Evidence for significant heritability of apoptotic and cell cycle responses to ionising radiation.
Genetic factors are likely to affect individual cancer risk, but few quantitative estimates of heritability are available. Public health radiation protection policies do not in general take this potentially important source of variation in risk into account. Two surrogate cellular assays that relate to cancer susceptibility have been developed to gain an insight into the role of genetics in determining individual variation in radiosensitivity. These flow cytometric assays for apoptosis induction and cell cycle delay following radiation are sufficiently sensitive to distinguish lymphocytes from a healthy donor population from those of a sample of obligate carriers of ATM mutations (P = 0.01 and P = 0.02, respectively). Analysis of 54 unselected twin pairs (38 dizygotic, 16 monozygotic) indicated much greater intrapair correlation in response in monozygotic than in dizygotic pairs. Structural equation modelling indicated that models including unique environmental factors only fitted the data less well than those incorporating two or more of additive genetic factors, common environmental factors and unique environmental factors. A model incorporating additive genetic factors and unique environmental factors yielded estimates of heritability for the two traits of 68% (95% CI 40-82%, cell cycle) and 59% (95% CI 22-79%, apoptosis). Thus, these data suggest that genetic factors contribute significantly to human variation in these two measures of radiosensitivity that relate to cancer susceptibility.
Finnon
Paul
P
Radiation Protection Division, Health Protection Agency, Centre for Radiation, Chemical and Environmental Hazards, Chilton, Didcot, Oxfordshire, OX11 0RQ, UK.
Robertson
Naomi
N
Dziwura
Sylwia
S
Raffy
Claudine
C
Zhang
Wei
W
Ainsbury
Liz
L
Kaprio
Jaakko
J
Badie
Christophe
C
Bouffler
Simon
S
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000235:genetics* / Q000528:radiation effects*; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000235:genetics* / Q000528:radiation effects*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000528:radiation effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000528:radiation effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000528:radiation effects; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000528:radiation effects; D014429:Twins, Dizygotic; D014430:Twins, Monozygotic; D014965:X-Rays
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases