Primary biliary cirrhosis is associated with a genetic variant in the 3' flanking region of the CTLA4 gene.
Primary biliary cirrhosis is associated with a genetic variant in the 3' flanking region of the CTLA4 gene.
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DOI：
10.1053/j.gastro.2008.06.077
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发表时间：
2008-10
期刊：
影响因子：
29.4
通讯作者：
Lazaridis KN
中科院分区：
文献类型：
--
作者：
Juran BD;Atkinson EJ;Schlicht EM;Fridley BL;Lazaridis KN
遗传变异被认为是原发性胆汁性肝硬化（PBC）和其他自身免疫性疾病的重要组成部分。数据表明，这种遗传风险中的一些是共享的，影响控制自我耐受性的免疫机制的功能。细胞毒性T淋巴细胞抗原4（CTLA 4）编码共抑制免疫受体，其是自身耐受的关键调节因子，与多种自身免疫性疾病具有已建立的遗传关联，但与PBC相关的证据相互矛盾。我们的目的是使用基于单倍型标记的方法对PBC中CTLA4的遗传变异进行更全面的评估。在402例PBC患者和279名对照中进行单核苷酸多态性（SNP）基因分型，并使用logistic回归评估PBC患者中与PBC的相关性，以及与抗线粒体抗体（AMA）状态和既往原位肝移植（奥尔特）的相关性，无论是单独的还是推断的单倍型。所有SNP均处于哈代温伯格平衡。我们鉴定了PBC与rs231725之间的新的且相对强的关联，rs231725是CTLA 4的3'侧翼区域中的SNP，位于先前在PBC中研究的区域之外。该SNP标记了一种常见的CTLA4单倍型，该单倍型包含许多功能上涉及的自身免疫性CTLA4 SNP，其也被发现与PBC相关，并且在较小程度上与AMA状态和先前奥尔特相关。我们的研究结果表明，CTLA4对PBC的风险有影响，并可能在影响PBC患者AMA的发展以及向奥尔特的进展中发挥作用。需要在合适的、独立的PBC队列中进行复制。
Genetic variation is invoked as a strong component underlying primary biliary cirrhosis (PBC) and other autoimmune disorders. Data suggests that some of this genetic risk is shared, affecting function of the immune mechanisms controlling self tolerance. Cytotoxic T-lymphocyte antigen 4 (CTLA4) encodes a coinhibitory immunoreceptor that is a key regulator of self tolerance with established genetic associations to multiple autoimmune diseases, but conflicting evidence of involvement with PBC. We aimed to perform a more comprehensive assessment of CTLA4 genetic variation in PBC using a haplotype-tagging based approach. Single nucleotide polymorphisms (SNPs) were genotyped in 402 PBC patients and 279 controls and evaluated for association with PBC, and with antimitochondrial antibody (AMA) status and prior orthotopic liver transplant (OLT) among the PBC patients, both individually and as inferred haplotypes, using logistic regression. All SNPs were in Hardy Weinberg Equilibrium. We identified a novel and relatively strong association between PBC and rs231725, a SNP in the 3’ flanking region of CTLA4 located outside of the area previously investigated in PBC. This SNP tags a common CTLA4 haplotype that contains a number of functionally implicated autoimmune CTLA4 SNPs, which was also found to be associated with PBC and to a lesser extent AMA status and prior OLT. Our findings suggest that CTLA4 has an impact on the risk of PBC and possibly plays a role in influencing AMA development as well as progression to OLT among PBC patients. Replication in a suitable, independent PBC cohort is needed.
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DOI：
10.1073/pnas.0706409104
发表时间：
2007-11-20
影响因子：
11.1
作者：
Maier, Lisa M.;Anderson, David E.;Hafler, David A.
通讯作者：
Hafler, David A.
影响因子：
32.4
作者：
TIVOL, EA;BORRIELLO, F;SHARPE, AH
通讯作者：
SHARPE, AH
影响因子：
4.3
作者：
Oaks, MK;Hallett, KM;Tector, AJ
通讯作者：
Tector, AJ
影响因子：
3.5
作者：
Graham, D. S. Cunninghame;Wong, A. K.;Vyse, Timothy J.
通讯作者：
Vyse, Timothy J.
影响因子：
25.7
作者：
Agarwal, K;Jones, DEJ;Bassendine, MF
通讯作者：
Bassendine, MF