弥漫性甲状腺肿伴甲状腺功能亢进症
致病易感基因识别鉴定研究的现状
宋怀东
[提要] 经过半个世纪对弥漫性甲状腺肿伴甲状腺功能亢进症(Graves’disease,GD,甲亢)候选基因
在小样本人群中的研究,提供了不少相互矛盾的结果。在这些研究中,仅仅证实主要组织相容性复合物
(MHC)是甲亢的一个致病易感位点,因为这个位点对甲亢发生影响较大。应用以低密度的微卫星标志进
行全基因组连锁分析,虽然发现了一些甲亢的致病易感区段,但并未能识别真正的甲亢致病易感基因。随
后由于大量单核苷酸多态性(SNP)的发现及其标签SNP(Tag SNP)技术的出现,人们对候选基因上的Tag
SNP在大样本人群中的分析,发现了一些真正的甲亢致病易感基因,包括免疫相关的基因如MHC、CTLA4、
SCGB3A2/UGRP1和FCRL3以及一个甲状腺特异的基因TSHR(促甲状腺素受体基因)。同时,也发现了一
些还有争议但需要进一步证实的甲亢易感基因如PTPN22和甲状腺球蛋白基因等。在不久的将来,全基因
组关联分析和全基因组再测序技术,在甲亢易感基因识别鉴定中的应用,无疑将会促进大量甲亢易感基因
的发现,加深人们对甲亢发病机制的理解。
格雷夫斯病;多态现象,遗传;基因组学
Recent progress in identification of candidate genes of Graves' disease SONG Huai-dongMolecular Medical
Center, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School
of Medicine, Shanghai 200025, China
[ Sunnnary ] Intensive but quite chaotic and decentralized candidate gene studies on susceptibility to Graves'
disease ( GD ) carried out in small size population in the past half century have provided a quantity of inconsistent data,
which, however, resulted in finding of a proven association of GD with the MHC class Ⅱ region that exerts a major
effect on the genetics of GD. Using low-resolution microsatellite-based human genome-wide linkage analysis, several
regions of linkage harboring putative susceptibility variants but no gene susceptibility to GD were identified. Further,
high throughput genotyping of large population cohorts with help of high dense panels of single nucleotide
polymorphisms (SNPs) and application of advanced tools for analysis of extended blocks of linkage disequilibrium
within a candidate gene ( tagging SNP, etc. ) have found several genes susceptible to GD, including immune-related
genes such as MHC, CTLA4, SCGB3A2/UGRP1, FCRL3, and thyroid specific genes ( such as TSHR, etc. ). Less
consistent results have been obtained in cases of PTPN22 and thyroglobulin. In the nearest future, implementation of
even more robust technology such as genome-whole associated analysis (GWAS) and whole-genome re-sequencing are
expected to catch more genes susceptibilities to GD.
Graves' disease; Polymorphism, genetic; Genomics
10. 3760/cma. j. issn. 1000-6699. 2011.12. 001
国家自然科学基金( 30971595,30971383,81100553)
作者单位:200025 上海交通大学医学院附属瑞金医院分子医学中
心,上海市内分泌代谢病研究所
·962·
think
附注
多基因遗传
·963·
think
附注
易感基因门
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2011-09-26
弥漫性甲状腺肿伴甲状腺功能亢进症致病易感基因识别鉴定研究的现
状
作者: 宋怀东, SONG Huai-dong
作者单位: 上海市内分泌代谢病研究所, 上海交通大学医学院附属瑞金医院分子医学中心,200025
刊名: 中华内分泌代谢杂志
英文刊名: Chinese Journal of Endocrinology and Metabolism
年,卷(期): 2011,27(12)
参考文献(29条)
1.Collins JE;Heward JM;Howson JM Common allelic variants of exons 10,12,and 33 of the thyroglobulin gene are not
associated with autoimmune thyroid disease in the United Kingdom[外文期刊] 2004(12)
2.Ban Y;Greenberg DA;Concepcion E Amino acid substitutions in the thyroglobulin gene are associated with
susceptibility to human and murine autoimmune thyroid disease
3.Gu LQ;Zhu W;Zhao SX Clinical associations of the genetic variants of CTLA-4,Tg,TSHR,PTPN22,PTPNi2 and FCRL3 in
patients with Graves' disease 2010
4.Ban Y;Tozaki T;Taniyama M The codon 620 single nucleotide polymorphism of the protein tyrosine phosphatase-22 gene
does not contribute to autoimmune thyroid disease susceptibility in the Japanese 2005
5.Zhang J;Zahir N;Jiang Q The autoimmune disease-associated PTPN22 variant promotes calpain-mediated Lyp/Pep
degradation associated with lymphocyte and dendritic cell hyperresponsiveness 2011
6.Velaga MR;Wilson V;Jennings CE The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is
