影响广西防城港地区汉族成年男性癌胚抗原水平的遗传变异分析及其临床意义探讨
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摘要
[研究内容]本研究内容分三部分：(1)对广西特定地区的相同种族、成年男性健康人群的血清CEA(Carcinoembryonic Antigen)水平及其影响因素进行流行病学调查。(2)在该人群中进行血清CEA水平与单核苷酸多态性(SNP)位点的定量全基因组关联分析。(3)分析影响该地区散发性结直肠癌患者血清CEA水平的遗传变异及探讨其临床意义。
第一部分
[目的]了解广西防城港地区的汉族成年男性健康人群的血清CEA水平分布及其相关影响因素。
[材料与方法]我们对来自广西防城港地区汉族人群的2,022名男性健康成人进行外周静脉血血清CEA水平的检测。对该研究人群进行身体健康检查以排除患病人群；相关问卷调查以了解个体生活环境的差异并将其作为相关影响因素进行分析。研究人群的血清CEA水平值进行正态性转换。单因素分析比较各影响因素对血清CEA水平的影响；利用多元线性回归模型分析血清CEA水平与这些影响因素之间的关系；并对各个因素作出评价。统计学软件为SPSS17.0。
[结果]广西防城港地区汉族成年健康男性(17-68岁)的血清CEA水平均数为2.505±1.682(ng/mL)；CEA水平分布范围为(0.239～26.69ng/mL)；其分布呈偏态分布。单因素分析的结果提示：年龄,吸烟及吸烟量,饮酒,肥胖(BMI>28)均为影响该人群血清CEA水平的相关因素。各年龄组间血清CEA水平差异有统计学意义(p<0.001)；年龄大于60岁组中CEA水平最高1.45±0.26ng/ml。吸烟组与非吸烟组间的差异有统计学意义p<0.001；在吸烟者中按总吸烟量(年包数)进行分组后比较血清CEA水平的差异；重度吸烟组的CEA水平最高1.44±0.25ng/ml,其差异有统计学意义p<0.001。 BMI各组的CEA水平差异有统计学意义(p=0.034)。乙型病毒性肝炎的感染不是影响血清CEA水平的因素(p=0.175)。通过多元线性回归模型分析,进入模型的自变量包括吸烟(吸烟总量)、肥胖(BMI)、饮酒；其中吸烟量对血清CEA水平的影响在上述影响因素中最大,其相关系数(校正后)为0.175,p<0.001。肥胖与正常人群的血清CEA水平呈负相关(B=-0.05；p=0.006)。上述影响因素的R2(调整后)为0.07。
[结论]通过大规模流行病学调查取得防城港地区男性汉族健康人群的血清CEA水平分布数据。其单因素分析的结果提示：年龄,吸烟及吸烟量,饮酒,肥胖(BMI)均为影响该人群血清CEA水平的相关因素；多因素分析提示总吸烟量及年龄是影响CEA水平的重要因素。相关影响因素对正常人群CEA水平差异的影响较小。
第二部分
[目的]对广西防城港地区男性汉族健康人群进行血清CEA水平与单核苷酸多态性(SNP)位点的定量全基因组关联分析(GWAS);了解影响该人群血清CEA水平的遗传变异因素。
[材料与方法]采集研究人群的外周静脉血检测血清CEA水平及提取DNA样本。利用高通量的基因分型技术The Illumina Omini1全基因组SNP分型芯片对上述研究人群的DNA样本(n=2,018)进行SNP分型。满足分型质量控制标准的入组人群(n=1,999)进行血清CEA水平与SNP分型成功位点(n=709,211)在多元线性回归模型中进行关联分析；样本血清CEA值在关联分析中按校正年龄,BMI及吸烟量进行校正。全基因组关联分析统计学检验显著性水平经Boferroni校正后统计检验标准为1E-7。基因分型的质量控制标准：Hardy-Weinberg Equilibrium(HWE)test p>0.001；最小等位基因频率>0.01；基因分型成功率>0.95。相关位点及其所在基因进行生物信息学功能分析及预测,所用分析软件为DAVID6.7.通过与ABO血型各等位基因(A1,A2,B,O)相关SNP(rs507666,rs8176704, rs687289.与rs8176746)对研究人群进行ABO血型进行等位基因分型并比较各组血清CEA水平。关联分析所用软件为PLINK v1.06.
