Association of HLA class I and II genes with Middle East respiratory syndrome coronavirus infection in Koreans.

INTRODUCTION: Middle East Respiratory Syndrome (MERS) caused by MERS-coronavirus (CoV) is a lower respiratory tract disease characterized by a high mortality rate. MERS-CoV spread from Saudi Arabia to other countries, including South Korea. Dysfunction of the human leukocyte antigen (HLA) system has many effects due to genetic complexity and its role in the adaptive immune response. We investigated the association of HLA class I and II alleles with MERS-CoV in 32 patients with MERS. METHODS: HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 were genotyped by polymerase chain reaction sequence-based typing. RESULTS: HLA-DQB1*03:02 are significantly associated with moderate/mild cases of MERS-CoV. Other alleles are no statistical significance. CONCLUSIONS: Treatment strategies based on current research on the HLA gene and MERS-CoV will provide potential therapeutic targets.

Allele and haplotype frequencies of human leukocyte antigen-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, -DPA1, and -DPB1 by next generation sequencing-based typing in Koreans in South Korea.

Allele frequencies and haplotype frequencies of HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, -DPA1, and -DPB1 have been rarely reported in South Koreans using unambiguous, phase-resolved next generation DNA sequencing. In this study, HLA typing of 11 loci in 173 healthy South Koreans were performed using next generation DNA sequencing with long-range PCR, TruSight® HLA v2 kit, Illumina MiSeqDx platform system, and Assign™ for TruSight™ HLA software. Haplotype frequencies were calculated using the PyPop software. Direct counting methods were used to investigate the association with DRB1 for samples with only one copy of a particular secondary DRB locus. We compared these allele types with the ambiguous allele combinations of the IPD-IMGT/HLA database. We identified 20, 40, 26, 31, 19, 16, 4, and 16 alleles of HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPA1, and HLA-DPB1, respectively. The number of HLA-DRB3/4/5 alleles was 4, 5, and 3, respectively. The haplotype frequencies of most common haplotypes were as follows: A*33:03:01-B*44:03:01-C*14:03-DRB1*13:02:01-DQB1*06:04:01-DPB1*04:01:01 (2.89%), A*33:03:01-B*44:03:01-C*14:03 (4.91%), DRB1*08:03:02-DQA1*01:03:01-DQB1*06:01:01-DPA1*02:02:02-DPB1*05:01:01 (5.41%), DRB1*04:05:01-DRB4*01:03:01 (12.72%), DQA1*01:03:01-DQB1*06:01:01 (13.01%), and DPA1*02:02:02-DPB1*05:01:01 (30.83%). In samples with only one copy of a specific secondary DRB locus, we examined its association with DRB1. We, thus, resolved 10 allele ambiguities in HLA-B, -C (each exon 2+3), -DRB1, -DQB1, -DQA1, and -DPB1 (each exon 2) of the IPD-IMGT/HLA database. Korean population was geographically close to Japanese and Han Chinese populations in the genetic distances by multidimensional scaling (MDS) plots. The information obtained by HLA typing of the 11 extended loci by next generation sequencing may be useful for more exact diagnostic tests on various transplantations and the genetic population relationship studies in South Koreans.

The HLA-B*13:144 allele identified in a volunteer donor for hematopoietic stem cell transplant.

HLA-B*13:144 differs from HLA-B*13:01:01:01 in codon 12 in exon 2.

The HLA-A*24:514N allele identified in a volunteer donor for hematopoietic stem cell transplant.

HLA-A*24:514N differs from HLA-A*24:02:01:01 in codon 167 in exon 3.

The HLA-A*02:954 allele identified in a volunteer donor for hematopoietic stem cell transplant.

HLA-A*02:954 differs from HLA-A*02:06:01:01 in codon 82 in exon 2.

The HLA-DRB1*09:45 allele identified in a volunteer donor for hematopoietic stem cell transplant.

HLA-DRB1*09:45 differs from HLA-DRB1*09:01:02:01 in codon 19 in exon 2.

The HLA-A*11:384 allele identified in a volunteer donor for hematopoietic stem cell transplant.

HLA-A*11:384 differs from HLA-A*11:01:01:01 in codon 151 in exon 3.

