Skip to main content
SpringerLink
Log in

CFTR IVS8 Poly-T Variation Affects Severity of Acute Pancreatitis in Women

  • Original Article
  • Published:
Journal of Gastrointestinal Surgery Aims and scope

Abstract

Background

Cystic fibrosis transmembrane conductance regulator (CFTR) is important for normal pancreatic function. Its coding gene is polymorphic, and the variations have been associated with the increased risk for acute pancreatitis. However, their impact on the disease severity is still unknown. Therefore, the aim of our study was to determine the functional importance of common cystic fibrosis transmembrane conductance regulator variations IVS8-poly T, R117H, and M470V for the severity of acute pancreatitis.

Method

The study involved 98 acute pancreatitis patients. The severity of the disease was determined based on the Atlanta Classification system. IVS8-poly T, R117H, and M470V genotyping was performed using PCR-RFLP method.

Results

IVS8-5T, IVS8-7T, IVS8-9T, and M470V alleles were found at the frequencies of 5.7, 75.5, 18.9, and 55.7%, respectively, while R117H was not observed. Among women, the severe form of the disease was more frequent in carriers of at least one IVS8 9T allele (RR for 9T/9T + 9T/non-9T vs. non-9T/non-9T: 2.115; 95% CI: 1.241–3.605). This association was not detected in men and was not affected by M470V. In addition, co-morbidities increased the severity of acute pancreatitis (p = 0.022).

Conclusion

Our study reveals that IVS8 poly-T variation affects severity of acute pancreatitis in women and that existent co-morbidities worsen the clinical course of the disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Roberts SE, Morrison-Rees S, John A, Williams JG, Brown TH, Samuel DG. The incidence and aetiology of acute pancreatitis across Europe. Pancreatology. 2017;17(2):155–65.

    Article  PubMed  Google Scholar 

  2. Whitcomb DC. Genetic risk factors for pancreatic disorders. Gastroenterology. 2013;144(6):1292–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ooi CY, Durie PR. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012;11(5):355–62.

    Article  CAS  PubMed  Google Scholar 

  4. Ooi CY, Dorfman R, Cipolli M, Gonska T, Castellani C, Keenan K, Freedman SD, Zielenski J, Berthiaume Y, Corey M, Schibli S, Tullis E, Durie PR. Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis. Gastroenterology. 2011;140(1):153–61.

    Article  CAS  PubMed  Google Scholar 

  5. Shrimpton AE. R117H and IVS8-5T cystic fibrosis mutation detection by restriction enzyme digestion. Mol Diagn. 2000;5(3):235–8.

    Article  CAS  PubMed  Google Scholar 

  6. Qiao D, Yi L, Hua L, Xu Z, Ding Y, Shi D, Ni L, Song N, Wang Y, Wu H. Cystic fibrosis transmembrane conductance regulator (CFTR) gene 5T allele may protect against prostate cancer: a case-control study in Chinese Han population. J Cyst Fibros. 2008;7(3):210–4.

    Article  CAS  PubMed  Google Scholar 

  7. Lee MG, Ohana E, Park HW, Yang D, Muallem S. Molecular mechanism of pancreatic and salivary gland fluid and HCO3 secretion. Physiol Rev. 2012;92(1):39–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Pallagi P, Venglovecz V, Rakonczay Z, Jr., Borka K, Korompay A, Ozsvari B, Judak L, Sahin-Toth M, Geisz A, Schnur A, Maleth J, Takacs T, Gray MA, Argent BE, Mayerle J, Lerch MM, Wittmann T, Hegyi P. Trypsin reduces pancreatic ductal bicarbonate secretion by inhibiting CFTR Cl(−) channels and luminal anion exchangers. Gastroenterology. 2011;141(6):2228–39.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Riordan JR. Assembly of functional CFTR chloride channels. Annu Rev Physiol. 2005;67:701–18.