[结果]通过GWAS发现25个SNP位点达到全基因组关联分析统计学检验显著性(1E-7)。这些位点主要位于ABO基因(rs8176741；rs8176746； rs8176722； rs8176743； rs8176749； rs507666Ts7873522;176720；rs8176725)；FUT2_基因(rs1047781)；FUT6基因(rs3760775,rs778805,rs778809)；CA11基因(rs11880333)；RPL18基因(rs2292324)；SULT2B1基因(rs3786749)；FAM3B基因(rs441810)；FAM83E基因(rs433852)。基因集功能富集分析结果提示相关基因(ABO基因与在FUT1,2基因)位于鞘糖脂合成通路。ABO各等位基因型携带者间的血清CEA水平存在差异(BB>BO; AAAB)。
[结论]我们发现影响血清CEA水平的相关SNP位点及其所在基因。与ABO血型的等位基因相关位点的多态性影响血清CEA水平；提示ABO血型的等位基因型与血清CEA水平可能存在相关性。
第三部分
[目的]分析影响广西地区散发性结直肠癌患者血清CEA水平的遗传变异因素；探讨该遗传变异与广西地区散发性结直肠患者临床表现的关系。
[材料与方法]收集194例在广西医科大学第一附属医院住院并手术的散发性结肠癌患者进行血清CEA水平检测及DNA标本采集。相关临床数据通过完整住院记录及复诊、随访资料提供。切除组织病理经该院病理科经两名资深病理科医生共同诊断。根据全基因组关联分析的统计学显著性水平及ABO血型相关基因位点原则挑选候选SNP。 DNA标本的相关SNP等位基因分型采用实时荧光定量PCR法；分型探针采用TaqMan-MGB双等位基因分型探针。单因素分析影响术前CEA水平的因素采用非参数法；比较各因素对淋巴结转移及术后肿瘤复发的影响采用Logistic回归分析。Kaplan-Meier法用于比较各影响因素组之间的无瘤生存时间。统计学软件为SPSS17.0。
[结果]194例散发性结直肠癌患者术后病理诊断为腺癌。淋巴结转移与远处转移是术前CEA水平差异的影响因素(5.36vs3.41ng/ml, p=0.011;11.87vs3.60ng/ml,p=0.033).淋巴结转移组术后无瘤生存时间的差异有统计学意义(p=0.021).Logistic回归分析提示淋巴结转移是影响术后肿瘤复发的风险因素(OR:3.517；95%C.I:1.437-8.607；p=0.006).在排除肿瘤转移的影响后,对各候选SNP的等位基因型术前CEA水平的差异分析结果提示rs107781(A/T)位点的等位基因型与术前CEA水平相关(AA:1.725,AT:3.49,TT:4.1lng/ml；p=0.009)。在不同淋巴结转移状态下,rs1047781各等位基因型组的术后无瘤生存时间差异无统计学意义：在伴有淋巴结转移病人中,AAvs AT:p=0.146；AA vs TT:p=0.173；AT vs TT:p:0.956；无淋巴结转移病人中,AA vs AT:p:0.823；AA vs TT:p=0.389；AT vs TT:p=0.254).分别以rs1047781的3个等位基因型作为遗传背景下,分析病人的不同淋巴结转移状态对术后无瘤生存时间的影响；结果提示AA基因型中两组差异无统计学意义(p=0.981)；AT及TT基因型组中两组差异有统计学意义(p=0.037；p=0.029).rs3760775(G/T)各等位基因组的发病部位的差异有统计学意义(X2=18.584,p=0.017). rs2071699(A/G),各等位基因组(AA,AG,GG)的发病部位(升结肠)的差异有统计学意义(X2=16.254,p=0.039).rs441810(A/G)各等位基因组的发病部位差异有统计学意义(χ2=144.123,p<0.001);其大体病理表现的差异有统计学意义(X2=9.304,p=0.050).rs8176746的等位基因型组间(AA,AG,GG)的区域淋巴结转移发生率的差异有统计学意义(AA vs GG:27.4%vs1.1%；X2=7.609,p=0.022).
