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.