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

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

doi:10.17691/stm2023.15.2.06

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

Sovrem Tekhnologii Med. 2023;15(2):60-70. doi: 10.17691/stm2023.15.2.06. Epub 2023 Mar 29.

Authors

M M Litvinova¹, K F Khafizov², A S Speranskaya³, A D Matsvay⁴, A Yu Asanov⁵, K A Nikolskaya⁶, L V Vinokurova⁷, E A Dubtsova⁸, M G Ipatova⁹, T F Mukhina¹⁰, M A Karnaushkina¹¹, D S Bordin¹²

Affiliations

¹ Associate Professor, Deputy Head for Research Work, Department of Medical Genetics1; Clinical Geneticist; The Loginov Moscow Clinical Scientific Center of Moscow Healthcare Department, 86 Entuziastov Shosse, Moscow, 111123, Russia.
² Head of the Laboratory of Genomic Research; Central Research Institute of Epidemiology, Russian Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, 3A Novogireevskaya St., Moscow, 111123, Russia.
³ Senior Researcher, Head of the Laboratory of Multiomix Investigations; Scientific Research Institute for Systems Biology and Medicine, Russian Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, 18 Nauchniy Proezd, Moscow, 117246, Russia; Researcher; Lomonosov Moscow State University, 1 Leninskiye Gory, Moscow, 119991, Russia.
⁴ Researcher, Laboratory of Genomic Methods Development; Centre for Strategic Planning and Management of Biomedical Health Risks of FMBA of Russia.
⁵ Professor, Department of Medical Genetics; I.M. Sechenov First Moscow State Medical University (Sechenov University), 8/2 Malaya Trubetskaya St., Moscow, 119991, Russia.
⁶ Physician; The Loginov Moscow Clinical Scientific Center of Moscow Healthcare Department, 86 Entuziastov Shosse, Moscow, 111123, Russia.
⁷ Gastroenterologist; The Loginov Moscow Clinical Scientific Center of Moscow Healthcare Department, 86 Entuziastov Shosse, Moscow, 111123, Russia.
⁸ Head of the Department of Pathology of the Pancreas and Bile Ducts; The Loginov Moscow Clinical Scientific Center of Moscow Healthcare Department, 86 Entuziastov Shosse, Moscow, 111123, Russia.
⁹ Associate Professor, Department of Hospital Pediatrics named after Academician V.A. Tabolin; Pirogov Russian National Research Medical University, 1 Ostrovitianova St., Moscow, 117997, Russia; Head of the Center for the Treatment of Developmental Anomalies and Diseases of the Hepatobiliary System in Children; N.F. Filatov Children's City Hospital of Moscow Healthcare Department, 15 Sadovaya-Kudrinskaya St., Moscow, 123001, Russia.
¹⁰ Gastroenterologist; Morozovskaya Children's City Clinical Hospital of Moscow Healthcare Department, 1/9, 4 Dobrininskiy Pereulok, 119049, Moscow, Russia.
¹¹ Professor, Department of Internal Medicine with a Course of Cardiology and Functional Diagnostics named after Academician V.S. Moiseev; Peoples' Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St., Moscow, 117198, Russia.
¹² Professor, Head of the Department of Pancreatic, Biliary and Upper Digestive Tract Disorders; The Loginov Moscow Clinical Scientific Center of Moscow Healthcare Department, 86 Entuziastov Shosse, Moscow, 111123, Russia; Professor, Department of Propaedeutic of Internal Diseases and Gastroenterology; A.I. Yevdokimov Moscow State University of Medicine and Dentistry, 20/1 Delegatskaya St., Moscow, 127473, Russia; Professor, Department of General Medical Practice and Family Medicine; Tver State Medical University, 4 Sovetaskaya St., Tver, 170100, Russia.

Abstract

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.

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

MeSH terms

Adult
Alleles
Cystic Fibrosis Transmembrane Conductance Regulator / genetics
Exons
Humans
Pancreatitis, Chronic* / genetics
Trypsin / genetics
Trypsin Inhibitor, Kazal Pancreatic* / genetics
Trypsinogen

Substances

Trypsin Inhibitor, Kazal Pancreatic
Cystic Fibrosis Transmembrane Conductance Regulator
PRSS2 protein, human
Trypsin
Trypsinogen
PRSS1 protein, human
SPINK1 protein, human
CFTR protein, human

Grants and funding

Study funding. The study was not funded by any sources.