Analysis of HLA-DM polymorphisms in sarcoidosis

Ishihara, Mami; Naruse, Taeko K.; Ohno, Shigeaki; Kawata, H.; Mizuki, Nobuhisa; Yamagata, Naomi; Ishida, Tadao; Nose, Yoshisuke; Inoko, Hidetoshi

doi:10.1016/0198-8859(96)82496-7

Cited by 19 publications

(8 citation statements)

References 11 publications

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“…First-degree relatives have a higher prevalence of disease, and familial clustering has been observed in different populations but most noticeably in African Americans (Rybicki et al 2001a). Polymorphisms of a number of candidate genes have been associated with sarcoidosis (Arbustini et al 1996;Ishihara et al 1996;Rybicki et al 1999;Pandey and Frederick 2002;Planck et al 2002;Zorzetto et al 2002). Serologic and molecular analyses of HLA molecules have also been investigated in sarcoidosis.…”

Section: Introductionmentioning

confidence: 99%

HLA-DRB1*1101: A Significant Risk Factor for Sarcoidosis in Blacks and Whites

Rossman

Thompson

Frederick

et al. 2003

The American Journal of Human Genetics

354

237

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Sarcoidosis is a granulomatous disorder of unknown etiology, associated with an accumulation of CD4+ T cells and a TH1 immune response. Since previous studies of HLA associations with sarcoidosis were limited by serologic or low-resolution molecular identification, we performed high-resolution typing for the HLA-DPB1, HLA-DQB1, HLA-DRB1, and HLA-DRB3 loci and the presence of the DRB4 or DRB5 locus, to define HLA class II associations with sarcoidosis. A Case Control Etiologic Study of Sarcoidosis (ACCESS) enrolled biopsy-confirmed cases (736 total) from 10 centers in the United States. Seven hundred six (706) controls were case matched for age, race, sex, and geographic area. We studied the first 474 ACCESS patients and case-matched controls. The HLA-DRB1 alleles were differentially distributed between cases and controls (P<.0001). The HLA-DRB1*1101 allele was associated (P<.01) with sarcoidosis in blacks and whites and had a population attributable risk of 16% in blacks and 9% in whites. HLA-DRB1-F(47) was the amino acid residue most associated with sarcoidosis and independently associated with sarcoidosis in whites. The HLA-DPB1 locus also contributed to susceptibility for sarcoidosis and, in contrast to chronic beryllium disease, a non-E(69)-containing allele, HLA-DPB1*0101, conveyed most of the risk. Although significant differences were observed in the distribution of HLA class II alleles between blacks and whites, only HLA-DRB1*1501 was differentially associated with sarcoidosis (P<.003). In addition to being susceptibility markers, HLA class II alleles may be markers for different phenotypes of sarcoidosis (DRB1*0401 for eye in blacks and whites, DRB3 for bone marrow in blacks, and DPB1*0101 for hypercalcemia in whites). These studies confirm a genetic predisposition for sarcoidosis and present evidence for the allelic variation at the HLA-DRB1 locus as a major contributor.

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Section: Introductionmentioning

confidence: 99%

HLA-DRB1*1101: A Significant Risk Factor for Sarcoidosis in Blacks and Whites

Rossman

Thompson

Frederick

et al. 2003

The American Journal of Human Genetics

354

237

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“…The DO/DM complex is mainly localized within the MHC class II containing endocytic compartment (MIIC) (7), where DO regulates antigen presentation of peptides loaded onto classical class II molecules depending on the pH condition (8, 10, 17–19). From our previous studies, not only the DMA and DMB genes (20, 21), but also the DOA gene display limited polymorphism (12), suggesting that they may be unable to fulfil their biological function as peptide binding molecules (11, see below), in contrast to the high genetic variations concentrated in the peptide binding domains of classical class II molecules. In this study, the DOB gene was found to contain at least six alleles, among which only the C/T substitution at position 756 of exon 4 is associated with a single amino acid substitution from Leu (CTT) to Phe (TTT).…”

