HLA-A*0206 with TLR3 polymorphisms exerts more than additive effects in Stevens-Johnson syndrome with severe ocular surface complications

PLoS One. 2012;7(8):e43650. doi: 10.1371/journal.pone.0043650. Epub 2012 Aug 17.


Background: Stevens-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 findings: We 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.

Significance: By 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Epistasis, Genetic
  • Eye Diseases / complications
  • Female
  • Gene Frequency
  • Genotype
  • HLA-A2 Antigen / genetics*
  • Haplotypes
  • Humans
  • Linkage Disequilibrium
  • Male
  • Middle Aged
  • Odds Ratio
  • Polymorphism, Single Nucleotide*
  • Stevens-Johnson Syndrome / complications
  • Stevens-Johnson Syndrome / genetics*
  • Toll-Like Receptor 3 / genetics*
  • Young Adult


  • HLA-A*02:06 antigen
  • HLA-A2 Antigen
  • Toll-Like Receptor 3

Grants and funding

This work was supported in part by grants-in-aid for scientific research from the Japanese Ministry of Health, Labour and Welfare, the Japanese Ministry of Education, Culture, Sports, Science and Technology, a research grant from the Kyoto Foundation for the Promotion of Medical Science, and the Intramural Research Fund of Kyoto Prefectural University of Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.