[结论]rs1047781位点的等位基因多态性与广西地区散发性结直肠癌患者术前CEA水平差异相关；该结果与正常人群的GWAS结果一致。该位点的等位基因多态性是影响人群CEA水平的遗传变异因素之一。通过与无淋巴结转移的病人比较,结果提示rs1047781等位基因T可能与该地区伴有淋巴结转移的散发性结直肠癌术后早期复发有关。rs441810多态性与散发性结直肠癌大体病理分型相关,等位基因A基因型是溃疡型肿瘤风险因素；其等位基因A与升结肠癌发病相关。rs8176746多态性与CRC术前淋巴结转移发生率相关,等位基因A是淋巴结转移的风险因素。
[Content] There were three parts included in our study:1) an epidemiological survey was designed to determine the distributions of serum CEA levels in healthy men from specific area and the same race; in addiction, we analyzed the confounders affecting serum CEA levels.2) The genome-wide association study (GWAS) was conducted to research the SNPs associated with serum CEA levels in the participants.3) Based on the result of GWAS, We tried to explore the association between polymorphisms and the serum CEA levels in patients with sporadic CRC from specific area; and the clinic significance of such polymorphisms were analyzed in the patients.
Part One
[Purpose] In this study, we tried to determine the distributions of serum CEA levels in healthy men from Fangchenggang Area and the Han nationality; we also evaluated the confounders affecting the serum CEA levels in the participants.
[Materials and Methods] The subjects from The Fangchenggang Area Male Health and Examination Survey (FAMHES) received routine physical examinations and Epidemiological survey by standardized questionnaire. Serum CEA level of peripheral venous blood was measured with electrochemiluminescence immunoassay. The differences of CEA values with regard to each affecting factors were assessed using one-way Analysis of Variance (ANOVA) or t-test. General linear regression analysis was used to assess the impact of age, BMI and the amount of smoking cigarettes among HBsAg negative subjects.
[Result] The mean of serum CEA levels was2.505±1.682(ng/mL); CEA levels ranged0.239～26.69ng/mL. The result of ANOVA showed age smoking drinking and BMI were the confounders in smokers and no-smokers was significantly different (t-test,p<0.001). The mean value of CEA in sub-group was significantly different (ANOVA,p<0.001); and the elder were with higher CEA level. When grouped by total quantity of cigarettes (mild, moderate and severe smoking), the CEA levels were significantly different (ANOVA,p<0.001). Alcohol-drinking was not a significant contributor to the CEA levels in this population (ANOVA, p=0.294). The age, smoking, BMI were subjected to multivariate analysis. In General Linear Regression model, Age (Beta=0.003,p<0.001), total quantity of cigarettes (Beta=0.004,p<0.001) and BMI (Beta=-0.05,/?=0.006) were significantly associated with CEA level; the adjusted R2of regression model was0.070.
[Conclusion] We got the distributions of serum CEA level of healthy men from Fangchenggang Area and the Han nationality. Age、smoking and BMI were factors affecting serm CEA level. Total quantity of cigarettes and age were important confounders which had little contribution to the variation of CEA level..
Part Two
[Purpose] To identify the loci associated with serum level of CEA in healthy men from FAMHES.
[Materials and Methods] The DNA of subjects were extracted from peripheral venous blood.The Illumina Omini1beadchip (Illumina, San Diego, USA) was used for the genome-wide association study (GWAS).1,999subjects from FAMHES passed the QC call rate of95%were included in the final data analysis and a total of709,211SNPs passed the following QC criteria:p>0.001for Hardy-Weinberg Equilibrium (HWE) test, minor allele frequency (MAF)>0.01and genotype call rate>95%. A linear regression model was used to analyze the association between serum CEA levels and SNP genotypes. The age, total quantity of smoking cigarette and BMI were covariates in the model and had been adjusted before association study. The PLINK v1.06software package was used to perform this statistical analysis. Bioinformatics soft DAVIA6.7was used to analysis the potential functions of associated SNPs. Four SNPs (rs507666, rs8176704, rs687289, rs8176746) were used to conduct allelic genotyping for ABO blood type and CEA levels of the allelic genotypes were analyzed.
