THE SIGNIFICANCE OF CTLA-4+49A>G (EXON1) SINGLE NUCLEOTIDE POLYMORPHISM IN LUNG CANCER Ayad M. Gaidan 1 , Mayasah A. Ali 2 and Hadeel A. Omear 1 1 Department of Biology, College of Science, Tikrit University, Iraq. 2 Department of Lab Techniques, Al-Raheed University College, Iraq. (Accepted 18 September 2018) ABSTRACT : Lung cancer (LCa) is the leading cause of cancer-related death. It is a multifactorial disease caused by a complex interaction between environmental and genetic factors. Polymorphisms in some immune genes have attract a remarkable interest in recent years due to their impact on the incidence of many malignancies. This case-control study aimed to dissect the attribution of cytotoxic T-lymphocyte antigen-4+49A>G (CTLA-4+49A>G) single nucleotide polymorphism (SNP) in the susceptibility to LCa among Iraqi patients. This study recruited 60 patients with histopathologically confirmed LCa, and other 40 age- and sex-matched apparently healthy individuals. Blood samples as well as demographic data were obtained from each subjects, and DNA was isolated from leukocytes. Tetra-primer amplification refractory system (ARMS-PCR) method was used for amplification of CTLA-4 gene and for the genotyping of CTLA-4+49A>G polymorphism. Both AA and AG genotypes showed higher frequency in LCa patients (45% and 48.3%) than controls (40% and 32.5% respectively) with significant differences. Even when the regression adjusted for smoking, AA genotype remained significantly higher in patients than controls (OR= OR=4.26,95%CI=1.07-16.9, P=0.039). Likewise, allele A was more frequent in patients than controls (69.71% versus 52.5%) with significant difference (OR= 1.99, 95%CI = 1.7-4.12, P = 0.041). These data strongly suggest the significant role of CTLA-4+49A>G polymorphism as a risk factor for LCa in Iraqi patients. Studies using anti-CTLA-4 monoclonal antibodies as therapeutic strategy for LCa are required to further elucidate this role. Key words : Lung cancer, CTLA-4+49A>G single nucleotidepolymorphism. Biochem. Cell. Arch. Vol. 18, No. 2, pp. 2467-2471, 2018 www.connectjournals.com/bca ISSN 0972-5075 INTRODUCTION Despite the remarkable advances in cancer diagnosis and treatment assays, LCa subsisted as the most death- associated malignancy worldwide accounting for 13% of all cancer cases and about 18% of all cancer deaths (Ferlay et al, 2008; Jemal et al, 2011). Like other cancers, the exact causes of LCa is beyond the current knowledge. However, unlike other cancers, about 90% of all LCa cases in men and 65% in women are attributed to tobacco smoking (Xie et al, 2014). On the other hand, not all smokers develop LCa neither the verse versa is correct, which implies the involvement of other risk factors. Apart from environmental factors, several genetic and epigenetic changes have been implicated in LCa (Zhu et al, 2015). Among the most important genes in this regard may be those associated with DNA repair and immune response due to their roles in incidence and resistance for cancer, respectively. Genes related to immune response became a very interesting issue in the treatment of LCa during the last few years (Lara-Guerra and Roth, 2016; Thakrar et al, 2016). This is mainly attributed to the limited success of chemo- and radiotherapy in the treatment of this malignancy. As cell-mediated immune response, represented mainly by cytotoxic T-lymphocytes (CTLs), is the chief effector in immunity against LCa, it is reasonable to investigate the genetic factors influencing these cells. Cytotoxic T-lymphocyte Antigen-4 (CTLA-4 also known as CD152) is a member of the immunoglobulin superfamily that expressed on activated T-lymphocyte, and interacts with B7 ligand on the antigen presenting cells (APCs). This interaction represses CTL at the G1 phase accompanied by reduction in the production of IL- 2 and IL-2R by these cells. More importantly, the interaction was found to induce apoptosis of CTL in a Fas-independent manner (Chen et al, 2017). CTLA-4 is encoded by CTLA-4 gene on the long arm of chromosome 2q33 compromising 4 exons and three introns (Brunet et al, 1987). Several SNPs on this gene, either in coding or promoter regions, were found to be significantly associated with different pathologies. Of these SNPs, CTLA- 4+49A>G (rs231775), in the first exon, was most extensively investigated and was found to influence the susceptibility to different malignancies including breast,