Genetic Polymorphisms In PON1,PPARGC1A And PPARGC1B With The Susceptibility Of ESCC

Background: The global incidence of esophageal cancer(EC)ranks seventh in the world,and esophageal squamous cell carcinoma(ESCC)as well as esophageal carcinoma(AC)are the basic tissue types of EC.ESCC is also a malignant tumor with high morbidity in China,ranking the third in incidence.The etiology of ESCC is very complex.Genetic and environmental factors may play a separate/interactive effect.Genetic polymorphism is one of the forms of human genetic variation,may partially explain the individual genetics differences with the susceptibility of ESCC.Objective: A large-scale case-control study was designed to assess the effects of single nucleotide polymorphisms(SNPs)of PON1,PPARGC1 A and PPARGC1 B genes on susceptibility to ESCC in eastern Chinese Han population,and to evaluate the impact of environmental factors,such as gender,age,smoking status,alcohol consumption and body mass index(BMI),through the interaction of genetic mutation and ESCC disease as well.It is in order to discover the etiology of ESCC and provide the theory based on genetics.Contents and Methods: The study enrolled 829 patients with ESCC and 1522 sporadic non-tumor control subjects.Fasting blood samples were collected and then to extract the DNA.PON1 rs854560 A>T,rs662 C >T,PPARGC1 A rs2970847 C>T,rs3736265 G>A,rs8192678 C>T,PPARGC1 B rs7732671 G>C,rs17572019 G>C totally 7 SNPs were selected in this study.PCR-LDR SNPs typing technology was used for DNA sequencing classification,and Logistic regression in statistics was to analysis the association between genotypes and ESCC under the environmental factors such as gender,age,smoking status,drinking status and BMI,with P<0.05(two-tailed)counting as statistically significant difference.Results: The study reveals that: 1.When PPARGC1 A rs3736265 GG genotype was used as reference,PPARGC1 A rs3736265 GA genotype and GA+AA genotypes were significantly increased the risk of ESCC(GA vs.GG: adjusted OR=1.25,95% CI 1.02~1.54,P=0.034;GA+AA vs.GG: adjusted OR=1.25,95% CI 1.03~1.52,P=0.027);2.When PPARGC1 A rs8192678 CT+CC genotypes were used as reference,PPARGC1 A rs8192678 TT genotype was significantly reduced the risk of ESCC(TT vs.CT+CC: crude OR=0.78,95%CI 0.62~0.97,P=0.028);3.The genotypes of PON1 rs854560A>T,rs662 C>T,PPARGC1 A rs2970847 C>T and PPARGC1 B rs7732671 G>C,rs17572019 G>A show no statistically difference associated with ESCC risk(P>0.05),therefore the genotypes may have no effect on the pathogeny of ESCC.The stratification analysis of environmental factors such as gender,age,cigarette smoking,excessive drinking and BMI show that:1.PPARGC1 A rs3736265 GA genotype and GA+AA genotypes were associated with higher risk of ESCC in male and non-drinking populations compared to PPARGC1 A rs3736265 GG genotype [Male subgroup:(GA vs.GG: adjusted OR=1.36,95%CI: 1.07-1.74,P=0.013;GA+AA vs.GG: adjusted OR=1.34,95%CI: 1.06-1.69,P=0.014);Never drinking subgroup:(GA vs.GG: adjusted OR=1.26,95%CI: 1.00-1.59,P=0.047;GA+AA vs.GG: adjusted OR=1.26,95%CI: 1.01-1.57,P=0.043)].2.PPARGC1 A rs8192678 TT genotype was associated with a lower risk of ESCC in the male population compared to PPARGC1 A rs8192678 CC+CT genotypes(TT vs.CC+CT: adjusted OR=0.73,95% CI: 0.55-0.97,P=0.028).3.PPARGC1 B rs17572019 GA genotype was associated with a higher risk of ESCC in alcohol consumption populations(GA vs.GG: adjusted OR=2.07,95%CI: 1.01-4.25,P=0.046).4.The stratification analysis of genotypes PON1 rs854560A>T,rs662 C>T,PPARGC1 A rs2970847 C>T and PPARGC1 B rs7732671 G>C in each pathogenic models using Logistic regression showed no correlation with the risk of ESCC(P>0.05).Conclusion: Our results indicate that PPARGC1 A,PPARGC1B SNPs are substantially correlated with the risk of ESCC.PPARGC1 A rs3736265 G>A,PPARGC1 A rs8192678 C>T,PPARGC1 B rs17572019 G>A may be a potentially valuable function SNP site of ESCC.However,due to our study lacking of repetition validated or function verification,carefulness is needed while explaining the association between gene mutations and ESCC.Larger-sample-size,multi-centers-collaboration and well-designed-epidemiological studies with function verification are looking forward to confirm our findings in future.