Regulation Of CRP Gene Expression By Rs3091244 And Its Relationship With Cancer Risk

C-reactive protein(CRP)was a highly conserved plasma protein in evolution.In acute phase circulating CRP concentration will rise rapidly,so it's usually used as a nonspecific inflammatory marker in clinical.In the process of tumor formation,chronic inflammation was found to be an important cause of tumor development.Plasma CRP levels in cancer patients could reach 10-40 mg / L compared to normal1mg/l.CRP was an important component of innate immunity and involved in inflammatory reaction.CRP was also found to increase significantly in tumor microenvironment,but there was still no consensus between CRP and the causality of cancer formation and development.It has been reported that CRP-related SNPs could affect the baseline level of CRP,but whether they were functional SNPs or not is unknown.The T-allele of rs3091244,a polymorphism site with the highest association with CRP level,could promote the expression of CRP in combination with USF.However,the rs3091244 T allele is dominant in the European population while it is A allele in the Asian population.We investigated the plasma concentration of CRP in Chinese population and found that A allele activity was significantly higher than T allele,but how A allele affected CRP gene expression remained unclear.Our results showed that rs3091244 could regulate the expression of CRP through bias binding of Apex1.Apex1 was more likely to bind to C/T allele than to A allele in vivo and in vitro.Thus,Apex1 played a major role in inhibiting the expression of CRP.These results suggested that Apex1 had a new transcriptional inhibitory activity in addition to DNA damage repair and redox function.Previous studies on the relationship between CRP gene polymorphism and cancer risk were mainly carried out in European population,but whether there was any association was still contradictory.Among them,we further confirmed that functional locus rs3091244 is limited by the triple allele factor(ref C,minor A/T),which is difficult for the detection of Taqman probe,so it was rarely studied.Moreover,the T-allele is a largeproportion in European population,while in Asia,on the contrary,is dominated by A-allele.Therefore,we choose functional SNP rs3091244 to detect population polymorphism in a more reliable way by first-generation sequencing and Taqman probe to detect two widely reported SNPs(rs1205 and rs2794521),to explore whether the change of CRP concentration caused by SNPs affected the risk of cancer in Gansu population.In the healthy population of Gansu province,the minor alleles of rs3091244 and rs1205 could significantly affect the level of CRP.The A-allele of rs3091244 increased the plasma level of CRP by 29.54% ±6.48%,and the T-allele by26.03% ±8.61%.The minor A-allele of rs1205 reduced the plasma level of CRP by24.94% ±10.56%.The minor allele of rs2794521 only raised the plasma crp level by6.98%.Adjusted by age,sex and BMI(body mass index),the odds ratio of rs3091244 to overall cancer risk was OR= 0.766(95% CI: 0.319,1.838),and the odds ratio of rs1205 to overall cancer risk was OR=1.133(95% CI:0.47,2.735).The odds ratio of rs2794521 to overall cancer risk was OR=1.441(95% CI:0.624,3.328).There was no significant correlation between SNPs and overall cancer risk,and no significant correlation was found between SNPs and specific type of cancer.It seems that CRP was difficult to drive cancer,but we found that in cancer patients,correlation between SNPs genotype and CRP concentration in circulatory system was significantly decreased,which may mainly due to the inflammatory molecules(such as IL-6)in cancer patients.While these inflammatory factors were key factors involved in CRP transcription regulation.Because of the limited contribution of SNPs to plasma crp,it was difficult to judge the causal relationship of CRP in the development of cancer by SNPs.The role of CRP in the carcinogenesis and development of cancer remains to be further studied.