该研究的目的是确定生活在俄罗斯联邦欧洲部分地区的患者中慢性胰腺炎(CP)发展的遗传风险因素谱。
■研究组包括105名CP患者,发病年龄在40岁以下(平均发病年龄为26.9岁)。对照组由76名没有胰腺炎临床体征的人组成。根据临床表现以及实验室和仪器检查的结果,对患者的慢性胰腺炎进行诊断。使用下一代测序(NGS)技术对患者进行基因检查,包括PRSS1,SPINK1,CTRC的所有外显子和外显子-内含子边界的靶向测序,CFTR,和CPA1基因。还进行了PRSS2基因的rs61734659基因座的基因分型。
■在61%的患者中发现了CP发展的遗传危险因素。在以下基因中发现了与CP发展风险相关的致病性和可能致病性变异:CTRC(37.1%的患者),CFTR(18.1%),SPINK1(8.6%),PRSS1(8.6%),和CPA1(6.7%)。俄罗斯CP患者的常见基因变异如下:CTRC基因-c.180C>T(rs497078),c.760C>T(rs121909293),c.738_761del24(rs746224507);所有风险等位基因的累积比值比(OR)为1.848(95%CI:1.054-3.243);CFTR基因-c.3485G>T(rs1800120),c.1521_1523delCTT(p。Phe508del,rs113993960),c.650A>G(rs121909046);OR=2.432(95%CI:1.066-5.553)。在SPINK1,PRSS1和CPA1基因中,仅在CP患者组中发现致病变异.SPINK1基因的常见变体包括c.101A>G(p。Asn34Ser,rs17107315)和c.194+2T>C(rs148954387);PRSS1基因的c.86A>T(p。Asn29Ile,rs111033566);CPA1基因的c.586-30C>T(rs782335525)和c.69623_69624delGG。根据隐性模型,c.180TT基因型(rs497078)CTRC的CP发展OR(TT与CT+CC)为7.05(95%CI:0.86-263,p=0.011)。在CTRC基因中,变体c.493+49G>C(rs6679763)似乎是良性的,c.493+51C>A(rs10803384)变异在患病和健康人中经常被检测到,并且没有表现出保护作用.保护因子c.571G>A(p。Gly191Arg,仅在健康个体组中检测到PRSS2基因的rs61734659),并证实了其保护作用。12.4%的CP患者存在2个或3个基因的风险身分。
■PRSS1,SPINK1,CTRC,CFTR,和CPA1基因允许在61%的病例中鉴定CP发展的遗传危险因素。确定CP的遗传原因有助于预测病程,在先证者的亲属中执行预防措施,并促进将来对患者的个性化治疗。
The aim of the study was to define the spectrum of genetic risk factors of chronic pancreatitis (CP) development in patients living in the European part of the Russian Federation.
The study group included 105 patients with CP, with the age of the disease onset under 40 years old (the average age of onset was 26.9 years). The control group consisted of 76 persons without clinical signs of pancreatitis. The diagnosis of chronic pancreatitis in patients was made on the basis of clinical manifestations and the results of laboratory and instrumental investigations. Genetic examination of patients was conducted using the next-generation sequencing (NGS) technology and included targeted sequencing of all exons and exon-intron boundaries of the PRSS1, SPINK1, CTRC, CFTR, and CPA1 genes. The genotyping of the rs61734659 locus of the PRSS2 gene was also conducted.
Genetic risk factors of the CP development were found in 61% of patients. Pathogenic and likely-pathogenic variants associated with the risk of CP development were identified in the following genes: CTRC (37.1% of patients), CFTR (18.1%), SPINK1 (8.6%), PRSS1 (8.6%), and CPA1 (6.7%). The frequent gene variants in Russian patients with CP were as follows: CTRC gene - c.180C>T (rs497078), c.760C>T (rs121909293), c.738_761del24 (rs746224507); cumulative odds ratio (OR) for all risk alleles was 1.848 (95% CI: 1.054-3.243); CFTR gene - c.3485G>T (rs1800120), c.1521_1523delCTT (p.Phe508del, rs113993960), and c.650A>G (rs121909046); OR=2.432 (95% CI: 1.066-5.553). In the SPINK1, PRSS1, and CPA1 genes, pathogenic variants were found only in the group of patients with CP. The frequent variants of the SPINK1 gene include c.101A>G (p.Asn34Ser, rs17107315) and c.194+2T>C (rs148954387); of the PRSS1 gene - c.86A>T (p.Asn29Ile, rs111033566); of the CPA1 gene - c.586-30C>T (rs782335525) and c.696+23_696+24delGG. The OR for the CP development for the c.180TT genotype (rs497078) CTRC according to the recessive model (TT vs. CT+CC) was 7.05 (95% CI: 0.86-263, p=0.011). In the CTRC gene, the variant c.493+49G>C (rs6679763) appeared to be benign, the c.493+51C>A (rs10803384) variant was frequently detected among both the diseased and healthy persons and did not demonstrate a protective effect. The protective factor c.571G>A (p.Gly191Arg, rs61734659) of the PRSS2 gene was detected only in the group of healthy individuals and confirmed its protective role. 12.4% of the patients with CP had risk factors in 2 or 3 genes.
Sequencing of the coding regions of the PRSS1, SPINK1, CTRC, CFTR, and CPA1 genes allowed to identify genetic risk factors of the CP development in 61% of cases. Determining the genetic cause of CP helps to predict the disease course, perform preventive measures in the proband\'s relatives, and facilitate a personalized treatment of the patient in future.