Department of Internal Medicine I, Martin Luther University, Halle, Germany.
Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France; CHRU Brest, Service de Génétique Médicale et de Biologie de la Reproduction, Brest, France.
Pancreatology. 2020 Oct;20(7):1262-1267. doi: 10.1016/j.pan.2020.08.001. Epub 2020 Aug 8.
The G-protein-coupled receptor Class C Group 6 Member A (GPRC6A) is activated by multiple ligands and is important for the regulation of calcium homeostasis. Extracellular calcium is capable to increase NLRP3 inflammasome activity of the innate immune system and deletion of this proinflammatory pathway mitigated pancreatitis severity in vivo. As such this pathway and the GPRC6A receptor is a reasonable candidate gene for pancreatitis. Here we investigated the prevalence of sequence variants in the GPRC6A locus in different pancreatitis aetiologies.
We selected 6 tagging SNPs with the SNPinfo LD TAG SNP Selection tool and the functional relevant SNP rs6907580 for genotyping. Cohorts from Germany, further European countries and China with up to 1,124 patients and 1,999 controls were screened for single SNPs with melting curve analysis.
We identified an association of rs1606365(G) with alcoholic chronic pancreatitis in a German (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.65-0.89, p = 8 × 10) and a Chinese cohort (OR 0.78, 95% CI 0.64-0.96, p = 0.02). However, this association was not replicated in a combined cohort of European patients (OR 1.18, 95% CI 0.99-1.41, p = 0.07). Finally, no association was found with acute and non-alcoholic chronic pancreatitis.
Our results support a potential role of calcium sensing receptors and inflammasome activation in alcoholic chronic pancreatitis development. As the functional consequence of the associated variant is unclear, further investigations might elucidate the relevant mechanisms.
G 蛋白偶联受体 C 类组 6 成员 A（GPRC6A）被多种配体激活，对于钙稳态的调节很重要。细胞外钙能够增加先天免疫系统中 NLRP3 炎性小体的活性，并且删除这条促炎途径可减轻体内胰腺炎的严重程度。因此，这条途径和 GPRC6A 受体是胰腺炎的一个合理候选基因。在此，我们研究了不同胰腺炎病因中 GPRC6A 基因座的序列变异的流行率。
我们使用 SNPinfo LD TAG SNP 选择工具选择了 6 个标记 SNP，并对功能相关的 SNP rs6907580 进行了基因分型。从德国以及其他欧洲国家和中国的队列中筛选了多达 1124 名患者和 1999 名对照，使用熔解曲线分析对单个 SNP 进行了检测。
我们发现德国和中国的队列中，rs1606365(G)与酒精性慢性胰腺炎有关（德国：比值比 (OR) 0.76，95%置信区间 (CI) 0.65-0.89，p=8×10；中国：OR 0.78，95%CI 0.64-0.96，p=0.02）。然而，在欧洲患者的合并队列中，这种关联并未得到复制（OR 1.18，95%CI 0.99-1.41，p=0.07）。最后，我们没有发现该 SNP 与急性和非酒精性慢性胰腺炎有关。
我们的结果支持钙感应受体和炎性小体激活在酒精性慢性胰腺炎发展中的潜在作用。由于相关变异的功能后果尚不清楚，因此进一步的研究可能阐明相关机制。
