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.

[APOΕ gene polymorphism and markers of brain damage in the outcomes of severe traumatic brain injury in children]. / Polimorfizm gena APOΕ i markery povrezhdeniya mozga v iskhodakh tyazheloi cherepno-mozgovoi travmy u detei.

OBJECTIVE: To compare apolipoprotein E (APOE) genotypes with outcomes and levels of neuromarkers in children with severe traumatic brain injury (TBI). MATERIAL AND METHODS: APOE polymorphisms were genotyped in 69 children with severe TBI. The following markers of brain damage were identified: neuron-specific enolase (NSE), glial protein S100b, content of autoantibodies (aAB) to glutamate receptors (to the NR2 subunit of NMDA receptors), aAB to S100b and brain-derived neurotrophic factor (BDNF). RESULTS AND CONCLUSION: There was no association between APOE 3/3, 3/4, 3/2 genotypes and outcomes assessed by the Glasgow Outcome Scale (GOS). The greatest number of favorable outcomes was noted in the group of APOE 3/3 genotype carriers (60%). The ratio of favorable outcomes to unfavorable outcomes was equal (50%:50%) in groups with APOE 3/4 and APOE 3/2 genotypes. An association between APOE polymorphism and BDNF was found: there were normal BDNF levels in the APOE 3/3 group and reduced levels in the APOE 3/2 group. The correlation between neuromarkers and GOS scores was shown for BDNF and aAB to S100b. In children with favorable TBI outcomes, normal BDNF levels and a lower level of aAB to S100b were observed. Regardless of APOE genotypes, almost all children with severe TBI (95%) showed a significant increase in aAB to glutamate receptors in the remote period and most children had an increase in aAB to S100b in the blood. This fact can be explained by the presence of cerebral hypoxia, activation of autoimmune processes and increased BBB permeability, which may be enhanced by increased NO content and intensification of oxidative processes in children with severe TBI.