EFFECT OF PNPLA3, SERPINA1, AND HFE GENES POLYMORPHISMS ON THE COURSE OF NONALCOHOLIC FATTY LIVER DISEASE

DOI: https://doi.org/10.29296/24999490-2021-03-09

D.V. Sidorenko(1), V.D. Nazarov(1), S.V. Lapin(1), V.L. Emanuel(1), K.L. Raikhelson(2), V.P. Kovyazina(2) 1-Pavlov First Saint Petersburg State Medical University, L'va Tolstogo str. 6–8, Saint Petersburg, 197022, Russian Federation; 2-Saint Petersburg State University, Universitetskaya Emb., 7/9, Saint-Petersburg, Russian Federation, 199034 E-mail: [email protected]

Introduction: nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. But it remains unclear what factors influence the progression of the disease. It is interesting to study the influence of the genetic aspect on the course of NAFLD. The aim of the study: to investigate the influence of PNPLA3, SERPINA1, HFE gene polymorphisms on the development of NAFLD. Methods: 59 NAFLD patients were examined. Anthropometric data and biochemical indices were assessed. Hereditary liver diseases were excluded. The degree of steatosis and the stage of hepatic fibrosis were assessed using transient elastometry on a Fibroscan. Genotyping of point mutations in genes PNPLA3 (rs738409), SERPINA1 (rs17580 and rs28929474) and HFE (rs1799945, rs1800730 and rs1800562) was performed by real-time PCR. Results: polymorphisms in the PNPLA3 gene were found in 61%, in the SERPINA1 gene – in 10.2%, and in the HFE gene – in 28.8% of cases. In carriers of the I148M polymorphism of the PNPLA3 gene the ALT level was significantly higher in the comparison groups of hetero- and homozygous carriers and the normal genotype (p=0.012 and p=0.017). The AST level was also significantly higher in carriers of the MZ genotype of the SERPINA1 gene (p=0.049). The ALT level was higher in carriers of the H63D and C282Y polymorphisms of the HFE gene compared with the normal genotype (p=0.02 and p=0.03). The same relationship was demonstrated for carriers of C282Y and AST level (p=0.017). When assessing the level of steatosis, the average CAP was higher in the group of homozygous carriers of I148M of the PNPLA3 gene (p=0.045) and carriers of polymorphism C282Y (p=0.021) compared with the normal genotype. Authors found no relationship between pathological polymorphisms in the PNPLA3, SERPINA1, and HFE genes and the severity of fibrotic changes. Patients with a BMI ≥ of 35 kg/m2 had a higher liver fibrosis rate (p=0.037).
Keywords: 
the presence of polymorphisms of the PNPLA3, SERPINA1, and HFE genes in NAFLD is associated with an increase in laboratory
Список литературы: 
  1. Aithal G.P., Das K., Chowdhury A. Epidemiology of nonalcoholic fatty liver disease (NAFLD). GI epidemiology: Diseases and clinical methodology. 2nd ed. Wiley-Blackwell. 2014; 357–72.
  2. Pal'gova L.K., Baranovskij A.Ju., Ushakova T.I., Jurkina A.S., Blinov D.V. Epidemiologicheskie osobennosti nealkogol'noj zhirovoj bolezni pecheni v Cevero-Zapadnom regione Rossii (rezul'taty otkrytogo mnogotsentrovogo prospektivnogo issledovanija DIREG 2). Vestnik SPbGU. Meditsina. 2017; 12 (2): 118–35. DOI: 10.21638/11701/spbu11.2017.201 [Palgova L.K., Baranovskiy A.U., Ushakova T.I., Yurkina A.S., Blinov D.V. (2017). Epidemiological features of non-alcoholic fatty liver disease in the north-west region of Russia (results of an open multicenter prospective study DIREG 2). Vestnik of Saint Petersburg University. Medicine. 2017; 12 (2), 118–35. DOI: 10.21638/11701/spbu11.2017.201 (in Russian)]
  3. Kovalic A.J., Banerjee P., Tran Q.T., Singal A.K., Satapathy S.K. Genetic and Epigenetic Culprits in the Pathogenesis of Nonalcoholic Fatty Liver Disease. J. Clin. Exp. Hepatol. 2018; 8 (4): 390–402. DOI: 10.1016/j.jceh.2018.04.001. PMID: 30564000; PMCID: PMC6286466.
