Synergistic association of CYP1A1and CHRNA5 D398N genetic variants towards increased susceptibility for Lung Cancer in North Indian Population

Abstract

Number of studies done so far in different populations has shown that polymorphism within the CYP1A1and CHRNA5gene play an important role in determining individual susceptibility towards lung cancer; however data so far obtained has been contradictory within the same or different populations. Few studies have focused on the synergistic effect of the CYP1A1and CHRNA5polymorphisms towards susceptibility for lung cancer and also for different histological sub-types along with the impact of smoking. Objectives: Our aim is to investigate the role of CYP1A1and CHRNA5polymorphisms as a genetic modifier of risk for lung cancer and histological subtypes with larger sample size in a North-Indian population. Methods: A total of 704 subjects (353 lung cancer and 351 controls) were evaluated for the CYP1A1 polymorphism and total of 513 subjects (206 lung cancer and 307 controls) were evaluated for CHRNA5 polymorphism. Genotyping for the CYP1A1and CHRNA5gene was done by using a PCR-RFLP method. Results: CYP1A1 mutant genotype was found to be significantly associated with lung cancer (OR=3.15; 95%CI=1.75-5.71; p=0.0001) and this risk was four-fold higher in case of SQCC. The CYP1A1m2 was also found to be associated with risk towards lung cancer however when stratified for histological subtypes a significant association was observed for SQCC and ADCC. The combined 'at risk' genotypes of CYP1A1m1 and m2geneswere found to be associated for lung cancer risk and this risk was higher in case of SQCC (OR=2.0; 95%CI=1.97-3.81; p=0.028).There has been no significant association have been found in relationship between CHRNA5 polymorphic gene and risk of lung cancer (OR= 1.22; 95%CI=0.56-2.6; p= 0.60). However, the study has also evaluated the genetic variants in CHRNA5 polymorphism with respect to different histology of lung cancer but no significant OR has been found in this relation to increase risk of lung cancer (OR=1.23; 95%CI= 0.4-3.6; p=0.70). Further, study subjects stratified according to smoking status and pack year but similarly it has been seen that in North Indian population smoking has not significant effects on the D398N polymorphism in α5 subunit of nAChRs coded by CHRNA5 gene having G>A mutation in North Indian population (OR= 1.46; 95%CI= 0.6-3.3; p= 0.37).Conclusions: The polymorphism in the CYP1A1 gene seem thus to be important risk modifiers for lung cancer and related histological subtypes, along with smoking. But on the other hand, the polymorphism in the CHRNA5 gene did not seem to be important risk modifiers for lung cancer and related histological subtypes, along with smoking North Indian population.