Introduction
Telomeres are repetitive DNA sequences located at the ends of chromosomes that play a crucial role in maintaining genome integrity and stability. Generally, telomere length (TL) tends to shorten with human physiological aging and is considered an important hallmark of aging(1, 2). Lymphocytes in the blood primarily consist of T cells, B cells, and NK cells, and the proportions of different cell types and their differentiation subsets change with age. As mature myeloid cells are non-dividing cells, while mature lymphocytes undergo extensive cell division during the mediation of their functions, measuring telomere length in lymphocytes holds greater significance(3, 4).
A study on systemic inflammatory diseases, including systemic lupus erythematosus, rheumatoid arthritis, and granulomatous diseases, revealed that alterations in telomerase activity and telomere length were observed in various systemic immune-mediated diseases and appeared to be associated with premature immune aging(5). For a long time, the prevailing viewpoint suggests that shorter telomere contribute to chromosomal instability, which is a shared characteristic of both aging and cancer(2, 6). Recently, two articles presented a paradox at the intersection of aging and cancer biology, both short and long extremes of telomere length appear to mediate two distinct age-associated disease phenotypes, illustrated in the predisposition to B-cell and T-cell lymphoproliferative or immunodeficiency, rather than chromosomal instability(7, 8). However, the relationship between genetically determined telomere length and immune cells remains unclear.
Mendelian randomization (MR) analysis is a genetic epidemiological approach aimed at investigating whether a specific exposure has a causal relationship with a particular outcome. MR utilizes genetic variations closely associated with the exposure as instrumental variables (IV) to infer the causal effect of the exposure on the specific outcome(9). Due to Mendel’s law of inheritance, which states that alleles are randomly allocated from parents to offspring during gamete formation, genetic variations are not influenced by conventional confounding factors. The temporal relationship between genetic variations and outcomes is therefore plausible. Thus, MR minimizes common sources of confounding and reverse causality biases commonly observed in observational studies, providing stronger evidence than observational studies(10, 11).
In this study, we employed a two-sample Mendelian randomization analysis to evaluate the relationship between telomere length and the quantity and function of lymphocytes and their subsets.