rs8005161多态性对肠道炎症中G蛋白偶联受体GPR65（TDAG8）pH相关激活的影响。
The impact of the rs8005161 polymorphism on G protein-coupled receptor GPR65 (TDAG8) pH-associated activation in intestinal inflammation.
作者信息
Tcymbarevich Irina V, Eloranta Jyrki J, Rossel Jean-Benoît, Obialo Nicole, Spalinger Marianne, Cosin-Roger Jesus, Lang Silvia, Kullak-Ublick Gerd A, Wagner Carsten A, Scharl Michael, Seuwen Klaus, Ruiz Pedro A, Rogler Gerhard, de Vallière Cheryl, Misselwitz Benjamin
机构信息
Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
出版信息
BMC Gastroenterol. 2019 Jan 7;19(1):2. doi: 10.1186/s12876-018-0922-8.
BACKGROUND
Tissue inflammation in inflammatory bowel diseases (IBD) is associated with a decrease in local pH. The gene encoding G-protein-coupled receptor 65 (GPR65) has recently been reported to be a genetic risk factor for IBD. In response to extracellular acidification, proton activation of GPR65 stimulates cAMP and Rho signalling pathways. We aimed to analyse the clinical and functional relevance of the GPR65 associated single nucleotide polymorphism (SNP) rs8005161.
METHODS
1138 individuals from a mixed cohort of IBD patients and healthy volunteers were genotyped for SNPs associated with GPR65 (rs8005161, rs3742704) and galactosylceramidase (rs1805078) by Taqman SNP assays. 2300 patients from the Swiss IBD Cohort Study (SIBDC) were genotyped for rs8005161 by mass spectrometry based SNP genotyping. IBD patients from the SIBDC carrying rs8005161 TT, CT, CC and non-IBD controls (CC) were recruited for functional studies. Human CD14+ cells were isolated from blood samples and subjected to an extracellular acidic pH shift, cAMP accumulation and RhoA activation were measured.
RESULTS
In our mixed cohort, but not in SIBDC patients, the minor variant rs8005161 was significantly associated with UC. In SIBDC patients, we observed a consistent trend in increased disease severity in patients carrying the rs8005161-TT and rs8005161-CT alleles. No significant differences were observed in the pH associated activation of cAMP production between IBD (TT, CT, WT/CC) and non-IBD (WT/CC) genotype carriers upon an acidic extracellular pH shift. However, we observed significantly impaired RhoA activation after an extracellular acidic pH shift in IBD patients, irrespective of the rs8005161 allele.
CONCLUSIONS
The T allele of rs8005161 might confer a more severe disease course in IBD patients. Human monocytes from IBD patients showed impaired pH associated RhoA activation upon an acidic pH shift.
背景
炎症性肠病（IBD）中的组织炎症与局部pH值降低有关。最近有报道称，编码G蛋白偶联受体65（GPR65）的基因是IBD的遗传风险因素。响应细胞外酸化时，GPR65的质子激活会刺激cAMP和Rho信号通路。我们旨在分析与GPR65相关的单核苷酸多态性（SNP）rs8005161的临床和功能相关性。
方法
通过Taqman SNP分析对来自IBD患者和健康志愿者混合队列的1138名个体进行与GPR65（rs8005161、rs3742704）和半乳糖神经酰胺酶（rs1805078）相关的SNP基因分型。通过基于质谱的SNP基因分型对来自瑞士IBD队列研究（SIBDC）的2300名患者进行rs8005161基因分型。招募来自SIBDC的携带rs8005161 TT、CT、CC的IBD患者和非IBD对照（CC）进行功能研究。从血样中分离出人CD14+细胞，使其经历细胞外酸性pH变化，测量cAMP积累和RhoA激活情况。
结果
在我们的混合队列中，而非SIBDC患者中，次要变异体rs8005161与UC显著相关。在SIBDC患者中，我们观察到携带rs8005161 - TT和rs8005161 - CT等位基因的患者疾病严重程度增加的一致趋势。在细胞外酸性pH变化后，IBD（TT、CT、WT/CC）和非IBD（WT/CC）基因型携带者之间，与pH相关的cAMP产生激活未观察到显著差异。然而，无论rs8005161等位基因如何，我们观察到IBD患者在细胞外酸性pH变化后RhoA激活明显受损。
结论
rs8005161的T等位基因可能使IBD患者的病程更严重。IBD患者的人单核细胞在酸性pH变化时显示出与pH相关的RhoA激活受损。
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