title: Metabolic gene variants associated with chromosomal aberrations in healthy humans.
abstract: Nonspecific chromosomal aberrations (CAs) are found in about 1% of lymphocytes drawn from healthy individuals. They include chromosome-type aberrations (CSAs), which are increased in exposure to ionizing radiation, and chromatid-type aberrations (CTAs) which in experimental systems are formed by DNA binding carcinogens and mutagens. The frequency of CAs is associated with the risk of cancer, but the causes of CAs in general population are unknown. Here, we want to test whether variants in metabolic genes associate with CAs in healthy volunteers. Cases were considered those whose total CA (CAtot) frequency was >2% and for CSA and CTA the limit was >1%. Controls had lower frequencies of CAs. Functional polymorphisms in seven genes were selected for analysis: cytochrome P450 1B1 (CYP1B1), epoxide hydrolase 1 (EPHX1), NAD(P)H:quinone oxidoreductase 1 (NQO1), each coding for phase 1 enzymes, and glutathione S-transferase P1 (GSTP1), glutathione S-transferases M1 (GSTM1) and T1 (GSTT1), coding for enzymes which conjugate reactive metabolites, that is, phase 2 enzymes. The number of volunteers genotyped for each gene varied from 550 to 1,500. Only EPHX1 was individually associated with CAtot; high activity genotypes decreased CAtot. A total of six significant (P < 0.01) pair-wise interactions were observed, most including a GST variant as one of the pair. In all genotype combinations with significant odds ratios for CAs a GST variant was involved. The present data provide evidence that variants in genes coding for metabolic enzymes, which individually have small effects, interact and are associated with CA frequencies in peripheral lymphocytes of healthy volunteers.
authors.affiliation: Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany; Center for Primary Health Care Research, Lund University, Malmö, Sweden.
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Christoph
authors.initials: C
authors.lastname: Frank
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
authors.forename: Ludovit
authors.initials: L
authors.lastname: Musak
authors.forename: Alena
authors.initials: A
authors.lastname: Kazimirova
authors.forename: Magdalena
authors.initials: M
authors.lastname: Barancokova
authors.forename: Alexandra
authors.initials: A
authors.lastname: Horska
authors.forename: Veronika
authors.initials: V
authors.lastname: Vymetalkova
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Smerhovsky
authors.forename: Alessio
authors.initials: A
authors.lastname: Naccarati
authors.forename: Pavel
authors.initials: P
authors.lastname: Soucek
authors.forename: Ludmila
authors.initials: L
authors.lastname: Vodickova
authors.forename: Janka
authors.initials: J
authors.lastname: Buchancova
authors.forename: Bozena
authors.initials: B
authors.lastname: Smolkova
authors.forename: Maria
authors.initials: M
authors.lastname: Dusinska
authors.forename: Pavel
authors.initials: P
authors.lastname: Vodicka
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002869:Chromosome Aberrations; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic; D055815:Young Adult