Multifactorial Genesis of Pancreatitis in Primary Hyperparathyroidism: Evidence for "Protective" (PRSS2) and "Destructive" (CTRC) Genetic Factors
Multifactorial Genesis of Pancreatitis in Primary Hyperparathyroidism: Evidence for "Protective" (PRSS2) and "Destructive" (CTRC) Genetic Factors
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DOI：
10.1055/s-0030-1255106
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发表时间：
2011-01-01
影响因子：
1.8
通讯作者：
Bulut, K.
中科院分区：
文献类型：
--
作者：
Felderbauer, P.;Karakas, E.;Bulut, K.
目的：原发性甲状旁腺功能亢进（pHPT）与胰腺炎的关系长期以来一直存在争议，但仍是一种罕见的附带现象。在pHPT和胰腺炎患者队列中，丝氨酸蛋白酶抑制剂Kazal I型（SPINK 1）和囊性纤维化跨膜传导调节因子（CFTR）基因突变增加了胰腺炎的风险。在胰凝乳蛋白酶C基因（CTRC）中发现的其他胰腺炎相关突变中，很明显阴离子胰蛋白酶原基因（PRSS 2）中也存在保护性遗传变异，可降低胰腺炎的易感性。我们的目的是检测一个大的pHPT pHPTpatients.Methods队列的保护性或诱导的遗传因素：在1259例pHPT患者中，57例（4.5%）被确定为胰腺炎。从31例患者（16例急性胰腺炎/15例慢性胰腺炎）中获得DNA。对这些患者和100例pHPT无胰腺炎患者进行CTRC分析（p.R254W和p.K247_R254del）和PRSS 2（p.G191R）突变，使用解链曲线分析和DNA测序或PCR和凝胶电泳（在p.K247_R254del CTRC的情况下）。31例pHPT和胰腺炎患者中有2例携带CTRC p.R254W错义突变（6.5%），而所有100例无胰腺炎的pHPT对照均未显示CTRC突变（P = 0.055）。未检测到进一步的SPINK 1 p.N34S（n = 4）突变，但pHPT胰腺炎患者中CTRC或SPINK 1突变的概率较高（P < 0.05）。1例患者为反式杂合子（SPINK 1：N34 S/CTRC p.R254W）。在两组中均未检测到CTRC p.K247_R254del。PRSS 2（p.G191R）突变在pHPT相关胰腺炎患者中的检出率为3.2%，在pHPT对照组中的检出率为6%（P = 1）。然而，这仅表明CTRC（p.R254W）突变也可能导致先前报道的pHPT中胰腺炎易感性升高的突变组（SPINK 1和CFTR）。此外，它还表明，保护性遗传变异，即，p.G191R PRSS 2的表达可能导致pHPT患者胰腺炎的低患病率。
Objective: A relationship between primary hyperparathyroidism (pHPT) and pancreatitis has long been debated and remains a rare epiphenomenon. In a cohort of patients with pHPT and pancreatitis mutations in the serine protease inhibitor Kazal type I (SPINK1) and cystic fibrosis transmembrane conductance regulator (CFTR) genes, that increase the risk for pancreatitis have already been detected. Among the identification of additional pancreatitis-associtated mutations in the Chymotrypsin C gene (CTRC) it became clear that also protective genetic variants exist in the anionic trypsinogen gene (PRSS2) that decrease susceptibility for pancreatitis. Our aim was to detect either protective or inducing genetic factors in a large cohort of pHPT patients.Methods: Among 1 259 patients with pHPT, 57 patients were identified with pancreatitis (4.5%). DNA was available from 31 patients (16 acute pancreatitis/15 chronic pancreatitis). These individuals and 100 patients with pHPT without pancreatitis were analysed for CTRC (p.R254W and p.K247_R254del) and PRSS2 (p.G191R) mutations using melting curve analysis and DNA sequencing or PCR and gel electrophoresis (in case of p.K247_R254del CTRC).Results: 2 of 31 patients with pHPT and pancreatitis carried the CTRC p.R254W missense mutation (6.5%), while all 100 pHPT controls without pancreatitis showed no CTRC mutation (P = 0.055). No further SPINK1 p.N34S (n = 4) mutations were detected but the probability of either CTRC or SPINK1 mutations in pHPT patients with pancreatitis is high (P < 0.05). 1 patient was trans-heterozygous (SPINK1: N34S/CTRC p.R254W). CTRC p.K247_R254del was not detected in both groups. PRSS2 (p.G191R) mutation was present in 1 patient with pancreatitis (3.2%) and in 6 pHPT controls (6%) (P = 1).Conclusion: This study underlines the relevance of a genetic background in pHPT related pancreatitis. However, it only indicates that the CTRC (p.R254W) mutation might also contribute to the panel of mutations (SPINK1 and CFTR) that have been formerly reported to elevate pancreatitis susceptibility in pHPT. Besides it suggests that protective genetic variants, i.e., p.G191R PRSS2, may contribute to the low prevalence of pancreatitis in pHPT patients.