同型半胱氨酸代谢途径关键酶基因多态性及维生素B6缺乏与乳腺癌遗传易感性关系研究
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摘要
丝氨酸羟甲基转移酶(SHMT)在叶酸代谢过程中可逆性地催化丝氨酸和四氢叶酸到甘氨酸和5,10-甲基四氢叶酸的合成,参与生物体众多甲基化反应,其与DNA合成、甲基化及同型半胱氨酸(Hcy)代谢密切相关；胱硫醚p-合成酶(CBS)、甲硫氨酸合成酶(MS)、甲硫氨酸合成还原酶(MTRR)在叶酸代谢过程中通过转硫化/转甲基途径,催化Hcy转化为半胱氨酸或甲硫氨酸,CBS、MS、MTRR酶活性降低可能使血浆Hcy水平升高,因而成为动脉硬化等心血管疾病的重要风险因素；维生素B6(B6)作为SHMT及CBS的重要辅助因子,亦存在影响叶酸代谢的潜力。
本论文以荧光偏振免疫分析(FPIA)、胞质分裂阻滞微核分析(CBMN)、 PCR-RFLP等技术,探讨了B6及SHMT C1420T、CBS C699T/C1080T、MS A2756G、 MTRR A66G基因型多态性对人类基因组稳定性、Hcy代谢的影响及机制；探索上述因素与乳腺癌风险间的可能关联。
研究发现：(1)病例组血浆Hcy浓度显著高于对照组血浆Hcy浓度；所有样本SHMT1420TT型血浆Hcy显著低于野生型,MS2756GG,CBS699TT/1080T1型血浆Hcy水平显著高于野生型,仅病例组MTRR66GG型血浆Hcy水平显著高于野生型;(2)SHMT C1420T (OR=0.527,95%CI=0.55-1.24), MS A2756G (OR=2.32,95%CI=0.29-0.82), MTRR A66G (OR=1.84,95%CI=0.25～1.66)基因多态性与乳腺癌风险存在显著关联;(3)B6在6-24nmol/L对,病例及对照组遗传损伤[微核化双核细胞(MNBN)、核质桥(NPB)、核芽(NBUD)和微核化单核细胞(MONO)]频率均显著高于48nmol/L以上各组；B6在6,12nmol/L时,病例及对照组凋亡(APO)和坏死(NEC)频率显著高于24nmol/L以上各组；(4)病例及对照组遗传损伤及细胞损伤频率与B6浓度间呈显著负相关；(5)病例组遗传损伤及细胞损伤频率均高于对照组,经Difference of Difference Analysis(DDA)排除二组样本之间遗传损伤基线差异后,病例组MNBN、MONO频率在6、12nmol/L B6,NPB频率在6nmol/L B6时显著高于对照组：(6)B6缺乏对遗传损伤及细胞损伤频率的变异贡献率显著高于基因多态性及样本(肿瘤状态)状况；(7)结合基因型,病例及对照组所有B6浓度组SHMT1420CC型MNBN频率均显著高于TT型,仅病例组CC型NBUD、APO和NEC频率在6、12nmol/LB6,NPB频率在6nmol/L B6时显著高于TT型；病例组MS2756GG型MNBN频率在6-48nmol/L B6,MONO、NBUD、NPB和NEC频率在6、12nmol/L B6,APO频率在6nmol/L B6时显著高于野生型：病例及对照组WTRR66GG基因型MNBN、MONO和APO频率在6nmol/L B6时均显著高于野生型,仅病例组GG型NBUD频率在6nmol/L B6时显著高于野生型。
研究证实了B6缺乏可诱发人类基因组不稳定性,48nmol/LB6为离体条件下维护人类基因组稳定性的最适浓度；SHMT C1420T位点突变可能使乳腺癌易感性下降,而MS A2756G位点及MTRR A66G位点突变可能导致乳腺癌易感性上升,但SHMT、MS、MTRR和CBS基因的多态性对基因组稳定性的作用不及B6;SHMT C1420T, MSA2756G,MTRR A66G,CBS C699T/C1080iT位点突变可能是血浆Hcy水平变化的一个因素,而Hcy水平与乳腺癌风险可能存在正关联。该实验结果暗示在B6长期缺乏的情况下可能会增加人体遗传损伤和细胞损伤,但不同基因型人群对B6缺乏的遗传敏感度不同,加之Hcy代谢酶基因的多态性与乳腺癌间的可能关联,提示适量的提高B6的摄入能够有效的降低血浆Hcy的浓度,同时有利于基因组健康和相关疾病的防范。
The serinehydroxymethyhransferase (SHMT) reversible generates serine and methyleneTHF for thymidylate and methionine biosynthesis in folate metabolic pathway. It is therefore involved in numerous methylation reactions, which are closely related with DNA synthesis, methylation and the homocysteine (Hey) metabolism. Cystathionine-β synthase (CBS), methionine synthase (MS), methionine synthase reductase (MTRR) catalyze the homocysteine to form cystathionine or methyltetrahdrofolate through folate-mediated one-carbon metabolism or the transsulfuration pathway. So abnormality in CBS, MS, MTRR's activity is manifested an important risk factors of vein thrombosis and other cardiovascular diseases. Vitamine B6(B6) as an important cofactor for SHMT and CBS also has the potential effect in the folate metabolism pathway.
