Bloom Syndrome Patients Display Accelerated Epigenetic Aging in Blood Lymphocytes

Bloom Syndrome (BSyn) is an autosomal recessive disorder caused by variants in the BLM genes at locus 15q26.1. The BLM gene encodes a protein that is part of the DNA RECQ helicase family, which has a role in homologous recombination, DNA structural integrity, DNA repair responses, and telomere maintenance. Patients with BSyn present with poor growth, sun sensitivity, mild immunodeficiency, diabetes, and increased risk of cancer, most commonly leukemias. Additionally, patients with BSyn develop myelodysplasia and life-threatening side effects from standard chemotherapy and radiation, often due to bone marrow toxicity.

Cells from patients with BSyn display increased sister chromatid exchange, telomere defects, and telomere-dependent chromosome fusions. Despite these aging-associated findings, patients with BSyn do not appear to have typical premature aging characteristics such as graying hair, osteoporosis, and early-onset cardiovascular disease. We hypothesized that patients with BSyn may have increased epigenetic aging in blood, which may be related to their increased risk of hematologic dysfunction and malignancies. In this study, we aimed to use DNA methylation in order to identify an aging signature that could be a potential biomarker of disease risk.

In partnership with the Bloom Syndrome Registry (BSR) as well as JScreen and our own clinical practice, we extracted 49 DNA samples from blood lymphocytes of patients with BSyn as well as carriers. The samples were then processed per standard Illumina protocol for the Infinium MethylationEPIC BeadChip kit. We utilized the online DNA Methylation Age Calculator (https://dnamage.genetics.ucla.edu/) to calculate multiple measures of methylation aging for each patient, including the Horvath pan-tissue epigenetic clock DNAmAge, the Hannum clock, the GrimAge lifespan predictor, and the PhenoAge phenotypic age estimate. Simple linear regression was used to determine statistical significance.

Of the 49 total samples, 18 samples were from patients with BSyn (ages 1-38 years) and 31 samples were from carriers with one variant in BLM (ages 23-69 years). We discovered that BSyn patients had increased DNAm age compared to carriers measured by the pan-tissue clock (p=0.0054). Similarly, epigenetic clocks that were designed to predict human mortality risk (GrimAge and PhenoAge) indicate significant age acceleration as well, p<0.0088 and p<0.0001 respectively. Finally, DNA methylation-based estimators of telomere length show significantly shorter telomere lengths in BSyn patients compared to carriers, p<0.0001.

Epigenetic age can be a better predictor of health and disease over biologic or chronologic age. In this study, we show for the first time that patients with BSyn have evidence of epigenetic aging across several measures in blood lymphocytes. Future studies are ongoing to investigate underlying mechanisms for this and whether epigenetic aging in these patients can predict hematologic dysfunction and cancer risk.

Cunniff:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Moderna: Membership on an entity's Board of Directors or advisory committees; Biogen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Horvath:Epigenetic Clock Development Foundation: Membership on an entity's Board of Directors or advisory committees.