Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
PLoS One. 2012;7(8):e43650. doi: 10.1371/journal.pone.0043650. Epub 2012 Aug 17.
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.
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-A0206 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-A0206 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-A0206 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-A0206 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.
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.
史蒂文斯-约翰逊综合征（SJS）是一种皮肤和黏膜的急性炎症性水疱性反应，常累及眼表面，而中毒性表皮坏死松解症（TEN）则是其进展的结果。虽然 SJS/TEN 被认为是由某些类型的药物与可能的感染共同作用引发的。在本研究中，我们研究了 HLA-A*0206 和 7 型 Toll 样受体 3（TLR3）单核苷酸多态性（SNP）在 SJS/TEN 患者中的相乘交互作用。
我们分析了 110 例日本 SJS/TEN 伴有严重眼部并发症的患者和 206 例健康志愿者的 HLA-A 和 7 TLR3 SNP 基因型，以检查两个位点之间的相互作用。我们发现 HLA-A0206 对 SJS/TEN 具有较高的优势比（携带频率：OR = 5.1；基因频率：OR = 4.0），并且与 TLR3 rs.5743312T/T SNP 存在强烈关联（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）和 TLR3 rs.11732384G/G SNP（OR = 1.9）。rs.3775296 和 rs.5743312 以及 rs.7668666 和 rs.3775290 之间存在强烈的连锁不平衡（LD）。交互分析结果表明，与 TLR3 rs.5743312 强烈 LD 的 HLA-A0206 和 TLR3 SNP rs3775296T/T 对，其作用超过了相加效应（OR = 47.7）。其他对，HLA-A0206 和 TLR3 rs.3775290A/A SNP（OR = 11.4）与 TLR3 rs7668666A/A SNP 强烈 LD，以及 TLR3 rs4861699G/G SNP（OR = 7.6），呈现相加效应。此外，HLA-A0206 与 TLR3 rs3775296T/T 的组合比 TLR3 rs6822014G/G 和 TLR3 rs3775290A/A 对更强，这反映了 TLR3 基因内的相互作用。
通过交互分析，与 TLR3 SNP rs5743312T/T 强烈 LD 的 HLA-A*0206 和 TLR3 SNP rs3775296T/T 表现出超过相加效应，比 TLR3 基因内的相互作用更强。因此，HLA-A 和 TLR3 基因的相乘相互作用可能是 SJS/TEN 伴眼部并发症发生的必要条件。