    Article  CAS  PubMed  Google Scholar 

  10. Hwang TC, Sheppard DN. Gating of the CFTR Cl- channel by ATP-driven nucleotide-binding domain dimerisation. J Physiol. 2009;587(Pt 10):2151–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Vergani P, Lockless SW, Nairn AC, Gadsby DC. CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains. Nature. 2005;433(7028):876–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hwang TC, Nagel G, Nairn AC, Gadsby DC. Regulation of the gating of cystic fibrosis transmembrane conductance regulator C1 channels by phosphorylation and ATP hydrolysis. Proc Natl Acad Sci U S A. 1994;91(11):4698–702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cuppens H, Lin W, Jaspers M, Costes B, Teng H, Vankeerberghen A, Jorissen M, Droogmans G, Reynaert I, Goossens M, Nilius B, Cassiman JJ. Polyvariant mutant cystic fibrosis transmembrane conductance regulator genes. The polymorphic (Tg)m locus explains the partial penetrance of the T5 polymorphism as a disease mutation. J Clin Invest. 1998;101(2):487–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yu YC, Sohma Y, Hwang TC. On the mechanism of gating defects caused by the R117H mutation in cystic fibrosis transmembrane conductance regulator. J Physiol. 2016;594(12):3227–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Boudaya M, Fredj SH, Haj RB, Khrouf M, Bouker A, Halouani L, Messaoud T. Cystic fibrosis transmembrane conductance regulator mutations and polymorphisms associated with congenital bilateral absence of vas deferens in a restricted group of patients from North Africa. Ann Hum Biol. 2012;39(1):76–9.

    Article  CAS  PubMed  Google Scholar 

  16. Johnson CD. Organ failure and acute pancreatitis. In: Forsmark CE, Gardner TB, editors. Prediction and management of severe acute pancreatitis. New York: Springer; 2015. p.15–27.

  17. Stankovic A, Zivkovic M, Alavantic D. Angiotensin I-converting enzyme gene polymorphism in a Serbian population: a gender-specific association with hypertension. Scand J Clin Lab Invest. 2002;62(6):469–75.

    Article  CAS  PubMed  Google Scholar 

  18. Shifman S, Johannesson M, Bronstein M, Chen SX, Collier DA, Craddock NJ, Kendler KS, Li T, O'Donovan M, O'Neill FA, Owen MJ, Walsh D, Weinberger DR, Sun C, Flint J, Darvasi A. Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women. PLoS Genet. 2008;4(2):e28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sun W, Anderson B, Redman J, Milunsky A, Buller A, McGinniss MJ, Quan F, Anguiano A, Huang S, Hantash F, Strom C. CFTR 5T variant has a low penetrance in females that is partially attributable to its haplotype. Genet Med. 2006;8(6):339–45.

    Article  CAS  PubMed  Google Scholar 

  20. Weiss LA, Pan L, Abney M, Ober C. The sex-specific genetic architecture of quantitative traits in humans. Nat Genet. 2006;38(2):218–22.

    Article  CAS  PubMed  Google Scholar 

  21. Wang GJ, Gao CF, Wei D, Wang C, Ding SQ. Acute pancreatitis: etiology and common pathogenesis. World J Gastroenterol. 2009;15(12):1427–30.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Lankisch PG, Assmus C, Lehnick D, Maisonneuve P, Lowenfels AB. Acute pancreatitis: does gender matter? Dig Dis Sci. 2001;46(11):2470–4.

    Article  CAS  PubMed  Google Scholar 

  23. Fortunato F, Deng X, Gates LK, McClain CJ, Bimmler D, Graf R, Whitcomb DC. Pancreatic response to endotoxin after chronic alcohol exposure: switch from apoptosis to necrosis? Am J Physiol Gastrointest Liver Physiol. 2006;290(2):G232–41.

    Article  CAS  PubMed  Google Scholar 

  24. Criddle DN, Gerasimenko JV, Baumgartner HK, Jaffar M, Voronina S, Sutton R, Petersen OH, Gerasimenko OV. Calcium signalling and pancreatic cell death: apoptosis or necrosis? Cell Death Differ. 2007;14(7):1285–94.