  4. Rinella M.E. Nonalcoholic fatty liver disease: a systematic review. JAMA. 2015; 313 (22): 2263–73. DOI: 10.1001/jama.2015.5370. Erratum in: JAMA. PMID: 26057287.
  5. Singh S., Allen A.M., Wang Z., Prokop L.J., Murad M.H., Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015; 13 (4): 643–54. e1-9; quiz e39-40. DOI: 10.1016/j.cgh.2014.04.014. PMID: 24768810; PMCID: PMC4208976.
  6. Pais R., Charlotte F., Fedchuk L., Bedossa P., Lebray P., Poynard T., Ratziu V. LIDO Study Group. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J. Hepatol. 2013; 59 (3): 550–6. DOI: 10.1016/j.jhep.2013.04.027. PMID: 23665288.
  7. Dongiovanni P., Anstee Q.M., Valenti L. Genetic predisposition in NAFLD and NASH: impact on severity of liver disease and response to treatment. Curr Pharm Des. 2013; 19 (29): 5219–38. DOI: 10.2174/13816128113199990381. PMID: 23394097; PMCID: PMC3850262.
  8. Seko Y., Yamaguchi K., Itoh Y. The genetic backgrounds in nonalcoholic fatty liver disease. Clin J. Gastroenterol. 2018; 11 (2): 97–102. DOI: 10.1007/s12328-018-0841-9. PMID: 29492830.
  9. Mitsche M.A., Hobbs H.H., Cohen J.C. Patatin-like phospholipase domain–containing protein 3 promotes transfer of essential fatty acids from triglycerides to phospholipids in hepatic lipid droplets. J. Biol. Chem. 2018; 293 (18): 6958–68. DOI: 10.1074/jbc.RA118.002333. Erratum in: J Biol Chem. 2018; 293 (24): 9232. PMID: 29555681; PMCID: PMC5936833.
  10. Tihomirova A.S., Kisljakov V.A., Bajkova I.E., Nikitin I.G. Kliniko-morfologicheskie paralleli polimorfizma gena PNPLA3 u patsientov s nealkogol'noj zhirovoj bolezn'ju pecheni. Terapevticheskij arhiv. 2018 i 85-88, 02. DOI: 10.26442/terarkh201890285-88. [Tikhomirova A.S., Kislyakov V.A., Baykova I.E., Nikitin I.G. Clinical-morphological parallels of the PNPLA3gene polymorphism in patients with nonalcoholic fatty liver disease. Therapeutic archive. 2018 and 85-88, 02 DOI: 10.26442/terarkh201890285-88 (in Russian)]
  11. Stoller J.K., Aboussouan L.S. Alpha1-antitrypsin deficiency. Lancet. 2005; 365 (9478): 2225–36. DOI: 10.1016/S0140-6736(05)66781-5. PMID: 15978931.
  12. Greene C.M., Marciniak S.J., Teckman J., Ferrarotti I., Brantly M.L., Lomas D.A., Stoller J.K., McElvaney N.G. α1-Antitrypsin deficiency. Nat Rev Dis Primers. 2016; 2: 16051. DOI: 10.1038/nrdp.2016.51. Erratum in: Nat Rev Dis Primers. 2018; 4 (1): 40. PMID: 27465791.
  13. Valenti L., Dongiovanni P., Fracanzani A.L., Santorelli G., Fatta E., Bertelli C., Taioli E., Fiorelli G., Fargion S. Increased susceptibility to nonalcoholic fatty liver disease in heterozygotes for the mutation responsible for hereditary hemochromatosis. Dig Liver Dis. 2003; 35 (3): 172–8. DOI: 10.1016/s1590-8658(03)00025-2. PMID: 12779071.
  14. Pietrangelo A. Metals, oxidative stress, and hepatic fibrogenesis. Semin Liver Dis. 1996; 16 (1): 13–30. DOI: 10.1055/s-2007-1007215. PMID: 8723320.
  15. Zezos P., Renner E.L. Liver transplantation and non-alcoholic fatty liver disease. World J. Gastroenterol. 2014; 20 (42): 15532–8. DOI: 10.3748/wjg.v20.i42.15532. PMID: 25400437; PMCID: PMC4229518.