a major determinant of Graves' disease[外文期刊] 2004(11)
7.Smyth D;Cooper JD;Collins JE Replication of an association between the lymphoid tyrosine phosphatase locus
(LYP/PTPN22) with type 1 diabetes,and evidence for its role as a general autoimmunity locus[外文期刊] 2004(11)
8.Brand O J;Barrett JC;Simmonds M J Association of the thyroid stimulating hormone receptor gene (TSHR)with Graves'
disease[外文期刊] 2009(9)
9.Hiratani H;Bowden DW;Ikegami S Multiple SNPs in intron 7 of thyrotropin receptor are associated with Graves'
disease 2005
10.Tomer Y;Ban Y;Concepcion E Common and unique susceptibility loci in Graves and Hashimoto diseases:results of
whole-genome screening in a data set of 102 multiplex families 2003
11.Chistiakov DA;Voronova NV;Turakulov RI The-112G 》 A polymorphism of the secretoglobin 3A2 (SCGB3A2) gene
encoding uteroglobin-related protein 1 (UGRP1) increases risk for the development of Graves' disease in subsets of
patients with elevated levels of immunoglobulin E 2011
12.Simmonds M J;Yesmin K;Newby PR Confirmation of association of chromosome 5q31-33 with United Kingdom Caucasian
Graves'disease 2010
13.Jin Y;Teng W;Ben S Genome-wide scan of Graves' disease:evidence for linkage on chromosome 5q31 in Chinese Han
pedigrees[外文期刊] 2003(04)
14.Sakai K;Shirasawa S;Ishikawa N Identification of susceptibility loci for autoimmune thyroid disease to 5q31-q33
and Hashimoto' s thyroiditis to 8q23-q24 by multipoint affected sib-pair linkage analysis in Japanese 2001
15.Owen CJ;Kelly H;Eden JA Analysis of the Fc receptor-like-3 (FCRL3) locus in Caucasians with autoimmune disorders
suggests a complex pattern of disease association 2007
16.Wellcome Trust Case Control Consortium;Australo-Anglo-American Spondylitis Consortium (TASC);Burton PR
Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants 2007
17.Kochi Y;Yamada R;Suzuki A A functional variant in FCRL3,encoding Fc receptor-like 3,is associated with rheumatoid
arthritis and severs]autoimmunities 2005
18.Zhao SX;Pan CM;Cao HM Association of the CTLA4 gene with Graves' disease in the Chinese Han population[外文期刊]
2010
19.Simmonds M J;Howson JM;Heward JM A novel and major association of HLA-C in Graves' disease that eclipses the
classical HLADRB1 effect 2007
20.Ban Y;Davies TF;Greenberg DA Arginine at position 74 of the HLA-DR betal chain is associated with Graves' disease
2004
21.Freedman ML;Monteiro AN;Gayther SA Principles for the postGWAS functional characterization of cancer risk loci
2011
22.Dechairo BM;Zabaneh D;Collins J Association of the TSHR gene with Graves' disease:the first disease specific
locus[外文期刊] 2005(11)
23.Simmonds MJ;Howson JM;Heward JM Regression mapping of association between the human leukocyte antigen region and
Graves' disease 2005
24.Ueda H;Howson JM;Esposito L Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune
disease[外文期刊] 2003(6939)
25.Song HD;Liang J;Shi JY Functional SNPs in the SCGB3A2 promoter are associated with susceptibility to Graves'
disease[外文期刊] 2009(6)
26.Chu X;Pan CM;Zhao SX A genome-wide association study identifies two new risk loci for Graves' disease[外文期刊]
2011
27.Brix TH;Kyvik KO;Christensen K Evidence for a major role of heredity in Graves' disease:a population-based study
of two Danish twin cohorts[外文期刊] 2001
28.Brix TH;Christensen K;Holm NV A population-based study of Graves' disease in Danish twins 1998
29.Dessi MP;Karandikar S Autoimmune thyroid disease in childhood:a study of children and their families 1999
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