Human Leukocyte Antigen-DRB1 Position 11 Residues Are a Common Protective Marker for Sarcoidosis (original) (raw)
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Molecular genetic studies of HLA class II alleles in sarcoidosis
Tissue Antigens, 1994
Previous HLA serological studies showed positive associations of the DR52 antigen, the DR52-associated antigens (DR3, DR5 and DR6) and the DR8 antigen with sarcoidosis. To investigate the HLA alleles that may contribute to the genetic susceptibility to sarcoidosis at the DNA level, HLA-DRB1, -DRB3, -DQA1 and DQB1 genotyping using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was performed in 63 Japanese patients with sarcoidosis. The frequencies of the DR52-associated DRB1 alleles (DRB1*11, DRB1*12 and DRB1*14 except DRB1*1302), DRB1*08, DRB3*0101, DQA1*0501 and DQB1*0301 were significantly increased in patients compared with healthy controls. The significant increase of DRB3*0101, DQA1*0501 and DQB1*0301 could be explained by linkage disequilibrium with the DR52-associated DRB1 alleles. It must be noted that the DR8 haplotype, which does not possess the DRB3 gene, also showed a significant increase in sarcoidosis. These results suggest that the HLA-alleles responsible for the susceptibility to sarcoidosis are located at the HLA-DRB1 locus rather than the HLA-DRB3, -DQA1 and -DQB1 loci. In contrast, DRB1*1302 may confer resistance to the disease.
Association of HLA-DRB1 with Sarcoidosis Susceptibility and Progression in African Americans
American Journal of Respiratory Cell and Molecular Biology, 2015
HLA-DRB1 is a sarcoidosis risk gene, and the *03:01 allele is strongly associated with disease resolution in European sarcoidosis cases. Whereas the HLA-DRB1 variation is associated with sarcoidosis susceptibility in African Americans, DRB1 risk alleles are not as well defined, and associations with disease resolution have not been studied. Associations between genotyped and imputed HLA-DRB1 alleles and disease susceptibility/resolution were evaluated in a sample of 1,277 African-American patients with sarcoidosis and 1,467 control subjects. In silico binding assays were performed to assess the functional significance of the associated alleles. Increased disease susceptibility was associated with the HLA-DRB1 alleles *12:01 (odds ratio [OR], 2.11; 95% confidence interval [CI], 1.65-2.69; P = 3.2 3 10 29) and *11:01 (OR, 1.69; 95% CI, 1.42-2.01; P = 3.0 3 10 29). The strongest protective association was found with *03:01 (OR, 0.56; 95% CI, 0.44-0.73; P = 1.0 3 10 25). The African-derived allele *03:02 was associated with decreased risk of persistent radiographic disease (OR, 0.52; 95% CI, 0.37-0.72; P = 1.3 3 10 24), a finding consistent across the three component studies comprising the analytic sample. The DRB1*03:01 association with disease persistence was dependent upon local ancestry, with carriers of at least one European allele at DRB1 at a decreased risk of persistent disease (OR, 0.36; 95% CI, 0.14-0.94; P = 0.037). Results of in silico binding analyses showed that DRB1*03:01 consistently demonstrated the highest binding affinities for six bacterial peptides previously found in sarcoidosis granulomas, whereas *12:01 displayed the lowest binding affinities. This study has identified DRB1*03:01 and *03:02 as novel alleles associated with disease susceptibility and course in African Americans. Further investigation of DRB1*03 alleles may uncover immunologic factors that favor sarcoidosis protection and resolution among African Americans.
Background: A genetic background may be responsible for the different clinical courses in sarcoidosis. We analyzed associations between sarcoidosis clinical course and HLA class I/II alleles and susceptibility gene SNPs ANXA11 rs1049550 C/T and BTNL2 rs2076530 G/A in a Portuguese population, investigating possible gene–gene interactions. Methods: We studied 138 unrelated Caucasian sarcoidosis patients (78 women, 14 56.5%; mean age, 37.2612.1 years). Disease that persisted after 2 years was considered chronic. Samples were genotyped for ANXA11 rs1049550 C/T and BTNL2 16 rs2076530 G/A SNPs using TaqMan Real-Time PCR Assays. HLA class I/II alleles were typed using PCR sequence-specific primers. Results: Sixty-six patients experienced disease resolution and 72 (52%) developed chronic disease. Comparison of rs1049550 and rs2076530 allele frequencies showed no significant differences. Only the HLA DRB1*03 allele was significantly associated with disease resolution (21.2% vs 4.9% for chronic disease; RR50.35; P<.01 after Bonferroni correction). In the logistic regression models evaluating the association between HLA alleles and chronic sarcoidosis adjusted for rs1049550 and rs2076530, only DRB1*03 was significantly associated with disease resolution. No significant interactions were found in any of the logistic regression analyses. Conclusions: In this population of Caucasian patients with sarcoidosis, only DRB1*03 was associated with disease resolution after 2 years’ follow-up, with no significant interactions found for susceptibility gene SNPs ANXA11 rs1049550 or BTNL2 rs2076530.