This research aimed to discusse the effects of B6and SHMT C1420T, CBS C699T/C1080T, MS A2756G, MTRR A66G polymorphism on human genome stability, Hey metabolism as well as to explore the mechanism of these actions on the risk factors of breast cancer by the radioimmunoassay, cytokinesis blocked micronucleus assay (CBMN) and PCR-RFLP technique.
Results showed that (1) The plasma Hey of SHMT1420TT was significantly lower than that of the wild type, while the plasma Hey level of MS2756GG, CBS699TT/1080TT significantly higher than that of the wild type in case and the control group. The plasma Hey levels of MTRR66GG only in case group was significantly higher than that of wild type. The plasma Hey levels of the same genotype in case group were significantly higher than those of control group except SHMT1420CC, MS2756AA, MTRR66GG;(2) SHMT C1420T (OR=0.527,95%CI=0.55-1.24), MS A2756G (OR=2.32,95%CI=0.29-0.82), MTRR A66G (OR=1.84,95%CI=0.25-1.66) polymorphism is significantly associated with breast cancer risk;(3)The genetic damage markers[the micronucleus of binucleate cells (MNBN), nucleoplasmic bridge (NPB), nuclear buds (NBUD) and the micronucleus of monucleate cells (MONO)] frequencies of6-24nmol/L B6were increased significantly than48～200nmol/L B6 in the case and normal group. The APO, NEC of6,12nmol/L B6were significantly higher than that in24-200nmol/L B6, but there were no significant difference among24-200nmol/L;(4) All genetic damage and cytotoxic indexes showed negative correlation with B6concentration;(5) All indexes in case group were higher than those of the control, however the DDA analysis revealed that MNBN, MONO, NPB frequencies is significant different sensitivity to B6deficiency between those2groups;(6) B6on the genetic and cell damage variance contribution of each index was significantly higher than that of genotype and sample (tumor state);(7) MNBN frequency of SHMT1420CC genotype in various concentrations of B6were significantly higher than that of TT group in case group and control group. NBUD, APO and NEC frequencies in the6,12nmol/L B6while the NPB frequency only in6nmol/L of SHMT1420CC genotype was significantly higher than those of TT in case group. The MNBN frequency of MS2756GG in6-48nmol/L B6were significantly higher than that of AA genotype in cases group. The MONO, NBUD, NPB and NEC frequencies in6and12nmol/L while the APO frequency in6nmol/L significantly higher than that of TT in case group. The MNBN, MONO and APO frequencies of MTRR66GG in6nmol/L B6were significantly higher than those of AA in case and control group, NBUD frequency in6nmol/L B6was significantly higher than that of TT in case group.
