After combination study of the three gene-polymorphism, the subjects who were most different with the reference, i.e. had the mutant allele of the GSTP1 and CYP1A1 and homozygous wild type of the MPO, showed approximately 5-fold-higher risk for lung cancer than the reference (95% CI, 2.05-12.05).
Our results are consistent with previous reports and show that homozygotes of the less common A allele of MPO -463 polymorphism have a 2.6-fold lower risk of lung cancer.
Although no significant association between any single genetic variant and lung cancer risk was observed, when genetic variants were analyzed in combination, a significant effect on lung cancer risk was found for the variant allele in a combination of five genes involved in oxidative stress and inflammatory response: GSTM1 (null), MPO (-463A), OGG1 (326Cys), TP53 (72Pro) (alias p53), MMP1 (2G).
Studies focused on GSTT1 null and SOD2 Ala16Val polymorphisms gave conflicting results, while promising results came from studies on alpha1-antitrypsin in asbestosis and MPO in lung cancer.
In this review, we collect and discuss the evidence reported up to date on the association between lung cancer and genetic polymorphism of cytochromes P450, N-acetyltransferase, glutathione S-transferases, microsomal epoxide hydrolase, NAD(P)H:quinone oxidoreductase, myeloperoxidase and glutathione peroxidase.
Combining the MPO -463 (G/A+A/A) genotypes, a protective effect approaching significance (OR = 0.75, 95% CI 0.55-1.01) was observed when comparing all lung cancer cases to controls.
Among genetic polymorphisms reviewed here, myeloperoxidase gene (a G to A mutation) and microsomal epoxide hydrolase exon 4 polymorphism (substitution of Arg for His) were significantly associated with lung cancer risk.
Enzymes involved in generation or detoxification of reactive oxygen species also have to be considered; one of these enzymes, myeloperoxidase, constitutes a relatively strong lung cancer risk factor, as confirmed in 4 independent studies.
MPO 463G>A polymorphism was not associated with lung cancer susceptibility under the condition of recessive genetic model (AA vs. GG+GA) (OR = 0.69, P > 0.05) and homozygous genetic model (AA vs. GG) (OR = 0.65, P > 0.05).
A consistent association has been shown where lung cancer risk is decreased by a G-->A polymorphism in the myeloperoxidase (MPO) gene, which is expressed in neutrophils recruited to the lung after chemical or immunological insults.
Our results demonstrate that the protective effects of the MPO variant allele reduced overall lung cancer risk in Caucasians by 48% (OR = 0.52, 95% CI 0.30-0.90, P = 0.02).
Relative to subjects with the MPO G/G genotype, a significant decreased risk of lung cancer was found for carriers of the G/A genotype [odds ratio (OR) = 0.5, 95% confidence interval (CI): 0.29-0.88].
These data provide a plausible biological explanation for the reduced risk for lung cancer as observed in MPO -463AA/AG compared with MPO -463GG subjects.
The inverse association between lung cancer and myeloperoxidaseG-463A polymorphism was equally found in males and females (odds ratio for the AA genotype 0.73 [95% confidence interval: 0.56-0.96] and 0.67 [95% confidence interval: 0.46-0.98], respectively), without differences in the association according to age in the two genders.