Association of DNA repair polymorphisms with DNA repair functional outcomes in healthy human subjects.
We investigated association between polymorphisms in DNA repair genes and the capacity to repair DNA damage induced by gamma-irradiation and by base oxidation in a healthy population. Irradiation-specific DNA repair rates were significantly decreased in individuals with XRCC1 Arg399Gln homozygous variant genotype (0.45 +/- 0.47 SSB/10(9) Da) than in those with wild-type genotype (1.10 +/- 0.70 SSB/10(9) Da, P=0.0006, Mann-Witney U-test). The capacity to repair oxidative DNA damage was significantly decreased among individuals with hOGG1 Ser326Cys homozygous variant genotype (0.37 +/- 0.28 SSB/10(9) Da) compared to those with wild-type genotype (0.83 +/- 0.79 SSB/10(9) Da, P=0.008, Mann-Witney U-test). Investigation of genotype combinations showed that the increasing number of variant alleles for both XRCC1 Arg399Gln and APE1 Asn148Glu polymorphisms resulted in a significant decrease of irradiation-specific repair rates (P=0.008, Kruskal-Wallis test). Irradiation-specific DNA repair rates also decreased with increasing number of variant alleles in XRCC1 Arg399Gln in combination with variant alleles for two other XRCC1 polymorphisms, Arg194Trp and Arg280His (P=0.002 and P=0.005, respectively; Kruskal-Wallis test). In a binary combination variant alleles of hOGG1 Ser326Cys and APE1 Asn148Glu polymorphisms were associated with a significant decrease in the capacity to repair DNA oxidative damage (P=0.018, Kruskal-Wallis test). In summary, XRCC1 Arg399Gln and hOGG1 Ser326Cys polymorphisms seem to exert the predominant modulating effect on irradiation-specific DNA repair capacity and the capacity to repair DNA oxidative damage, respectively.
Vodicka
Pavel
P
Institute of Experimental Medicine, Videnska 1083, 14200, Academy of Sciences of the Czech Republic, Prague, Czech Republic. pvodicka@biomed.cas.cz
Stetina
Rudolf
R
Polakova
Veronika
V
Tulupova
Elena
E
Naccarati
Alessio
A
Vodickova
Ludmila
L
Kumar
Rajiv
R
Hanova
Monika
M
Pardini
Barbara
B
Slyskova
Jana
J
Musak
Ludovit
L
De Palma
Giuseppe
G
Soucek
Pavel
P
Hemminki
Kari
K
D000328:Adult; D019943:Amino Acid Substitution; D004249:DNA Damage; D017931:DNA Primers; D004260:DNA Repair / Q000235:genetics* / Q000528:radiation effects; D005091:Exons; D005260:Female; D005720:Gamma Rays; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D011110:Polymorphism, Genetic; D012016:Reference Values; D012907:Smoking
D017931:DNA Primers