The research conclude the human genome instability can be induced by vitamin B6deficiency,48nmol/L B6was the most suitable concentration to maintain genomic stability of lymphocytes in vitro. SHMT C1420T mutation may reduce breast cancer susceptibility; while MS A2756G and MTRR A66G mutation may increase breast cancer susceptibility, But the role of polymorphisms of SHMT, MS, MTRR and CBS genotype polymorphism in the genome stability is less than B6. SHMT C1420T, MS A2756G, MTRR A66G, CBS C1080T, CBS C699T locus mutation may be a factor in affectting plasma level of Hcy. Hcy level is positively associated with breast cancer risk. The results suggest that the long-term lack of B6in the circumstances may increase the body's genetic damage and cell injury, and individual with various genotypes has different sensitivity to B6deficiency. The Hcy metabolic enzyme genes polymorphism may be associated with breast cancer. So adequate B6intake at the same time may be reduce the concentration of plasma Hcy, which is good for preventing genome health and related diseases.
本论文以荧光偏振免疫分析(FPIA)、胞质分裂阻滞微核分析(CBMN)、 PCR-RFLP等技术,探讨了B6及SHMT C1420T、CBS C699T/C1080T、MS A2756G、 MTRR A66G基因型多态性对人类基因组稳定性、Hcy代谢的影响及机制；探索上述因素与乳腺癌风险间的可能关联。
研究发现：(1)病例组血浆Hcy浓度显著高于对照组血浆Hcy浓度；所有样本SHMT1420TT型血浆Hcy显著低于野生型,MS2756GG,CBS699TT/1080T1型血浆Hcy水平显著高于野生型,仅病例组MTRR66GG型血浆Hcy水平显著高于野生型;(2)SHMT C1420T (OR=0.527,95%CI=0.55-1.24), MS A2756G (OR=2.32,95%CI=0.29-0.82), MTRR A66G (OR=1.84,95%CI=0.25～1.66)基因多态性与乳腺癌风险存在显著关联;(3)B6在6-24nmol/L对,病例及对照组遗传损伤[微核化双核细胞(MNBN)、核质桥(NPB)、核芽(NBUD)和微核化单核细胞(MONO)]频率均显著高于48nmol/L以上各组；B6在6,12nmol/L时,病例及对照组凋亡(APO)和坏死(NEC)频率显著高于24nmol/L以上各组；(4)病例及对照组遗传损伤及细胞损伤频率与B6浓度间呈显著负相关；(5)病例组遗传损伤及细胞损伤频率均高于对照组,经Difference of Difference Analysis(DDA)排除二组样本之间遗传损伤基线差异后,病例组MNBN、MONO频率在6、12nmol/L B6,NPB频率在6nmol/L B6时显著高于对照组：(6)B6缺乏对遗传损伤及细胞损伤频率的变异贡献率显著高于基因多态性及样本(肿瘤状态)状况；(7)结合基因型,病例及对照组所有B6浓度组SHMT1420CC型MNBN频率均显著高于TT型,仅病例组CC型NBUD、APO和NEC频率在6、12nmol/LB6,NPB频率在6nmol/L B6时显著高于TT型；病例组MS2756GG型MNBN频率在6-48nmol/L B6,MONO、NBUD、NPB和NEC频率在6、12nmol/L B6,APO频率在6nmol/L B6时显著高于野生型：病例及对照组WTRR66GG基因型MNBN、MONO和APO频率在6nmol/L B6时均显著高于野生型,仅病例组GG型NBUD频率在6nmol/L B6时显著高于野生型。
研究证实了B6缺乏可诱发人类基因组不稳定性,48nmol/LB6为离体条件下维护人类基因组稳定性的最适浓度；SHMT C1420T位点突变可能使乳腺癌易感性下降,而MS A2756G位点及MTRR A66G位点突变可能导致乳腺癌易感性上升,但SHMT、MS、MTRR和CBS基因的多态性对基因组稳定性的作用不及B6;SHMT C1420T, MSA2756G,MTRR A66G,CBS C699T/C1080iT位点突变可能是血浆Hcy水平变化的一个因素,而Hcy水平与乳腺癌风险可能存在正关联。该实验结果暗示在B6长期缺乏的情况下可能会增加人体遗传损伤和细胞损伤,但不同基因型人群对B6缺乏的遗传敏感度不同,加之Hcy代谢酶基因的多态性与乳腺癌间的可能关联,提示适量的提高B6的摄入能够有效的降低血浆Hcy的浓度,同时有利于基因组健康和相关疾病的防范。
The serinehydroxymethyhransferase (SHMT) reversible generates serine and methyleneTHF for thymidylate and methionine biosynthesis in folate metabolic pathway. It is therefore involved in numerous methylation reactions, which are closely related with DNA synthesis, methylation and the homocysteine (Hey) metabolism. Cystathionine-β synthase (CBS), methionine synthase (MS), methionine synthase reductase (MTRR) catalyze the homocysteine to form cystathionine or methyltetrahdrofolate through folate-mediated one-carbon metabolism or the transsulfuration pathway. So abnormality in CBS, MS, MTRR's activity is manifested an important risk factors of vein thrombosis and other cardiovascular diseases. Vitamine B6(B6) as an important cofactor for SHMT and CBS also has the potential effect in the folate metabolism pathway.
