Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229, USA.
J Allergy Clin Immunol. 2010 Jul;126(1):160-5.e3. doi: 10.1016/j.jaci.2010.04.037.
The genetic cause of eosinophilic esophagitis (EE) has been largely unexplored until a recent genome-wide association study identified a disease susceptibility locus on 5q22, a region that harbors the thymic stromal lymphopoietin (TSLP) gene. However, it is unclear whether the observed genetic associations with EE are disease-specific or confounded by the high rate of allergy in patients with EE. In addition, the genetic contributions of other allergy-associated genes to EE risk have not been explored.
We aimed to delineate single nucleotide polymorphisms (SNPs) that associated with EE apart from allergy.
We used a custom array containing 738 SNPs in 53 genes implicated in allergic responses, immune responses, or both to genotype 220 allergic or 246 nonallergic control subjects and a discovery cohort of 170 patients with EE. We replicated a statistically significant SNP association in an independent case-control cohort and examined the induction of the candidate gene in primary esophageal epithelial cells.
A single SNP residing in the TSLP gene reached Bonferroni linkage disequilibrium-adjusted significance but only when patients with EE were compared with allergic control subjects (rs10062929; P = 4.11 x 10(-5); odds ratio, 0.35). A nonsynonymous polymorphism in the thymic stromal lymphopoietin receptor (TSLPR) gene on Xp22.3 and Yp11.3 was significantly associated with disease only in male patients with EE. Primary esophageal epithelial cells expressed TSLP mRNA after Toll-like receptor 3 stimulation.
These data collectively identify TSLP as a candidate gene critically involved in EE susceptibility beyond its role in promoting T(H)2 responses.
直到最近的全基因组关联研究发现 5q22 上存在一个疾病易感性位点，该位点包含胸腺基质淋巴细胞生成素 (TSLP) 基因，嗜酸粒细胞性食管炎 (EE) 的遗传原因在很大程度上仍未得到探索。然而，目前尚不清楚观察到的与 EE 相关的遗传关联是否是疾病特异性的，还是受 EE 患者过敏率高的影响。此外，其他与过敏相关的基因对 EE 风险的遗传贡献尚未得到探索。
我们旨在确定除过敏外与 EE 相关的单核苷酸多态性 (SNP)。
我们使用包含 53 个基因中与过敏反应、免疫反应或两者相关的 738 个 SNP 的定制芯片，对 220 名过敏性或 246 名非过敏性对照者和 170 名 EE 患者的发现队列进行基因分型。我们在独立的病例对照队列中复制了具有统计学意义的 SNP 关联，并在原代食管上皮细胞中检测了候选基因的诱导。
位于 TSLP 基因中的单个 SNP 达到了 Bonferroni 连锁不平衡调整显著性，但仅当 EE 患者与过敏性对照者相比时才达到（rs10062929；P=4.11x10(-5)；优势比，0.35）。Xp22.3 和 Yp11.3 上的 TSLP 受体 (TSLPR) 基因中的非同义多态性仅与 EE 男性患者的疾病显著相关。经 Toll 样受体 3 刺激后，原代食管上皮细胞表达 TSLP mRNA。
这些数据共同确定 TSLP 是一个候选基因，除了在促进 T(H)2 反应中的作用外，它还与 EE 易感性密切相关。