Tissue Antigens, 2007
Sarcoidosis is an immune-mediated, multiorgan, granulomatous disease triggered by a combination of environmental and genetic factors. Numerous studies have reported about an association of human leukocyte antigen (HLA) alleles with sarcoidosis, with variation of alleles in different ethnic groups. Therefore, we investigated 142 Croatian sarcoidosis patients treated at the University Hospital for Lung Diseases 'Jordanovac', Zagreb, Croatia. Diagnosis was based on the presence of typical clinical features, chest X-ray findings and biopsy evidence of granuloma. Patients and control subjects (n ¼ 190) were typed for HLA class I antigens by serology, while for HLA class II, they were tested by the polymerase chain reactionsequence specific primers (PCR-SSP) method. Results indicated that HLA-B8, 2DRB1*0301, and 2DQB1*0201 positive patients have a significantly higher risk of acute onset of the disease (AOD), radiological stage I erythema nodosum (EN), Lo¨fgren's syndrome, no-medicament therapy, and pulmonary sarcoidosis. On the other hand, the group of non-treated patients (corticosteroids and/or immunosuppressive) showed a significantly lower presence of HLA-B15 antigen in comparison to controls and treated patients (P ¼ 0.0490 and P ¼ 0.0379, respectively) and for DRB1*04 specificity (P ¼ 0.0078 and P ¼ 0.0065, respectively). In the group of patients with AOD, those who were positive for DRB1*16 specificity have a statistically significant chance to develop EN, as opposed to those who are positive for DRB1*15 specificity.
HLA-DRB1*1101: A Significant Risk Factor for Sarcoidosis in Blacks and Whites
The American Journal of Human Genetics, 2003
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 (). The HLA-DRB1*1101 allele was associated P ! .0001 () with sarcoidosis in blacks and whites and had a population attributable risk of 16% in blacks and 9% P ! .01 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 nonE 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 (). In addition to being susceptibility mark-P ! .003 ers, 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.
The investigation of HLA microsatellites influence in predisposition to sarcoidosis among Croatians
Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG / World Association of Sarcoidosis and Other Granulomatous Disorders, 2011
The aim of the present study was to analyze the distribution of HLA alleles (A, B, DRB1, DQB1) and HLA microsatellite alleles (TNFa, TNFb, TNFd, D6S273, D6S1014) in the Croatian patients with acute (N=93), as well as chronic sarcoidosis (N=40), in comparison to healthy controls (N=177), and investigate whether the polymorphism within the HLA region could be associated with different forms of sarcoidosis. Genomic DNA was isolated from peripheral blood. Patients were analyzed for HLA class I loci (A, B) by serology, while PCR-SSP method was used for HLA class II loci (DRB1, DQB1). Five HLA microsatellites were analyzed by PCR and electrophoresis in an automated sequencer. No significant deviation in the distribution of frequencies at HLA class I alleles was observed between the two patients' subgroups and controls. Regarding the HLA class II alleles, a statistically significant increase in frequency of HLA-DRB1*03 and DQB1*0201 allele was found among patients with acute sarcoidosi...
Human leukocyte antigen-DRB1 alleles in patients with sarcoidosis from Northeast Iran
Rheumatology Research
Sarcoidosis a systemic granulomatous disorder of unknown etiology with varying clinical pictures. HLA genes, especially HLA-DRB1, have been shown to be candidates for the etiology of sarcoidosis. This study examined the association between the polymorphism of HLA-DRB1 alleles and sarcoidosis in Iranian subjects. The study population included 58 patients with sarcoidosis and 68 healthy controls. Genomic DNA was extracted, and the polymorphisms of the HLA-DRB1 alleles were determined using a polymerase chain reaction with sequence-specific primer (PCR-SSP). The frequency of HLA-DRB1*07 was higher in sarcoidosis patients (25.8%) than in controls (15.3%); however no significant difference was observed between the two groups (P>0.05). The frequency of HLA-DRB1*11 was higher in the control group (31.9%) than in cases (22.4%), but no significant difference was detected between the groups (P>0.05). The results of the present study showed that there is no association between HLA-DRB1 alleles and susceptibility to sarcoidosis in Mashhad, Northeast Iran. Further studies with large sample sizes are required in order to clarify this issue.