Περίληψη:
It is becoming increasingly evident that single-locus effects cannot
explain complex multifactorial human diseases like cancer. We applied
the multi-factor dimensionality reduction (MDR) method to a large cohort
study on gene-environment and gene-gene interactions. The study
(case-control nested in the EPIC cohort) was established to investigate
molecular changes and genetic susceptibility in relation to air
pollution and environmental tobacco smoke (ETS) in non-smokers. We have
analyzed 757 controls and 409 cases with bladder cancer (n = 124), lung
cancer (n = 116) and myeloid leukemia (n = 169). Thirty-six gene
variants (DNA repair and metabolic genes) and three environmental
exposure variables (measures of air pollution and ETS at home and at
work) were analyzed. Interactions were assessed by prediction error
percentage and cross-validation consistency (CVC) frequency. For lung
cancer, the best model was given by a significant gene-environment
association between the base excision repair (BER) XRCC1-Arg399Gln
polymorphism, the double-strand break repair (DSBR) BRCA2-Asn372His
polymorphism and the exposure variable ‘distance from heavy traffic
road’, an indirect and robust indicator of air pollution (mean
prediction error of 26%, P < 0.001, mean CVC of 6.60, P = 0.02). For
bladder cancer, we found a significant 4-loci association between the
BER APE1-Asp148Glu polymorphism, the DSBR RAD52-3’-untranslated region
(3’-UTR) polymorphism and the metabolic gene polymorphisms
COMT-Val158Met and MTHFR-677C > T (mean prediction error of 22%, P <
0.001, mean CVC consistency of 7.40, P < 0.037). For leukemia, a 3-loci
model including RAD52-2259C > T, MnSOD-Ala9Val and CYP1A1-Ile462Val had
a minimum prediction error of 31% (P < 0.001) and a maximum CVC of 4.40
(P = 0.086). The MDR method seems promising, because it provides a
limited number of statistically stable interactions; however, the
biological interpretation remains to be understood.
Συγγραφείς:
Manuguerra, M.
Matullo, G.
Veglia, F.
Autrup, H. and
Dunning, A. M.
Garte, S.
Gormally, E.
Malaveille, C. and
Guarrera, S.
Polidoro, S.
Saletta, F.
Peluso, M. and
Airoldi, L.
Overvad, K.
Raaschou-Nielsen, O. and
Clavel-Chapelon, F.
Linseisen, J.
Boeing, H.
Trichopoulos,
D.
Kalandidi, A.
Palli, D.
Krogh, V.
Tumino, R. and
Panico, S.
Bueno-De-Mesquita, H. B.
Peeters, P. H.
Lund, E.
and Pera, G.
Martinez, C.
Amiano, P.
Barricarte, A. and
Tormo, M. J.
Quiros, J. R.
Berglund, G.
Janzon, L. and
Jarvholm, B.
Day, N. E.
Allen, N. E.
Saracci, R.
Kaaks,
R.
Ferrari, P.
Riboli, E.
Vineis, P.
