Department of Veterinary Clinical Sciences, Royal Veterinary College, University of London, Hatfield, United Kingdom.
PLoS One. 2010 Dec 23;5(12):e15740. doi: 10.1371/journal.pone.0015740.
Inflammatory bowel disease (IBD) is considered to be the most common cause of vomiting and diarrhoea in dogs, and the German shepherd dog (GSD) is particularly susceptible. The exact aetiology of IBD is unknown, however associations have been identified between specific single-nucleotide polymorphisms (SNPs) in Toll-like receptors (TLRs) and human IBD. However, to date, no genetic studies have been undertaken in canine IBD. The aim of this study was to investigate whether polymorphisms in canine TLR 2, 4 and 5 genes are associated with IBD in GSDs. Mutational analysis of TLR2, TLR4 and TLR5 was performed in 10 unrelated GSDs with IBD. Four non-synonymous SNPs (T23C, G1039A, A1571T and G1807A) were identified in the TLR4 gene, and three non-synonymous SNPs (G22A, C100T and T1844C) were identified in the TLR5 gene. The non-synonymous SNPs identified in TLR4 and TLR5 were evaluated further in a case-control study using a SNaPSHOT multiplex reaction. Sequencing information from 55 unrelated GSDs with IBD were compared to a control group consisting of 61 unrelated GSDs. The G22A SNP in TLR5 was significantly associated with IBD in GSDs, whereas the remaining two SNPs were found to be significantly protective for IBD. Furthermore, the two SNPs in TLR4 (A1571T and G1807A) were in complete linkage disequilibrium, and were also significantly associated with IBD. The TLR5 risk haplotype (ACC) without the two associated TLR4 SNP alleles was significantly associated with IBD, however the presence of the two TLR4 SNP risk alleles without the TLR5 risk haplotype was not statistically associated with IBD. Our study suggests that the three TLR5 SNPs and two TLR4 SNPs; A1571T and G1807A could play a role in the pathogenesis of IBD in GSDs. Further studies are required to confirm the functional importance of these polymorphisms in the pathogenesis of this disease.
炎症性肠病（IBD）被认为是犬呕吐和腹泻的最常见原因，德国牧羊犬（GSD）特别容易患病。IBD 的确切病因尚不清楚，但是已经在人类 IBD 中发现了特定的 Toll 样受体（TLR）单核苷酸多态性（SNP）之间的关联。然而，迄今为止，尚未在犬 IBD 中进行任何遗传研究。本研究旨在探讨犬 TLR2、4 和 5 基因的多态性是否与 GSD 中的 IBD 有关。在 10 只无关的患有 IBD 的 GSD 中进行了 TLR2、TLR4 和 TLR5 的突变分析。在 TLR4 基因中发现了 4 个非同义 SNP（T23C、G1039A、A1571T 和 G1807A），在 TLR5 基因中发现了 3 个非同义 SNP（G22A、C100T 和 T1844C）。在病例对照研究中，进一步评估了 TLR4 和 TLR5 中发现的非同义 SNP，使用 SNaPSHOT 多重反应。将来自 55 只患有 IBD 的无关 GSD 的测序信息与由 61 只无关 GSD 组成的对照组进行比较。TLR5 中的 G22A SNP 与 GSD 中的 IBD 显著相关，而其余两个 SNP 则被发现对 IBD 有显著保护作用。此外，TLR4 中的两个 SNP（A1571T 和 G1807A）完全连锁不平衡，并且也与 IBD 显著相关。不具有两个相关 TLR4 SNP 等位基因的 TLR5 风险单倍型（ACC）与 IBD 显著相关，但是没有 TLR5 风险单倍型的两个 TLR4 SNP 风险等位基因与 IBD 没有统计学上的关联。我们的研究表明，TLR5 的三个 SNP 和 TLR4 的两个 SNP（A1571T 和 G1807A）可能在 GSD 中的 IBD 发病机制中起作用。需要进一步的研究来确认这些多态性在该疾病发病机制中的功能重要性。