[Result] Twenty-five SNPs were associated with the serum CEA levels at GWAS significant level(p=1E-7). The SNPs located in gene coding region included rs8176741, rs8176746, rs8176722, rs8176743, rs8176749, rs507666, rs7873522, rs8176720, rs8176725(ABO gene); rs1047781(FUT2gene); rs3760775, rs778805, rs778809(FUT6gene); rs11880333(CA11gene); rs2292324(RPL18gene); rs3786749(SULT2B1gene); rs441810(FAM3B gene); rs433852(FAM83E gene). Result of bioinformatics analysis for associated SNPs and genes showed that the Glycosphing-olipid biosythesis pathway was the pathway with genes function enrichment.
[Conclusion] The SNPs associated with CEA levels in Chinese men were identified in our study and the genes (ABO gene and FUT11,2gene)which associated SNPs located in were determined. The allelic genotypes of ABO blood type were associated with serum CEA levels.
Part Three
[Purpose] To explore the association between polymorphisms and the serum CEA levels in patients with sporadic CRC from Guangxi Province; and the clinic significance of such polymorphisms were analyzed in the patients.
[Materials and Methods] The samples of DNA were extracted from normal colon mucosa. The StepOnePlus/7500Real-Time PCR System(Applied Biosystem, Foster, USA) and the TaqMan-MGB probe was used for allelic genotyping. Nonparametric statistics was used in univariate analysis. Multivariable models were constructed by Logistic regression analysis. Kaplan-Meier estimators were applied in calculating survival function; the log-rank test was used to determine the survival differences among individual groups. The SPSS v.17.0program was used for analysis and P value<0.05was considered statistically significant.
[Result] The univariate analyses revealed that the preoperative CEA level was significant different between subgroups of regional lymph nodes and distant metastases (present vs. absent:11.87vs.3.60ng/ml;5.36vs.3.41ng/ml; respectively). There was significantly different CEA levels in three subgroups (AA, AT and TT) of rs1047781(AA:1.725, AT:3.490and TT:4.110ng/ml; Kruskal-Wallis H test,p=0.009; Jonckheere-Terpstra (J-T) test, p=0.011). The J-T test showed that the TT allelic subgroup had the higher sCEA levels and the AA had the lowest (p=0.011).
The Logistic regression analysis revealed that the age, preoperative CEA level and primary tumor staging (tumor invasion) were risk factors for regional lymph nodes metastasis. The preoperative CEA level and regional lymph nodes metastasis were risk factors for tumor recurrence in24months after radical operation(OR:1.013,95%CI:1.000～1.026, p=0.044;OR:3.517,95%CI.:1.437～8.607,p=0.006; respectively).
The result of survival analysis for tumor-free times represented there was not significantly different in AA genotype of rs1047781when the patients were grouped by status of tumor lymph node metastasis (p=0.98); as to the AT and TT genotype, the result were opposite (p=0.037and p=0.029; respectively). In allelic subgroups of rs3760775(G/T), rs2071699(A/G) and rs441810(A/G), there were significant differences of sites of primary tumour(X2=18.584,p=0.017; X2=16.254, p=0.039;X2=144.123,p<0.001; respectively). In allelic subgroups of rs441810, the clinicopathological features of tumour were significantly different(X2=9.304, p=0.050). In allelic subgroups of rs8176746, there were significant differences of rates of lymph nodes metastases(AA vs GG:27.4%vs1.1%;X2=7.609, p=0.022).
[Conclusion] Polymorphisms of rs1047781were associated with preoperative serum CEA levels in patients with sporadic colorectal cancer supporting the finding of GWAS in healthy population. We propose that the polymorphisms of rs1047781is genetic variance assoeiated-with serum CEA level in population from Southern China. The derived allele (T) of rs1047781might contribute to tumor recurrence in sporadic CRC patients with lymph node metastasis. The allele A of rs441810was the risk factor for tumour of ulcerative type and was associated with the tumour in ascending colon. Allele A of rs8176746was the risk factor for regional lymph node metastasis.
