Structural analysis of the HLA-DR, -DQ, and -DP alleles on the celiac disease-associated HLA-DR3 (DRw17) haplotype.
Structural analysis of the HLA-DR, -DQ, and -DP alleles on the celiac disease-associated HLA-DR3 (DRw17) haplotype.
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乳糜泻相关 HLA-DR3 (DRw17) 单倍型上的 HLA-DR、-DQ 和 -DP 等位基因的结构分析。
DOI：
10.1073/pnas.86.16.6274
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发表时间：
1989
影响因子：
11.1
通讯作者：
Erlich,HA
中科院分区：
文献类型：
--
作者：
Kagnoff,MF;Harwood,JI;Bugawan,TL;Erlich,HA
乳糜泻与HLA II类D区血清学标志物DR 3（DRw 17）和DQw 2密切相关。此外，通过限制性片段长度多态性分析，大于90%的DR 3（DRw 17）、DQ w 2乳糜泻患者具有多态性的4.0-腺苷酸酶Rsa I DP B基因DNA片段。本研究旨在确定是否有一个独特的HLA II类D区A或B基因结构变异的DR 3（DRw 17）单倍型发现乳糜泻。应用聚合酶链反应（PCR）技术对DR 3（DRw 17）单倍型的乳糜泻患者DRB、DQA、DQB、DPA、DPB基因第二外显子多态性进行了测序。为了确定与乳糜泻相关的DP B基因，相似地扩增来自27名乳糜泻患者的编码DP B基因的第二外显子，并通过使用一组序列特异性寡核苷酸进行探测。注意到乳糜泻患者的HLA-DR、-DQ和-DPA和B基因第二外显子序列与在未受影响的个体中也可以发现的序列相同，尽管频率显著较低。这与疾病模型相容，其中DR 3（DRw 17）单倍型上的HLA II类基因对于乳糜泻的表型表达是必需的，但不是足够的。DP B基因的分析揭示了乳糜泻中等位基因DPB 1和DPB 3的频率显著增加。此外，4.0-腺苷酸酶Rsa I DP B基因限制性片段长度多态性在乳糜泻中的频率增加可以通过等位基因DPB 1和DPB 3在疾病中的过度表达来解释。与HLA相关的乳糜泻易感性似乎是多基因的，DP和DQ/DR亚区中具有特异性但结构正常的等位基因变体，从而导致疾病易感性。
Celiac disease is strongly associated with the HLA class II D-region serologic markers DR3 (DRw17) and DQw2. Moreover, by restriction fragment length polymorphism analysis, greater than 90% of DR3 (DRw17), DQw2 celiac disease patients have a polymorphic 4.0-kilobase Rsa I DP B gene DNA fragment. The present study sought to determine if there is a unique HLA class II D-region A or B gene structural variant on the DR3 (DRw17) haplotype found in celiac disease. The polymorphic second exons of the coding DRB, DQA and DQB, and DPA and DPB genes in celiac disease patients with the DR3 (DRw17) haplotype were sequenced after amplification by the polymerase chain reaction. To define the DP B genes associated with celiac disease, the second exons of the coding DP B genes from 27 celiac disease patients were amplified similarly and probed by using a panel of sequence specific oligonucleotides. The HLA-DR, -DQ, and -DP A and B gene second exon sequences of celiac disease patients were noted to be identical to sequences that can be found also, although at a significantly lower frequency, in unaffected individuals. This is compatible with a disease model wherein the HLA class II genes on the DR3 (DRw17) haplotype are necessary, but not sufficient, for the phenotypic expression of celiac disease. Analysis of the DP B genes revealed a significant increase in the frequency of the alleles DPB1 and DPB3 in celiac disease. Furthermore, the increased frequency of the 4.0-kilobase Rsa I DP B gene restriction fragment length polymorphism in celiac disease can be accounted for by the overrepresentation in disease of the alleles DPB1 and DPB3. The HLA-associated susceptibility to celiac disease appears to be multigenic, with specific, but structurally normal, allelic variants in the DP and DQ/DR subregions contributing to disease susceptibility.