叶酸代谢网络酶基因遗传多态性与原发性肝癌的遗传易感性的研究
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摘要
肝癌(HCC)在世界上为排名第五位而死亡第三位的恶性肿瘤。由于肝癌发病原因复杂,缺乏早期诊疗手段使得肝癌的生存期短,死亡率高。我国人口占世界人口五分之一,然而肝癌的发病率却是占了世界总发病率的42.5%,每年有超过300,000的肝癌死亡病例,肝癌的发生机理和治疗手段一直是我国科研和临床的主要课题。对于复杂疾病的关联分析研究,候选通路的策略既可揭示出遗传多态性与癌症的关系,还可以进行基因—基因间的互作分析,是复杂疾病的关联分析较合适的手段,对于探求HCC的早期易感遗传标志物有现实意义。
叶酸代谢通路是一个复杂的生化代谢网络,是以叶酸作为一碳单位的重要载体,以辅酶的形式介导一碳单位转移,通过一系列的氧化还原反应,作为DNA等甲基化的供体,同时参与嘌呤与胸腺嘧啶的合成,进一步合成DNA与RNA。叶酸代谢是连接表观遗传以及DNA合成和修复作用的重要通路,有证据认为叶酸代谢紊乱与很多复杂疾病相关,是肿瘤发生的潜在风险因素。
本研究采用病例—对照的研究设计,在708例肝癌病例和1249例对照中,基于候选基因和候选功能位点的策略,挑选了叶酸代谢网络中重要的酶基因20个,为MTHFR,TS,MTR,MTRR,MTHRD1,PEMT,CHDH,BHMT,SHMT1,CHKA,SLC19A1,TCN2,FOLR1,HCP1,GNMT,DPYD,ABCB4,DNMT1,CBS,以及DHFR。在这些酶的基因上候选了41个有潜在功能作用,有氨基酸改变的功能位点。另外鉴于MTHFR和TS基因在以前文献中报道的重要作用,本研究对这两个基因的全长区域通过连锁不平衡方法以MAF＞0.05和R~2＞0.8的原则筛选了相应的tagSNP,对于两个基因上的功能位点采取强制选入的原则。
单位点卡方检验分析中我们发现TS 5′UTR 3R/2R位点与肝癌有关联(P=0.001),FDR校正仍然阳性。进一步的Logistic回归分析表明携带TS 5′UTR3R/2R的个体与野生型3R/3R比较对HCC有保护作用(P=0.02,校正OR=0.73,95%CI=0.57-0.95),携带TS 5′UTR 2R/2R的个体与野生型3R/3R相比也有保护作用(P=0.03,校正OR=0.54,95%CI=0.30-0.96)。整个代谢网络上的酶基因的遗传多态性的平均校正OR为0.97(Min 0.49,Max 1.50)。
本研究进行了基因与环境因子的分层分析,发现TS 5'UTR 3R/2R在诸多环境因子分层中与HCC有关联。相比野生型3R3R,那些带有2R2R的个体在女性,大于50岁,ALT指标正常,大于20packyear,饮酒量大于15g/day,HBV指标阳性,非HCC家族史或非恶性肿瘤史的人群都表现为保护作用(OR范围为0.31到0.69)。其他在HBV感染分层中有关联的位点为MTHFR基因的rs9651118(tagSNP),GNMT rs2296804(tagSNP)和PEMT rs7946(M175V)。在乙肝E抗原阳性的携带者中,携带MTHFRrs9651118 C的个体增加HCC患病风险(OR=1.82,1.16-2.58)。GNMT rs2296804携带突变纯合体的个体GG相比杂合子和野生纯合子(CG+CC)在乙肝携带者的群体中有保护作用,降低患HCC的风险(OR=0.60,95%CI=0.39-0.91)。在感染过乙肝后痊愈或者刚刚感染的个体里面,携带PEMT rs7946的突变等位基因T增加了患HCC的风险(OR为2.20,95%.CI=1.07-4.54)。对于饮酒量大于15g/d的风险人群,MTHFD1rs1950902(R134K)的突变型和杂合型个体(AG+GG)有增加HCC患病的风险,OR为1.67(1.02-2.72),统计上显著。对于ALT正常水平的个体携带BHMT rs585800(AT+TT)与野生型从比较有保护作用(OR=0.54,0.31-0.92)。在女性中有保护作用的位点还有SHMT1rs1979277(F474L)和MTHFRrs1801131(A429E),携带突变型和杂合型的基因型个体比野生型有保护患HCC风险的作用,它们的OR分别为0.19(95%CI=0.05-0.74)和0.44(95%CI=0.21-0.93)。另一个位点MTRrs16834521(Ala1048Ala)突变纯合型和杂合型的男性个体中有增加患HCC风险的作用,OR为1.34(95%CI 1.02-1.76)。
本研究采用了四种研究基因—基因互作的统计学方法对叶酸代谢网络中酶基因的遗传多态性位点之间的互作关系与肝癌的关联作了详细的分析和比较。这四种方法主要有多因子降维法(MDR),基于复合连锁不平衡的方法,基于交互信息论的方法(MIA)以及传统Logistic回归的方法。从MDR,LD和MIA预测的两两互作的位点主要发生在叶酸的吸收转运与DNA合成或DNA甲基化两大功能域上。将这些位点放入在Logistic回归模型中分析,发现基于LD的方法预测的3组互作位点的互作相为统计上显著,它们是MTRrs16834521(Ala1048Ala)和FOLRrs2071010,MTHFD1rs1950902(A429E)和HCP1rs2239907,以及TS3'UTR6bpdel/ins和DHFR 19bpD/I。