Graves病证候与基因多态性的相关研究
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摘要
目的：
弥漫性毒性甲状腺肿(Graves病,简称GD)是临床常见的内分泌疾病之一,约占所有甲亢的80%～85%。大量的流行病学证据表明遗传因素在GD的发病中起重要作用。单核苷酸多态性(SNP)占人类可遗传变异的90%以上,是目前诠释疾病遗传易感性最好的遗传标记,可用于疾病诊断、预后等风险的定量预测。本研究应用分子遗传学方法,选取已获得的GD易感基因进行SNP分析,探讨与GD证候、转归的关系及复方甲亢片对易感基因的影响。
方法：
对国内外文献数据库进行检索,建立易感基因数据样本,筛选与GD发生机制有关的SNP位点。采用血液基因组DNA试剂盒提取EDTA抗凝血获得DNA。使用引物延伸法的微测序技术与基于基质辅助激光解吸电离飞行时间质谱(Matrix Assisted Laser Desorption/ionisation Time of Flight Mass Spectrometry, MALDI-TOF MS)的实验平台进行SNP分型检测。将研究对象按照证候、转归及药物进行分组,采用二元及多项Logistic回归分析和对数线性模型统计分析相关数据。
结果：
1、筛选出位于不同染色体上8个基因(CTLA4、CD40、TNF、IFIH1、TSHR、Tg、PTPN22、ADRB2)的8个多态性位点(rs231775、rs1883832、rs1800629、rs1990760、rs2268458、rs2076740、rs2476601、rs1042714)进行研究；
2、本研究中CTLA4(rs231775)、CD40(rsl883832)、TNF(rs1800629)、IFIH1(rs1990760)、TSHR(rs2268458)等5个基因的位点存在多态性,PTPN22基因(rs2476601)位点未发现多态性存在,Tg(rs2268458)、ADRB2(rs1042714)因检测中出现假阳性结果而被剔除；
3、共有120例患者进入证型研究,其中气阴两虚证87例(72.50%)、肝郁火旺证18例(15.00%)、其它证型15例(12.50%)。使用气阴两虚证和肝郁火旺证分组进行对照分析,两组间平均年龄气阴两虚证组(35.66±13.79岁)大于肝郁火旺组(28.44±10.73岁),有统计学意义(t=2.088,P=0.039)。两组间性别无统计学意义。使用多元logistic回归对两组病例的基因型和等位基因进行分析,气阴两虚证与CTLA4(rs231775)位点的GG基因型(OR=0.18,P=0.03)和G(OR=0.19,P=0.04)等位基因存在关联,肝郁火旺证与TNF(rS1800629)位点的GG基因型(P=0.00)和TSHR (rs2268458)位点的CC基因型(OR=8.36,P=0.04)存在关联,均有统计学意义；
4、将87例气阴两虚证患者分成治愈和复发两组,两组间性别、年龄、病情分级均无统计学差异,使用二元logitic回归对气阴两虚证病例进行分析发现CTLA4 (rs231775)位点的GG基因型(OR=3.46,P=0.02)与复发有关,具有统计学意义；
5、针对CTLA4基因的GG基因型纳入药物、转归因子进行三因素的对数线性模型进行分析,均无统计学差异,提示复方甲亢片对该基因位点无影响。
结论：
根据上述研究结果得出结论如下：
1、遗传因素在GD的发生中起重要作用,其遗传易感性可能由多个外显率不同的基因所决定；
2、TNF基因、TSHR基因、CTLA4基因与GD证候存在关联,其中TNF基因的GG基因型和TSHR基因的CC基因型与肝郁火旺证有关,CTLA4基因的GG基因型和G等位基因与气阴两虚证存在关联；
3、气阴两虚证在GD辨证分型中占主要地位,益气养阴法是GD的主要治法；
4、CTLA4基因在GD预后中起着重要作用,其GG基因型与疾病的复发有关；
Objective
Graves disease is characterized by diffuse goiter and thyrotoxicosis and may be accompanied by an infiltrative orbitopathy and ophthalmopathy, and occasionally infiltrative dermopathy. It accounts for 80-85% of hyperthyroidisms. The concordance for Graves disease in monozygotic twins is 20-30%, compared to <5% in dizygotic twins. It suggests that gene is an important factor. Single nucleotide polymorphisms (SNPs) which account for over 90% genetic variations in human genome are the best genetic markers for explaining the hereditary susceptibility of diseases and suitable for quantitatively prediction. In this study, the selected susceptibility genes of GD were analyed to investigate the ralation of the SNPs and the Chinese syndrome, recurrence, the molecular mechanism of Fufangjiakang Tablets.
