We evaluated 23 single nucleotide polymorphisms (SNPs) in the five nicotinic receptor related genes (CHRNB3, CHRNA6, and CHRNA5/A3/B4) previously reported to be associated with lung cancer risk and smoking behavior and 14 SNPs in the four 'control' genes (TERT, CLPTM1L, CYP1A1, and TP53), which were not reported in the smoking GWA studies.
The estimated relative risk for lung cancer associated with the CYP1A1 Val/Val allele was 2.68, and was four-fold when cases with small cell lung cancer (SCLC) were considered alone.
Present studies on increased risk of smoking-related lung cancer associated with phenotypic or genotypic variation of the genes encoding for CYP1A1 or CYP2D6 enzymes are summarized.
Since several epidemiological studies have shown an association between the CYP1A1-Val allele and lung cancer, we considered it of importance to evaluate the in vitro kinetic properties of the two CYP1A1 variants after expression of each cDNA in yeast.
Thus, the apparently greater susceptibility of the CYP1A1-Val462 genotype to lung cancer is probably not related to greater extents of carcinogen bioactivation.
Hence our study-the first to analyse a South Indian population-suggests the importance of combined CYP1A1, GSTM1 and GSTT1 polymorphisms in the development of smoking-induced lung cancer.
Through population studies, we have learned that certain CYP1A1 variants, such as Mspl polymorphism, may render the carriers more susceptible to cigarette-induced lung cancer or severe coronary atherosclerosis.
Smokers with homozygous CYP1A1 variant and GSTM1 null had the highest adduct levels and were, as shown in Japanese smokers, most susceptible to lung cancer.
These results indicated that the three-order interaction of CYP2A6, CYP1A1, and CYP2D6 polymorphisms might increase genetic susceptibility to lung cancer.
Similarly individuals carrying the mutant CYP1A1*2C genotype and single copy of the variant CYP1A1 Mspl allele, had a relative risk of 2.85 for lung cancer.
Results showed that CYP1A1 m1 'CC' genotype was significantly associated with lung cancer susceptibility with a 2.3-fold risk, CYP1A1 m2 'AG' gene polymorphisms with 8.8-fold risk and GSTT1 (-/-) genotype demonstrated a twofold risk of disease susceptibility.
Overall, a significant association between lung cancer and the variants of CYP1A1 MspI was found among smokers (type B and type C combined vs. type A: OR = 1.89, 95% CI = 1.15-3.11, P = 0.000 for heterogeneity), whereas not found among non-smokers.
This meta-analysis suggests that the MspI polymorphisms of CYP1A1 correlate with increased lung cancer susceptibility, and that there is an interaction between the CYP1A1 polymorphism and smoking.
Several polymorphisms within the CYP1A1 locus have been identified and have been shown to be associated with lung cancer risk, particularly in Asian populations.
Our findings suggested that CYP1A1 or GSTM1 variants may significantly modify the associations between level of serum trace metals (Cu, Zn, Se or Cr) and NSCLC, indicating the intriguing pathogenesis of lung cancer.
Our study suggested that the null GSTM1 genotype, independently or in combined with at least one Val allele of CYP1A1, might affect the genetic susceptibility for lung carcinoma in Chinese population.