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The research for the genetic factors of rheumatoid arthritis using the methods applying the polymorphism in microsatellites and the single nucleotide polymorphism

应用微卫星多态性和单核苷酸多态性方法研究类风湿性关节炎的遗传因素

基本信息

批准号：
12670417
负责人：
TAKEUCHI Fujio
金额：
$ 1.92万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670417/
关键词：
rheumatoid arthritis Japanese affected sib pair microsatellite linkage analysis TIRA family study CTLA-4 chromosome HLA-DR shared epitope

项目摘要

In this study the importance and the genetic mode of the contribution of HL A-DR was examined to clarify the susceptibility gene of rheumatoid arthritis (RA). The new susceptibility genes (areas) were also screened by the analysis of the linkage to micro-satellites using affected sib-pairs. HLA shared epitop a (SE) analysis showed the participation of SE, especially HLA-DRB1*0405 in familial RAwas almost as same as that in rnon-familial RA (SE : 69.8% and 60.6%, DRI31*0405: 45.3% and 49.3%, respectively). HLA-DRB1*0802 was signifioantly decreased not only in random and non-familial RA, but also in familial RA. HLA-DR contributed the pathogenesis of RA in the dominant or additive mode of inheritance. MS allele frequency in Japanese normal was different from Caucasian and about 28.2% of MS showed heterozygosity less than 0.7 and about 13.4% of MS, showed heterozygosity less than 0.6. Preliminary data using 53 families showed increases of maximum LOD score more than 1.2 in 9 regions, tent … More atively identified as TIRA 1-9. TIRAl-9 located at 105-141cM on Chr. 3, 25-50 GM on Chr. 11, 94.124 eM on Chr. 17, 0-33 cM on Chr. 18, 25.46 cM on Chr. X, 8-41 & 140-155 cM on Chr. 8,' 115-165 cM'on Chr. 7, and 28-73 cM on Chr. 2, respectively. Candidate regions (TIRAl-9) length 288 cM and is about 8.3 % of whole genome length. Other 3 regions located at 85-110 cM on Chr. 2, 0-20 eM on Chr. 3, and 139.165M cM on Chr X showed relatively high LOD score (LOD > 0.8) and have possibility as candidate of susceptibility area. These results in respect to MS are the preliminary results in this stage, and more examination is necessary to confirm the results completely. Cornrlis et all showed nominal linkage in TIRA1 and 6, and Jaw aheer showed nominal linkage in TIRA1, 3, 5 and 6. MacKay showed nominal linkage in TIRA5. Many plausible susceptibility genes, VIL2, TACTILE, B4GALT4 (in fiIRAl), 0D44, BTF3, CD59 (in TIRA2), ITGB4, AP4, TIMP2 (in TIRA3) TGIF (in TIRA4), FIGF (in TIRA5), CTSB, PDGFRL (in TIRA6), SLAT4A (in TIRA7), LAMB1, PBEF, IRF5 (in TIRA8), and TIMP3, ZNT3, LTBP1 (in TIRA9), locate in each TIRA-region. The CTLA-4 -3080 allele showed a significant association with RA by Ki-square test (p=0.048) and more examination is necessary on CTLA-4. Less

为了阐明类风湿关节炎（RA）的易感基因，本研究探讨了HL A-DR在类风湿关节炎（RA）中的作用及其遗传模式。还利用受影响的兄弟姐妹对对与微卫星的联系进行分析，筛选了新的易感基因（区域）。HLA共享表位a （SE）分析显示，SE，尤其是HLA- drb1 *0405在家族性RA中的参与程度与非家族性RA几乎相同（SE分别为69.8%和60.6%，DRI31*0405分别为45.3%和49.3%）。HLA-DRB1*0802不仅在随机和非家族性RA中显著降低，在家族性RA中也显著降低。HLA-DR以显性或加性遗传方式参与RA的发病机制。日本正常人的MS等位基因频率与白种人不同，约28.2%的MS杂合度小于0.7，约13.4%的MS杂合度小于0.6。53个家庭的初步数据显示，9个地区的最大LOD评分增加了1.2以上，初步鉴定为TIRA 1-9。TIRAl-9在Chr 3上位于105-141cM， Chr 11上位于25- 50gm， Chr 17上位于94.124 eM， Chr 18上位于0- 33cm， Chr 25.46 cM。X, 8-41空空。8 & 140 - 155厘米,“我们空空的。7,115 - 165厘米,28 - 73厘米在空空的。2,分别。候选区域（TIRAl-9）长度288 cM，约占全基因组长度的8.3%。Chr 2上85 ~ 110 cM、Chr 3上0 ~ 20 eM和Chr X上139.165M cM的3个区域LOD评分较高（LOD >.8），有可能作为候选敏感区。这些关于MS的结果是这个阶段的初步结果，需要更多的检查来完全确认结果。Cornrlis等在TIRA1和6中均表现为名义连锁，Jaw aheer在TIRA1、3、5和6中表现为名义连锁。MacKay在TIRA5中显示名义连锁。许多可能的易感基因VIL2、TACTILE、B4GALT4（在tiraal中）、0D44、BTF3、CD59（在TIRA2中）、ITGB4、AP4、TIMP2（在TIRA3中）、TGIF（在TIRA4中）、FIGF（在TIRA5中）、CTSB、PDGFRL（在TIRA6中）、SLAT4A（在TIRA7中）、LAMB1、PBEF、IRF5（在TIRA8中）以及TIMP3、ZNT3、LTBP1（在TIRA9中）都位于每个tira区域。经基方检验，CTLA-4 -3080等位基因与RA有显著相关性（p=0.048）， CTLA-4等位基因与RA的相关性有待进一步研究。少