CIITA variation in the presence of HLA-DRB1*1501 increases risk for multiple sclerosis
CIITA variation in the presence of HLA-DRB1*1501 increases risk for multiple sclerosis
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DOI：
10.1093/hmg/ddq101
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发表时间：
2010-06-01
影响因子：
3.5
通讯作者：
Barcellos, Lisa F.
中科院分区：
文献类型：
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作者：
Bronson, Paola G.;Caillier, Stacy;Barcellos, Lisa F.
MHC Ⅱ类反式激活因子基因（CIITA）是HLA Ⅱ类MHC限制性抗原提呈所需的重要转录因子调控基因。与HLA II类变异，特别是HLA-DRB 1 *1501的关联已经在多发性硬化症（MS）中得到了很好的确立。此外，-168 A/G CIITA启动子变体（rs3087456）已被报道与MS相关。因此，在6108个个体中进行CIITA、DRB 1 *1501和MS内的变异的多阶段调查。在第一阶段，CIITA中的24个SNP在1320例病例和1363例对照（n = 2683）中进行基因分型。Rs 4774（错义+1614G/C; G500 A）与MS相关（P = 4.9 x 10（-3）），特别是在DRB 1 *1501 +个体中（P = 1 x 10（-4））。未观察到与-168A/G启动子变体的关联。在第2阶段，在973个大家族中对rs 4774进行了基因分型; rs 4774 *C也与DRB 1 *1501+家族中MS风险增加相关（P = 2.3 x 10（-2））。在第三次分析中，在病例和对照（第1阶段）中结合每个家族一个病例（第2阶段）对rs 4774进行了测试，以提高功效。Rs 4774 *C与MS相关（P = 1 × 10 - 3），特别是在DRB 1 *1501+病例和对照组中（P = 1 × 10 - 4）。Logistic回归分析结果显示rs 4774 *C和DRB 1 *1501之间的相互作用与MS风险相关（OR比= 1.72，95%CI 1.28-2.32，P = 3 x 10（-4））。此外，rs 4774 *C与DRB 1 *1501+ MS相关，（OR = 1.67，95% CI = 1.19-2.37，P = 1.9 x 10（-3））和缺失（OR = 1.49，95%CI = 1.15-1.95，P = 2.3 x 10（-3）），CLEC 16 A rs6498169*G是一个与CIITA相邻的推定MS风险等位基因。我们的研究结果提供了强有力的证据支持CIITA变异在MS风险中的作用，这似乎取决于DRB 1 *1501的存在。
The MHC class II transactivator gene (CIITA) is an important transcription factor regulating gene required for HLA class II MHC-restricted antigen presentation. Association with HLA class II variation, particularly HLA-DRB1*1501, has been well-established for multiple sclerosis (MS). In addition, the -168A/G CIITA promoter variant (rs3087456) has been reported to be associated with MS. Thus, a multi-stage investigation of variation within CIITA, DRB1*1501 and MS was undertaken in 6108 individuals. In stage 1, 24 SNPs within CIITA were genotyped in 1320 cases and 1363 controls (n = 2683). Rs4774 (missense +1614G/C; G500A) was associated with MS (P = 4.9 x 10(-3)), particularly in DRB1*1501 +individuals (P = 1 x 10(-4)). No association was observed for the -168A/G promoter variant. In stage 2, rs4774 was genotyped in 973 extended families; rs4774*C was also associated with increased risk for MS in DRB1*1501+ families (P = 2.3 x 10(-2)). In a third analysis, rs4774 was tested in cases and controls (stage 1) combined with one case per family (stage 2) for increased power. Rs4774*C was associated with MS (P = 1 x 10(-3)), particularly in DRB1*1501+ cases and controls (P = 1 x 10(-4)). Results obtained from logistic regression analysis showed evidence for interaction between rs4774*C and DRB1*1501 associated with risk for MS (ratio of ORs = 1.72, 95% CI 1.28-2.32, P = 3 x 10(-4)). Furthermore, rs4774*C was associated with DRB1*1501+ MS when conditioned on the presence (OR = 1.67, 95% CI = 1.19-2.37, P = 1.9 x 10(-3)) and absence (OR = 1.49, 95% CI = 1.15-1.95, P = 2.3 x 10(-3)) of CLEC16A rs6498169*G, a putative MS risk allele adjacent to CIITA. Our results provide strong evidence supporting a role for CIITA variation in MS risk, which appears to depend on the presence of DRB1*1501.