Spectrum of PRSS1, SPINK1, CTRC, CFTR, and CPA1 Gene Variants in Chronic Pancreatitis Patients in Russia

Litvinova M.M., Khafizov K.F., Speranskaya A.S., Matsvay A.D., Asanov A.Yu., Nikolskaya K.A., Vinokurova L.V., Dubtsova E.A., Ipatova M.G., Mukhina T.F., Karnaushkina M.A., Bordin D.S.

Key words: chronic pancreatitis; mutations; gene variants; PRSS1; SPINK1; CTRC; CFTR; CPA1; genetic risk factors; hereditary pancreatitis; idiopathic pancreatitis; Russian population.

2023, volume 15, issue 2, page 60.

DOI: https://doi.org/10.17691/stm2023.15.2.06

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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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Litvinova M.M., Khafizov K.F., Speranskaya A.S., Matsvay A.D., Asanov A.Yu., Nikolskaya K.A., Vinokurova L.V., Dubtsova E.A., Ipatova M.G., Mukhina T.F., Karnaushkina M.A., Bordin D.S. Spectrum of PRSS1, SPINK1, CTRC, CFTR, and CPA1 Gene Variants in Chronic Pancreatitis Patients in Russia. Sovremennye tehnologii v medicine 2023; 15(2): 60, https://doi.org/10.17691/stm2023.15.2.06