Age-related macular degeneration in individuals with clonal hematopoiesis.

Abstract

6517 Background: Clonal hematopoiesis (CH), an age-related condition involving somatic mutations in blood stem cells, increases the risk of myelodysplastic syndrome (MDS), blood cancers and cardiovascular disease through inflammatory pathways. Age-related macular degeneration (AMD), the leading cause of blindness in the developed world, is also characterized by chronic inflammation. An increased prevalence of AMD has been observed in older adults with MDS, but the association between CH and AMD remains unexplored. Understanding this relationship could reveal shared inflammatory mechanisms in age-related diseases and guide prevention strategies. Methods: This retrospective cohort study used exome sequencing and electronic medical records (EMRs) from 467,200 adults ≥40 years of age in the UK Biobank (UKB), recruited between 2006–2010 and followed until 2020. Participants with prevalent blood cancer, AMD, or with missing AMD diagnosis dates were excluded. CH was defined as pathogenic somatic mutations with a variant allele fraction (VAF) ≥0.02. Incident AMD was identified using ICD-10 codes (H35.3). Kaplan-Meier estimates and log-rank tests assessed cumulative incidence, while Cox regression models calculated hazard ratios (HRs), adjusted for age, sex, smoking and hypertension. A separate cohort of 4,079 patients from Dana-Farber Cancer Institute (DFCI) validated findings and enabled granular clinical data abstraction from EMRs. Results: CH was detected in 29,550 (6.8%) individuals of the UKB. The 12-year cumulative incidence (C.I.) of AMD was higher in individuals with CH (n=671, C.I. 2.45%) compared to those without (n=6,728, 1.61%; p<2x10-16). In unadjusted Cox models, individuals with CH had a 51% higher risk of AMD compared to those without (HR =1.51 (95% CI: 1.39–1.63; p < 2×10⁻¹⁶), remaining significant after adjusting for covariates (p=0.023). CH genotypes most associated with AMD risk included ASXL1 (HR: 1.32; p = 0.0146) and splicing factors (HR: 1.54; p = 0.0345). Individuals with CH and AMD had a 33% higher risk of progressing to blindness compared to those without CH, though this was not statistically significant (p = 0.242). In the DFCI cohort (n= 4,079), CH was present in 1,028 (25.2%) individuals. 86 (8.37%) individuals with CH had AMD diagnoses compared to those without CH (n= 86, 3.21%; p = 2.53×10⁻¹⁰), with exudative AMD, a more severe subtype, being more prevalent in CH patients (n=11; p = 1.1×10⁻⁵). Conclusions: There is a significant association between CH and AMD, suggesting that AMD prevalent in individuals with MDS is related to presence of CH in the pre-MDS state. Real world data support these findings, highlighting a trend towards severe AMD subtypes in individuals with CH. The identification of specific genes linked to AMD incidence suggests that certain CH genotypes may confer a higher risk for AMD, highlighting the role of AMD screening in individuals with myeloid malignancy precursor conditions.