Reichstetter S, Brünnler G, Kalden J R, Wassmuth R
Department of Medicine III, University of Erlangen-Nürnberg, Germany.
Hum Immunol. 1996 Dec;51(2):73-80. doi: 10.1016/s0198-8859(96)00116-4.
Sequence variability in the upstream regulatory regions (URR) of HLA class II genes has been described as an additional mechanism of diversity in these polymorphic genes. For HLA-DQB1, 12 URR variants have been identified previously by sequence analysis of approx. 600 bp located immediately upstream of the first exon of the DQB1 gene. To investigate the distribution of these promoter alleles and their linkage with the structural portion of the DQB1 gene, a population-based study was carried out. Sequence information was utilized to develop 25 sequence-specific oligonucleotide probes to analyze enzymatically amplified locus-specific DNA. Supplemented with one sequence-specific primer pair to differentiate QBP1-6.2 from -6.3, all known 12 QBP1 alleles could be identified. Subsequently, 215 healthy, unrelated German controls were investigated for the distribution and linkage of DQB1 and QBP1 alleles. A total of 10 out of 12 known QBP1 alleles were observed. Since there was tight linkage between the promoter region and exon 2 of DQB1, the phenotype and genotype frequencies of the promoter alleles corresponded by and large to the frequencies observed for their linked DQB1 alleles. Exceptions were mainly seen for DQ5 and DQ6 haplotypes, as single DQB1 alleles could be linked to different, however, closely related QBP1 alleles and vice versa. Interestingly, for each DQB1 allele a single DQB1/QBP1 haplotype dominated (75.9 to 96.4%) the distribution. It is concluded that promoter and coding region variability are tightly linked by linkage disequilibrium. Exceptions are restricted to DQB1 DQ5 and DQ6 haplotypes. Since functional differences between different QBP1 alleles exist, the maintenance of haplotypic integrity may be of functional importance.
HLA II类基因上游调控区(URR)的序列变异性已被描述为这些多态性基因多样性的一种额外机制。对于HLA - DQB1,先前通过对DQB1基因第一个外显子上游约600 bp进行序列分析,已鉴定出12种URR变体。为了研究这些启动子等位基因的分布及其与DQB1基因结构部分的连锁关系,开展了一项基于人群的研究。利用序列信息开发了25种序列特异性寡核苷酸探针,以分析酶促扩增的位点特异性DNA。补充一对序列特异性引物以区分QBP1 - 6.2和 - 6.3,所有已知的12种QBP1等位基因均可被鉴定。随后,对215名健康、无亲缘关系的德国对照者进行DQB1和QBP1等位基因的分布及连锁关系研究。共观察到12种已知QBP1等位基因中的10种。由于DQB1启动子区域与外显子2之间存在紧密连锁,启动子等位基因的表型和基因型频率在很大程度上与与其连锁的DQB1等位基因所观察到的频率相对应。例外情况主要见于DQ5和DQ6单倍型,因为单个DQB1等位基因可与不同但密切相关的QBP1等位基因连锁,反之亦然。有趣的是,对于每个DQB1等位基因,单一的DQB1/QBP1单倍型在分布中占主导地位(75.9%至96.4%)。得出的结论是,启动子和编码区的变异性通过连锁不平衡紧密相连。例外情况仅限于DQB1 DQ5和DQ6单倍型。由于不同QBP1等位基因之间存在功能差异,单倍型完整性的维持可能具有功能重要性。