Genome-wide association study using the Hybrid Rat Diversity Panel identifies loci for cardiac-resident macrophage...

Cardiac-resident macrophages (Mφs) play critical roles in both cardiac physiology and pathophysiology. These cells comprise a heterogeneous population; yet, the frequencies of distinct subsets, as well as the factors regulating their abundances, remain poorly understood. In this study, we sought to determine whether the frequencies of cardiac-resident Mφ subpopulations are influenced by genetic background and to identify genetic loci underlying these cell frequencies. Using the Hybrid Rat Diversity Panel, a powerful systems genetics resource, we measured frequencies of monocyte-derived CCR2^HIGH versus CCR2^- cardiac-resident Mφs, and independently measured the frequency of CD169⁺ Mφs, a specialized resident Mφ subpopulation that largely overlaps with the CCR2^- population thought to be at least in part embryonically derived, across 74 female inbred rat strains. Our results reveal substantial natural variation in the frequencies of all Mφ subsets queried across strains, indicating a genetic contribution to their distribution. Genome-wide association (GWA) mapping identified suggestive and significant loci associated with CCR2^HIGH, CCR2^-, and CD169⁺ Mφ frequencies. We identified four loci that overlapped in the CCR2^- and CD169⁺ frequencies, providing replicative data that identify genetic loci associated with a Mφ phenotype of possible embryonic rather than hematopoietic origin. Collectively, these findings demonstrate that genetic background influences the relative frequencies of cardiac Mφ subpopulations within the heart and illustrate the utility of the HRDP for investigating complex traits.