Relationship Between LncRNA Single Nucleotide Polymorphisms And Gastric Cancer Risk And Development In Chinese Population With High Incidence Of Gastric Cancer

Gastric cancer（GC）is a common malignant tumor of the digestive tract.Its morbidity and lethality rank among the top of all malignant tumors,which seriously threatens human health.GC has the characteristics of high morbidity,high mortality and low five-year survival rate in China,especially in northwestern China,which has brought a serious public health burden to China.The occurrence of GC involves a combination of genetic and environmental factors.Single nucleotide polymorphism（SNP）is one of the most common heritable mutations in humans.It is a polymorphism in a DNA sequence caused by a single nucleotide mutation at the genome level.Studies have shown that SNP is related to the occurrence and development of GC.Long non-coding RNA（lncRNA）is a non-protein-coding RNA with a length of more than 200 nucleotides,which is involved in many important biological processes.Genome association studies have found that SNPs are prevalent in lncRNA,which can affect lncRNA expression levels and participate in the development of diseases through various pathways.Many studies have confirmed that many SNPs on lncRNA are closely related to tumor susceptibility,invasion,metastasis and prognosis,and can be used as tumor biomarkers.Based on a large number of literature searches and previous research,combined with NCBI’s db SNP database,this study selected maternally expressed genes 3（MEG3）,HOXA distal transcripts（HOTTIP）,H19 and LAMC2-1:1 that may be related to GC development.And select the candidate SNPs with minor allele frequency（MAF）>20%among Chinese Han population,including MEG3 rs7158663,rs10132552,HOTTIP rs1859168,rs17427960,rs2067087,H19 rs2107425,rs2839698 and LAMC2-1:1 rs2147578.A total of 8 SNPs were analyzed for their correlation with the risk of GC in Chinese high-incidence areas.This study was performed using a case-control study method,and Taq Man-MGB probe fluorescent PCR was used to genotype candidate SNPs.Thec2 test was used to describe the distribution of candidate SNPs in cases and controls,and the relationship between candidate SNPs and the risk and clinical progress of GC were analyzed using an unconditional logistic regression model.Further combined with the general demographic data,dietary habits and family history of tumors of the research subjects,a comprehensive risk score analysis of genetic-environmental factors was conducted.Single-factor logistic regression was used to analyze environmental risk factors related to GC.The genetic and environmental factors related to GC are included in the multi-factor logistic regression analysis,and the regression coefficient of each variable calculated by logistic regression is used as the weight to calculate the risk score（RS）of the genetic and environmental factors of the research object.Then,describe the distribution of RS in cases and control groups,and analyze the correlation between RS quartile grouping and GC risk.The area under curve（AUC）and decision curve of the receiver operating characteristic curve（ROC）were used to evaluate the risk assessment ability of RS,and the collinear chart was used to visualize the individual GC incidence risk score.Through different methods to assess the ability of genetic-environmental factors to synthesize RS to predict the risk of GC,it provides a reference for the prediction of GC risk in people with high incidence of GC in China.A total of 474 GC cases and 543 healthy controls were collected from peripheral blood samples and related data.There were 266 males and 208 females in the case group,with an average age of 58.00±6.98 years.283 males and 260 females in the control group,with an average age of 57.41±5.49 years.The relationship between the candidate SNPs and the risk and clinical progress of GC and the genetic-environmental comprehensive risk score results are as follows:1.Relationship between lncRNA MEG3 SNPs and gastric cancer risk and clinical progressionIn the codominant model,carriers of MEG3 rs7158663 GA genotype have a 41.7%increased risk of gastric cancer compared with GG genotype(OR_adj=1.417,95%CI:1.056～1.901,P_adj=0.020).Compared with the GG genotype,the carrier of AA genotype has an increased risk of gastric cancer by 86.4%(OR_adj=1.864,95%CI:1.162～2.992,P_adj=0.010).In the dominant model,GA+AA carriers had a 50.1%increased risk of gastric cancer compared with GG carriers(OR_adj=1.501,95%CI:1.139～1.979,P_adj=0.004).In the recessive model,the AA type has a 59.9%increased