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

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.

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Association between HLA-B44:03-HLA-C07:01 haplotype and cold medicine-related Stevens-Johnson syndrome with severe ocular complications in Thailand

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2017-311823 ◽

2018 ◽

Vol 102 (9) ◽

pp. 1303-1307 ◽

Cited By ~ 11

Author(s):

Passara Jongkhajornpong ◽

Kaevalin Lekhanont ◽

Phattrawan Pisuchpen ◽

Patchima Chantaren ◽

Vilavun Puangsricharern ◽

...

Keyword(s):

Age Of Onset ◽

Genetic Relationships ◽

Hla Class I ◽

Hla Typing ◽

Class I ◽

Stevens Johnson Syndrome ◽

Ocular Complications ◽

Thai Population ◽

Exact Test ◽

Johnson Syndrome

BackgroundPolymorphisms in human leucocyte antigen (HLA) class I genes have been found to be associated with cold medicine (CM)-related Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with severe ocular complications (SOC). Because ethnic differences in genetic predisposition to SJS/TEN among different populations have been proposed, we focused on Thai patients and investigated the association between HLA class I genotypes and CM-SJS/TEN with SOC.MethodsThis multicentre case–control study was conducted between September 2014 and August 2017. Seventy-one Thai patients with SJS/TEN with SOC and 159 healthy Thai controls were enrolled. HLA typing was performed. Genetic relationships were analysed using Fisher’s exact test.ResultsOf 71 patients with SJS/TEN with SOC (28 male, 43 female), 49 (69%) had a history of taking cold medications prior to SJS/TEN onset. The mean age of onset was 26.7±17.1 years (range, 2–77 years). HLA-B*44:03 (OR, 7.2, p=5.5×10-6, pc=1.1×10-4) and HLA-C*07:01 (OR, 6.1, p=7.1×10-6, pc=1.1×10-4) showed significant positive associations with Thai patients with CM-SJS/TEN with SOC. Additionally, 17 of 49 patients with CM-SJS/TEN with SOC (34.7%) significantly harboured the HLA-B*44:03 and HLA-C*07:01 haplotype compared with only 11 of 159 healthy controls (6.9%) (OR=7.1, p=5.5×10-6).ConclusionsHLA-B*44:03-HLA-C*07:01 haplotype is a potential risk factor for CM-SJS/TEN with SOC in the Thai population. This study supports that HLA-B*44:03 might be a common marker for CM-SJS/TEN with SOC in Eurasia populations, including European, Indian, Japanese and Thai.

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Association of HLA class I and II gene polymorphisms with acetaminophen-related Stevens–Johnson syndrome with severe ocular complications in Japanese individuals

Human Genome Variation ◽

10.1038/s41439-019-0082-6 ◽

2019 ◽

Vol 6 (1) ◽

Cited By ~ 3

Author(s):

Mayumi Ueta ◽

Ryosuke Nakamura ◽

Yoshiro Saito ◽

Katsushi Tokunaga ◽

Chie Sotozono ◽

...

Keyword(s):