交互作用效果为MTRrs16834521野生型从和FOLRrs2071010突变型T的个体中随着T等位基因的增加为保护效应(OR分别为0.69和0.18);然而当MTRrs16834521为突变型GG时,携带FOLRrs2071010突变型T的个体中随着T等位基因的增加患HCC风险增加(OR分别为1.37和2.33)。MTHFD1rs1950902和HCP1rs2239907互作的结果是携带MTHD1rs1950902突变型和HCP1 rs2239907突变型的个体降低了患HCC的风险。TS3'UTR6bp del/ins和DHFR19bpD/I互作的结果是携带TS3'UTR6bp del/ins突变型和DHFR 19bpD/I突变型的个体增加了患HCC的风险。本研究比较了这几种方法的效果,认为在研究多个位点的基因互作时最好能多尝试不同的方法,然后用Logistic回归进行分析获得相对风险度,这样可以提高检出率。
单倍型分析发现TS(global P=0.01)和MTHFR(global P=0.05)的单倍型与HCC有显著的关联。与野生单倍型相比,TS的“2TTD”显著降低HCC的发病风险(OR=0.61,95%CI 0.41-0.91),而只有rs699517突变型C的单倍型“3ATCD”,则为增加HCC发病风险(OR=1.77,95%CI 1.21-2.60),统计显著。MTHFR的单倍型为“CGATTCTT”与野生型单倍型“CGACTCTT”相比有增加HCC发病风险作用(OR=1.36:95%CI 1.36-1.85),这其中MTHFRrs1801133(C677T)为突变型T。
总之,在本研究中,TS作为叶酸代谢网络中有主效应的基因与HCC的有关联作用。通过基因—环境和基因—基因交互作用,我们认为叶酸代谢网络中酶的遗传多态性与HCC有关联。在基因互作当中,我们明显看到与叶酸代谢的两大功能DNA合成和DNA甲基化相关的酶的基因多态位点互相作用,从而控制整个网络正常行使两大功能,一旦发生一方面的紊乱都会导致疾病的发生。
Hepatocellular Carcinoma(HCC) is the fifth most common cancer worldwide and is the third leading cause of death from cancer.It was the diverse etiology,high morbidity/mortality and lack of diagnostic markers for early diagnosis.With one -fifth the world population,the cancer incidence and mortality pattern in China play a key role in determining the cancer burden at a global level.HCC in China accounts for over 300,000 deaths annually and approximately 42.5%of the total incidence worldwide.Candidate pathway association study proved to be a powerful tool to reveal genetic variants that may have only small construction on complex disease.Then the discovered association polymorphisms can lead further functional research,which will uncover the molecular mechanism of HCC which will benefit the predisposition to disease,drug response,diagnosis,prognostic outcome.
One-carbon metabolism is a network of interrelated biochemical reactions in which a one-carbon unit from a donor compound is transferred to tetraphydrofolate(THF) for subsequent reduction or oxidation and transfer to other compound.Folate coenzymes in mammalian tissues thereby act as acceptors or donors of one-carbon units in a variety of reactions involved in amino acid and nucleotide methabolism.One-carbon pathway as an important role on DNA synthesis and methylation links the genetic and epigenetic progression closely associated with the development and prevention of several malignancies.