Methods
The data of susceptibility genes was established from the domestic and foreign literature database. The SNPs were selected by the etiology. Genomic DNA was extracted by using ralax gene blood DNA system. Primer extension method, micro-sequencing technology and Matrix assisted laser desorption ionisation time-of-flight mass spectrometry (Matrix Assisted Laser Desorption/ionisation Time of Flight Mass Spectrometry, MALDI-TOF MS) were used to get SNP genotyping. The experimental data was analysed by the binary or multiple logistic regression analysis and loglinear model.
Results
1, Eight SNPs (rs231775, rs1883832, rs1800629, rs1990760, rs2268458, rs2076740, rs2476601, rs1042714) which locate on different genes (CTLA4, CD40, TNF, IFIH1, TSHR, Tg, PTPN22, ADRB2) were obtained;
2, In this study, polymorphisms was found on CTLA4 (rs231775), CD40 (rs1883832), TNF (rs1800629), IFIH1 (rsl990760), TSHR (rs2268458) except PTPN22 gene (rs2476601), Tg (rs2268458), ADRB2 (rs1042714) were excluded for the false positive results;
3, One hundred and twenty patients were recruited, including 87 cases (72.50%) of the Chinese Syndrome of Deficiency of both Qi and Yin,18 cases (15.00%) of the Chinese Syndrome of Stagnant Fire in Liver,15 cases (12.50%) of others. Comparing the former groups, there was no significant difference on gender, but there was significant difference on age (t=2.09, P=0.04) which the average age of the Chinese Syndrome of Deficiency of both Qi and Yin is 35.66±13.79. years and the average age of the Chinese Syndrome of Stagnant Fire in Liver is 28.44±10.73 years. The Chinese Syndrome of Deficiency of both Qi and Yin was associated with GG genotype (OR=0.18,P=0.03) and G allele (OR=0.19,P=0.04) of CTLA4 (rs231775). The Chinese Syndrome of Stagnant Fire in Liver was associated with GG genotype (P=0.00) of TNF (rs1800629) and CC genotype (OR=8.36, P=0.04) of TSHR (rs2268458);
4, Eighty seven cases of the Chinese Syndrome of Deficiency of both Qi and Yin were divided into two groups of cure and recurrence, there was no significant difference on gender, age and severity of grading. The result suggests that GG genotype (OR=3.46,P=0.02) of CTLA4 (rs231775) was associated with the relapse;
5, When put the GG genotype of CTLA4 (rs231775), drugs and the relapse conditions into loglinear model to analyse the relationship, there was no significant difference of them.