Healthy Volunteers ◽

Carrier Frequency ◽

Gene Frequency ◽

Hla Class I ◽

Class Ii ◽

Hla Class Ii ◽

Class I ◽

Stevens Johnson Syndrome ◽

Ocular Complications ◽

Johnson Syndrome

Abstract Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute-onset mucocutaneous diseases induced by infectious agents and/or inciting drugs. We have reported that the main causative drugs for SJS/TEN with severe ocular complications (SOC) were cold medicines, including multi-ingredient cold medications and nonsteroidal anti-inflammatory drugs (NSAIDs). Moreover, we also reported that acetaminophen is the most frequent causative drug in various cold medicines. In this study, we focused on acetaminophen-related SJS/TEN with SOC and analyzed HLA-class II (HLA-DRB1, DQB1) in addition to HLA-class I (HLA-A, B, C). We studied the histocompatibility antigen genes HLA-DRB1 and DQB1 in addition to HLA-A, B, and C in 80 Japanese patients with acetaminophen-related SJS/TEN with SOC. We performed polymerase chain reaction amplification followed by hybridization with sequence-specific oligonucleotide probes (PCR-SSO) using commercial bead-based typing kits. We also used genotyped data from 113 healthy volunteers for HLA-DRB1 and DQB1, and 639 healthy volunteers for HLA-A, B, and C. HLA-DRB1*08:03 and DRB1*12:02 were associated with acetaminophen-related SJS/TEN with SOC, although the results ceased to be significant when we corrected the p-value for the number of alleles detected. HLA-A*02:06 was strongly associated with acetaminophen-related SJS/TEN with SOC (carrier frequency: p = 4.7 × 10−12, Pc = 6.6 × 10−11, OR = 6.0; gene frequency: p = 8.0 × 10−13, Pc = 1.1 × 10−11, OR = 4.9). HLA-B*13:01 (carrier frequency: p = 2.0 × 10−3, Pc = 0.042, OR = 4.1; gene frequency: p = 2.2 × 10−3, Pc = 0.047, OR = 3.9), HLA-B*44:03 (carrier frequency: p = 2.1 × 10−3, Pc = 0.045, OR = 2.4) and HLA-C*14:03 (carrier frequency: p = 3.4 × 10−3, Pc = 0.045, OR = 2.3) were also significantly associated, while HLA-A*24:02 was inversely associated (gene frequency: p = 6.3 × 10−4, Pc = 8.8 × 10−3, OR = 0.5). Acetaminophen-related SJS/TEN with SOC was not associated with HLA-class II (HLA-DRB1, DQB1). However, for acetaminophen-related SJS/TEN with SOC, we found an association with HLA-B*13:01 and HLA- C*14:03 in addition to HLA-A*02:06 and HLA-B*44:03, which have been described previously.

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Association of human antigen class I genes with cold medicine-related Stevens-Johnson syndrome with severe ocular complications in a Korean population

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2018-313263 ◽

2019 ◽

Vol 103 (4) ◽

pp. 573-576 ◽

Cited By ~ 5

Author(s):

Ikhyun Jun ◽

John Hoon Rim ◽

Mee Kum Kim ◽

Kyung-Chul Yoon ◽

Choun-Ki Joo ◽

...

Keyword(s):

Carrier Frequency ◽

Gene Frequency ◽

Hla Class I ◽

Korean Population ◽

Class I ◽

Stevens Johnson Syndrome ◽

Ocular Complications ◽

Johnson Syndrome ◽

Hla Genotyping ◽

Control Study

Background/aimsStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are a spectrum of diseases that cause an acute vesiculobullous reaction in the skin and mucous membranes. The occurrence of these diseases is associated with various drugs, a large proportion of which is comprised cold medicines (CM). We try to investigate the association between human leucocyte antigen (HLA) class I genes and CM-related SJS/TEN (CM-SJS/TEN) with severe ocular complications (SOC) in the Korean population.MethodsThis multicentre case-control study enrolled 40 Korean patients with CM-SJS/TEN with SOC and 120 age-matched and sex-matched Korean healthy volunteers between January 2012 and May 2014. HLA genotyping was performed using PCR followed by hybridisation with sequence-specific oligonucleotide probes.Results The carrier frequency and gene frequency of HLA-A*02:06 were 37.5 % and 20.0 %, respectively, in patients, and 16.7 % and 9.6 %, respectively, in controls (p=0.018). The carrier frequency of HLA-C*03:04 was 30 % in patients and 10.8 % in controls, and gene frequency of HLA-C*03:04 was 15 % in patients and 5.4 % in controls (p=0.003). The carrier frequency and gene frequency of HLA-C*03:03 were 2.5 % and 1.3 %, respectively, in patients, and 20 % and 10.4 %, respectively, in controls (p=0.006).Conclusions As per our results, we suggest that HLA-A*02:06 and HLA-C*03:04 might be positive markers for CM-SJS/TEN with SOC, and HLA-C*03:03 might be an indicator of protection against CM-SJS/TEN with SOC in the Korean population.

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Human leukocyte antigen class I and II genes associated with dipyrone-related Stevens-Johnson syndrome and severe ocular complications in a Brazilian population

The Ocular Surface ◽

10.1016/j.jtos.2021.02.008 ◽

2021 ◽

Author(s):

Tais Hitomi Wakamatsu ◽

Mayumi Ueta ◽

Chikara Inoue ◽

Karita Antunes Costa ◽

Laís Yumi Sakano ◽

...

