TPO与TSHR基因序列多态性与遗传性甲状腺疾病的连锁与关联研究
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摘要
遗传性甲状腺疾病是一种由多基因、多因素相互作用引起的复杂疾病，被认为是研究人类肿瘤发生和疾病异质性的有用模型。全基因组扫描策略先后定位了多个易感位点，但在不同的样本中，这些位点的显著性也不同。为澄清遗传因素对甲状腺疾病的影响，本文利用中国家系样本及群体样本，一方面研究多结节性甲状腺肿及乳头状甲状腺癌的遗传易感性； 另一方面筛选甲状腺功能相关基因中能解释甲状腺疾病表型变异的遗传多态性位点及其单倍型。
利用基于荧光标记微卫星引物的全基因组扫描策略，我们在3个甲状腺疾病家系中扫描了九条染色体共119个位点。连锁分析结果表明：其中5个区域可能与遗传性甲状腺疾病相连锁(P<0.05，最大NPL值为4.6)。这些区域分别位于8p23，10p，14q32.33，15q26.2-26.3和22q12等染色体区段上，均不同于此前报道的在高加索人群中定位的易感区域。这表明在不同的群体中，疾病的易感位点也可能不同。而在同一家系中扫描得出多个易感区域，也说明甲状腺疾病由多个基因相互作用所导致。
另外，在甲状腺过氧化物酶基因和促甲状腺激素受体基因编码序列及其旁侧序列中，我们检测到十二个单核苷酸多态位点，并在由114名患者及142名不相关的正常对照构成的群体中进行基因分型。基于连锁不平衡的关联分析表明，由TPO基因中多态位点G859T和G1207T上突变型等位基因组合成的单倍型(22)与甲状腺疾病在各种疾病模型下都有强而稳定的显著关联，且不受群体分层的影响。此外，通过大量的模拟实验我们发现：关联分析显著性水平的分布的众数主要受到对照样本量大小的影响；而分布的方差则主要取决于患病者样本量大小。
我们的研究结果表明：中国人群中存在多个多结节性甲状腺肿及乳头状甲状腺癌的易感位点；而位于TPO基因编码序列中的某些单核苷酸多态性位点所组成的单倍型则与甲状腺肿瘤的形成显著相关。对于这些位点及单倍型在功能和临床方面的显著相关性还需要做进一步的研究。这一领域的研究将为在中国人群中实现甲状腺疾病致病基因的精细定位与克隆奠定基础。
Inherited thyroid diseases, which result from an interaction between predisposing genes and environmental triggers, provide an informative model for dissecting the molecular genetics of multi-stage human tumorigenesis and heterogeneity. Genome scans have identified many genomic regions that may harbor putative susceptibility genes for thyroid diseases. Evidence for most regions, however, varies in different datasets. The aim of this study was 1) to dissect the genetic predisposition to these diseases in Chinese populations and families with multiple members affected with MNG, PTC, FTA and GD and 2) to identify and characterize genetic polymorphisms, which could explain phenotypic variation of the thyroid diseases.
Adopting a set of 119 microsatellite markers, we performed a genome-wide GeneScan in three Chinese pedigrees. After conducting linkage analysis, we identified that two candidate regions, which were on chromosome 10 and 15 respectively, show significant linkage to MNG with P values of 0.015; while another three candidate regions on chromosome 8, 14 and 22 respectively, show significant linkage to MNG/PTC with P values of 0.03, 0.007 and 0.03, respectively. These findings indicated that the Chinese families harbored susceptibility loci for MNG and PTC, which were distinct from those previously found in the Caucasian population. Our result suggested that different susceptibility loci existed between different ethnic groups. Furthermore, even within a single family from a genetically homogenous population, more than one gene was involved in the genetic susceptibility to thyroid diseases, supporting the notion that thyroid diseases were caused by multiple genes of varying influences.
Meanwhile, a systematic polymorphism screening was performed in the coding regions of thyroid peroxidase (TPO) and thyroid stimulating hormone receptor (TSHR) genes. Association between the detected polymorphisms and thyroid diseases was analyzed in 256 Chinese including 142 unrelated normal individuals and 114 patients affected with thyroid diseases using case-control approach. Ten single nucleotide polymorphisms (SNPs) in coding sequences and two SNPs around the exons were detected. Haplotypes based on all or parts of the SNPs were predicted and were evaluated for their association with the assumed disease allele. The analysis showed diverse degree of association of haplotypes based on various combinations of these polymorphic sites. Among them, the haplotype constructed from the mutant sites G859T and G1207T within TPO gene displayed highly and consistently significant
association over various models in regarding to genetic control of the disease. To investigate the effect of case and control size on statistical power of the haplotype-based association study, distribution of the significance level was explored. The mode of the distribution was found to be mainly related with the control sample size while the variance of the distribution largely determined by the case sample size.
Our results suggested that some chromosome regions might be susceptibility to MNG/PTC diseases, and that variants of TPO gene and the specific haplotype may act as low penetrance alleles in the predisposition to thyroid tumors. These findings laid a foundation for further fine mapping and finally positional cloning the associated genes for thyroid diseases. Characterizing the functional and clinical significance of the haplotypes requires further study.