The HLA-B*35:01:64 allele identified in a volunteer donor for hematopoietic stem cell transplant.

HLA-B*35:01:64 differs from HLA-B*35:01:01:01 in codon 58 in exon 2.

Distributions of HLA-A, -B, and -DRB1 alleles typed by amplicon-based next generation sequencing in Korean volunteer donors for unrelated hematopoietic stem cell transplantation.

HLA genes play a pivotal role for successful hematopoietic stem cell transplantation (HSCT). There is an increasing need for sophisticated screening of donor HLA genotypes for unrelated HSCT. Next generation sequencing (NGS) has emerged as an alternative for classical Sanger sequence for HLA typing. In this study, HLA-A, -B, and -DRB1 alleles were genotyped at the allelic (6-digit) level using MiSeqDx in 26,202 volunteers from the Korean Network for Organ Sharing. Exon 2 and 3 of HLA-A and -B and exon 2 of HLA-DRB1 were amplified by polymerase chain reaction (PCR) and each allele was determined by matching the targeted exons and the reference sequence consisting of the IPD-IMGT/HLA Database. Seventy alleles of HLA-A, 102 alleles of HLA-B, and 69 alleles of HLA-DRB1 were identified. According to common and well-documented catalogs, 34 alleles in HLA-A, 61 in HLA-B, and 45 in HLA-DRB1 locus were common alleles, and 12, 14, and 11 kinds, were well-documented alleles, respectively. Thirteen novel alleles including 3 alleles in HLA-A, 8 alleles in HLA-B, and 2 alleles in HLA-DRB1 loci were found. Ten haplotypes with a frequency of more than 1.0% accounted for 22.4% of the total haplotype frequencies. Cis/trans ambiguities of HLA-A and -B loci by combination of exons 2 and 3 were analyzed to be 0.17% of 3 and 3.95% of 22 genotypes, respectively. This information on rare and novel alleles found by accurate HLA typing with NGS may be helpful for unrelated HSCT among Koreans.

The HLA-A*24:480 allele identified in a volunteer donor for hematopoietic stem cell transplant.

HLA-A*24:480 differs from HLA-A*24:02:01:01 in codon 178 in exon 3.

The HLA-DRB1*04:05:21 allele identified in a volunteer donor for hematopoietic stem cell transplant.

HLA-DRB1*04:05:21 differs from HLA-DRB1*04:05:01:01 in codon 83 in exon 2.

The HLA-A*33:03:42 allele identified in a volunteer donor for hematopoietic stem cell transplant.

HLA-A*33:03:42 differs from HLA-A*33:03:01:01 in codon 90 in exon 2.

The HLA-B*46:01:26 allele identified in a volunteer donor for hematopoietic stem cell transplant.

HLA-B*46:01:26 differs from HLA-B*46:01:01:01 in codon 66 in exon 2.

The HLA-A*31:154 allele identified in a volunteer donor for hematopoietic stem cell transplant.

HLA-A*31:154 differs from HLA-A*31:01:02:01 in codon 115 in exon 3.

The HLA-DRB1*04:277 allele identified in a volunteer donor for hematopoietic stem cell transplant.

HLA-DRB1*04:277 differs from HLA-DRB1*04:06:01:01 in codon 62 in exon 2.

The HLA-A*02:842 allele identified in a volunteer donor for hematopoietic stem cell transplant.

HLA-A*02:842 differs from HLA-A*02:149 in codon 99 in exon 3.

HLA-A*02:877 allele identified in a volunteer donor for hematopoietic stem cell transplant.

HLA-A*02:877 differs from HLA-A*02:06:01:01 in codon 183 in exon 3.

The HLA-B*15:529 allele identified in a volunteer donor for hematopoietic stem cell transplant.

HLA-B*15:529 differs from HLA-B*15:01:01:01 in codon 138 in exon 3.

The HLA-B*07:367 allele identified in a volunteer donor for hematopoietic stem cell transplant.

HLA-B*07:367 differs from HLA-B*07:02:01:01 in codon 181 in exon 3.

The HLA-B*51:284 allele identified in a volunteer donor for hematopoietic stem cell transplant.

HLA-B*51:284 differs from HLA-B*51:01:01:01 in codon 44 in exon 2.