title: DQB1 promoter sequence variability and linkage in caucasoids.
abstract: 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.
authors.affiliation: Department of Medicine III, University of Erlangen-Nürnberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Reichstetter
authors.forename: G
authors.initials: G
authors.lastname: Brünnler
authors.forename: J R
authors.initials: JR
authors.lastname: Kalden
authors.forename: R
authors.initials: R
authors.lastname: Wassmuth
mesh_terms: D000483:Alleles; D008040:Genetic Linkage / Q000276:immunology*; D005838:Genotype; D005858:Germany; D006683:HLA-DQ Antigens / Q000235:genetics*; D059866:HLA-DQ beta-Chains; D006239:Haplotypes; D006801:Humans; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000276:immunology*; D044465:White People / Q000235:genetics
chemical_list: D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen