CHIP and hips: clonal hematopoiesis is common in patients undergoing hip arthroplasty and is associated with autoimmune disease

Abstract

Clonal hematopoiesis (CH) is an age-related condition predisposing to blood cancer and cardiovascular disease (CVD). Murine models demonstrate CH-mediated altered immune function and proinflammation. Low-grade inflammation has been implicated in the pathogenesis of osteoarthritis (OA), the main indication for total hip arthroplasty (THA). THA-derived hip bones serve as a major source of 'healthy' hematopoietic cells in experimental hematology. We prospectively investigated frequency and clinical associations of CH in 200 patients without known hematologic disease undergoing THA. Prevalence of CH was 50%, including 77 patients with CH of indeterminate potential (CHIP, defined as somatic variants with allele frequencies [VAF] ≥2%), and 23 patients harboring CH with lower mutation burden (VAF 1-2%). Most commonly mutated genes were DNMT3A (29.5%), TET2 (15.0%) and ASXL1 (3.5%). CHIP significantly associated with lower hemoglobin, higher mean corpuscular volume, prior/present malignant disease, and CVD. Strikingly, we observed a previously unreported association of CHIP with autoimmune diseases (AID; multivariate adjusted odds ratio, 6.6; 95% confidence interval [1.7, 30]; p=0.0081). These findings underscore the association between CH and inflammatory diseases. Our results have considerable relevance for management of patients with OA and AID or mild anemia, and question use of hip bone-derived cells as 'healthy' experimental controls.

Nature or Nurture? Role of the Bone Marrow Microenvironment in the Genesis and Maintenance of Myelodysplastic Syndromes

“…Although ChIP itself is not considered a malignant stage, at least for now, population-based studies using wholeexome sequencing technology, have revealed~10-fold increased relative risk of developing myeloid malignancies over several years of follow-up in ChIP cases [15][16][17]. Furthermore, researchers have also observed a previously unreported association of ChIP with autoimmune diseases, such as in osteoarthritis patients [18]. Existence of clonal populations in the bone marrow, typically identified by the expansion of more than one genetically distinct cell populations, is increasingly being viewed as a phenomenon named 'inflammaging', the age-associated surge in systemic inflammation (Figure 1).…”

Autophagy in mesenchymal progenitors protects mice against bone marrow failure after severe intermittent stress

“…In the healthy samples aged over 60 years, the presence of clonal hematopoiesis was excluded by targeted sequencing of 68 genes recurrently mutated in hematologic malignancies. 16 Furthermore, BM samples were obtained from patients with different BM failure states, such as SDS, an inherited BM failure syndrome, hypocellular MDS, or severe aplastic anemia. We also included 3 samples from leukemia/lymphoma patients undergoing allogeneic HSCT, 2 of which had received total body irradiation as part of their conditioning regimen, which may contribute to niche damage, and the third patient showed incomplete BM reconstitution after transplant (likely due to extensive pretreatment) (supplemental Table 2).…”

Immune Phenomena in Myeloid Neoplasms: An “Egg or Chicken” Question

“…It is known that mutational burden increases with age, as described in the so called clonal hematopoiesis of indeterminate potential (CHIP) or clonal cytopenia of undetermined significante (CCUS). Recently, DNMT3A, TET2 and ASXL1 mutations were found in 29.5%, 15.0% and 3.5% of studied patients, with a striking association with autoimmune diseases (38). Regarding BMF, a variable combination of somatic mutations has been largely described: in MDS the most frequently observed involve the splicing genes SF3B1, SRSF2, U2AF1, ZRSR2, the DNA methylation genes DNMT3A, TET2, IDH1, IDH2, and the chromatin modification genes ASXL1, EZH2, KDM6A (39).…”