第一部分
[目的]了解广西防城港地区的汉族成年男性健康人群的血清CEA水平分布及其相关影响因素。
[材料与方法]我们对来自广西防城港地区汉族人群的2,022名男性健康成人进行外周静脉血血清CEA水平的检测。对该研究人群进行身体健康检查以排除患病人群；相关问卷调查以了解个体生活环境的差异并将其作为相关影响因素进行分析。研究人群的血清CEA水平值进行正态性转换。单因素分析比较各影响因素对血清CEA水平的影响；利用多元线性回归模型分析血清CEA水平与这些影响因素之间的关系；并对各个因素作出评价。统计学软件为SPSS17.0。
[结果]广西防城港地区汉族成年健康男性(17-68岁)的血清CEA水平均数为2.505±1.682(ng/mL)；CEA水平分布范围为(0.239～26.69ng/mL)；其分布呈偏态分布。单因素分析的结果提示：年龄,吸烟及吸烟量,饮酒,肥胖(BMI>28)均为影响该人群血清CEA水平的相关因素。各年龄组间血清CEA水平差异有统计学意义(p<0.001)；年龄大于60岁组中CEA水平最高1.45±0.26ng/ml。吸烟组与非吸烟组间的差异有统计学意义p<0.001；在吸烟者中按总吸烟量(年包数)进行分组后比较血清CEA水平的差异；重度吸烟组的CEA水平最高1.44±0.25ng/ml,其差异有统计学意义p<0.001。 BMI各组的CEA水平差异有统计学意义(p=0.034)。乙型病毒性肝炎的感染不是影响血清CEA水平的因素(p=0.175)。通过多元线性回归模型分析,进入模型的自变量包括吸烟(吸烟总量)、肥胖(BMI)、饮酒；其中吸烟量对血清CEA水平的影响在上述影响因素中最大,其相关系数(校正后)为0.175,p<0.001。肥胖与正常人群的血清CEA水平呈负相关(B=-0.05；p=0.006)。上述影响因素的R2(调整后)为0.07。
[结论]通过大规模流行病学调查取得防城港地区男性汉族健康人群的血清CEA水平分布数据。其单因素分析的结果提示：年龄,吸烟及吸烟量,饮酒,肥胖(BMI)均为影响该人群血清CEA水平的相关因素；多因素分析提示总吸烟量及年龄是影响CEA水平的重要因素。相关影响因素对正常人群CEA水平差异的影响较小。
第二部分
[目的]对广西防城港地区男性汉族健康人群进行血清CEA水平与单核苷酸多态性(SNP)位点的定量全基因组关联分析(GWAS);了解影响该人群血清CEA水平的遗传变异因素。
[材料与方法]采集研究人群的外周静脉血检测血清CEA水平及提取DNA样本。利用高通量的基因分型技术The Illumina Omini1全基因组SNP分型芯片对上述研究人群的DNA样本(n=2,018)进行SNP分型。满足分型质量控制标准的入组人群(n=1,999)进行血清CEA水平与SNP分型成功位点(n=709,211)在多元线性回归模型中进行关联分析；样本血清CEA值在关联分析中按校正年龄,BMI及吸烟量进行校正。全基因组关联分析统计学检验显著性水平经Boferroni校正后统计检验标准为1E-7。基因分型的质量控制标准：Hardy-Weinberg Equilibrium(HWE)test p>0.001；最小等位基因频率>0.01；基因分型成功率>0.95。相关位点及其所在基因进行生物信息学功能分析及预测,所用分析软件为DAVID6.7.通过与ABO血型各等位基因(A1,A2,B,O)相关SNP(rs507666,rs8176704, rs687289.与rs8176746)对研究人群进行ABO血型进行等位基因分型并比较各组血清CEA水平。关联分析所用软件为PLINK v1.06.
