Association Of Single Nucleotide Polymorphisms With Colorectal Cancer Risk

Colorectal cancer?CRC?includes colon cancer?CC?and rectal cancer?RC?.In recent years,the incidence and mortality rate of CRC in China have been increasing year by year,which seriously harms human health.Thus,the prevention and treatment of the disease are urgently needed.However,the etiology of CRC is not yet clear,and it is mainly believed to be the result of a combination of environmental and genetic factors.As the most common form of genomic variation,single nucleotide polymorphism?SNP?refers to a DNA sequence polymorphism caused by a single nucleotide variation at the genome level.Previous studies have shown that SNPs are associated with the occurrence,development,treatment and prognosis of CRC.Combining with domestic and international research progress,using NCBI dbSNP database,this study selects 7SNPs that may be related to the occurrence and development of CRC,affecting the biological functions of gene transcription,translation or protein activity,and with minor allele frequency?MAF?>20%in Chinese Han population.They are mismatch repair genes SNPs:MLH1rs1800734,MSH2 rs3732183,metabolic enzyme genes SNPs:UGT1A1 rs3755319,GSTM3rs7483,DPYD rs1801159,and transporter gene SNPs:ABCG2 rs2231137,rs2231142.Case-control study is used to investigate frequency distribution of candidate SNPs of sample which are genotyped by TaqMan-MGB probe PCR in Chinese Han population.Combined with population information,the association of certain polymorphisms with CRC risk or clinicopathologic parameters of CRC patients are evaluated by unconditional logistic regression.It is expected to find out the candidate SNPs that are related to CRC risk and may indicate the progression of CRC in Chinese Han population in this study.The present study will provide theoretical basis for the prevention and treatment of CRC in China.Peripheral blood samples and personal data were collected from a total of 690 CRC cases and 431 healthy controls.The CRC group includes 427 males and 263 females with an average age of 57.83±11.64 years old.In the control group,there are 154 males and 277 females,with an average age of 60.19±11.92 years old.There are different in gender and age between the case group and the control group,respectively?P<0.05?,which may become confounding factors.Therefore,gender and age are corrected and stratified in the subsequent statistical analysis.The age stratification is divided into two groups according to references and the average age of the control group in this study,which are?60 years old?young group?and>60 years old?elderly group?.Analyze the correlation between candidate SNPs and CRC risk or clinicopathological parameters in turn,and the specific results are as follows:1.Association of mismatch repair genes SNPs with CRC risk1)Findings of MLH1 rs1800734:CRC risk in GG genotype carriers is significantly increased (GG vs.AA+GA:OR_adj=1.440,95%CI:1.021-2.032,P_adj=0.038),stratified analysis shows that it is mainly associated with increasing rectal cancer risk and CRC risk in older people(GG vs.AA+GA:OR_adj=1.561,95%CI:1.046-2.329,P_adj=0.029;OR_adj=1.800,95%CI:1.110-2.921, P_adj=0.017).Correlation analysis with CRC clinicopathological parameters finds that patients with GA and GG genotypes are associated with well to moderate differentiation(GA+GG vs. AA:OR_adj=0.582,95%CI:0.415-0.817,P_adj=0.002),and are mainly related to young and male patients(GA+GG vs.AA:OR_adj=0.430,95%CI:0.270-0.685,P_adj<0.001;OR_adj=0.490,95% CI:0.319-0.753,P_adj=0.001).Male GA and GG genotype carriers often carry with small size tumors?<4 cm?(GA+GG vs.AA:OR_adj=0.520,95%CI:0.315-0.858,P_adj=0.010).In summary,MLH1 rs1800734 is associated with CRC risk,and it is mainly related to CRC risk in rectal cancer and older people.The carriers of GA and GG genotypes may have low malignancy and slow progress.2)Findings of MSH2 rs3732183:MSH2 rs3732183 is not associated with the risk of CRC (P_adj>0.05),but MSH2 rs3732183 is related to tumor differentiation,and male GA and GG genotype carriers often carry tumor with well to moderate differentiation(GA+GG vs.AA:OR_adj=0.621,95%CI:0.406-0.948,P_adj=0.028),suggesting those carriers are less malignant.2.Association of metabolic enzyme genes SNPs with CRC risk1)Findings of UGT1A1 rs3755319:This is the first study analyzing the relationship between UGT1A1 rs3755319 and CRC risk,although find no association between UGT1A1 rs3755319 and CRC risk(P_adj>0.05).Further analysis finds that the tumor size is smaller in patients carrying the GT and GG genotypes(GT+GG vs.TT:OR_adj=0.648,95%CI:0.454-0.927,P_adj=0.018),stratified analysis shows small tumor mainly in men and older patients with the GT and GG genotypes(GT vs.TT:OR_adj=0.562,95%CI:0.348-0.905,P_adj=0.018;GT+GG vs.TT:OR_adj=0.563,95%CI:0.330-0.959,P_adj=0.034).It suggests that the GT and GG genotype carriers have a slower disease progression.2)Findings of GSTM3 rs7483:This is the first study to find that GSTM3 rs7483 GG genotypesignificantly increase CRC risk in male(GG vs.AA+GA:OR_adj=3.668,95%CI:1.110-12.217,P_adj=0.034).The patients with GG genotype are related to stage I and stage II of TNM(GG vs.AA+GA:OR_adj=0.466,95%CI:0.261-0.834,P_adj=0.010),stratified analysis shows that GG genotype carriers is mainly related to stage I and stage II in elderly patients(OR_adj=0.321,95% CI:0.126-0.821,P_adj=0.018),and the younger age of GA and GG genotype carriers have smaller tumor(GA+GG vs.AA:OR_adj=0.576,95%CI:0.356-0.932,P_adj=0.025).In summary,GSTM3 rs7483 is associated with CRC risk in men,and patients with the GG genotype are mostly in the early stage of the disease and carry small tumor,suggesting those carriers have a slower disease progression.3)Findings of DPYD rs1801159:No relationship between DPYD rs1801159 and CRC risk is found(P_adj>0.05).However,patients with AG and GG genotypes are associated with poor differentiation(AG+GG vs.AA:OR_adj=1.398,95%CI:1.004-1.946,P_adj=0.047),stratified analysis shows that it is mainly related to poor differentiation of younger patients and female patients(AG+GG vs.AA:OR_adj=1.775,95%CI:1.132-2.785,P_adj=0.012;OR_adj=2.092,95% CI:1.218-3.595,P_adj=0.008).In addition,it is also found that carriers of AG and GG genotypes in elderly patients often have larger tumors??4cm?(AG+GG vs.AA:OR_adj=1.775,95%CI:1.034-3.046,P_adj=0.037).Therefore,there is no association between DPYD rs1801159 and CRC risk(P_adj>0.05),but AG and GG genotypes carriers have higher malignancy and larger tumors,suggesting those carriers have a faster disease progression.3.Association of transporter gene SNPs with CRC risk1)Findings of ABCG2 rs2231137:ABCG2 rs2231137 is not associated with the CRC risk (P_adj>0.05).However,young patients carrying the AA genotype are associated with stage I and II of TNM(AA vs.GG+GA:OR_adj=0.326,95%CI:0.162-0.654,P_adj=0.002).Women with GA and AA genotypes or older patients are related to poor differentiation(GA+AA vs. GG:OR_adj=1.733,95%CI:1.004-2.992,P_adj=0.048;AA vs.GG+GA:OR_adj=2.682,95% CI:1.089-6.602,P_adj=0.032).It suggests that ABCG2 rs2231137 has different effects on disease progression in different populations.2)Findings of ABCG2 rs2231142:The ABCG2 rs2231142 AA genotype carrier is associated with reducing CRC risk in male(AA vs.CC+CA:OR_adj=0.470 95%CI:0.268-0.826,P_adj =0.009).In addition,no association between ABCG2 rs2231142 and clinical progress is found (P_adj>0.05).3)Findings of ABCG2 rs2231137 and rs2231142 haplotypes:The Lewontin coefficient D'=0.97 for ABCG2 rs2231137 and rs2231142,and they are strong LD.There are three haplotypes:GA,AC and GC,but there are no significant correlations between haplotypes and CRC risk?P>0.05?.In summary,mismatch repair genes,metabolic enzyme genes and transporter gene SNPs in Chinese Han population may be related to the risk and progression of CRC.This study provides a theoretical basis for the prevention and treatment of CRC in China.