KIR-HLA gene diversities and susceptibility to lung cancer

Abstract

AbstractKiller-cell immunoglobulin-like receptors (KIR) are essential for acquiring natural killer (NK) cell effector function, which is modulated by a balance between the net input of signals derived from inhibitory and activating receptors through engagement by human leukocyte antigen (HLA) class I ligands. KIR and HLA loci are polygenic and polymorphic and exhibit substantial variation between individuals and populations. We attempted to investigate the contribution ofKIRcomplex andHLA class Iligands to the genetic predisposition to lung cancer in the native population of southern Iran. We genotyped 16KIRgenes for a total of 232 patients with lung cancer and 448 healthy controls (HC), among which 85 patients and 178 HCs were taken into account for evaluating combinedKIR-HLAassociations.KIR2DL2and2DS2were increased significantly in patients than in controls, individually (OR 1.63, and OR 1.42, respectively) and in combination withHLA-C1ligands (OR 1.99, and OR 1.93, respectively).KIR3DS1(OR 0.67) and2DS1(OR 0.69) were more likely presented in controls in the absence of their relative ligands. The incidence of CxTx subset was increased in lung cancer patients (OR 1.83), and disease risk strikingly increased by more than fivefold among genotype ID19 carriers (a CxTx genotype that carries2DL2in the absence of2DS2, OR 5.92). We found that genotypes withiKIRs > aKIRs(OR 1.67) were more frequently presented in lung cancer patients. Additionally, patients with lung cancer were more likely to carry the combination of CxTx/2DS2compared to controls (OR 2.04), andiKIRs > aKIRsgenotypes in the presence of2DL2(OR 2.05) increased the likelihood of lung cancer development. Here we report new susceptibility factors and the contribution ofKIRandHLA-Iencoding genes to lung cancer risk, highlighting an array of genetic effects and disease setting which regulates NK cell responsiveness. Our results suggest that inheritedKIRgenes andHLA-Iligands specifying the educational state of NK cells can modify lung cancer risk.