中国人类风湿关节炎与PADI4功能基因多态性及部分HLA-DRB1等位基因相关性研究  

Association of the PAD14 gene polymorphism and HLA-DRB1 shared epitope alleles with rheumatoid arthritis

作　　者：范列英[1] 宗明[1] 卢添宝[1] 杨蔺[1] 丁媛媛[1] 马建伟[1] 

机构地区：[1]上海市东方医院,同济大学附属东方医院检验科,200120

出　　处：《中华医学遗传学杂志》2009年第1期57-61,共5页Chinese Journal of Medical Genetics

基　　金：上海市卫生局科技发展基金（044100）

摘　　要：目的分析类风湿关节炎（rheumatoid arthritis，RA）中4型肽精氨酸转亚胺基酶（peptidylargininedeiminaseⅣ，PADI4）功能基因多态性，探讨PADI4基因多态性与RA易感性的关系，以及编码与RA易感性相关HLA共同表位（sharedepitope，SE）的HLA—DRB1等位基因与PADI4基因多态性的相关性。方法采用逆转录合成cDNA、DNA测序和T载体克隆方法分析67例RA患者、81名正常人PAD髓基因外显子4个单核苷酸多态性（single nucleotide polymorphisms，SNPs），包括PADi4_89＊A／G，PADI4_90＊C／T，PADI4_92＊C／G，PADI4_104＊C／T；采用PCR-序列特异性引物方法分析HLA—DRB1＊01、＊04、＊10基因型。结果RA患者PAD／489、90、104位基因多态性分布与正常对照组比差异有统计学意义，携带PADI4少见等位基因者对RA的危险性较携带常见等位基因者显著增加；分析编码SE等位基因与PADI4 SNPs的相关性发现，SE＋／PADI4_89G-携带者较SE-／PADI4_89e携带者发生RA的危险性高4．7倍（OR=4．7，95％CI：1．6～13．4，P=0．003），携带SE＋／PADI4_89G＋者高5．6倍（OR=5．6，95％CI：2．0～15．7，P=0．003）。在PADI4_90、92、104位均出现相似的情况。结论PADI4功能基因多态性与中国人RA的易感性相关，编码SE的HLA—DRB1等位基因仍然是RA的重要遗传标记，而且HLA—DRB1等位基因与PADI4的少见等位基因间可能存在一定的协同作用。Objective To investigate the association of single nucleotide polymorphisms （SNPs） of the peptidylarginine deiminase Ⅳ （PADI4） and HLA DRB1 shared epitope （SE） alleles with rheumatoid arthritis（RA） in a Chinese population. Methods Four exonic SNPs of the PADI4 gene （PADI4_89 ＊ A/ G, PADI4_90 ＊ C/T, PADI4_92 ＊ C/G and PADI4_104 ＊ C/T） were genotyped in 67 unrelated patients with RA and 81 healthy controls, using cDNA sequencing and T vector cloning. HLA-DRB1 ＊ 01, ＊ 04 and ＊ 10 subtypes were determined by polymerase chain reaction with sequence-specific primers （PCR- SSP）. Results The distributions of the 4 SNPs were different in the two groups, and increased RA susceptibility was significantly associated with the minor alleles of PADI489 ＊ G （P=0. 023）, PADI4_90 T （P=0. 004）, PADI4_104 ＊ T （P=0. 003）, and the haplotypes carrying the 4 minor alleles （P= 0.008）. HLA-DRB1 SE alleles are composed of HLA-DRB1 ＊ 0101, ＊ 0102, ＊ 0401,＊ 0404, ＊ 0405, ＊ 0408, ＊ 0409, ＊ 0410 and ＊ 1001. Individuals carrying the SE alleles were associated with increased RA susceptibility （P=0. 002）. Individuals carrying both the SE alleles and minor alleles of the 4 SNPs were more susceptible to RA than individuals carrying neither the minor SNP alleles nor the SE alleles. Conclusion The PADI4 SNPs and haplotypes are associated with RA susceptibility in Chinese. HLA- DRB1 shared epitope is also an important risky factor for RA. There may exist certain synergistic effect between the PADI4 minor alleles and the HLA-DRB1 shared epitope.

关 键 词：类风湿关节炎 肽精氨酸转亚胺基酶 基因多态性 HLA—DRB1等位基因 

分 类 号：R686[医药卫生—骨科学]