Heritability of DNA-damage-induced apoptosis and its relationship with age in lymphocytes from female twins

Abstract

Apoptosis is a physiological form of cell death important in normal processes such as morphogenesis and the functioning of the immune system. In addition, defects in the apoptotic process play a major role in a number of important areas of disease, such as autoimmune diseases and cancer. DNA-damage-induced apoptosis plays a vital role in the maintenance of genomic stability by the removal of damaged cells. Previous studies of the apoptotic response (AR) to radiation-induced DNA damage of lymphoid cells from individuals carrying germline TP53 mutations have demonstrated a defective AR compared with normal controls. We have also previously demonstrated that AR is reduced as individuals age. Results from the current study on 108 twins aged 18-80 years confirm these earlier findings that the AR of lymphoid cells to DNA damage is significantly reduced with increasing age. In addition this twin study shows, for the first time, that DNA-damage-induced AR has a strong degree of heritability of 81% (95% confidence interval 67-89%). The vital role of DNA-damage-induced apoptosis in maintaining genetic stability, its relationship with age and its strong heritability underline the importance of this area of biology and suggest areas for further study.

Figure 1

Apoptotic data for two identical twin pairs is shown above. The histograms were produced by gating data from 10 000 cells per plot using forward and 90° light scatter to remove contaminating monocytes and pulse height/width of the DNA signal to remove cell clumps from the analysis. The left hand panels illustrate results for mock-irradiated cells and the right-hand panels show data following 4 Gy irradiation. The AR for each individual was calculated by subtracting the percentage of apoptotic cells for mock-irradiated cells from the percentage following 4 Gy irradiation. As can be seen, twin pair A had an AR of around 40%, while twin pair B had an AR of 70%.

Figure 2

Relationship between AR to 4 Gy irradiation and age in years (a regression coefficient of −0.277, P-value=0.007, R²=0.1505).

Figure 3

Illustrates the relationship between twin pairs for (A) DZ twins –correlation 0.58 P=0.002) and (B) MZ twins – correlation 0.87 (P=0.001).