Clonal Hematopoiesis of Indeterminate Potential and Bone Mineral Density in Cohorts from Trans-Omics for Precision Medicine

Abstract

A somatic mutation causing clonal expansion in hematopoietic stem cells (HSC), but not resulting in hematologic malignancy, is termed clonal hematopoiesis of indeterminate potential (CHIP). CHIP is associated with non-hematologic disorders, including accelerated atherosclerosis, heart failure, ischemic stroke, gout, liver disease, and kidney disease. Because osteoclasts are derived from the macrophage-monocyte lineage of HSCs, changes in the bone marrow niche due to CHIP may drive changes in BMD. To investigate whether CHIP may be related to BMD, we used CHIP mutation calls from the Trans-omics for Precision Medicine (TOPMed) whole genome sequencing data and DXA derived BMD from multiple cohorts. Data from the the Amish cohort, Cardiovascular Health Study, the Framingham Heart Study, San Antonio Family Study, and the Women’s Health Initiative were combined for analysis. Multiple linear regression was used to determine the association between CHIP mutation status and BMD, adjusting for cohort, age, age,2 sex, and, for family-based cohorts, empiric kinship estimated from genotype data. CHIP mutation status was analyzed both as a binary variable (any CHIP mutation) and as an ordinal variable (no CHIP mutation, 1 CHIP mutation in any gene, two or more CHIP mutations in a single gene, two or more CHIP mutations in different genes). A total of 3368 samples had both CHIP and BMD data, and 10.9% of samples contained any CHIP mutation. The presence of any CHIP mutations was not associated with either femoral neck or lumbar spine BMD; however, the presence of two or more CHIP mutations in different genes was positively associated with LSBMD (beta = 0.36, p = .015). We found no overall association between the presence of CHIP mutations and BMD in a large, diverse sample of genomes. Our findings of greater BMD in persons harboring multiple CHIP mutations confirm mouse models demonstrating that Dnmt3a and Tet2 mutations independently cause increased BMD.