The Association Study Between SP-A1,SP-A2 And SP-D Gene Polymorphisms And Susceptibility To Radiation Pneumonitis

Objective: Lung cancer is one of the most common malignant tumors in the world.In China,lung cancer is the first most commonly diagnosed cancer in male and the second most commonly diagnosed cacer in female.Radiotherapy is an important therapeutic modality for lung cancer.Approximately 16 to 30% of lung cancer patients develop radiation pneumonitis(RP)after thoracic irradiation.Previous studies identified that multiple patient-related and therapeutic factors may influence the risk of RP.Nevertheless,the risk and speed of developing RP are not the same when patients with similar clinical features exposed to same doses or volumes of irradiation,suggesting that genetic factors play an important role in the individual's response to radiotherapy and RP development.Surfactant protein A(SP-A)and surfactant protein D(SP-D)are a class of hydrophilic proteins on the alveolar surface,and secreted mainly by alveolar II epithelial cells.These proteins have important functions in maintaining lipid homeostasis and regulating immune and inflammatory reaction.Multiple studies have reported that SP-A and SP-D gene single nucleotide polymorphisms(SNPs)were associated with many inflammatory and fibrotic diseases susceptibility.To our knowledge,the associations between SP-A and SP-D gene polymorphisms and the risk of RP have not yet been reported.Based on the biological functions of SP-A and SP-D and the pathogenesis of RP,we hypothesized that SP-A and SP-D gene polymorphisms may be related to RP risk in lung cancer patients treated with radiotherapy.Methods: Lung cancer patients undergoing thoracic irradiation were recruited at the Department of Oncology in Daping Hospital(chongqing,china)or at the Cancer Center of Chengdu Military General Hospital.We also collected patients' epidemiological data and radiation dosimetric parameters,and extracted whole-genome DNA from peripheral anticoagulant blood.Each patient was followed-up for at least 3 months after the radiotherapy.RP was graded by two radiation oncologists according to the Common Terminology Criteria for Adverse Eventsv3.0(CTCAE 3).The end point for this study were the development of ? 2 RP and ? 3 RP.SPSS version 16.0(SPSS Inc.,Chicago,IL)was used for statistical analyses.P ? 0.05 was considered statistically significant in all tests.Results: 1.In this study,the associations between clinical factors and the risk of grade ? 2 RP and ? 3 RP were analyzed by univariate and multivariate analysis,the results showed that PS > 2,smoke,age > 60,and dosimetric parameters of MLD,V5,V8,V10,V15,V20 and V30 were significantly associated with the risk of RP(P ? 0.05).2.In the association study between genetic polymorphisms and susceptibility to grade ? 2 RP: we found that mutant alleles SP-A1 rs4246947 T,SP-D rs911887 C and rs2255326 A were associated with significantly increased risk of grade ? 2 RP compared with the wild-type alleles(P ? 0.05),and presented different degrees of risk effects.SP-A1 rs4253515 T,rs3740271 G,SP-A2 rs9408 A,rs17879335 A,and SP-D rs1998374 C mutant alleles were associated with lower grade ? 2 RP risk compared with the wild-type alleles(P ? 0.05),showing protective effects in different degrees.After adjustment for PS,smoking status and dosimetric parameters of V5,7 locus were still statistically significant(P ? 0.05)except rs9408(P = 0.069).The results of genotype analysis showed that mutant genotypes SP-A1 rs4246947 GT,rs4246947 TT,SP-D rs1923536 TT,rs911887 CC and rs2255326 AA carriers had a significantly higher risk of developing grade ? 2 RP(P ? 0.05),compared with patients with wild genotypes.SP-A2 rs9408 AA,17879335 AA and SP-D rs1998374 CT genotypes carriers had significantly lower risk of grade ? 2 RP(P ? 0.05),showing protective effects.After multifactor correction,the rs9408 was close to statistically significant(P=0.058),and the remaining 6 SNPs were statistically significant.Under the dominant model,the mutant alleles SP-A1 rs4246947 T(GT or TT)and SP-D rs2255326 A(GA or AA)carriers were associated with significantly higher risk of grade ? 2 RP(P ? 0.05),compared with wild homozygous genotypes carriers.SP-A1 rs4253515 C(CT or CC)and SP-D rs1998374 C(CT or CC)carriers had lower risk of RP(P ? 0.05).Compared to CC,SP-A2 rs17879335 A(CA or AA)carriers also had decreased RP risk,and correlation was close to statistical significant level(P = 0.051).After multivariate analyses correction,the associations between four SNPs and grade ? 2 RP risk were still statistically significant(P ? 0.05)except rs4253515(P=0.074).3.In the association study between genetic polymorphisms and susceptibility to grade ? 3 RP,we found that mutant alleles SP-D rs911887 C and rs2255326 A had increased risk of grade ? 3 RP(P ? 0.05),and SP-D rs1998374 C showing a protective effect had a decreased grade ? 3 RP risk(P ? 0.05).After adjusted for PS,age and dosimetric parameters V20,SP-D rs1998374 and rs2255326 were still associated with grade ?3 RP risk.Genotype analysis showed that mutant genotypes SP-D rs1923536 TT,SP-D rs2255326 GA and SP-D rs2255326 AA carriers had a higher RP risk compared with wild-type genotypes carriers(P ? 0.05),so rs1923536 TT and rs2255326 GA/AA may be risk factors for RP.However,SP-D rs1998374 CT carriers showing a protective effect had a lower risk of grade ? 3 RP compared with TT carriers(P ? 0.05).With the exception of rs2255326 GA genotype(P = 0.069),the other three genotypes were still significant statistical correlated with grade ? 3 RP risk after multivariate analyses correction.Under the dominant model,compared to wild-type genotypes,mutant alleles of SP-D rs911887 C(CT or CC)and rs2255326 A(GA or AA)carriers were associated with significantly higher risk of grade ? 3 RP(P ? 0.05),SP-D rs1998374 C(CT and CC)carriers were associated with lower grade ? 3 RP risk(P ? 0.05).Multivariate analysis found that the association between rs2255326,rs1998374 and grade ? 3 RP still yielded statisticant significance.Conclusion: The SP-A1 rs4246947,rs4253515,rs3740271 and SP-A2 rs9408,rs17879335 polymorphisms were significantly associated with the susceptibility to grade ? 2 RP in lung cancer patients treated with radiotherapy.The SP-D rs1923536,rs1998374,rs9118374 and rs2255326 polymorphisms were not only associated with the risk of grade ? 2 RP,but also related to grade ? 3 RP risk in lung cancer patients after thoracic irradiation.