Regulatory polymorphisms underlying complex disease traits.
Regulatory polymorphisms underlying complex disease traits.
复制标题
DOI：
10.1007/s00109-004-0603-7
复制
发表时间：
2005-02
影响因子：
4.7
通讯作者：
Knight, JC
中科院分区：
文献类型：
--
作者：
Knight, JC
越来越多的证据表明，遗传变异在决定个体对复杂疾病性状的易感性方面起着重要作用。与编码序列多态性相反，非同义变异的后果可以在蛋白质表型水平上解决，定义特定的功能调节多态性已被证明是有问题的。这已经出现了一些原因，包括由于连锁不平衡的精细定位的困难，以及缺乏实验工具来解决非编码序列变异对基因表达的影响。最近的研究表明，基因表达的变异是可遗传的，可以作为一个数量性状定位。等位基因特异性对基因表达的影响似乎相对常见，通常具有适度的幅度和背景特异性。调节多态性在确定易感性的一些复杂的疾病性状的作用进行了讨论，包括在VNTR的INS，编码胰岛素，在1型糖尿病和CTLA 4的多态性，编码细胞毒性T淋巴细胞抗原，在自身免疫性疾病的变化。已被发现的例子，调节多态性发挥作用的单基因性状，如因子VII缺乏症进行了讨论，并与缺血性心脏病相关的多态性在同一基因位点的对比。分子机制的等位基因特异性的方式在转录水平上进行说明，包括达菲结合蛋白在疟疾中的作用的例子。解决由连锁不平衡引起的特定功能调节变体的困难是使用许多例子来证明的，包括CCR5的多态性，编码CC趋化因子受体5和HIV-1感染。理解单倍型结构的设计和解释推定的监管变异的功能测定的重要性被强调，连同讨论的战略使用的实验工具，以解决在转录水平上的监管多态性。一些例子进行了讨论，包括工作的TNF基因座表现出生物和实验环境的特异性。调控变异也可能在其他水平的基因表达控制和剪接的PTPRC，编码蛋白酪氨酸磷酸酶受体C型的调制，并在F12，编码因子XII的翻译效率，进行了讨论。
There is growing evidence that genetic variation plays an important role in the determination of individual susceptibility to complex disease traits. In contrast to coding sequence polymorphisms, where the consequences of non-synonymous variation may be resolved at the level of the protein phenotype, defining specific functional regulatory polymorphisms has proved problematic. This has arisen for a number of reasons, including difficulties with fine mapping due to linkage disequilibrium, together with a paucity of experimental tools to resolve the effects of non-coding sequence variation on gene expression. Recent studies have shown that variation in gene expression is heritable and can be mapped as a quantitative trait. Allele-specific effects on gene expression appear relatively common, typically of modest magnitude and context specific. The role of regulatory polymorphisms in determining susceptibility to a number of complex disease traits is discussed, including variation at the VNTR of INS, encoding insulin, in type 1 diabetes and polymorphism of CTLA4, encoding cytotoxic T lymphocyte antigen, in autoimmune disease. Examples where regulatory polymorphisms have been found to play a role in mongenic traits such as factor VII deficiency are discussed, and contrasted with those polymorphisms associated with ischaemic heart disease at the same gene locus. Molecular mechanisms operating in an allele-specific manner at the level of transcription are illustrated, with examples including the role of Duffy binding protein in malaria. The difficulty of resolving specific functional regulatory variants arising from linkage disequilibrium is demonstrated using a number of examples including polymorphism of CCR5, encoding CC chemokine receptor 5, and HIV-1 infection. The importance of understanding haplotypic structure to the design and interpretation of functional assays of putative regulatory variation is highlighted, together with discussion of the strategic use of experimental tools to resolve regulatory polymorphisms at a transcriptional level. A number of examples are discussed including work on the TNF locus which demonstrate biological and experimental context specificity. Regulatory variation may also operate at other levels of control of gene expression and the modulation of splicing at PTPRC, encoding protein tyrosine phosphatase receptor-type C, and of translational efficiency at F12, encoding factor XII, are discussed.
登录
查看更多内容
影响因子：
20.3
作者：
Carew, JA;Pollak, ES;Bauer, KA
通讯作者：
Bauer, KA
影响因子：
20.3
作者：
Arbini, AA;Pollak, ES;Bauer, KA
通讯作者：
Bauer, KA
影响因子：
5.3
作者：
Bray, NJ;Buckland, PR;O'Donovan, MC
通讯作者：
O'Donovan, MC
影响因子：
3.6
作者：
Allen, RD
通讯作者：
Allen, RD
影响因子：
7.7
作者：
Barratt, BJ;Payne, F;Todd, JA
通讯作者：
Todd, JA