.g., LepR and RAPGEF3), pathways, and tissue types (e.g., bone marrow).Conclusion(s): Higher BMI causally decreases hemoglobin, confirming related anemia risk, and affects multilineage blood traits. These effects are mediated by genetic predisposition to low WHR (peripheral or bone marrow adipose tissue accumulation). Future work will examine how adipose location and type impacts hematopoiesis, and explore genes and mechanisms driving profound effects of obesity on pediatric health and maternal-infant dyads, including novel BMI-related effects on hematopoiesis.
Effects of obesity and adipose distribution on blood traitsFigure. Increased genetically determined body mass index (BMI) decreases hemoglobin (HGB), red blood cell (RBC), platelet (PLT) and white blood cell (WBC) counts, suggesting effects on hematopoietic progenitor cells (HPCs) common to these mature cell types. Like BMI, increased waist-hip ratio (WHR) increases cardiovascular disease risk. However, increased WHR has opposite effects on blood traits, increasing HGB and cell counts. Created with BioRender.com.