Polymorphism in the upstream regulatory region of DQA1 genes and DRB1, QAP, DQA1, and DQB1 haplotypes in the German population

Haas, Johannes-Peter; Kimura, Akinori; Andreas, A.; Hochberger, M.; Keller, E.; Brünnler, Günter; Bettinotti, M. de la Paz; Nevinny-Stickel, C.; Hildebrandt, Bernhard; Sierp, G.; Sasazuki, Takehiko; Albert, E. D.

doi:10.1016/0198-8859(94)90098-1

Cited by 30 publications

(26 citation statements)

References 22 publications

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“…On the level of the phenotype frequencies, we have observed a significant increase in QAP1.2, DQA1 "0102, and DQB1 *0602, which is no surprise, as all these alleles are known to exhibit a very strong linkage disequilibrium with DR2 in the healthy population (Klein 1986;Begovich et al 1992;Haas et al 1993). Likewise, we have observed a significantly increased frequency for QAP4.1, DQAI*0501, and DQBl*0201.…”

Section: Qap Cell Linessupporting

confidence: 51%

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Polymorphism of the DQA1 promoter region (QAP) and DRB1, QAP, DQA1, DQB1 haplotypes in systemic lupus erythematosus

Yao

Kimura

Hartung³

et al. 1993

Immunogenetics

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We have investigated the DNA polymorphism for the DQA1 promoter region (QAP) and HLA-class II DRB1, DQA1, and DQB1 genes in 178 central European patients with Systemic lupus erythematosus (SLE) using polymerase chain reaction and Dig-ddUTP labeled oligonucleotides. Increased frequencies of DRB1*02 and *03 are confirmed by DNA typing. In addition, the frequencies of DQA1*0501, *0102 and DQB1*0201, *0602 alleles are increased in the patients as compared to controls. The strongest association to SLE is found with DRB1*03 and DOB1*0201 alleles (p < 10(-7), p corr. < 10(-5) and p < 10(-6), p corr. < 10(-4), respectively). By investigating the DQA1 promoter region in the SLE patients we have detected nine different QAP variants. Increased frequencies of QAP1.2 and QAP4.1 are observed in patients as compared to controls (p < 0.05, p corr. = n.s.). Analysis of linkage disequilibria demonstrates a very strong association between QAP variants and DQA1, DRB1 alleles. Certain QAP variants are completely associated with DQA1 and DRB1 alleles, whereas others can combine with different DQA1 and DRB1 alleles. All DRB1*02-positive patients and controls carry QAP1.2, and all DRB1*03-positive patients and controls carry QAP4.1. Conversely, the QAP1.2 variant appears only in DRB1*02 haplotypes, while the QAP4.1 variant can be observed in DRB1*03, *11, and *1303 haplotypes. Based on the strong linkage disequilibria between DRB1-DQA1-DQB1 genes and between DRB1-QAP-DQA1, we have deduced the four-point haplotypes for DRB1-QAP-DQA1-DQB1 in patients and controls. Two haplotypes DRB1*02-QAP1.2-DQA1*0102-DQB1*0602 and DRB1*03-QAP4.1-DQA1*0501-DQB1*0201 are significantly increased in patients as compared to controls (p < 0.01, p corr. = n.s., RR = 1.8 and p < 10(-7), p corr. < 10(-5), RR = 3.1, respectively). The analysis of relative risks attributed to the various alleles of QAP, DQA1, and DQB1 as well as the investigation of the deduced DRB1-QAP-DQA1-DQB1 haplotypes leads to the conclusion that QAP4.1 and DQA1*0501 on the DR3 haplotypes are probably not involved in SLE susceptibility.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Qap Cell Linessupporting

confidence: 51%

“…Using the PCR-oligonucleotide typing technique, nine different variants in the QAP region have been identified and a strong correlation between QAP variants and alleles of the DQA1/DRB1 loci have been demonstrated in homozygous cell lines and in the Caucasian population Haas et al 1993).…”

Section: Introductionmentioning

confidence: 99%

Polymorphism of the DQA1 promoter region (QAP) and DRB1, QAP, DQA1, DQB1 haplotypes in systemic lupus erythematosus

Yao

Kimura

Hartung³

et al. 1993

Immunogenetics

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“…Human DQA1 promoter sequences came from diversity surveys of European and North American populations (19,20,63). Genomic DNA samples for eight nonhuman primate species were obtained from several sources ( Table 1).…”

Section: Methodsmentioning

confidence: 99%

Ancient polymorphism and functional variation in the primate MHC-DQA15′ cis-regulatory region

