4-Aminobutyrate Aminotransferase (ABAT): Genetic and Pharmacological Evidence for an Involvement in Gastro Esophageal Reflux Disease
4-Aminobutyrate Aminotransferase (ABAT): Genetic and Pharmacological Evidence for an Involvement in Gastro Esophageal Reflux Disease
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DOI：
10.1371/journal.pone.0019095
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发表时间：
2011-04-28
期刊：
影响因子：
3.7
通讯作者：
Lagerstrom-Fermer, Maria
中科院分区：
文献类型：
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作者：
Jirholt, Johan;Asling, Bengt;Lagerstrom-Fermer, Maria
胃食管反流病（GERD）部分是由遗传因素引起的。除 COL3A1 外，潜在的易感基因目前尚不清楚。我们使用三个独立的 GERD 患者队列来鉴定 GERD 易感基因。对显示 GERD 显性传播的 36 个家族进行了全基因组微卫星基因分型和连锁分析。确定了五个关联区域。两个家庭在 16 号染色体上共享一个关联区域（LOD 3.9 和 2.0）。我们使用了另外两个独立的 GERD 患者队列，一个由 219 个三人组（受影响的儿童及其父母）组成，另一个是由 256 例病例和 485 名对照组成的成人 GERD 病例对照队列，通过关联分析来验证关联区域中的各个基因。分布在连锁区域的九个基因上的 66 个单核苷酸多态性 (SNP) 标记在独立的 GERD 三人组中进行了基因分型。传递不平衡测试分析随后进行多次测试调整，揭示了位于 4-氨基丁酸转氨酶 (ABAT) 基因内含子中的一个 SNP 存在显着的遗传关联 (P-adj = 0.027)。这种关联在成人病例对照队列中并未复制，可能是由于队列之间的种族差异。最后，在狗研究中使用选择性 ABAT 抑制剂氨己烯酸 (γ-乙烯基 GABA)，我们能够将短暂性下食管括约肌松弛 (TLESR) 减少 57.3 +/- 11.4 % (p = 0.007)，并将反流事件从 3.1 +/- 0.4 减少到 0.8 +/- 0.4 (p = 0.007)。我们的结果表明 ABAT 直接参与影响下食管括约肌 (LES) 控制的途径，并将 ABAT 确定为 GERD 的遗传危险因素。
Gastro-esophageal reflux disease (GERD) is partly caused by genetic factors. The underlying susceptibility genes are currently unknown, with the exception of COL3A1. We used three independent GERD patient cohorts to identify GERD susceptibility genes. Thirty-six families, demonstrating dominant transmission of GERD were subjected to whole genome microsatellite genotyping and linkage analysis. Five linked regions were identified. Two families shared a linked region (LOD 3.9 and 2.0) on chromosome 16. We used two additional independent GERD patient cohorts, one consisting of 219 trios (affected child with parents) and the other an adult GERD case control cohort consisting of 256 cases and 485 controls, to validate individual genes in the linked region through association analysis. Sixty six single nucleotide polymorphism (SNP) markers distributed over the nine genes present in the linked region were genotyped in the independent GERD trio cohort. Transmission disequilibrium test analysis followed by multiple testing adjustments revealed a significant genetic association for one SNP located in an intron of the gene 4-aminobutyrate aminotransferase (ABAT) (P-adj = 0.027). This association did not replicate in the adult case-control cohort, possibly due to the differences in ethnicity between the cohorts. Finally, using the selective ABAT inhibitor vigabatrin (gamma-vinyl GABA) in a dog study, we were able to show a reduction of transient lower esophageal sphincter relaxations (TLESRs) by 57.3 +/- 11.4 % (p = 0.007) and the reflux events from 3.1 +/- 0.4 to 0.8 +/- 0.4 (p = 0.007). Our results demonstrate the direct involvement of ABAT in pathways affecting lower esophageal sphincter (LES) control and identifies ABAT as a genetic risk factor for GERD.