Section: Discussionmentioning

confidence: 99%

The HLA‐DOB gene displays limited polymorphism with only one amino acid substitution

et al. 2002

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The HLA-DO molecule is a non-classical class II heterodimer composed of alpha and beta chains. We have previously recognized that all eight of the allelic variations of the HLA-DOA gene represent non-synonymous amino acid substitution. In the present study, to analyze genetic polymorphism and allelic variation of the HLA-DOB gene which may affect the efficiency of class II restricted antigen presentation thereby being involved in the susceptibility of HLA associated diseases, we conducted direct DNA sequencing of HLA-DOB in 36 HLA class II homozygous typing cells and identified six new allelic variations (DOB*0101101, *0101102, *01012, *01022, *0104101 and *0104102) including five single nucleotide polymorphisms with only one amino acid substitution. Furthermore, strong linkage disequilibrium was detected between DOB*01022 and DRB1*1502 only, with no linkage disequilibrium between the DOA and the DOB genes. The HLA-DOB gene has been identified in other mammals, and their nucleotide sequences are well conserved. These facts suggest that limited polymorphism in the DOB gene is profitable to execute their unique function as a co chaperone and so strong selective pressure is operating to prevent generic variation against the DOB molecule interacting with the DM molecule and thus maintaining the specified immunological function of regulating antigen presentation.

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“…The HLA‐DM and ‐DO molecules differ from the other classical HLA class II molecules in several aspects: 1) they are largely absent from the plasma membrane as cell surface molecules, but localized in the antigen processing compartment or the MHC class II containing endocytic compartment (MIIC) ( 8); and 2) DM and DO physically associate in the endoplastic reticulum and MIIC, and catalyze peptide loading onto classical class II molecules ( 9, 10). The DMA and DMB genes display limited polymorphism that does not involve the region of the putative peptide binding groove ( 14, 15, 20, 21), in contrast with high genetic variation concentrated in the peptide binding domains of classical class II molecules. In this study, the DOA gene was recognized to contain 8 alleles, but none of them were found to be associated with amino acid substitution.…”

Section: Discussionmentioning

confidence: 99%

“…DM exhibits limited polymorphism in comparison with classical HLA class II molecules, such as HLA‐DRB and ‐DQB. Previously, we reported five allelic variations in the third exon of the HLA‐DMB gene and four in the third exon of the HLA‐DMA gene, all of which result in amino acid replacement ( 13–15). On the other hand, no extensive analysis on genetic polymorphism of the DOA or DOB genes has yet been performed and no allele in either locus has been officially recognized ( 16), although two cDNA or genomic sequences from different individuals were compared for the DOA and DOB genes and no polymorphism associated with amino acid substitution was detected ( 3, 4, 6, 17).…”

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confidence: 99%

Limited polymorphism in the HLA‐DOA gene

et al. 1999

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The HLA-DO molecule, a heterodimer consisting of two novel members of the class II gene family, DOA and DOB, has recently been suggested to function as an important modulator in the HLA class II restricted antigen presentation pathway by interaction with the HLA-DM molecule. In this study, we have analyzed genetic polymorphism and allelic variation of the HLA-DOA gene in 37 HLA class II homozygous typing cells using the direct DNA sequencing technique. As a result, we recognized at least eight allelic variations, DOA*01011, *0101201, *0101202, *0101203, *01013, *0101401, *0101402 and *01015. None of them, however, result in amino acid substitution. The HLA-DOA gene has been identified in other mammals as well, and the nucleotide sequences were well conserved among these species. These results suggest that the DOA molecule has undergone strong selective pressure to preserve functional structure and conformation required for interaction with the DM molecule, preventing non-synonymous amino acid substitution.

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Analysis of HLA-DM polymorphisms in sarcoidosis

Cited by 19 publications

References 11 publications

HLA-DRB1*1101: A Significant Risk Factor for Sarcoidosis in Blacks and Whites

HLA-DRB1*1101: A Significant Risk Factor for Sarcoidosis in Blacks and Whites

The HLA‐DOB gene displays limited polymorphism with only one amino acid substitution

Limited polymorphism in the HLA‐DOA gene

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