We hypothesized that polymorphisms of the 20 critical candidate genes MTHFR,TS,MTR,MTRR,MTHRD1,PEMT,CHDH,BHMT,SHMT1,CHKA, SLC19A1,TCN2,FOLR1,HCP1,GNMT,DPYD,ABCB4,DNMT1,CBS,and DHFR which involved in the one-carbon metabolism network may contribute to susceptibility to HCC.We selected 41 potential functional polymorphisms among them and conducted case-control association study with early onset of HCC.For critical roles on folate-metabolizing about MTHFR and TS,we tried to select 8 SNPs(5 tagSNPs and 3 ncSNPs) for MTHFR and 5 SNPs(3 tagSNPs and 2 at 3'UTR and 5'UTR respectively) covered the whole gene by LD with the MAF＞0.05 and R~2＞0.8.
We found there was a statistically significant distribution difference for TS 5'UTR 3R/2R in 708 liver cancer patients and 1249 controls(P=0.001) by Chi-square test after FDR correction.Further Logistic regression analyses revealed that the individuals with TS 5'UTR 3R/2R or 2R/2R have protective effects comparing with individuals with 3R/3R(P=0.02,adjusted OR = 0.73,95%C1= 0.57-0.95 for 3R2R and P=0.03,adjusted OR=0.54,95%Cl= 0.30-0.96 for 2R2R).For other 39 SNPs on one carbon pathway,we did not observe any significant interaction with HCC risk by single locus association analysis.The average ORs of all polymorphisms on one carbon pathway was 0.97(Min 0.49,Max 1.50).
We conducted interaction between genes and environmental factors and found that TS 5'UTR 3R/2R tandem repeat is related many environmental factors.The individuals with TS 5'UTR 2R2R had protective effects among individuals who are female,above 50 years-old,normal ALT(≤40U/I),above 20 packyears,above 15g/day,HBV positive,and non-HCC history and non cancer history(OR range from 0.31 to 0.69 and significant).The other SNPs interacted with HBV factors are two SNPs within MTHFR which is rs9651118(tagSNP),GNMT rs2296804 and PEMT rs7946.The HBV infection individuals carried MTHFR rs9651118 varied C allele increased HCC risk(OR=1.82,1.16-2.58).For chronic HBV carries with GNMT rs2296804 mutated GG decreased 2-fold risk to HCC comparing with CG and GG(OR= 0.60,95%Cl=0.39-0.91).With alcohol consumption above 15g/d,the individuals who with MTHFD1rs1950902 variant genotype increased the HCC risk(OR 1.67,95%Cl1.02-2.72).For male stratified analysis,MTRrs16834521(AA+AG) increased HCC risk(OR 1.34,95%Cl=1.02-1.76)。The individuals with normal ALT level(≤40U/L)who carried BHMT rs585800(AT+TT) have protective effect to HCC(OR0.54,0.31-0.92).
We also explored four different statistical methods(MDR,LD-based method,MIA based method and traditional logistic regression) to identify the gene-gene interaction on one carbon pathway.Pair-wised gene-gene interactions revealed that the interactions showed between MTR rs16834521(A1048A)and FOLR rs20710109(Pinter2.39×10~(-6)),MTHFD1 rs1950902(A429E)and HCP1 rs2239907(P_(inter)1.29×10~(-6)),and TS 3'UTR6bp del/ins and DHFR19bpD/l(P_(inter)2.11×10~(-5)),which have been analyzed by Logistic regression and validated as positive interactions.The former two interactions predicted protective actions for HCC with both variant alleles of two genes.But the last interactions predicted increasing risk for HCC with both variant alleles of two genes.Overall,we can assume the tendency to DNA methylation in folate metabolisms would have protective effect on HCC.Our experience was that we should use all of them to find more chances to confirm due to inconsistency among them,Logistic Regression can be as validation but not as a tool to find the interactions from large candidate markers.
Haplotype analysis revealed that TS(global P=0.01) and MTHFR(global P = 0.05) haplotypes had significant association with HCC risk.Further analysis revealed that the haplotype "2TTD "of TS decreased the risk of HCC (OR=0.61,95%Cl 0.41-0.91 ) and Haplotype "3ATCD"which included the mutant allele of TS rs699517 increased HCC risk(OR=1.77,95%Cl 1.21—2.60).The haplotype "CGACTCTT"of MTHFR increased the risk of HCC comparing with the wilde haplotype"CGACTCTT"(OR=1.36;95%Cl 1.36-1.85).
