Genetically determined telomere length and risk for haematologic diseases: results from large prospective cohorts and Mendelian Randomization analysis - Report - MDSpire
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Genetically determined telomere length and risk for haematologic diseases: results from large prospective cohorts and Mendelian Randomization analysis
Inherited Telomere Length and Hematologic Disease Risk: Mendelian Randomization Insights
Overview
This study utilized Mendelian randomization to investigate the causal relationship between genetically determined telomere length, epigenetic age acceleration, and the risk of various hematologic diseases. Findings revealed that increased telomere length is associated with higher risks of multiple hematologic malignancies, while epigenetic age acceleration showed mixed associations with specific blood cancers.
Background
Telomere attrition and epigenetic modifications are key molecular markers of aging and have been implicated in the development of hematologic diseases. Previous observational studies on telomere length and hematologic disease risk have yielded conflicting results. Epigenetic age acceleration (EAA), a measure of biological aging deviation from chronological age, has been linked to increased risk of several health conditions but has not been systematically evaluated in hematologic disorders. This study aimed to clarify these relationships using Mendelian randomization approaches with genetic instrumental variables.
Data Highlights
Hematologic Disease
OR per 1-SD Increase in Telomere Length
95% CI
P-value
Lymphoid Leukaemia
2.4249
1.4933–3.9377
0.0003
Acute Lymphocytic Leukaemia
2.8931
1.2466–6.7145
0.0134
Chronic Lymphocytic Leukaemia
2.1969
1.0122–4.7681
0.0465
Essential Thrombocythaemia
2.1647
1.1774–3.9799
0.0129
Malignant Immunoproliferative Diseases
3.7905
1.3200–10.8853
0.0133
Hodgkin Lymphoma
2.2305
1.2354–4.0273
0.0078
Non-Hodgkin Lymphoma
1.7558
1.1604–2.6567
0.0077
Non-follicular Lymphoma
1.4877
1.0816–2.0463
0.0146
Other/Unspecified Non-Hodgkin Lymphoma
1.7887
1.0840–2.9515
0.0229
Multiple Myeloma and Malignant Plasma Cell Neoplasms
1.6458
1.0328–2.6225
0.0361
Key Findings
Genetically increased telomere length is significantly associated with higher odds of 10 out of 21 hematologic malignancies, including lymphoid leukaemia and Hodgkin lymphoma.
Epigenetic age acceleration measured by GrimAge showed no causal association with hematologic disease risk.
Hannum age acceleration was linked to a decreased risk of chronic myeloid leukaemia.
PhenoAge acceleration was associated with increased risks of myeloid leukaemia, chronic lymphocytic leukaemia, and lymphoid leukaemia.
DNAm PAI-1 levels showed marginally significant association with increased chronic myeloid leukaemia risk.
Findings were consistent across discovery and validation cohorts and supported by multiple Mendelian randomization methods without evidence of pleiotropy or heterogeneity.
Clinical Implications
These results suggest that inherited longer telomere length may predispose individuals to certain hematologic malignancies, highlighting telomere biology as a potential target for risk stratification and therapeutic intervention. Epigenetic age acceleration markers may have differential roles in hematologic disease risk, warranting further investigation. Clinicians should consider genetic telomere length as a factor in hematologic disease risk assessment.
Conclusion
This Mendelian randomization study provides robust evidence that genetically determined longer telomere length causally increases the risk of multiple hematologic malignancies, while epigenetic aging markers show variable associations. These insights enhance understanding of aging-related mechanisms in hematologic disease pathogenesis.
References
UK Biobank/2020 -- Large-scale population-based cohort study
FinnGen/2021 -- GWAS summary statistics for hematologic diseases
GWAS Meta-analysis/2023 -- Genetic associations of biological aging
