The functional polymorphism rs73598374:G>A (p.Asp8Asn) of the ADA gene is associated with telomerase activity and leukocyte telomere length

Abstract

Recent evidence demonstrated a relevant role of adenosine deaminase (ADA) in replicative senescence of T cells through its capacity to modulate telomerase activity (TA). Herein, we tested the impact of the functional polymorphism ADA rs73598374:G>A (c.22G>A, p.Asp8Asn) on telomere biology, by measuring TA and leukocyte telomere length (LTL) in healthy subjects selected according to rs73598374 genotype. rs73598374-A carriers showed lower TA (P=0.019) and shorter LTL (P=0.003), respectively, compared to G/G carriers. rs73598374-A carriers showed a stronger cross-sectional age reduction of LTL (r=-0.314, P=0.005) compared to G/G carriers (r=-0.243, P=0.022). The reduced ADA activity associated to rs73598374-A variant predisposes those carriers to display higher levels of adenosine compared to G/G carriers. Consequently, it may lead to an accelerated process of replicative senescence, causing a stronger reduction of TA and in turn shorter LTL. In conclusion, the crucial role played by replicative senescence of the immune system in several human diseases and in the aging process underscores the relevance of the present findings and also spurs interest into the possible involvement of rs73598374 in shaping the susceptibility to several age-related diseases.

Figure 1

Effect of ADA rs73598374:G>A (NM_000022.2:c.22G>A) polymorphism on TA and LTL. Graphs were obtained by general linear model using sex and age as covariates. Dots in the graphs represent the estimated marginal means for the variable under-investigation according to rs73598374 genotypes. Vertical lines represent standard error bars around the point estimates. (a) ADA rs73598374 × TA (b) ADA rs73598374 × LTL.

Figure 2

Correlation between age and LTL. A significant linear inverse correlation with age was observed (r=−0.254, P=0.001).

Figure 3

Cross-sectional age reduction of LTL by the ADA rs73598374:G>A (NM_000022.2:c.22G>A) polymorphism. Regression lines are reported for ADA rs73598374-A carriers (dashed line) and for ADA rs73598374 G/G (solid line).