In conclusion,TS as main factors involved in the one carbon pathway may play a role in the etiology of HCC.Results from gene-gene and gene-environment interactions analysis revealed the genes in one carbon pathway may interact with other genes or environment to increase or decrease HCC risk.As a result,one carbon pathway facilitated the crosstalk between DNA synthesis and DNA methylation which are all important for the cancer onset.
叶酸代谢通路是一个复杂的生化代谢网络,是以叶酸作为一碳单位的重要载体,以辅酶的形式介导一碳单位转移,通过一系列的氧化还原反应,作为DNA等甲基化的供体,同时参与嘌呤与胸腺嘧啶的合成,进一步合成DNA与RNA。叶酸代谢是连接表观遗传以及DNA合成和修复作用的重要通路,有证据认为叶酸代谢紊乱与很多复杂疾病相关,是肿瘤发生的潜在风险因素。
本研究采用病例—对照的研究设计,在708例肝癌病例和1249例对照中,基于候选基因和候选功能位点的策略,挑选了叶酸代谢网络中重要的酶基因20个,为MTHFR,TS,MTR,MTRR,MTHRD1,PEMT,CHDH,BHMT,SHMT1,CHKA,SLC19A1,TCN2,FOLR1,HCP1,GNMT,DPYD,ABCB4,DNMT1,CBS,以及DHFR。在这些酶的基因上候选了41个有潜在功能作用,有氨基酸改变的功能位点。另外鉴于MTHFR和TS基因在以前文献中报道的重要作用,本研究对这两个基因的全长区域通过连锁不平衡方法以MAF＞0.05和R~2＞0.8的原则筛选了相应的tagSNP,对于两个基因上的功能位点采取强制选入的原则。
单位点卡方检验分析中我们发现TS 5′UTR 3R/2R位点与肝癌有关联(P=0.001),FDR校正仍然阳性。进一步的Logistic回归分析表明携带TS 5′UTR3R/2R的个体与野生型3R/3R比较对HCC有保护作用(P=0.02,校正OR=0.73,95%CI=0.57-0.95),携带TS 5′UTR 2R/2R的个体与野生型3R/3R相比也有保护作用(P=0.03,校正OR=0.54,95%CI=0.30-0.96)。整个代谢网络上的酶基因的遗传多态性的平均校正OR为0.97(Min 0.49,Max 1.50)。
本研究进行了基因与环境因子的分层分析,发现TS 5'UTR 3R/2R在诸多环境因子分层中与HCC有关联。相比野生型3R3R,那些带有2R2R的个体在女性,大于50岁,ALT指标正常,大于20packyear,饮酒量大于15g/day,HBV指标阳性,非HCC家族史或非恶性肿瘤史的人群都表现为保护作用(OR范围为0.31到0.69)。其他在HBV感染分层中有关联的位点为MTHFR基因的rs9651118(tagSNP),GNMT rs2296804(tagSNP)和PEMT rs7946(M175V)。在乙肝E抗原阳性的携带者中,携带MTHFRrs9651118 C的个体增加HCC患病风险(OR=1.82,1.16-2.58)。GNMT rs2296804携带突变纯合体的个体GG相比杂合子和野生纯合子(CG+CC)在乙肝携带者的群体中有保护作用,降低患HCC的风险(OR=0.60,95%CI=0.39-0.91)。在感染过乙肝后痊愈或者刚刚感染的个体里面,携带PEMT rs7946的突变等位基因T增加了患HCC的风险(OR为2.20,95%.CI=1.07-4.54)。对于饮酒量大于15g/d的风险人群,MTHFD1rs1950902(R134K)的突变型和杂合型个体(AG+GG)有增加HCC患病的风险,OR为1.67(1.02-2.72),统计上显著。对于ALT正常水平的个体携带BHMT rs585800(AT+TT)与野生型从比较有保护作用(OR=0.54,0.31-0.92)。在女性中有保护作用的位点还有SHMT1rs1979277(F474L)和MTHFRrs1801131(A429E),携带突变型和杂合型的基因型个体比野生型有保护患HCC风险的作用,它们的OR分别为0.19(95%CI=0.05-0.74)和0.44(95%CI=0.21-0.93)。另一个位点MTRrs16834521(Ala1048Ala)突变纯合型和杂合型的男性个体中有增加患HCC风险的作用,OR为1.34(95%CI 1.02-1.76)。