    Article  CAS  PubMed  Google Scholar 

  25. Kaiser AM, Saluja AK, Sengupta A, Saluja M, Steer ML. Relationship between severity, necrosis, and apoptosis in five models of experimental acute pancreatitis. Am J Physiol. 1995;269(5 Pt 1):C1295–304.

    Article  CAS  PubMed  Google Scholar 

  26. Rottner M, Kunzelmann C, Mergey M, Freyssinet JM, Martinez MC. Exaggerated apoptosis and NF-kappaB activation in pancreatic and tracheal cystic fibrosis cells. Faseb j. 2007;21(11):2939–48.

    Article  PubMed  Google Scholar 

  27. Singh AK, Schultz BD, Katzenellenbogen JA, Price EM, Bridges RJ, Bradbury NA. Estrogen inhibition of cystic fibrosis transmembrane conductance regulator-mediated chloride secretion. J Pharmacol Exp Ther. 2000;295(1):195–204.

    CAS  PubMed  Google Scholar 

  28. Chen H, Guo JH, Lu YC, Ding GL, Yu MK, Tsang LL, Fok KL, Liu XM, Zhang XH, Chung YW, Huang P, Huang H, Chan HC. Impaired CFTR-dependent amplification of FSH-stimulated estrogen production in cystic fibrosis and PCOS. J Clin Endocrinol Metab. 2012;97(3):923–32.

    Article  CAS  PubMed  Google Scholar 

  29. Nikolic A, Divac A, Stankovic M, Dinic J, Tomic B, Ljujic M. Analysis of common CFTR polymorphisms 5T, M470V and R75Q in healthy Serbian population. Genetika. 2006;42(7):996–8.

    CAS  PubMed  Google Scholar 

  30. Murata A, Ohtani M, Muramatsu K, Matsuda S. Influence of comorbidity on outcomes of older patients with acute pancreatitis based on a national administrative database. Hepatobiliary Pancreat Dis Int. 2015;14(4):422–8.

    Article  PubMed  Google Scholar 

Download references

Funding

The study was financially supported by the Faculty of Medical Sciences, University of Kragujevac, Serbia, JP 10/11, and the Ministry of Science and Technological Development, Republic of Serbia, grants No. 175007 and 175056.

Author information

Authors and Affiliations

  1. Faculty of Medical Sciences, Department of Surgery, University of Kragujevac, Svetozara Markovica 69, Kragujevac, 34 000, Serbia

    Ivan Radosavljevic, Bojan Stojanovic & Marko Spasic

  2. Faculty of Medical Sciences, Department of Pharmacology and toxicology, University of Kragujevac, Svetozara Markovica 69, Kragujevac, 34 000, Serbia

    Slobodan Jankovic & Natasa Djordjevic

Authors
  1. Ivan Radosavljevic
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bojan Stojanovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marko Spasic
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Slobodan Jankovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Natasa Djordjevic
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Ivan Radosavljevic contributed acquisition of data, interpretation of data, and drafting of the manuscript. Bojan Stojanovic and Marko Spasic contributed acquisition of data. Slobodan Jankovic contributed study concept and design and interpretation of the data. Natasa Djordjevic contributed study concept and design, statistical analysis, interpretation of the data, and drafting of the manuscript. All authors contributed to critical manuscript revision.

Corresponding author

Correspondence to Natasa Djordjevic.

Ethics declarations

The study was conducted in accordance with the Declaration of Helsinki and its subsequent revisions, with all the patients giving their written informed consent. The study was approved on August 29th, 2011, by the ethics committee at the Clinical Centre Kragujevac, decision No 01-9024.

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

The study was approved on August 29th, 2011, by the ethics committee at the Clinical Centre Kragujevac, decision No 01-9024. The study was conducted in accordance with the Declaration of Helsinki and its subsequent revisions, with all the patients giving their written informed consent.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Radosavljevic, I., Stojanovic, B., Spasic, M. et al. CFTR IVS8 Poly-T Variation Affects Severity of Acute Pancreatitis in Women. J Gastrointest Surg 23, 975–981 (2019). https://doi.org/10.1007/s11605-018-3913-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11605-018-3913-8

Keywords

Search

Navigation