俄罗斯慢性胰腺炎患者的 PRSS1、SPINK1、CTRC、CFTR 和 CPA1 基因变异谱。

IF 1.1 Q4 MEDICINE, RESEARCH & EXPERIMENTAL
Sovremennye Tehnologii v Medicine Pub Date : 2023-01-01 Epub Date: 2023-03-29 DOI:10.17691/stm2023.15.2.06
M M Litvinova, K F Khafizov, A S Speranskaya, A D Matsvay, A Yu Asanov, K A Nikolskaya, L V Vinokurova, E A Dubtsova, M G Ipatova, T F Mukhina, M A Karnaushkina, D S Bordin
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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 <i>PRSS1</i>, <i>SPINK1</i>, <i>CTRC</i>, <i>CFTR</i>, and <i>CPA1</i> genes. The genotyping of the rs61734659 locus of the <i>PRSS2</i> gene was also conducted.</p><p><strong>Results: </strong>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: <i>CTRC</i> (37.1% of patients), <i>CFTR</i> (18.1%), <i>SPINK1</i> (8.6%), <i>PRSS1</i> (8.6%), and <i>CPA1</i> (6.7%). The frequent gene variants in Russian patients with CP were as follows: <i>CTRC</i> 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); <i>CFTR</i> 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 <i>SPINK1</i>, <i>PRSS1</i>, and <i>CPA1</i> genes, pathogenic variants were found only in the group of patients with CP. The frequent variants of the <i>SPINK1</i> gene include c.101A>G (p.Asn34Ser, rs17107315) and c.194+2T>C (rs148954387); of the <i>PRSS1</i> gene - c.86A>T (p.Asn29Ile, rs111033566); of the <i>CPA1</i> gene - c.586-30C>T (rs782335525) and c.696+23_696+24delGG. The OR for the CP development for the c.180TT genotype (rs497078) <i>CTRC</i> according to the recessive model (TT vs. CT+CC) was 7.05 (95% CI: 0.86-263, p=0.011). In the <i>CTRC</i> 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 <i>PRSS2</i> 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.</p><p><strong>Conclusion: </strong>Sequencing of the coding regions of the <i>PRSS1</i>, <i>SPINK1</i>, <i>CTRC</i>, <i>CFTR</i>, and <i>CPA1</i> genes allowed to identify genetic risk factors of the CP development in 61% of cases. 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引用次数: 0

摘要

该研究旨在确定居住在俄罗斯联邦欧洲地区的慢性胰腺炎(CP)患者的遗传风险因素谱:研究组包括 105 名慢性胰腺炎患者,发病年龄在 40 岁以下(平均发病年龄为 26.9 岁)。对照组包括 76 名无胰腺炎临床症状的患者。患者的慢性胰腺炎诊断是根据临床表现以及实验室和仪器检查的结果做出的。患者的基因检查采用新一代测序(NGS)技术,包括对 PRSS1、SPINK1、CTRC、CFTR 和 CPA1 基因的所有外显子和外显子内含子边界进行靶向测序。此外,还对 PRSS2 基因的 rs61734659 位点进行了基因分型:结果:61%的患者发现了CP发病的遗传风险因素。在以下基因中发现了与 CP 发病风险相关的致病变异和可能致病变异:CTRC(37.1% 的患者)、CFTR(18.1%)、SPINK1(8.6%)、PRSS1(8.6%)和 CPA1(6.7%)。俄罗斯 CP 患者中常见的基因变异如下: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几率比(OR)为1.848(95% CI:1.054-3.243);CFTR基因--c.3485G>T(rs1800120)、c.1521_1523delCTT(p.Phe508del,rs113993960)和 c.650A>G(rs121909046);OR=2.432(95% CI:1.066-5.553)。在 SPINK1、PRSS1 和 CPA1 基因中,仅在 CP 患者组中发现了致病变异。SPINK1 基因的常见变异包括 c.101A>G(p.Asn34Ser,rs17107315)和 c.194+2T>C(rs148954387);PRSS1 基因的常见变异为 c.86A>T(p.Asn29Ile,rs111033566);CPA1 基因的常见变异为 c.586-30C>T(rs782335525)和 c.696+23_696+24delGG。根据隐性模型(TT 与 CT+CC),c.180TT 基因型(rs497078)CTRC 的 CP 发生率为 7.05(95% CI:0.86-263,p=0.011)。在 CTRC 基因中,c.493+49G>C(rs6679763)变异似乎是良性的,c.493+51C>A(rs10803384)变异在患病者和健康者中都经常检测到,但没有显示出保护作用。PRSS2基因的保护因子c.571G>A(p.Gly191Arg,rs61734659)仅在健康人群中检测到,并证实了其保护作用。12.4%的 CP 患者有 2 或 3 个基因的风险因素:对 PRSS1、SPINK1、CTRC、CFTR 和 CPA1 基因的编码区进行测序,可确定 61% 的 CP 发病的遗传风险因素。确定心绞痛的遗传原因有助于预测疾病的发展过程,对原发性心绞痛患者的亲属采取预防措施,并为患者今后的个性化治疗提供便利。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Spectrum of PRSS1, SPINK1, CTRC, CFTR, and CPA1 Gene Variants in Chronic Pancreatitis Patients in Russia.

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.

Materials and methods: 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.

Results: 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.

Conclusion: 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.

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Sovremennye Tehnologii v Medicine
Sovremennye Tehnologii v Medicine MEDICINE, RESEARCH & EXPERIMENTAL-
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