Conclusion
1, Genetic factors play an important role in the pathogenes of GD, but its genetic susceptibility may determined by many different genes;
2, The susceptibility gene of GD is relate to the Chinese Syndrome. The GG genotype of TNF (rs1800629) and the CC genotype of TSHR (rs2268458) are associated with the Chinese Syndrome of Stagnant Fire in Liver, and the GG genotype and G allele of CTLA4 (rs231775) are associated with the Chinese Syndrome of Deficiency of both Qi and Yin;
3, The Chinese Syndrome of Deficiency of both Qi and Yin Qi dominate the Chinese syndrome of the GD, so the method of replenishing Qi and nourishing Yin is the main treatment;
4, The GG genotype of CTLA4 (rs231775) plays an important role in recurrence;
弥漫性毒性甲状腺肿(Graves病,简称GD)是临床常见的内分泌疾病之一,约占所有甲亢的80%～85%。大量的流行病学证据表明遗传因素在GD的发病中起重要作用。单核苷酸多态性(SNP)占人类可遗传变异的90%以上,是目前诠释疾病遗传易感性最好的遗传标记,可用于疾病诊断、预后等风险的定量预测。本研究应用分子遗传学方法,选取已获得的GD易感基因进行SNP分析,探讨与GD证候、转归的关系及复方甲亢片对易感基因的影响。
方法：
对国内外文献数据库进行检索,建立易感基因数据样本,筛选与GD发生机制有关的SNP位点。采用血液基因组DNA试剂盒提取EDTA抗凝血获得DNA。使用引物延伸法的微测序技术与基于基质辅助激光解吸电离飞行时间质谱(Matrix Assisted Laser Desorption/ionisation Time of Flight Mass Spectrometry, MALDI-TOF MS)的实验平台进行SNP分型检测。将研究对象按照证候、转归及药物进行分组,采用二元及多项Logistic回归分析和对数线性模型统计分析相关数据。
结果：
1、筛选出位于不同染色体上8个基因(CTLA4、CD40、TNF、IFIH1、TSHR、Tg、PTPN22、ADRB2)的8个多态性位点(rs231775、rs1883832、rs1800629、rs1990760、rs2268458、rs2076740、rs2476601、rs1042714)进行研究；
2、本研究中CTLA4(rs231775)、CD40(rsl883832)、TNF(rs1800629)、IFIH1(rs1990760)、TSHR(rs2268458)等5个基因的位点存在多态性,PTPN22基因(rs2476601)位点未发现多态性存在,Tg(rs2268458)、ADRB2(rs1042714)因检测中出现假阳性结果而被剔除；
3、共有120例患者进入证型研究,其中气阴两虚证87例(72.50%)、肝郁火旺证18例(15.00%)、其它证型15例(12.50%)。使用气阴两虚证和肝郁火旺证分组进行对照分析,两组间平均年龄气阴两虚证组(35.66±13.79岁)大于肝郁火旺组(28.44±10.73岁),有统计学意义(t=2.088,P=0.039)。两组间性别无统计学意义。使用多元logistic回归对两组病例的基因型和等位基因进行分析,气阴两虚证与CTLA4(rs231775)位点的GG基因型(OR=0.18,P=0.03)和G(OR=0.19,P=0.04)等位基因存在关联,肝郁火旺证与TNF(rS1800629)位点的GG基因型(P=0.00)和TSHR (rs2268458)位点的CC基因型(OR=8.36,P=0.04)存在关联,均有统计学意义；
4、将87例气阴两虚证患者分成治愈和复发两组,两组间性别、年龄、病情分级均无统计学差异,使用二元logitic回归对气阴两虚证病例进行分析发现CTLA4 (rs231775)位点的GG基因型(OR=3.46,P=0.02)与复发有关,具有统计学意义；
5、针对CTLA4基因的GG基因型纳入药物、转归因子进行三因素的对数线性模型进行分析,均无统计学差异,提示复方甲亢片对该基因位点无影响。
结论：
根据上述研究结果得出结论如下：
1、遗传因素在GD的发生中起重要作用,其遗传易感性可能由多个外显率不同的基因所决定；
2、TNF基因、TSHR基因、CTLA4基因与GD证候存在关联,其中TNF基因的GG基因型和TSHR基因的CC基因型与肝郁火旺证有关,CTLA4基因的GG基因型和G等位基因与气阴两虚证存在关联；
3、气阴两虚证在GD辨证分型中占主要地位,益气养阴法是GD的主要治法；
4、CTLA4基因在GD预后中起着重要作用,其GG基因型与疾病的复发有关；
Objective
Graves disease is characterized by diffuse goiter and thyrotoxicosis and may be accompanied by an infiltrative orbitopathy and ophthalmopathy, and occasionally infiltrative dermopathy. It accounts for 80-85% of hyperthyroidisms. The concordance for Graves disease in monozygotic twins is 20-30%, compared to <5% in dizygotic twins. It suggests that gene is an important factor. Single nucleotide polymorphisms (SNPs) which account for over 90% genetic variations in human genome are the best genetic markers for explaining the hereditary susceptibility of diseases and suitable for quantitatively prediction. In this study, the selected susceptibility genes of GD were analyed to investigate the ralation of the SNPs and the Chinese syndrome, recurrence, the molecular mechanism of Fufangjiakang Tablets.
