Carriage of a tumor necrosis factor polymorphism amplifies the cytotoxic T-lymphocyte antigen 4 attributed risk of primary biliary cirrhosis: evidence for a gene-gene interaction.
Carriage of a tumor necrosis factor polymorphism amplifies the cytotoxic T-lymphocyte antigen 4 attributed risk of primary biliary cirrhosis: evidence for a gene-gene interaction.
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DOI：
10.1002/hep.23667
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发表时间：
2010-07
期刊：
影响因子：
13.5
通讯作者：
Lazaridis, Konstantinos N.
中科院分区：
文献类型：
--
作者：
Juran, Brian D.;Atkinson, Elizabeth J.;Larson, Joseph J.;Schlicht, Erik M.;Liu, Xiangdong;Heathcote, E. Jenny;Hirschfield, Gideon M.;Siminovitch, Katherine A.;Lazaridis, Konstantinos N.
常见的遗传变异显著影响复杂疾病，如原发性胆汁性肝硬化（PBC）。我们最近报道了PBC与免疫受体基因细胞毒性T淋巴细胞抗原4（CTLA 4）的单核苷酸多态性（rs 231725）之间的关联。我们假设归因于这种多态性的PBC风险可能会因过度强烈的炎症反应倾向而增加。因此，我们研究了它与肿瘤坏死因子（TNF）基因的-308AG启动子多态性（rs 1800629）的潜在相互作用，其中变体TNF 2A等位基因导致TNF产生增加。对来自美国和加拿大独立登记处的866名PBC患者和761名对照进行了多态性基因分型;通过logistic回归评估了单个单核苷酸多态性（SNP）及其相互作用对PBC风险的影响。在加拿大队列中，PBC与CTLA 4“A/A”基因型的相关性在合并数据中具有显著性（比值比[OR]，1.68; P = 0.0005）。TNF 2A等位基因频率在PBC患者中升高，但使用组合数据仅达到临界显著性（OR，1.21; P = 0.042）。分析显示，与CTLA 4“A/A”对照相比，CTLA 4“A/A”PBC患者中TNF 2A携带显著增加（39.7%对16.5%，P = 0.0004）;在CTLA 4“A/G”或“G/G”个体中未观察到TNF 2A携带的明显增加。最后，Logistic模型下的相互作用是非常显著的，因为TNF 2A携带与CTLA 4“A/A”基因型组合存在于6.5%的PBC患者中，而对照组为1.7%（OR，3.98; P < 0.0001）。TNF 2A放大了CTLA 4 rs 231725“A/A”基因型对PBC的风险。虽然机制尚不清楚，但T细胞调节缺陷导致PBC风险增加的前提是通过重要促炎细胞因子的过度表达而放大，这为未来的功能研究提供了基础。
Common genetic variants significantly influence complex diseases such as primary biliary cirrhosis (PBC). We recently reported an association between PBC and a single nucleotide polymorphism (rs231725) of the immunoreceptor gene cytotoxic T-lymphocyte antigen 4 (CTLA4). We hypothesized that PBC risk attributed to this polymorphism might be increased by propensity to an overly robust inflammatory response. Thus, we examined its potential interaction with the commonly studied −308AG promoter polymorphism (rs1800629) of the tumor necrosis factor (TNF) gene for which the variant TNF2A allele causes increased TNF production. The polymorphisms were genotyped in 866 PBC patients and 761 controls from independent US and Canadian registries; the effects of individual single nucleotide polymorphisms (SNPs) and their interaction on PBC risk was assessed by logistic regression. The reported association of PBC with the CTLA4 “A/A” genotype was replicated in the Canadian cohort and significant for PBC risk in the combined data (odds ratio [OR], 1.68; P = 0.0005). TNF2A allele frequency was elevated in PBC patients, but only reached borderline significance using the combined data (OR, 1.21; P = 0.042). Analysis showed that TNF2A carriage was significantly increased in CTLA4 “A/A” PBC patients compared with CTLA4 “A/A” controls (39.7% versus 16.5%, P = 0.0004); no apparent increase of TNF2A carriage was noted in CTLA4 “A/G” or “G/G” individuals. Finally, interaction under a logistic model was highly significant, as TNF2A carriage in combination with the CTLA4 “A/A” genotype was present in 6.5% of PBC patients, compared with 1.7% of controls (OR, 3.98; P < 0.0001). TNF2A amplifies the CTLA4 rs231725 “A/A” genotype risk for PBC. Although the mechanisms remain unclear, the premise that deficiency in T-cell regulation resulting in an increased risk of PBC is amplified by overexpression of an important proinflammatory cytokine provides a basis for future functional studies.
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