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

Abstract

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.

• Authors: Mayumi Ueta, Katsushi Tokunaga, Chie Sotozono, Hiromi Sawai, Gen Tamiya, Tsutomu Inatomi, Shigeru Kinoshita
• Journal: PloS one (PLoS One) Vol. 7 Issue 8 Pg. e43650 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22912896 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• 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, genetics)
• Toll-Like Receptor 3 (genetics)
• Young Adult