[结果]通过GWAS发现25个SNP位点达到全基因组关联分析统计学检验显著性(1E-7)。这些位点主要位于ABO基因(rs8176741；rs8176746； rs8176722； rs8176743； rs8176749； rs507666Ts7873522;176720；rs8176725)；FUT2_基因(rs1047781)；FUT6基因(rs3760775,rs778805,rs778809)；CA11基因(rs11880333)；RPL18基因(rs2292324)；SULT2B1基因(rs3786749)；FAM3B基因(rs441810)；FAM83E基因(rs433852)。基因集功能富集分析结果提示相关基因(ABO基因与在FUT1,2基因)位于鞘糖脂合成通路。ABO各等位基因型携带者间的血清CEA水平存在差异(BB>BO; AA
[结论]我们发现影响血清CEA水平的相关SNP位点及其所在基因。与ABO血型的等位基因相关位点的多态性影响血清CEA水平；提示ABO血型的等位基因型与血清CEA水平可能存在相关性。
第三部分
[目的]分析影响广西地区散发性结直肠癌患者血清CEA水平的遗传变异因素；探讨该遗传变异与广西地区散发性结直肠患者临床表现的关系。
[材料与方法]收集194例在广西医科大学第一附属医院住院并手术的散发性结肠癌患者进行血清CEA水平检测及DNA标本采集。相关临床数据通过完整住院记录及复诊、随访资料提供。切除组织病理经该院病理科经两名资深病理科医生共同诊断。根据全基因组关联分析的统计学显著性水平及ABO血型相关基因位点原则挑选候选SNP。 DNA标本的相关SNP等位基因分型采用实时荧光定量PCR法；分型探针采用TaqMan-MGB双等位基因分型探针。单因素分析影响术前CEA水平的因素采用非参数法；比较各因素对淋巴结转移及术后肿瘤复发的影响采用Logistic回归分析。Kaplan-Meier法用于比较各影响因素组之间的无瘤生存时间。统计学软件为SPSS17.0。
[结果]194例散发性结直肠癌患者术后病理诊断为腺癌。淋巴结转移与远处转移是术前CEA水平差异的影响因素(5.36vs3.41ng/ml, p=0.011;11.87vs3.60ng/ml,p=0.033).淋巴结转移组术后无瘤生存时间的差异有统计学意义(p=0.021).Logistic回归分析提示淋巴结转移是影响术后肿瘤复发的风险因素(OR:3.517；95%C.I:1.437-8.607；p=0.006).在排除肿瘤转移的影响后,对各候选SNP的等位基因型术前CEA水平的差异分析结果提示rs107781(A/T)位点的等位基因型与术前CEA水平相关(AA:1.725,AT:3.49,TT:4.1lng/ml；p=0.009)。在不同淋巴结转移状态下,rs1047781各等位基因型组的术后无瘤生存时间差异无统计学意义：在伴有淋巴结转移病人中,AAvs AT:p=0.146；AA vs TT:p=0.173；AT vs TT:p:0.956；无淋巴结转移病人中,AA vs AT:p:0.823；AA vs TT:p=0.389；AT vs TT:p=0.254).分别以rs1047781的3个等位基因型作为遗传背景下,分析病人的不同淋巴结转移状态对术后无瘤生存时间的影响；结果提示AA基因型中两组差异无统计学意义(p=0.981)；AT及TT基因型组中两组差异有统计学意义(p=0.037；p=0.029).rs3760775(G/T)各等位基因组的发病部位的差异有统计学意义(X2=18.584,p=0.017). rs2071699(A/G),各等位基因组(AA,AG,GG)的发病部位(升结肠)的差异有统计学意义(X2=16.254,p=0.039).rs441810(A/G)各等位基因组的发病部位差异有统计学意义(χ2=144.123,p<0.001);其大体病理表现的差异有统计学意义(X2=9.304,p=0.050).rs8176746的等位基因型组间(AA,AG,GG)的区域淋巴结转移发生率的差异有统计学意义(AA vs GG:27.4%vs1.1%；X2=7.609,p=0.022).
