The SOD2 Val/Val genotype enhances the risk of nonsmall cell lung carcinoma by p53 and XRCC1 polymorphisms.
ABSTRACT Exogenous reactive oxygen species (ROS) induces DNA damage. Manganese superoxide dismutase (SOD2) catalyzes the dismutation of superoxide radicals, a major type of ROS, into hydrogen peroxide. p53 is a tumor suppressor gene, and X-ray cross-complementing group 1 (XRCC1) is involved in the base-excision repair of ROS-induced DNA damage.
The authors investigated whether the SOD2 Ala16Val polymorphism modifies the associations between p53 Arg72Pro and XRCC1 Arg399Gln polymorphisms and the risk of nonsmall cell lung carcinoma (NSCLC) in a case-control study of 935 Caucasian patients with NSCLC and 1233 healthy control participants. The results were analyzed using logistic regression models that were adjusted for possible confounding variables.
There was no association between p53 or XRCC1 polymorphism and NSCLC risk for individuals with SOD2 Ala/Ala or Ala/Val genotype. For individuals with the SOD2 Val/Val genotype, greater risks were found in association with p53 (variant Pro allele vs. Arg/Arg), XRCC1 (variant Gln allele vs. Arg/Arg), and the combination of the two polymorphisms ("double variant" vs. "double wild type"), with the adjusted odds ratios (ORs) of 1.84 (95% confidence interval [95% CI], 1.20-2.82), 1.39 (95% CI, 0.98-2.21), and 2.54 (95% CI, 1.38-4.68), respectively. Furthermore, the greater risk for the double variant of p53 and XRCC1 in the SOD2 Val/Val genotype group was specific only for patients with adenocarcinoma and not for patients with squamous cell carcinoma, with adjusted ORs of 3.31 (95% CI, 1.68-6.51) and 0.69 (95% CI, 0.24-2.02), respectively.
The SOD2 Val/Val genotype may increase the risk of NSCLC carried by XRCC1 and p53 polymorphisms, particularly for adenocarcinoma.
[show abstract] [hide abstract]
ABSTRACT: The SOD2 gene encodes an antioxidant enzyme, mitochondrial superoxide dismutase. SOD2 polymorphisms are of interest because of their potential roles in the modulation of free radical-mediated macromolecular damage during aging. We identified a new splice variant of SOD2 in human lymphoblastoid cell lines (LCLs). The alternatively spliced product was originally detected by exon trapping of a minigene in order to examine the consequences of an intronic polymorphism found upstream of exon 4 (nucleotide 8136, 10T vs 9T). Examination of the transcripts derived from the endogenous loci in five LCLs with or without the intron 3 polymorphism revealed low levels of an in-frame deletion of exon 4 that were different from those detected by the exon trap assay. This suggested that exon trapping of the minigene unmasked the effect of the 10T vs 9T polymorphism on the splicing of the adjacent exon. We also determined the frequencies of single nucleotide polymorphisms in a sample of US African-Americans and non-African-Americans ages 65 years and older who participated in the 1999 wave of the National Long Term Care Survey (NLTCS). Particularly striking differences between African-Americans and non-African-Americans were found for the frequencies of genotypes at the 10T/9T intron 3 polymorphism. Exon trapping can unmask in vitro splicing differences caused by a 10T/9T intron 3 polymorphism. Given the recent evidence that SOD2 is in a region on chromosome 6 linked to susceptibility to hypertension, it will be of interest to investigate possible associations of this polymorphism with cardiovascular disorders.BMC Medical Genetics 02/2007; 8:7. · 2.33 Impact Factor