Identification of HLA-A*02:06:01 as the primary disease susceptibility HLA allele in cold medicine-related Stevens-Johnson syndrome with severe ocular complications by high-resolution NGS-based HLA typing

Ken Nakatani,Seik-Soon Khor,Anri Masuya,Katsushi Tokunaga,Yuko Okudaira,Shigeru Kinoshita,Mayumi Ueta,Hidetoshi Inoko,Chie Sotozono,Yuki Wada,Yuki Hitomi

doi:10.1038/s41598-019-52619-2

Ken Nakatani, Seik-Soon Khor + Show 9 more

Open Access

https://doi.org/10.1038/s41598-019-52619-2

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Abstract

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening acute inflammatory vesiculobullous reactions of the skin and mucous membranes. These severe cutaneous drug reactions are known to be caused by inciting drugs and infectious agents. Previously, we have reported the association of HLA-A*02:06 and HLA-B*44:03 with cold medicine (CM)-related SJS/TEN with severe ocular complications (SOCs) in the Japanese population. However, the conventional HLA typing method (PCR-SSOP) sometimes has ambiguity in the final HLA allele determination. In this study, we performed HLA-disease association studies in CM-SJS/TEN with SOCs at 3- or 4-field level. 120 CM-SJS/TEN patients with SOCs and 817 Japanese healthy controls are HLA genotyped using the high-resolution next-generation sequencing (NGS)-based HLA typing of HLA class I genes, including HLA-A, HLA-B, and HLA-C. Among the alleles of HLA class I genes, HLA-A*02:06:01 was strongly associated with susceptibility to CM-SJS/TEN (p = 1.15 × 10−18, odds ratio = 5.46). Four other alleles (HLA-A*24:02:01, HLA-B*52:01:01, HLA-B*46:01:01, and HLA-C*12:02:02) also demonstrated significant associations. HLA haplotype analyses indicated that HLA-A*02:06:01 is primarily associated with susceptibility to CM-SJS/TEN with SOCs. Notably, there were no specific disease-causing rare variants among the high-risk HLA alleles. This study highlights the importance of higher resolution HLA typing in the study of disease susceptibility, which may help to elucidate the pathogenesis of CM-SJS/TEN with SOCs.

Highlights

It has been reported that specific HLA genotypes are associated with drug-induced severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN)
A*02:15N has been detected at an allele frequency of 0.003% in the Japanese population[25], and the differences in the exon sequences between A*02:15 N and A*02:07 exist in exon 4 of the HLA-A gene, which is not covered by Luminex oligonucleotide probes
We investigated potential novel HLA alleles associated with the occurrence of cold medicine (CM)-SJS/TEN with severe ocular complications (SOCs) using next-generation sequencing (NGS)-based high-resolution HLA allele typing

Summary

Introduction

It has been reported that specific HLA genotypes are associated with drug-induced severe cutaneous adverse reactions (SCARs), including SJS/TEN. HLA allele typing is primarily performed using two conventional typing methods, PCR sequence-specific oligonucleotide probing (PCR-SSOP) (e.g., Luminex methodology) and PCR sequence-based typing (SBT)[14,15] These conventional typing methods are designed for targeting only key exons (exons 2 and 3) in HLA class I genes in which polymorphisms are known to be functionally relevant to HLA diversity. This limited target region presents difficulties in terms of final HLA allele assignment in cases in which a number of possible alleles remain as ambiguity alleles; in addition, resolution of only up to 2-field (often referred to as 4-digit) can be achieved. We explored possible associations between HLA 3- or 4-field genotypes and CM-SJS/TEN with SOCs using super-high-resolution NGS-based HLA typing

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