[结论]rs1047781位点的等位基因多态性与广西地区散发性结直肠癌患者术前CEA水平差异相关；该结果与正常人群的GWAS结果一致。该位点的等位基因多态性是影响人群CEA水平的遗传变异因素之一。通过与无淋巴结转移的病人比较,结果提示rs1047781等位基因T可能与该地区伴有淋巴结转移的散发性结直肠癌术后早期复发有关。rs441810多态性与散发性结直肠癌大体病理分型相关,等位基因A基因型是溃疡型肿瘤风险因素；其等位基因A与升结肠癌发病相关。rs8176746多态性与CRC术前淋巴结转移发生率相关,等位基因A是淋巴结转移的风险因素。
[Content] There were three parts included in our study:1) an epidemiological survey was designed to determine the distributions of serum CEA levels in healthy men from specific area and the same race; in addiction, we analyzed the confounders affecting serum CEA levels.2) The genome-wide association study (GWAS) was conducted to research the SNPs associated with serum CEA levels in the participants.3) Based on the result of GWAS, We tried to explore the association between polymorphisms and the serum CEA levels in patients with sporadic CRC from specific area; and the clinic significance of such polymorphisms were analyzed in the patients.
Part One
[Purpose] In this study, we tried to determine the distributions of serum CEA levels in healthy men from Fangchenggang Area and the Han nationality; we also evaluated the confounders affecting the serum CEA levels in the participants.
[Materials and Methods] The subjects from The Fangchenggang Area Male Health and Examination Survey (FAMHES) received routine physical examinations and Epidemiological survey by standardized questionnaire. Serum CEA level of peripheral venous blood was measured with electrochemiluminescence immunoassay. The differences of CEA values with regard to each affecting factors were assessed using one-way Analysis of Variance (ANOVA) or t-test. General linear regression analysis was used to assess the impact of age, BMI and the amount of smoking cigarettes among HBsAg negative subjects.
[Result] The mean of serum CEA levels was2.505±1.682(ng/mL); CEA levels ranged0.239～26.69ng/mL. The result of ANOVA showed age smoking drinking and BMI were the confounders in smokers and no-smokers was significantly different (t-test,p<0.001). The mean value of CEA in sub-group was significantly different (ANOVA,p<0.001); and the elder were with higher CEA level. When grouped by total quantity of cigarettes (mild, moderate and severe smoking), the CEA levels were significantly different (ANOVA,p<0.001). Alcohol-drinking was not a significant contributor to the CEA levels in this population (ANOVA, p=0.294). The age, smoking, BMI were subjected to multivariate analysis. In General Linear Regression model, Age (Beta=0.003,p<0.001), total quantity of cigarettes (Beta=0.004,p<0.001) and BMI (Beta=-0.05,/?=0.006) were significantly associated with CEA level; the adjusted R2of regression model was0.070.
[Conclusion] We got the distributions of serum CEA level of healthy men from Fangchenggang Area and the Han nationality. Age、smoking and BMI were factors affecting serm CEA level. Total quantity of cigarettes and age were important confounders which had little contribution to the variation of CEA level..
Part Two
[Purpose] To identify the loci associated with serum level of CEA in healthy men from FAMHES.
[Materials and Methods] The DNA of subjects were extracted from peripheral venous blood.The Illumina Omini1beadchip (Illumina, San Diego, USA) was used for the genome-wide association study (GWAS).1,999subjects from FAMHES passed the QC call rate of95%were included in the final data analysis and a total of709,211SNPs passed the following QC criteria:p>0.001for Hardy-Weinberg Equilibrium (HWE) test, minor allele frequency (MAF)>0.01and genotype call rate>95%. A linear regression model was used to analyze the association between serum CEA levels and SNP genotypes. The age, total quantity of smoking cigarette and BMI were covariates in the model and had been adjusted before association study. The PLINK v1.06software package was used to perform this statistical analysis. Bioinformatics soft DAVIA6.7was used to analysis the potential functions of associated SNPs. Four SNPs (rs507666, rs8176704, rs687289, rs8176746) were used to conduct allelic genotyping for ABO blood type and CEA levels of the allelic genotypes were analyzed.