Keyword(s):

Human Leukocyte Antigen ◽

Human Leukocyte Antigen Class ◽

Human Leukocyte ◽

Brazilian Population ◽

Class I ◽

Stevens Johnson Syndrome ◽

Ocular Complications ◽

Leukocyte Antigen ◽

Johnson Syndrome ◽

Leukocyte Antigen Class I

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A high resolution typing method for the simultaneous identification of HLA class I alleles with 40 universal SSO probes

Human Immunology ◽

10.1016/s0198-8859(96)80149-2 ◽

1996 ◽

Vol 49 ◽

pp. 124

Keyword(s):

High Resolution ◽

Hla Class I ◽

Class I ◽

Typing Method ◽

Simultaneous Identification

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High Resolution HLA Typing by Sequencing for HLA-A, B, C, DR, DQ in 115 Unrelated Cord Blood/Patient Pairs- Does It Improve Outcomes after Cord Blood-Transplantation?.

Blood ◽

10.1182/blood.v104.11.973.973 ◽

2004 ◽

Vol 104 (11) ◽

pp. 973-973 ◽

Cited By ~ 1

Author(s):

Gesine Koegler ◽

Juergen Enczmann ◽

Vanderson Rocha ◽

Eliane Gluckman ◽

Peter Wernet

Keyword(s):

High Resolution ◽

Cord Blood ◽

Cord Blood Transplantation ◽

Hla Class I ◽

Hla Typing ◽

Class I ◽

Published Data ◽

Number Of Patients ◽

The Impact ◽

Grade Iii

Abstract The CB Bank Düsseldorf has provided to date (July 2004) 224 CB units (216 unrelated and 8 related, 29% adults, 71% children) to transplant centers worldwide. Until now no correlation could be detected between the number of HLA-mismatches based on low resolution (LR) typing for HLA-A and-B and high resolution typing (HR) for DRB1 and the incidence of aGvHD as published previously by us and other groups. The lack of correlation between aGvHD occurrence and donor/recipient HLA diversity in patients given an unrelated CBT could be explained by the fact that some mismatches for HLA class I antigens (A, B and C) are not detected by LR typing. In order to determine the impact of HLA high resolution typing with outcomes, mainly aGvHD after UCBT we analysed DNA samples of 115 CB recipients (86 children; 29 adults; 66 male, 49 female; diagnosis ALL=43, AML=19, SecAL =1, MDS=5, CML=10, NHL=5, Hodgkin=1, AA=7, genetic and metabolic diseases= 24) and their unrelated CB grafts were HLA-typed for HLA-class I (A, B, C) and HLA-class II (DRB1 and DQB1) by sequencing. The transplant centers used their own protocols for GvHD prophylaxis, the most commonly used was the combination of CsA and steroids alone (60%), CsA alone (15%), or the combination with MTX (6%). 55 of 115 patients did not develop aGvHD (grade 0= 48%), 26 patients developed grade I (23%), 12 patients developed grade II (10%), 10 patients grade III (9%) and 12 patients grade IV (10%). When mismatches (MM) were analysed for HLA-A, B based on LR-typing and -DRB1 based on HR-typing in concordance with all published data so far, the following mismatch situation resulted: No MM (16 pairs, 13.9%), one MM (47 pairs, 40.9%), two MM (41 pairs, 35.7%), three MM (5 pairs, 4.3%), four MM (3 pairs, 2.6%). If the MM for A and B alleles detected by HR-typing were included, the situation was as follows: 0 MM (6 pairs, 5.2%), 1 MM (35 pairs, 30.4%), 2 MM (54 pairs, 47%), 3MM (14 pairs, 12.2%), 4 MM (5 pairs, 4.3%), 5 MM (1 pair, 0.9%). If analysing A, B, C, DR and DQ based on HR typing a high additional frequency of MM occurred: No MM (4 pairs, 3.5%), 1 MM (13 pairs, 11.3%), 2 MM (19 pairs, 16.5%), 3 MM (24 pairs, 20.9%), 4 MM (30 pairs, 26.1%), 5 MM (14 pairs, 12.2%), 6 MM (6 pairs, 5.2 %), 6 MM (6 pairs, 5.2%), 7 MM (3 pairs, 2.6%), 8 MM (2 pairs, 1.7%). There was no significant correlation between the number of MM (also analysed in GvHD or rejection direction) using high-resolution level for HLA-A, B and DRB1 as well as for HLA-A, B, C, DRB1 and DQB1 and the development of aGvHD grade III-IV. More interestingly, we have not found any significant correlation between numbers of MM with 2-year survival probability. Although the heterogeneity and number of patients analysed, it shows that the degree of mismatching is even higher than expected, also in comparison to unrelated BMT. It also shows that additional subtyping for HLA-A, B, C and DQ, not performed on a routine basis at present, does not improve the 2-year survival rate.

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