HLA class II variants defined by next generation sequencing are associated with sarcoidosis in Korean patients

Abstract

Polymorphic genes with immune functions, namely those of the human leukocyte antigen (HLA) system, have been implicated in sarcoidosis pathogenesis. As HLA polymorphisms in sarcoidosis have not been yet investigated in the Korean population, we used next-generation sequencing (NGS), allowing detailed characterization of HLA alleles to investigate the role of HLA variation in Korean sarcoidosis patients. We enrolled 103 patients diagnosed by the ATS/ERS/WASOG guidelines at Asan Medical Centre, Seoul, Korea. Among those, genotyping of 7 HLA loci (HLA-A, -B, -C, -DQA1, -DQB1, -DRB1, -DPB1) was performed using Omixon Holotype™ kit and HLATwin software™. HLA allele frequencies were compared with frequency data on healthy Koreans from the allelic frequency databases, and 4-digit characteristics of HLA genotyping were used. Associations were assessed by two-tailed Fischer’s exact test with correction for multiple comparisons. Variants previously associated with sarcoidosis risk (HLA-C*03:04, HLA-DRB1*12:01, HLA-DRB1*14:54) and a known protective variant HLA-DPB1*04:01, were associated with sarcoidosis in Koreans. Further, we suggest new HLA variants associated with sarcoidosis risk (e.g., HLA-DQA1*05:08) and novel protective variants HLA-DQB1*03:02 and HLA-DQA1*01:02 in Koreans. This first study of HLA variation in Korean patients with sarcoidosis by precise genotyping methodology reports data that could serve future meta-analyses on HLA variation’s role in sarcoidosis.

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

“…Observations of an association between sarcoidosis and HLA-DQB1*06:04 as a susceptibility and of HLA-DQA1*03:01 as a protective marker in the Czech population represent novel findings. Further, this study, including altogether 610 subjects, confirmed associations between HLA-DQB1*06:02 (susceptibility) and HLA-DRB1*01:01, HLA-DQB1*03:02 (protection), previously reported in smaller-scale studies in other, namely North-European and also East-Asian populations (13)(14)(15)(16)(17)…”

“…Except for HLA-DRB1*01:01, which occurred more frequently in our Czech control population than in our patients, the other two protective variants were HLA-DQA1*03:01 and HLA-DQB1*03:02. HLA-DQB1*03:02 was recently reported as protective from sarcoidosis also in Korean population (13). HLA-DQA1*03:01 has so far never been mentioned in connection with sarcoidosis.…”

“…Before sequencing, the library was denatured by NaOH, diluted with hybridization buffer, and a 9 pM library was loaded on a MiSeq flow cell (Illumina, San Diego, CA, USA) sequenced in a single 300 cycle (V2) paired-end sequencing run. Collected reads were exported in fastq format (13).…”

High‐resolution HLA genotyping identifies risk alleles in both class I and II for primary autoimmune neutropenia in early childhood in a Danish cohort

“…The proposed interaction among viral infection, C*01 , is through the killer cell immunoglobulin‐like receptors of NK cells 28 . In this study, protection against AIN was observed for the allele C*03:04:01G , and the C*03:04 allele has previously been linked to sarcoidosis in Korean patients 29 …”

“…28 In this study, protection against AIN was observed for the allele C*03:04:01G, and the C*03:04 allele has previously been linked to sarcoidosis in Korean patients. 29 For HLA class II, we replicated all our previously published low-resolution findings of associated DRB1 alleles in this cohort of Danish AIN patients 5,12 and, at a G-group resolution, found the risk alleles to be DRB1*10:01:01G, DRB1*14:01:01G, DRB1*16:01:01G and the protective alleles to be DRB1*04:01:01G and DRB1*13:02:01G. For DQB1, we similarly replicated our previous findings for DQB1*03 and DQB1*05, and we found an association with DQB1*03:02:01G, DQB1*05:02:01G, and DQB1*05:03:01G.…”