Loisel

Rockman

Wray

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Precise regulation of MHC gene expression is critical to vertebrate immune surveillance and response. Polymorphisms in the 5 proximal promoter region of the human class II gene HLA-DQA1 have been shown to influence its transcriptional regulation and may contribute to the pathogenesis of autoimmune diseases. We investigated the evolutionary history of this cis-regulatory region by sequencing the DQA1 5 proximal promoter region in eight nonhuman primate species. We observed unexpectedly high levels of sequence variation and multiple strong signatures of balancing selection in this region. Specifically, the considerable DQA1 promoter region diversity was characterized by abundant shared (or trans-species) polymorphism and a pronounced lack of fixed differences between species. The majority of transcription factor binding sites in the DQA1 promoter region were polymorphic within species, and these binding site polymorphisms were commonly shared among multiple species despite evidence for negative selection eliminating a significant fraction of binding site mutations. We assessed the functional consequences of intraspecific promoter region diversity using a cell line-based reporter assay and detected significant differences among baboon DQA1 promoter haplotypes in their ability to drive transcription in vitro. The functional differentiation of baboon promoter haplotypes, together with the significant deviations from neutral sequence evolution, suggests a role for balancing selection in the evolution of DQA1 transcriptional regulation in primates.balancing selection ͉ cis-regulatory evolution ͉ major histocompatibility complex ͉ primate molecular evolution

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“…The constitutive and induced expression of all MHC class II genes is similarly regulated by a complex system of cis ‐ and trans ‐acting transcriptional factors (Mach et al ., 1996; van den Elsen et al ., 1998). Therefore polymorphic promoter regions identified in HLA‐DRB1, DQA1 and DQB1 genes, linked to distinct exon alleles, may be responsible for allele‐specific differences in promoter strength and amounts of mRNA (Del Pozzo et al ., 1992; Senju et al ., 1992; Haas et al ., 1994; Vincent et al ., 1996; Maffei et al ., 1997). Although an influence of exon variations on mRNA stability could not be ruled out, differences in the amounts of mRNA of HLA‐DQA1 alleles have been correlated to nucleotide substitutions within the promoters by reporter gene assay (Morzycka‐Wroblewska et al ., 1997; Indovina et al ., 1998).…”

Section: Introductionmentioning

confidence: 99%

Unbalanced amounts of HLA‐DQA1 allele mRNA: DQA103 shows high and DQA10501 low amounts of mRNA in heterozygous individuals

Donner

Seidl²,

Rau³

et al. 2002

European Journal of Immunogenetics

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Genes of the HLA-DR, DQ region confer strong susceptibility to type 1 diabetes mellitus (IDDM). A possible mechanism of susceptibility is a difference in the amounts of transcripts of predisposing and neutral or protective haplotypes. In this study we developed an assay to compare the amounts of mRNA of two distinct HLA-DQA1 alleles in peripheral blood lymphocytes (PBLs) of heterozygous individuals, using a quantitative RT-PCR with an internal standard covering all HLA-DQA1 specifities. We also developed an algorithm to calculate the amounts of mRNA for two distinct alleles in heterozygous individuals based on the comparison to the same internal standard. In total, 37 HLA-DQA1 heterozygous individuals were analysed, including patients with IDDM (n = 14) and healthy controls (n = 23). Intra-individually, we observed different amounts of mRNA for different HLA-DQA1 alleles in the order: HLA-DQA1*03 > *01 > *0201 > *05. This order was observed in all individuals. We also observed a variation in the ratio of these unbalanced amounts of mRNA in individuals with the same HLA-DQA1 allele combinations. In all allele combinations the average ratio was increased in patients with IDDM compared to the control samples. HLA-DQA1*03 positive and DQA1*03, *05 heterozygous patients had the highest average ratios. Nevertheless, based on limited sample numbers, these differences did not reach significance. We therefore conclude that variations between HLA-DQA1 alleles are not limited to the nucleotide sequence but are also found at the level of amounts of mRNA.

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Polymorphism in the upstream regulatory region of DQA1 genes and DRB1, QAP, DQA1, and DQB1 haplotypes in the German population

Cited by 30 publications

References 22 publications

Polymorphism of the DQA1 promoter region (QAP) and DRB1, QAP, DQA1, DQB1 haplotypes in systemic lupus erythematosus

Polymorphism of the DQA1 promoter region (QAP) and DRB1, QAP, DQA1, DQB1 haplotypes in systemic lupus erythematosus

Ancient polymorphism and functional variation in the primate MHC-DQA15′ cis-regulatory region

Unbalanced amounts of HLA‐DQA1 allele mRNA: DQA103 shows high and DQA10501 low amounts of mRNA in heterozygous individuals

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Polymorphism in the upstream regulatory region of DQA1 genes and DRB1, QAP, DQA1, and DQB1 haplotypes in the German population

Cited by 30 publications

References 22 publications

Polymorphism of the DQA1 promoter region (QAP) and DRB1, QAP, DQA1, DQB1 haplotypes in systemic lupus erythematosus

Polymorphism of the DQA1 promoter region (QAP) and DRB1, QAP, DQA1, DQB1 haplotypes in systemic lupus erythematosus

Ancient polymorphism and functional variation in the primate MHC-DQA15′ cis-regulatory region

Unbalanced amounts of HLA‐DQA1 allele mRNA: DQA1*03 shows high and DQA1*0501 low amounts of mRNA in heterozygous individuals

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Product

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Unbalanced amounts of HLA‐DQA1 allele mRNA: DQA103 shows high and DQA10501 low amounts of mRNA in heterozygous individuals