risk of gastric cancer compared with the GG+GA type(OR_adj=1.599,95%CI:1.015～2.517,P_adj=0.043).The frequencies of alleles G and A were 66.2%and 33.8%in the case group,and 72.1%and 27.9%in the control group.The distribution of the two alleles is significantly different(P_adj=0.002).No significant correlation was found between the genotype of the A allele carried by MEG3 rs7158663 and the clinical progress of GC(P_adj>0.05).AND no association was found between rs10132552 and GC risk and clinical progression(P_adj>0.05).2.Relationship between lncRNA HOTTIP SNPs and gastric cancer risk and clinical progressionIn the case group,HOTTIP rs1859168 CC type accounted for 30.0%,AC type accounted for 52.7%and AA type accounted for 17.3%,while in the control group accounted for 32.6%,49.7%and 17.7%.Thec2 test results showed no significant difference（P>0.05）.In the case group,rs17427960 AA type accounted for 29.3%,AC type accounted for 53.4%and CC type accounted for 17.3%,while in the control group accounted for 32.0%,49.0%and 19.0%,and the difference was not statistically significant（P>0.05）.In the case group,rs2067087 CC type accounted for 32.5%,CG type accounted for 47.3%and GG type accounted for 20.3%,while in the control group accounted for 32.2%,48.1%and 19.7%,the difference was not statistically significant（P>0.05）.The results of the study did not find a correlation between HOTTIP rs1859168,rs17427960,and rs2067087 and the risk of GC and clinical progression(P_adj>0.05).3.Relationship between lncRNA H19 SNPs and gastric cancer risk and clinical progressionIn the case group,H19 rs2107425 CC type accounted for 30.2%,CT type accounted for54.4%,and TT type accounted for 15.4%,while in the control group accounted for 36.3%,47.9%and 15.8%.Thec2 test results showed no significant difference（P>0.05）.In the case group,rs2839698 CC type accounted for 50.2%,CT type accounted for 43.0%and TT type accounted for 6.8%,while the control group accounted for 47.0%,44.0%and 9.0%,and the results showed no statistically significant difference（P>0.05）.The results of the study did not find that H19 rs2107425 and rs2839698 were related to the risk of GC and clinical progress(P_adj>0.05).4.Relationship between lncRNA LAMC2-1:1 SNPs and gastric cancer risk and clinical progressionIn the case group,LAMC2-1:1 rs2147578 GG type accounted for 32.5%,CG type accounted for 47.5%and CC type accounted for 20.0%,while in the control group accounted for 29.7%,51.9%and 18.4%.Thec2 test results showed no significant difference（P>0.05）.The results of the study did not find a correlation between LAMC2-1:1 rs2147578 and GC risk and clinical progression(P_adj>0.05).5.Relationship between genetic-environmental factor comprehensive risk score and risk of gastric cancerUnivariate logistic regression analysis showed that alcohol drinking,tea drinking and eating preserved food were associated with the incidence of GC（P<0.05）.The genetic and environmental factors related to GC were included in the multivariate logistic regression analysis,and RS was calculated according to the regression coefficients.The average RS of the case group was 1.49±0.77,and that of the control group was 0.47±1.27.The difference in the distribution of RS between cases and controls was statistically significant（P<0.05）.The quartile grouping results showed the higher the RS score,the greater the risk of GC.Compared with the RS<Q25 group,the GC risk of Q25<RS<Q50 group was 3.870（OR=3.870,95%CI:2.566～5.837,P<0.001）,the Q50<RS<Q75 group GC risk was 8.352（OR=8.352,95%CI:5.514～12.651,P<0.001）and the RS>=Q75 group GC risk was 8.127（OR=8.127,95%CI:5.370～12.300,P<0.001）.ROC curve analysis shows that the AUC of RS calculated by comprehensive genetic-environmental factors is 0.745,which is higher than the AUC of environmental factors or genetic factors alone.The decision curve also shows that the combined genetic-environmental factor RS has the most increased diagnostic benefit compared to the individual genetic factor or the environmental factor alone.The nomogram shows that individuals with a total score higher than 180 points have significantly higher GC susceptibility,and the corrected curve evaluation has a better prediction effect.In summary,MEG3 rs7158663 is related to the risk of GC in high-risk populations in China,and the RS constructed by combining genetic factors MEG3 rs7158663 and environmental factors such as drinking,drinking tea,and eating preserved food has a good ability to predict the risk of GC.The study can provide a reference for the screening of high-risk populations in China and the prevention of GC.