Methods
The data of susceptibility genes was established from the domestic and foreign literature database. The SNPs were selected by the etiology. Genomic DNA was extracted by using ralax gene blood DNA system. Primer extension method, micro-sequencing technology and Matrix assisted laser desorption ionisation time-of-flight mass spectrometry (Matrix Assisted Laser Desorption/ionisation Time of Flight Mass Spectrometry, MALDI-TOF MS) were used to get SNP genotyping. The experimental data was analysed by the binary or multiple logistic regression analysis and loglinear model.
Results
1, Eight SNPs (rs231775, rs1883832, rs1800629, rs1990760, rs2268458, rs2076740, rs2476601, rs1042714) which locate on different genes (CTLA4, CD40, TNF, IFIH1, TSHR, Tg, PTPN22, ADRB2) were obtained;
2, In this study, polymorphisms was found on CTLA4 (rs231775), CD40 (rs1883832), TNF (rs1800629), IFIH1 (rsl990760), TSHR (rs2268458) except PTPN22 gene (rs2476601), Tg (rs2268458), ADRB2 (rs1042714) were excluded for the false positive results;
3, One hundred and twenty patients were recruited, including 87 cases (72.50%) of the Chinese Syndrome of Deficiency of both Qi and Yin,18 cases (15.00%) of the Chinese Syndrome of Stagnant Fire in Liver,15 cases (12.50%) of others. Comparing the former groups, there was no significant difference on gender, but there was significant difference on age (t=2.09, P=0.04) which the average age of the Chinese Syndrome of Deficiency of both Qi and Yin is 35.66±13.79. years and the average age of the Chinese Syndrome of Stagnant Fire in Liver is 28.44±10.73 years. The Chinese Syndrome of Deficiency of both Qi and Yin was associated with GG genotype (OR=0.18,P=0.03) and G allele (OR=0.19,P=0.04) of CTLA4 (rs231775). The Chinese Syndrome of Stagnant Fire in Liver was associated with GG genotype (P=0.00) of TNF (rs1800629) and CC genotype (OR=8.36, P=0.04) of TSHR (rs2268458);
4, Eighty seven cases of the Chinese Syndrome of Deficiency of both Qi and Yin were divided into two groups of cure and recurrence, there was no significant difference on gender, age and severity of grading. The result suggests that GG genotype (OR=3.46,P=0.02) of CTLA4 (rs231775) was associated with the relapse;
5, When put the GG genotype of CTLA4 (rs231775), drugs and the relapse conditions into loglinear model to analyse the relationship, there was no significant difference of them.
Conclusion
1, Genetic factors play an important role in the pathogenes of GD, but its genetic susceptibility may determined by many different genes;
2, The susceptibility gene of GD is relate to the Chinese Syndrome. The GG genotype of TNF (rs1800629) and the CC genotype of TSHR (rs2268458) are associated with the Chinese Syndrome of Stagnant Fire in Liver, and the GG genotype and G allele of CTLA4 (rs231775) are associated with the Chinese Syndrome of Deficiency of both Qi and Yin;
3, The Chinese Syndrome of Deficiency of both Qi and Yin Qi dominate the Chinese syndrome of the GD, so the method of replenishing Qi and nourishing Yin is the main treatment;
4, The GG genotype of CTLA4 (rs231775) plays an important role in recurrence;
引文
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