| Backgroud:Colorectal cancer (CRC) is one of the most common malignant cancers in modern society. More than 1 million people develop CRC all over the world every year, and about 500 thousand people die of it, which made CRC ranking the 3rd of both morbidity and mortality in all cancers. In China, the morbidity of CRC is increasing sharply. It counted about 24 incidences in 100 thousand people in year 2008 in China. In a newly enacted document"Essentials in the plan of cancer prevention and control in China", CRC was listed as one of the eight"emergency cancers"which are responsible for 80% of the mortality caused by cancers.Like most cancers, etiology study suggested that both genetic and environmental factors take effects in developing CRC. Studies revealed that diet and phisycal activities are related environmental factors while genes coding folic acid metabolizing enzymes and some phaseâ…¡metabolizing enzymes play important roles in the genetic susceptibily to CRC.Most epidemiology studies found alcohol consumption to be a risk factor of developing CRC, especially in Asians. The different effects of alcohol consumption among populations indicate that genetic factors may play important roles in the association between alcohol consumption and CRC development. Studies on the fanctional polymorphisms in alcohol metaolizing enzymes found significant genetic differences between western people and Asians. However, there are only a few reported researches focused on Chinese population, and no tagSNPs based research into alcohol metabolizing enzymes was reported. On account of this, we conducted a case-control study based on the Japan, Korea and China Colorectal Cancer collaboration study, adding the newly recruited samples from northeastern China, to study the genetic association between polymorphisms of genes coding major alcohol metabolizing enzymes, JWA gene and CRC.Objectives:1. To screen tagSNPs in major alcohol metabolizing genes ADH1B, ALDH2, CYP2E1 and to study the association between the tag SNPs and CRC susceptibility in southwestern Chinese.2. To study the association between CYP2E1 functional polymorphisms and CRC susceptibility in both southwestern and northeastern Chinese, and the difference between the two district.3. To study the association between JWA functional polymorphisms and CRC susceptibility in southwestern Chinese.Method:1. Obtaining CHB population SNPs data of whole length plus 1200bp upper strand of ADH1B, ALDH2, CYP2E1 from HapMap (http://www.hapmap.org), accepting the loci that the minor allele frequency (MAF) is above 0.03, constructing LD blocks with software Haploview v4.0, select the locus which ranks the highest r2 with other loci in the very block as the tagSNP, using SNPlex to genotype these tagSNPs in southwestern Chinese.2. Using PCR-RFLP to genotype CYP2E1 functional polymorphisms Rsaâ… , Draâ… , Taqâ… (rs2031920, rs6413432, rs2070676) in southwestern and northeastern Chinese; using PCR-RFLP to genotype JWA functional polymorphisms -76 G>C and 723 T>G in southwestern Chinese.3. Using software Statistical Analysis System version 9.0 to apply unconditional logistic regression model to evaluate the risk by odds ratio (OR); using software Haploview v4.0 for reconstructing haplotypes; using software unphased v3.0.13 for evaluating the ORs of haplotypes; using Multifactor dimensionality reduction (MDR) v1.0.0 to assess the interactions between loci; dividing samples into subgroups by drinking or smoking habits to assess interactions between genetic polymorphisms and smoking and alcohol consumption. Results:1. In the three candidate genes coding major alcohol metabolizing enzymes (ADH1B, ALDH2, CYP2E1), sixteen candidate loci were screened and fourteen of them were genotyped successfully; ALDH2 rs671 AA and CYP2E1 rs1329149 CC genotypes were found to be associated with increased risk of CRC in southwestern Chinese (OR=1.86 and 4.01, 95% CI=1.12-3.08 and 2.40-6.66, respectively), both the loci showed higher effect in rectum cancer (rs671 AA genotype was not associated with colon cancer but showed 2.20-fold of increased risk in rectum cancer, 95% CI=1.25-3.86; rs1329149 CC genotype showed 3.05-fold and 4.72-fold of increased risk in colon cancer and rectum cancer, respectively); Interaction between ALDH2 and CYP2E1 was found, individuals with risk genotypes of rs671 AA and rs1329149 CC, showed an increased risk of 4.97-fold; Interactions existed between the two loci and alcohol consumption, the risk to CRC susceptibility of people with rs671 AA and rs1329149 CC increased from 2.55-fold in non-drinkers to 7.39-fold in drinkers.2. The age of diagnosing CRC was significantly lower in southwestern Chinese than that in northeastern Chinese. Drinking people was fewer in southwestern Chinese than that in northeastern Chinese. Genetic differences were found in CYP2E1 between southwestern and northwestern Chinese. In southwestern Chinese, rs2070676 CC genotype was associated with slightly increased risk of CRC (OR=1.38, 95% CI=1.04-1.84), combined with alcohol consumption, rs6413423 T allele and rs2070676 C allele were associated with increased risk of CRC (OR=2.26 and 3.54, respectively), which were not found in northeastern Chinese.3. JWA -76G>C and 723 T>G were not associated with CRC in southwestern Chinese. No interaction was found between the polymorphisms and smoking or alcohol consumption.Conclusion:1. Among the polymorphisms in major alcohol metabolizing genes, ALDH2 rs671 AA, CYP2E1 rs1329149 CC and rs2070676 GC genotypes are genetic susceptibility factors of CRC in southwestern Chinese. Gene-gene interaction exists between CYP2E1 and ALDH2, and gene-environment interaction also exists between CYP2E1, ALDH2 polymorphisms and alcohol consumption, the result showed increased risk with more risk factors in southwestern Chinese.2. Significant genetic differences exist between southwestern and northeastern Chinese, drinking habit, the age of developing CRC are significantly different between the two populations.3. JWA gene polymorphisms may be not associated with CRC risk in southwestern Chinese.To be summary, the genetic background differs in southwestern and northeastern Chinese, indicating the importance of multi population research. Polymorphisms in major alcohol metabolizing enzymes are associated with CRC susceptibility, and they interact with alcohol consumption, indicating that, beyond genetic factors which are hardly to be modified, life style is an important factor in developing CRC, which we can be easily taken into control. This may lead to a new direction of individual intervention in CRC prevention.
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