本研究采用了四种研究基因—基因互作的统计学方法对叶酸代谢网络中酶基因的遗传多态性位点之间的互作关系与肝癌的关联作了详细的分析和比较。这四种方法主要有多因子降维法(MDR),基于复合连锁不平衡的方法,基于交互信息论的方法(MIA)以及传统Logistic回归的方法。从MDR,LD和MIA预测的两两互作的位点主要发生在叶酸的吸收转运与DNA合成或DNA甲基化两大功能域上。将这些位点放入在Logistic回归模型中分析,发现基于LD的方法预测的3组互作位点的互作相为统计上显著,它们是MTRrs16834521(Ala1048Ala)和FOLRrs2071010,MTHFD1rs1950902(A429E)和HCP1rs2239907,以及TS3'UTR6bpdel/ins和DHFR 19bpD/I。交互作用效果为MTRrs16834521野生型从和FOLRrs2071010突变型T的个体中随着T等位基因的增加为保护效应(OR分别为0.69和0.18);然而当MTRrs16834521为突变型GG时,携带FOLRrs2071010突变型T的个体中随着T等位基因的增加患HCC风险增加(OR分别为1.37和2.33)。MTHFD1rs1950902和HCP1rs2239907互作的结果是携带MTHD1rs1950902突变型和HCP1 rs2239907突变型的个体降低了患HCC的风险。TS3'UTR6bp del/ins和DHFR19bpD/I互作的结果是携带TS3'UTR6bp del/ins突变型和DHFR 19bpD/I突变型的个体增加了患HCC的风险。本研究比较了这几种方法的效果,认为在研究多个位点的基因互作时最好能多尝试不同的方法,然后用Logistic回归进行分析获得相对风险度,这样可以提高检出率。
单倍型分析发现TS(global P=0.01)和MTHFR(global P=0.05)的单倍型与HCC有显著的关联。与野生单倍型相比,TS的“2TTD”显著降低HCC的发病风险(OR=0.61,95%CI 0.41-0.91),而只有rs699517突变型C的单倍型“3ATCD”,则为增加HCC发病风险(OR=1.77,95%CI 1.21-2.60),统计显著。MTHFR的单倍型为“CGATTCTT”与野生型单倍型“CGACTCTT”相比有增加HCC发病风险作用(OR=1.36:95%CI 1.36-1.85),这其中MTHFRrs1801133(C677T)为突变型T。
总之,在本研究中,TS作为叶酸代谢网络中有主效应的基因与HCC的有关联作用。通过基因—环境和基因—基因交互作用,我们认为叶酸代谢网络中酶的遗传多态性与HCC有关联。在基因互作当中,我们明显看到与叶酸代谢的两大功能DNA合成和DNA甲基化相关的酶的基因多态位点互相作用,从而控制整个网络正常行使两大功能,一旦发生一方面的紊乱都会导致疾病的发生。
Hepatocellular Carcinoma(HCC) is the fifth most common cancer worldwide and is the third leading cause of death from cancer.It was the diverse etiology,high morbidity/mortality and lack of diagnostic markers for early diagnosis.With one -fifth the world population,the cancer incidence and mortality pattern in China play a key role in determining the cancer burden at a global level.HCC in China accounts for over 300,000 deaths annually and approximately 42.5%of the total incidence worldwide.Candidate pathway association study proved to be a powerful tool to reveal genetic variants that may have only small construction on complex disease.Then the discovered association polymorphisms can lead further functional research,which will uncover the molecular mechanism of HCC which will benefit the predisposition to disease,drug response,diagnosis,prognostic outcome.
One-carbon metabolism is a network of interrelated biochemical reactions in which a one-carbon unit from a donor compound is transferred to tetraphydrofolate(THF) for subsequent reduction or oxidation and transfer to other compound.Folate coenzymes in mammalian tissues thereby act as acceptors or donors of one-carbon units in a variety of reactions involved in amino acid and nucleotide methabolism.One-carbon pathway as an important role on DNA synthesis and methylation links the genetic and epigenetic progression closely associated with the development and prevention of several malignancies.
