Dataset Information

HLA-A*02:06 and PTGER3 polymorphism exert additive effects in cold medicine-related Stevens-Johnson syndrome with severe ocular complications.

ABSTRACT: We previously reported that PTGER3 (prostaglandin E receptor 3 (subtype EP3)) single-nucleotide polymorphisms (SNPs) were associated with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) with severe ocular complications (SOC). We also documented that approximately 80% of our SJS/TEN patients had taken cold medicines within several days before disease onset, and we thus designated them cold medicine-related SJS/TEN (CM-SJS/TEN) patients. Moreover, we reported that HLA-A*02:06 with TLR3 polymorphisms exerted more than additive effects in SJS/TEN with SOC. In this study, we focused on CM-SJS/TEN with SOC and analyzed the association with PTGER3 SNPs and an interactive effect between PTGER3 SNPs and HLA-A*02:06 in not only the Japanese but also the Korean population. In the Japanese population, PTGER3 SNP rs1327464 was most significantly associated with CM-SJS/TEN with SOC (G versus A; odds ratio (OR)=0.232, P=7.92×10(-10)), and we found an interaction with additive effects between HLA-A*02:06 and the high-risk genotypes PTGER3 rs1327464 GA or AA (OR=10.8, P=2.56×10(-7)). We also found a significant association between Korean CM-SJS/TEN with SOC and PTGER3 SNP rs1327464 (GG versus GA+AA, OR=0.246, P=0.00101), and we detected an additive effect between HLA-A*02:06 and the high-risk genotypes PTGER3 rs1327464 GA or AA (OR=14.2, P=5.58×10(-6)).

SUBMITTER: Ueta M

PROVIDER: S-EPMC4785539 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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HLA-A*02:06 and PTGER3 polymorphism exert additive effects in cold medicine-related Stevens-Johnson syndrome with severe ocular complications.

Ueta Mayumi M Tokunaga Katsushi K Sotozono Chie C Sawai Hiromi H Yoon Kyung-Chul KC Kum Kim Mee M Yul Seo Kyoung K Joo Choun-Ki CK Tashiro Kei K Kinoshita Shigeru S

Human genome variation 20150716

We previously reported that PTGER3 (prostaglandin E receptor 3 (subtype EP3)) single-nucleotide polymorphisms (SNPs) were associated with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) with severe ocular complications (SOC). We also documented that approximately 80% of our SJS/TEN patients had taken cold medicines within several days before disease onset, and we thus designated them cold medicine-related SJS/TEN (CM-SJS/TEN) patients. Moreover, we reported that HLA-A*02:06 with ...[more]

PMID: 27081535

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Project description:BackgroundStevens-Johnson syndrome (SJS) is an acute inflammatory vesiculobullous reaction of the skin and mucosa, often including the ocular surface, and toxic epidermal necrolysis (TEN) occurs with its progression. Although SJS/TEN is thought to be initiated by certain types of medication coupled with possible infection. In the present study we examined the multiplicative interaction(s) between HLA-A*0206 and 7 Toll-like receptor 3 (TLR3) Single-nucleotide polymorphisms (SNPs) in patients with SJS/TEN.Principal findingsWe analyzed the genotypes for HLA-A and 7 TLR3 SNPs in 110 Japanese SJS/TEN patients with severe ocular complications and 206 healthy volunteers to examine the interactions between the two loci. We found that HLA-A*0206 exhibited a high odds ratio for SJS/TEN (carrier frequency: OR = 5.1; gene frequency: OR = 4.0) and that there was a strong association with TLR3 rs.5743312T/T SNP (OR = 7.4), TLR3 rs.3775296T/T SNP (OR = 5.8), TLR3 rs.6822014G/G SNP (OR = 4.8), TLR3 rs.3775290A/A SNP (OR = 2.9), TLR3 rs.7668666A/A SNP (OR = 2.7), TLR3 rs.4861699G/G SNP (OR = 2.3), and TLR3 rs.11732384G/G SNP (OR = 1.9). There was strong linkage disequilibrium (LD) between rs.3775296 and rs.5743312 and between rs.7668666 and rs.3775290. The results of interaction analysis showed that the pair, HLA-A*0206 and TLR3 SNP rs3775296T/T, which exhibited strong LD with TLR3 rs.5743312, exerted more than additive effects (OR = 47.7). The other pairs, HLA-A*0206 and TLR3 rs.3775290A/A SNP (OR = 11.4) which was in strong LD with TLR3 rs7668666A/A SNP, and TLR3 rs4861699G/G SNP (OR = 7.6) revealed additive effects. Moreover, the combination HLA-A*0206 and TLR3 rs3775296T/T was stronger than the TLR3 rs6822014G/G and TLR3 rs3775290A/A pair, which reflected the interactions within the TLR3 gene alone.SignificanceBy interaction analysis, HLA-A*0206 and TLR3 SNP rs3775296T/T, which were in strong LD with TLR3 SNP rs5743312T/T, manifested more than additive effects that were stronger than the interactions within the TLR3 gene alone. Therefore, multiplicative interactions of HLA-A and TLR3 gene might be required for the onset of SJS/TEN with ocular complications.

Project description: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.

Dataset Information

HLA-A*02:06 and PTGER3 polymorphism exert additive effects in cold medicine-related Stevens-Johnson syndrome with severe ocular complications.

Publications

HLA-A*02:06 and PTGER3 polymorphism exert additive effects in cold medicine-related Stevens-Johnson syndrome with severe ocular complications.

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