利用基于荧光标记微卫星引物的全基因组扫描策略，我们在3个甲状腺疾病家系中扫描了九条染色体共119个位点。连锁分析结果表明：其中5个区域可能与遗传性甲状腺疾病相连锁(P<0.05，最大NPL值为4.6)。这些区域分别位于8p23，10p，14q32.33，15q26.2-26.3和22q12等染色体区段上，均不同于此前报道的在高加索人群中定位的易感区域。这表明在不同的群体中，疾病的易感位点也可能不同。而在同一家系中扫描得出多个易感区域，也说明甲状腺疾病由多个基因相互作用所导致。
另外，在甲状腺过氧化物酶基因和促甲状腺激素受体基因编码序列及其旁侧序列中，我们检测到十二个单核苷酸多态位点，并在由114名患者及142名不相关的正常对照构成的群体中进行基因分型。基于连锁不平衡的关联分析表明，由TPO基因中多态位点G859T和G1207T上突变型等位基因组合成的单倍型(22)与甲状腺疾病在各种疾病模型下都有强而稳定的显著关联，且不受群体分层的影响。此外，通过大量的模拟实验我们发现：关联分析显著性水平的分布的众数主要受到对照样本量大小的影响；而分布的方差则主要取决于患病者样本量大小。
我们的研究结果表明：中国人群中存在多个多结节性甲状腺肿及乳头状甲状腺癌的易感位点；而位于TPO基因编码序列中的某些单核苷酸多态性位点所组成的单倍型则与甲状腺肿瘤的形成显著相关。对于这些位点及单倍型在功能和临床方面的显著相关性还需要做进一步的研究。这一领域的研究将为在中国人群中实现甲状腺疾病致病基因的精细定位与克隆奠定基础。
Inherited thyroid diseases, which result from an interaction between predisposing genes and environmental triggers, provide an informative model for dissecting the molecular genetics of multi-stage human tumorigenesis and heterogeneity. Genome scans have identified many genomic regions that may harbor putative susceptibility genes for thyroid diseases. Evidence for most regions, however, varies in different datasets. The aim of this study was 1) to dissect the genetic predisposition to these diseases in Chinese populations and families with multiple members affected with MNG, PTC, FTA and GD and 2) to identify and characterize genetic polymorphisms, which could explain phenotypic variation of the thyroid diseases.
Adopting a set of 119 microsatellite markers, we performed a genome-wide GeneScan in three Chinese pedigrees. After conducting linkage analysis, we identified that two candidate regions, which were on chromosome 10 and 15 respectively, show significant linkage to MNG with P values of 0.015; while another three candidate regions on chromosome 8, 14 and 22 respectively, show significant linkage to MNG/PTC with P values of 0.03, 0.007 and 0.03, respectively. These findings indicated that the Chinese families harbored susceptibility loci for MNG and PTC, which were distinct from those previously found in the Caucasian population. Our result suggested that different susceptibility loci existed between different ethnic groups. Furthermore, even within a single family from a genetically homogenous population, more than one gene was involved in the genetic susceptibility to thyroid diseases, supporting the notion that thyroid diseases were caused by multiple genes of varying influences.
Meanwhile, a systematic polymorphism screening was performed in the coding regions of thyroid peroxidase (TPO) and thyroid stimulating hormone receptor (TSHR) genes. Association between the detected polymorphisms and thyroid diseases was analyzed in 256 Chinese including 142 unrelated normal individuals and 114 patients affected with thyroid diseases using case-control approach. Ten single nucleotide polymorphisms (SNPs) in coding sequences and two SNPs around the exons were detected. Haplotypes based on all or parts of the SNPs were predicted and were evaluated for their association with the assumed disease allele. The analysis showed diverse degree of association of haplotypes based on various combinations of these polymorphic sites. Among them, the haplotype constructed from the mutant sites G859T and G1207T within TPO gene displayed highly and consistently significant
association over various models in regarding to genetic control of the disease. To investigate the effect of case and control size on statistical power of the haplotype-based association study, distribution of the significance level was explored. The mode of the distribution was found to be mainly related with the control sample size while the variance of the distribution largely determined by the case sample size.
Our results suggested that some chromosome regions might be susceptibility to MNG/PTC diseases, and that variants of TPO gene and the specific haplotype may act as low penetrance alleles in the predisposition to thyroid tumors. These findings laid a foundation for further fine mapping and finally positional cloning the associated genes for thyroid diseases. Characterizing the functional and clinical significance of the haplotypes requires further study.
引文
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2. Ardlie KG, Lunetta KL and Seielstad M. (2002). Testing for population subdivision and association in four case-control studies. Am J Hum Genet. 71: 304-311.
3. Baas F, Bikker H, van Ommen GJB, et al. (1984). Unusual scarcity of restriction site polymorphism in the human thyroglobulin gene: a linkage study suggesting autosomal dominance of a defective thyroglobulin allele. Hum Genet. 67: 301-305.
4. Barbesino G, Tomer Y, Concepcion ES, et al. (1998a). Linkage analysis of candidate genes in autoimmune thyroid disease. I. Selected immunoregulatory genes. International Consortium for the Genetics of Autoimmune Thyroid Disease. J Clin Endocr Metab. 83(5): 1580-1584.
5. Barbesino G, Tomer Y, Concepcion ES, et al. (1998b). Linkage analysis of candidate genes in autoimmune thyroid disease. II. Selected gender-related genes and the X chromosome. J Clin Endocr Metab. 83: 3290-3295.
6. Beimfohr C, Klugbauer S, Demidchik EP, et al. (1999). NTRK1 re-arrangement in papillary thyroid carcinomas of children after the Chernobyl reactor accident. Int J Cancer. 80(6): 842-847.
7. Bevan S, Pal T, Greenberg CR, et al. (2001). A comprehensive analysis of MNG1, TCO1, fPTC, PTEN, TSHR, and TRKA in familial nonmedullary thyroid cancer: confirmation of linkage to TCO1. J Clin Endocr Metab. 86: 3701-3704.
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