Association between sarcoidosis and HLA polymorphisms in a Czech population from Central Europe: focus on a relationship with clinical outcome and treatment

Abstract

BackgroundSarcoidosis is an immune-mediated systemic disease with unknown etiology affecting the lung predominantly. The clinical manifestation of sarcoidosis is rather diverse ranging from Löfgren’s syndrome to fibrotic disease. Also, it differs among patients with distinct geographical and ethnic origins, consistent with environmental and genetic factors’ role in its pathogenesis. Of those, the polymorphic genes of the HLA system have been previously implicated in sarcoidosis. Therefore, we have performed an association study in a well-defined cohort of Czech patients aiming to define how variation in HLA genes, may contribute to disease origin and development.Materials and methodsTotal of the 301 Czech unrelated sarcoidosis patients were diagnosed according to international guidelines. In those, HLA typing was performed using next-generation sequencing. The allele frequencies at six HLA loci (HLA-A,-B,-C,-DRB1,-DQA1, and -DQB1) observed in the patients were compared with HLA allele distribution determined in 309 unrelated healthy Czech subjects; sub-analyses of relationships between HLA and distinct sarcoidosis clinical phenotypes were performed. Associations were assessed by two-tailed Fischer’s exact test with correction for multiple comparisons.ResultsWe report two variants, HLA-DQB1*06:02, and HLA-DQB1*06:04, as risk factors for sarcoidosis, and three variants, HLA-DRB1*01:01, HLA-DQA1*03:01, and HLA-DQB1*03:02 as protective factors. HLA-B*08:01, HLA-C*07:01, HLA-DRB1*03:01, HLA-DQA1*05:01, and HLA-DQB1*02:01 variants associated with Löfgren’s syndrome, a more benign phenotype. HLA- DRB1*03:01 and HLA-DQA1*05:01 alleles were connected with better prognosis—chest X-ray (CXR) stage 1, disease remission, and non-requirement of corticosteroid treatment. The alleles HLA-DRB1*11:01 and HLA-DQA1*05:05 are associated with more advanced disease represented by the CXR stages 2−4. HLA-DQB1*05:03 associated with sarcoidosis extrapulmonary manifestation.ConclusionIn our Czech cohort, we document some associations between sarcoidosis and HLA previously described in other populations. Further, we suggest novel susceptibility factors for sarcoidosis, such as HLA-DQB1*06:04, and characterize associations between HLA and sarcoidosis clinical phenotypes in Czech patients. Our study also extends the role of the 8.1 ancestral haplotype (HLA-A*01:01∼HLA-B*08:01∼HLA-C*07:01∼HLA-DRB1*03:01∼HLA-DQA1*05:01∼HLA-DQB1*02:01), already implicated in autoimmune diseases, as a possible predictor of better prognosis in sarcoidosis. The general translational application of our newly reported findings for personalized patient care should be validated by an independent study from another, international referral center.

Causal influence of celiac disease on the risk of sarcoidosis: A Mendelian randomization study

“…As a systemic illness with an unclear cause, sarcoidosis is genetically linked to several human white cell antigen (HLA) variations and genetic polymorphisms, mostly in the HLA region. [46,47] Studies have shown that HLA-DR3 is associated with a higher incidence of sarcoidosis, particularly in people with Lofgren's disease. [48][49][50][51] HLA-DR3 is surprisingly linked to a higher risk of CeD, according to studies.…”

Exploring the Role of Genetics in Sarcoidosis and Its Impact on the Development of Cardiac Sarcoidosis

“…In addition, other genes implicated include those influencing antigen processing and presentation, T-cell recruitment and activation, and granulomatous inflammation [55]. One specific HLA allele that increases the likelihood of sarcoidosis and radiographic progression among black families includes DQB1*0602 [58,59]. Butyrophilin-like 2 (BTNL2), located in the class II MHC region on chromosome 6, also confers an increased risk, along with other genetic variants, as detailed in Table 1 [60].…”

“…The significance of these genetic imprints is important in the phenotypic classification of patients and in recognizing the predictive value of the prognosis of sarcoidosis. HLA-B7 [73] HLA-B8 [74] HLA-B*51 [75] HLA-C [58] HLA-DPA1/DPB1 [58] HLA-DPB1 (*0101) [61] HLA-DQA1*0301 [76] HLA-DQA1*0501 [77]: HLA-DQA1*0505 [58] HLA-DQB1*0201 [76] HLA-DQB1*0302 [58] HLA-DQB1*0503/4 [76] HLA-DQB1*0601 [78]:…”

“…HLA-DQB1*0602 [58] HLA-DQB1*0604 [58] HLA-DQB1*1501 [76] HLA-DRB1*0101 [76] HLA-DRB1*03 [58] HLA-DRB1*04 [58] HLA-DRB1*0301 [79]:…”

“…HLA-DRB1*0302 [80] HLA-DRB1*04 [80] HLA-DRB1*08 [76] HLA-DRB1*14 [76] HLA-DRB1*15 [58] HLA-DRB1*1101 [61] HLA-DRB1*1201 [76] Increased More importantly, given the genetic diversity present in sarcoidosis, it may be more prudent to identify genetic changes in inflammatory regulatory pathways. For instance, mTOR and Rac1, which impede the clearance of pathogens or non-organic particles, can alter both macrophage and T-cell responses.…”