| Title: | Clonal Hematopoiesis of Indeterminate Potential and Genetic Susceptibility in Incident Age-Related Macular Degeneration: A Cohort Study |
| Journal: | American Journal of Ophthalmology |
| Published: | 8 Jul 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42419444/ |
| DOI: | https://doi.org/10.1016/j.ajo.2026.07.008 |
Publication 20410
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
PURPOSE: While inherited genetics strongly influence AMD risk, clonal hematopoiesis of indeterminate potential (CHIP), an age-related condition driven by somatic mutations and inflammation, is a novel, biologically plausible risk factor. Prospective evidence exploring their interplay with AMD incidence is lacking.</p>
DESIGN: Prospective cohort study.</p>
PARTICIPANTS: We conducted a prospective cohort study among 395,505 participants from the UK Biobank.</p>
METHODS: CHIP was defined by somatic mutations (variant allele fraction ≥2%) in leukemia-associated driver genes from blood-derived exome sequencing. A polygenic risk score (PRS) for AMD was calculated using established genetic variants. We used Cox proportional hazards models to assess the independent and joint associations of CHIP and PRS with incident AMD.</p>
MAIN OUTCOME MEASURES: Age-related macular degeneration.</p>
RESULTS: During a median follow-up of 15.5 years, we documented 7,178 incident AMD cases. CHIP was associated with a 14% higher risk of incident AMD (HR: 1.14; 95% CI: 1.03, 1.26; P=0.009). Gene-specific analyses showed significant associations for mutations in DNMT3A (HR: 1.20; 95% CI: 1.06, 1.36; P=0.005), spliceosome genes (HR: 1.72; 95% CI: 1.02, 2.97; P=0.042), and DNA damage repair genes (HR: 1.68; 95% CI: 1.06, 2.67; P=0.028). A high AMD PRS was also associated with AMD risk. Participants with both any CHIP and a high PRS had a 3.26-fold higher risk (95% CI: 2.75, 3.86; P<0.001) compared to those with neither, with evidence of additive interaction (relative excess risk due to interaction [RERI] = 0.60; 95% CI: 0.07, 1.20). The joint effect was also strongest for DNMT3A mutation carriers with high PRS (HR: 3.69; 95% CI: 2.58, 3.96; P<0.001; RERI = 0.34; 95% CI: 0.04, 1.12). These synergistic effects were more pronounced in older adults.</p>
CONCLUSION: CHIP was an independent risk factor for incident AMD. The risk is amplified in individuals with high genetic susceptibility, suggesting a synergistic interplay between inherited genetic risk and somatic clonal expansion in AMD pathogenesis, with the strongest effects observed in older adults. These findings provide a rationale for future efforts to integrate somatic mutation status into risk stratification paradigms for AMD, especially among the elderly.</p>
9 Authors
- Fu-Rong Li
- Ming-Ji Peng
- Kang-Qian Lin
- Ying Zhou
- Fang-Lan Yuan
- Cui-Yi Jin
- Hao Luo
- Li Yu
- Wei Chi
1 Application
| Application ID | Title |
|---|---|
| 627915 | Influence of Risk Factors in Chronic Disease Development and Progression |
Enabling scientific discoveries that improve human health