Body mass index and adipose distribution have opposing genetic impacts on human blood traits.

Christopher S Thom,Benjamin F Voight,Stella T Chou,Madison B Wilken

doi:10.7554/elife.75317

Abstract

Body mass index (BMI), hyperlipidemia, and truncal adipose distribution concordantly elevate cardiovascular disease risks, but have unknown genetic effects on blood trait variation. Using Mendelian randomization, we define unexpectedly opposing roles for increased BMI and truncal adipose distribution on blood traits. Elevated genetically determined BMI and lipid levels decreased hemoglobin and hematocrit levels, consistent with clinical observations associating obesity and anemia. We found that lipid-related effects were confined to erythroid traits. In contrast, BMI affected multiple blood lineages, indicating broad effects on hematopoiesis. Increased truncal adipose distribution opposed BMI effects, increasing hemoglobin and blood cell counts across lineages. Conditional analyses indicated genes, pathways, and cell types responsible for these effects, including Leptin Receptor and other blood cell-extrinsic factors in adipocytes and endothelium that regulate hematopoietic stem and progenitor cell biology. Our findings identify novel roles for obesity on hematopoiesis, including a previously underappreciated role for genetically determined adipose distribution in determining blood cell formation and function.

Highlights

46 47 Blood cell homeostasis is achieved through incompletely understood coordination of blood cell48 intrinsic gene regulation and blood cell-extrinsic environmental mechanisms (Comazzetto et al, 2021; Ulirsch et al, 2019)
Using Mendelian randomization (MR), we found that each standard deviation (SD) unit increase in body mass index (BMI) caused a 0.057 SD decrease in HGB levels by the inverse variance weighted method (p=1.0x10-5) that was directionally consistent across sensitivity analyses without evidence of horizontal pleiotropy or weak instrument bias (Figure 1a, Figure 1-figure supplement 1a, Supplementary file 1-Table 1)
Similar effects were observed for hematocrit (HCT, Figure 1b and Figure 1-figure supplement 1b), suggesting BMI is genetically linked with reduced hemoglobin. 110 Cholesterol levels impact erythroid traits independent of BMI 111 112 We investigated previously proposed mechanisms to explain observational links between 113 BMI and anemia

Summary

Introduction

46 47 Blood cell homeostasis is achieved through incompletely understood coordination of blood cell intrinsic gene regulation and blood cell-extrinsic environmental mechanisms (Comazzetto et al, 2021; Ulirsch et al, 2019). 56 Adipocytes and endothelial cells within the bone marrow environment regulate hematopoiesis (Comazzetto et al, 2021; Zhong et al, 2020). White adipose tissue has a derogatory effect on hematopoiesis, whereas mesenchymal-derived bone marrow adipocyte populations support blood cell formation (Comazzetto et al, 2021; Cuminetti and Arranz, 2019; Wang et al, 2018; Zhong et al, 2020). 63 Single nucleotide polymorphisms (SNPs) that genetically increase body mass index (BMI) raise metabolic and cardiovascular disease risks (Pulit et al, 2019). Some observational studies have linked obesity (BMI >30 kg/m2 (Aigner et al, 2014)) or hypercholesterolemia (Shalev et al, 2007) with anemia. Genetic relationships have not been elucidated for BMI on erythroid or other blood traits. Like BMI, WHR influences cardiovascular risks (Huang et al, 2021; Pulit et 70 al., 2019), but genetic impacts of WHR on blood traits are unknown

Methods

Results

Conclusion