We hypothesized that polymorphisms of the 20 critical candidate genes MTHFR,TS,MTR,MTRR,MTHRD1,PEMT,CHDH,BHMT,SHMT1,CHKA, SLC19A1,TCN2,FOLR1,HCP1,GNMT,DPYD,ABCB4,DNMT1,CBS,and DHFR which involved in the one-carbon metabolism network may contribute to susceptibility to HCC.We selected 41 potential functional polymorphisms among them and conducted case-control association study with early onset of HCC.For critical roles on folate-metabolizing about MTHFR and TS,we tried to select 8 SNPs(5 tagSNPs and 3 ncSNPs) for MTHFR and 5 SNPs(3 tagSNPs and 2 at 3'UTR and 5'UTR respectively) covered the whole gene by LD with the MAF＞0.05 and R~2＞0.8.
We found there was a statistically significant distribution difference for TS 5'UTR 3R/2R in 708 liver cancer patients and 1249 controls(P=0.001) by Chi-square test after FDR correction.Further Logistic regression analyses revealed that the individuals with TS 5'UTR 3R/2R or 2R/2R have protective effects comparing with individuals with 3R/3R(P=0.02,adjusted OR = 0.73,95%C1= 0.57-0.95 for 3R2R and P=0.03,adjusted OR=0.54,95%Cl= 0.30-0.96 for 2R2R).For other 39 SNPs on one carbon pathway,we did not observe any significant interaction with HCC risk by single locus association analysis.The average ORs of all polymorphisms on one carbon pathway was 0.97(Min 0.49,Max 1.50).
We conducted interaction between genes and environmental factors and found that TS 5'UTR 3R/2R tandem repeat is related many environmental factors.The individuals with TS 5'UTR 2R2R had protective effects among individuals who are female,above 50 years-old,normal ALT(≤40U/I),above 20 packyears,above 15g/day,HBV positive,and non-HCC history and non cancer history(OR range from 0.31 to 0.69 and significant).The other SNPs interacted with HBV factors are two SNPs within MTHFR which is rs9651118(tagSNP),GNMT rs2296804 and PEMT rs7946.The HBV infection individuals carried MTHFR rs9651118 varied C allele increased HCC risk(OR=1.82,1.16-2.58).For chronic HBV carries with GNMT rs2296804 mutated GG decreased 2-fold risk to HCC comparing with CG and GG(OR= 0.60,95%Cl=0.39-0.91).With alcohol consumption above 15g/d,the individuals who with MTHFD1rs1950902 variant genotype increased the HCC risk(OR 1.67,95%Cl1.02-2.72).For male stratified analysis,MTRrs16834521(AA+AG) increased HCC risk(OR 1.34,95%Cl=1.02-1.76)。The individuals with normal ALT level(≤40U/L)who carried BHMT rs585800(AT+TT) have protective effect to HCC(OR0.54,0.31-0.92).
We also explored four different statistical methods(MDR,LD-based method,MIA based method and traditional logistic regression) to identify the gene-gene interaction on one carbon pathway.Pair-wised gene-gene interactions revealed that the interactions showed between MTR rs16834521(A1048A)and FOLR rs20710109(Pinter2.39×10~(-6)),MTHFD1 rs1950902(A429E)and HCP1 rs2239907(P_(inter)1.29×10~(-6)),and TS 3'UTR6bp del/ins and DHFR19bpD/l(P_(inter)2.11×10~(-5)),which have been analyzed by Logistic regression and validated as positive interactions.The former two interactions predicted protective actions for HCC with both variant alleles of two genes.But the last interactions predicted increasing risk for HCC with both variant alleles of two genes.Overall,we can assume the tendency to DNA methylation in folate metabolisms would have protective effect on HCC.Our experience was that we should use all of them to find more chances to confirm due to inconsistency among them,Logistic Regression can be as validation but not as a tool to find the interactions from large candidate markers.
Haplotype analysis revealed that TS(global P=0.01) and MTHFR(global P = 0.05) haplotypes had significant association with HCC risk.Further analysis revealed that the haplotype "2TTD "of TS decreased the risk of HCC (OR=0.61,95%Cl 0.41-0.91 ) and Haplotype "3ATCD"which included the mutant allele of TS rs699517 increased HCC risk(OR=1.77,95%Cl 1.21—2.60).The haplotype "CGACTCTT"of MTHFR increased the risk of HCC comparing with the wilde haplotype"CGACTCTT"(OR=1.36;95%Cl 1.36-1.85).
In conclusion,TS as main factors involved in the one carbon pathway may play a role in the etiology of HCC.Results from gene-gene and gene-environment interactions analysis revealed the genes in one carbon pathway may interact with other genes or environment to increase or decrease HCC risk.As a result,one carbon pathway facilitated the crosstalk between DNA synthesis and DNA methylation which are all important for the cancer onset.
引文
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