This research aimed to discusse the effects of B6and SHMT C1420T, CBS C699T/C1080T, MS A2756G, MTRR A66G polymorphism on human genome stability, Hey metabolism as well as to explore the mechanism of these actions on the risk factors of breast cancer by the radioimmunoassay, cytokinesis blocked micronucleus assay (CBMN) and PCR-RFLP technique.
Results showed that (1) The plasma Hey of SHMT1420TT was significantly lower than that of the wild type, while the plasma Hey level of MS2756GG, CBS699TT/1080TT significantly higher than that of the wild type in case and the control group. The plasma Hey levels of MTRR66GG only in case group was significantly higher than that of wild type. The plasma Hey levels of the same genotype in case group were significantly higher than those of control group except SHMT1420CC, MS2756AA, MTRR66GG;(2) SHMT C1420T (OR=0.527,95%CI=0.55-1.24), MS A2756G (OR=2.32,95%CI=0.29-0.82), MTRR A66G (OR=1.84,95%CI=0.25-1.66) polymorphism is significantly associated with breast cancer risk;(3)The genetic damage markers[the micronucleus of binucleate cells (MNBN), nucleoplasmic bridge (NPB), nuclear buds (NBUD) and the micronucleus of monucleate cells (MONO)] frequencies of6-24nmol/L B6were increased significantly than48～200nmol/L B6 in the case and normal group. The APO, NEC of6,12nmol/L B6were significantly higher than that in24-200nmol/L B6, but there were no significant difference among24-200nmol/L;(4) All genetic damage and cytotoxic indexes showed negative correlation with B6concentration;(5) All indexes in case group were higher than those of the control, however the DDA analysis revealed that MNBN, MONO, NPB frequencies is significant different sensitivity to B6deficiency between those2groups;(6) B6on the genetic and cell damage variance contribution of each index was significantly higher than that of genotype and sample (tumor state);(7) MNBN frequency of SHMT1420CC genotype in various concentrations of B6were significantly higher than that of TT group in case group and control group. NBUD, APO and NEC frequencies in the6,12nmol/L B6while the NPB frequency only in6nmol/L of SHMT1420CC genotype was significantly higher than those of TT in case group. The MNBN frequency of MS2756GG in6-48nmol/L B6were significantly higher than that of AA genotype in cases group. The MONO, NBUD, NPB and NEC frequencies in6and12nmol/L while the APO frequency in6nmol/L significantly higher than that of TT in case group. The MNBN, MONO and APO frequencies of MTRR66GG in6nmol/L B6were significantly higher than those of AA in case and control group, NBUD frequency in6nmol/L B6was significantly higher than that of TT in case group.
The research conclude the human genome instability can be induced by vitamin B6deficiency,48nmol/L B6was the most suitable concentration to maintain genomic stability of lymphocytes in vitro. SHMT C1420T mutation may reduce breast cancer susceptibility; while MS A2756G and MTRR A66G mutation may increase breast cancer susceptibility, But the role of polymorphisms of SHMT, MS, MTRR and CBS genotype polymorphism in the genome stability is less than B6. SHMT C1420T, MS A2756G, MTRR A66G, CBS C1080T, CBS C699T locus mutation may be a factor in affectting plasma level of Hcy. Hcy level is positively associated with breast cancer risk. The results suggest that the long-term lack of B6in the circumstances may increase the body's genetic damage and cell injury, and individual with various genotypes has different sensitivity to B6deficiency. The Hcy metabolic enzyme genes polymorphism may be associated with breast cancer. So adequate B6intake at the same time may be reduce the concentration of plasma Hcy, which is good for preventing genome health and related diseases.
引文
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