[Result] Twenty-five SNPs were associated with the serum CEA levels at GWAS significant level(p=1E-7). The SNPs located in gene coding region included rs8176741, rs8176746, rs8176722, rs8176743, rs8176749, rs507666, rs7873522, rs8176720, rs8176725(ABO gene); rs1047781(FUT2gene); rs3760775, rs778805, rs778809(FUT6gene); rs11880333(CA11gene); rs2292324(RPL18gene); rs3786749(SULT2B1gene); rs441810(FAM3B gene); rs433852(FAM83E gene). Result of bioinformatics analysis for associated SNPs and genes showed that the Glycosphing-olipid biosythesis pathway was the pathway with genes function enrichment.
[Conclusion] The SNPs associated with CEA levels in Chinese men were identified in our study and the genes (ABO gene and FUT11,2gene)which associated SNPs located in were determined. The allelic genotypes of ABO blood type were associated with serum CEA levels.
Part Three
[Purpose] To explore the association between polymorphisms and the serum CEA levels in patients with sporadic CRC from Guangxi Province; and the clinic significance of such polymorphisms were analyzed in the patients.
[Materials and Methods] The samples of DNA were extracted from normal colon mucosa. The StepOnePlus/7500Real-Time PCR System(Applied Biosystem, Foster, USA) and the TaqMan-MGB probe was used for allelic genotyping. Nonparametric statistics was used in univariate analysis. Multivariable models were constructed by Logistic regression analysis. Kaplan-Meier estimators were applied in calculating survival function; the log-rank test was used to determine the survival differences among individual groups. The SPSS v.17.0program was used for analysis and P value<0.05was considered statistically significant.
[Result] The univariate analyses revealed that the preoperative CEA level was significant different between subgroups of regional lymph nodes and distant metastases (present vs. absent:11.87vs.3.60ng/ml;5.36vs.3.41ng/ml; respectively). There was significantly different CEA levels in three subgroups (AA, AT and TT) of rs1047781(AA:1.725, AT:3.490and TT:4.110ng/ml; Kruskal-Wallis H test,p=0.009; Jonckheere-Terpstra (J-T) test, p=0.011). The J-T test showed that the TT allelic subgroup had the higher sCEA levels and the AA had the lowest (p=0.011).
The Logistic regression analysis revealed that the age, preoperative CEA level and primary tumor staging (tumor invasion) were risk factors for regional lymph nodes metastasis. The preoperative CEA level and regional lymph nodes metastasis were risk factors for tumor recurrence in24months after radical operation(OR:1.013,95%CI:1.000～1.026, p=0.044;OR:3.517,95%CI.:1.437～8.607,p=0.006; respectively).
The result of survival analysis for tumor-free times represented there was not significantly different in AA genotype of rs1047781when the patients were grouped by status of tumor lymph node metastasis (p=0.98); as to the AT and TT genotype, the result were opposite (p=0.037and p=0.029; respectively). In allelic subgroups of rs3760775(G/T), rs2071699(A/G) and rs441810(A/G), there were significant differences of sites of primary tumour(X2=18.584,p=0.017; X2=16.254, p=0.039;X2=144.123,p<0.001; respectively). In allelic subgroups of rs441810, the clinicopathological features of tumour were significantly different(X2=9.304, p=0.050). In allelic subgroups of rs8176746, there were significant differences of rates of lymph nodes metastases(AA vs GG:27.4%vs1.1%;X2=7.609, p=0.022).
[Conclusion] Polymorphisms of rs1047781were associated with preoperative serum CEA levels in patients with sporadic colorectal cancer supporting the finding of GWAS in healthy population. We propose that the polymorphisms of rs1047781is genetic variance assoeiated-with serum CEA level in population from Southern China. The derived allele (T) of rs1047781might contribute to tumor recurrence in sporadic CRC patients with lymph node metastasis. The allele A of rs441810was the risk factor for tumour of ulcerative type and was associated with the tumour in ascending colon. Allele A of rs8176746was the risk factor for regional lymph node metastasis.
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