Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium.
Vesalius Research Center, VIB, Leuven University, Leuven, Belgium Laboratory for Translational Genetics, University of Leuven, Leuven, Belgium.
Gut. 2014 Sep;63(9):1401-9. doi: 10.1136/gutjnl-2013-304848. Epub 2013 Nov 20.
Idiopathic achalasia is a rare motor disorder of the oesophagus characterised by neuronal loss at the lower oesophageal sphincter. Achalasia is generally accepted as a multifactorial disorder with various genetic and environmental factors being risk-associated. Since genetic factors predisposing to achalasia have been poorly documented, we assessed whether single nucleotide polymorphisms (SNPs) in genes mediating immune response and neuronal function contribute to achalasia susceptibility.
391 SNPs covering 190 immune and 67 neuronal genes were genotyped in an exploratory cohort from Central Europe (589 achalasia patients, 794 healthy volunteers (HVs)). 24 SNPs (p<0.05) were validated in an Italian (160 achalasia patients, 278 HVs) and Spanish cohort (281 achalasia patients, 296 HVs). 16 SNPs in linkage disequilibrium (LD) with rs1799724 (r(2)>0.2) were genotyped in the exploratory cohort. Genotype distributions of patients (1030) and HVs (1368) were compared using Cochran-Armitage trend test.
The rs1799724 SNP located between the lymphotoxin-α (LTA) and tumour necrosis factor-α (TNFα) genes was significantly associated with achalasia and withstood correction for testing multiple SNPs (p=1.17E-4, OR=1.41 (1.18 to 1.67)). SNPs in high LD with rs1799724 were associated with achalasia. Three SNPs located in myosin-5B, adrenergic receptor-β-2 and interleukin-13 (IL13) showed nominally significant association to achalasia that was strengthened by replication.
Our study provides evidence for rs1799724 at the LTA/TNFα locus as a susceptibility factor for idiopathic achalasia. Additional studies are needed to dissect which genetic variants in the LTA/TNFα locus are disease-causing and confirm other variants as potential susceptibility factors for achalasia.
特发性贲门失弛缓症是一种罕见的食管动力障碍性疾病，其特征为食管下括约肌神经元丧失。贲门失弛缓症通常被认为是一种多因素疾病，多种遗传和环境因素与之相关。由于导致贲门失弛缓症的遗传因素记录甚少，我们评估了调节免疫反应和神经元功能的基因中的单核苷酸多态性（SNP）是否有助于贲门失弛缓症的易感性。
在中欧的一个探索性队列中（589 例贲门失弛缓症患者，794 名健康志愿者（HV）），对 190 个免疫和 67 个神经元基因中的 391 个 SNP 进行了基因分型。在意大利队列（160 例贲门失弛缓症患者，278 名 HV）和西班牙队列（281 例贲门失弛缓症患者，296 名 HV）中对 24 个 SNP（p<0.05）进行了验证。在探索性队列中对与 rs1799724 处于连锁不平衡（LD）状态的 16 个 SNP（r(2)>0.2）进行了基因分型。使用 Cochran-Armitage 趋势检验比较患者（1030 例）和 HV（1368 例）的基因型分布。
位于淋巴毒素-α（LTA）和肿瘤坏死因子-α（TNFα）基因之间的 rs1799724 单核苷酸多态性与贲门失弛缓症显著相关，并且在进行多次 SNP 检测时仍然成立（p=1.17E-4，OR=1.41（1.18 至 1.67））。与 rs1799724 高度 LD 的 SNP 与贲门失弛缓症相关。位于肌球蛋白-5B、肾上腺素能受体-β-2 和白细胞介素-13（IL13）中的三个 SNP 与贲门失弛缓症有显著的关联，并且通过复制得到了加强。
我们的研究为 LTA/TNFα 基因座上的 rs1799724 作为特发性贲门失弛缓症的易感因素提供了证据。需要进一步的研究来剖析 LTA/TNFα 基因座中的哪些遗传变异是致病的，并确认其他变异是否为贲门失弛缓症的潜在易感因素。