  16. Dai G., Liu P., Li X., Zhou X., He S. Association between PNPLA3 rs738409 polymorphism and nonalcoholic fatty liver disease (NAFLD) susceptibility and severity: A meta-analysis. Medicine (Baltimore). 2019; 98 (7): e14324. DOI: 10.1097/MD.0000000000014324. PMID: 30762732; PMCID: PMC6407996.
  17. Hotta K., Yoneda M., Hyogo H., Ochi H., Mizusawa S., Ueno T., Chayama K., Nakajima A., Nakao K., Sekine A. Association of the rs738409 polymorphism in PNPLA3 with liver damage and the development of nonalcoholic fatty liver disease. BMC Med Genet. 2010; 11: 172. DOI: 10.1186/1471-2350-11-172. PMID: 21176169; PMCID: PMC3018434.
  18. Prins B.P., Kuchenbaecker K.B., Bao Y., Smart M., Zabaneh D., Fatemifar G., Luan J., Wareham N.J., Scott R.A., Perry J.R.B., Langenberg C., Benzeval M., Kumari M., Zeggini E. Genome-wide analysis of health-related biomarkers in the UK Household Longitudinal Study reveals novel associations. Sci Rep. 2017; 7 (1): 11008. DOI: 10.1038/s41598-017-10812-1. PMID: 28887542; PMCID: PMC5591265.
  19. Giambattistelli F., Bucossi S., Salustri C., Panetta V., Mariani S., Siotto M., Ventriglia M., Vernieri F., Dell'acqua M.L., Cassetta E., Rossini P.M., Squitti R. Effects of hemochromatosis and transferrin gene mutations on iron dyshomeostasis, liver dysfunction and on the risk of Alzheimer's disease. Neurobiol Aging. 2012; 33 (8): 1633–41. DOI: 10.1016/j.neurobiolaging.2011.03.005. PMID: 21514009.
  20. Valenti L., Al-Serri A., Daly A.K., Galmozzi E., Rametta R., Dongiovanni P., Nobili V., Mozzi E., Roviaro G., Vanni E., Bugianesi E., Maggioni M., Fracanzani A.L., Fargion S., Day C.P. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology. 2010; 51 (4): 1209–17. DOI: 10.1002/hep.23622. PMID: 20373368.
  21. Hamesch K., Mandorfer M., Pereira V.M., Moeller L.S., Pons M., Dolman G.E., Reichert M.C., Schneider C.V., Woditsch V., Voss J., Lindhauer C., Fromme M., Spivak I., Guldiken N., Zhou B., Arslanow A., Schaefer B., Zoller H., Aigner E., Reiberger T., Wetzel M., Siegmund B., Simões C., Gaspar R., Maia L., Costa D., Bento-Miranda M., van Helden J., Yagmur E., Bzdok D., Stolk J., Gleiber W., Knipel V., Windisch W., Mahadeva R., Bals R., Koczulla R., Barrecheguren M., Miravitlles M., Janciauskiene S., Stickel F., Lammert F., Liberal R., Genesca J., Griffiths W.J., Trauner M., Krag A., Trautwein C., Strnad P. European Alpha1-Liver Study Group. Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation. Gastroenterology. 2019; 157 (3): 705–19. e18. DOI: 10.1053/j.gastro.2019.05.013. PMID: 31121167.
  22. Ye Q., Qian B.X., Yin W.L., Wang F.M., Han T. Association between the HFE C282Y, H63D Polymorphisms and the Risks of Non-Alcoholic Fatty Liver Disease, Liver Cirrhosis and Hepatocellular Carcinoma: An Updated Systematic Review and Meta-Analysis of 5,758 Cases and 14,741 Controls. PLoS One. 2016; 11 (9): 0163423. DOI: 10.1371/journal.pone.0163423. PMID: 27657935; PMCID: PMC5033482.
  23. Singal A.G., Manjunath H., Yopp A.C., Beg M.S., Marrero J.A., Gopal P., Waljee A.K. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis. Am. J. Gastroenterol. 2014; 109 (3): 325–34. DOI: 10.1038/ajg.2013.476. PMID: 24445574; PMCID: PMC5610907.
  24. Strnad P., Buch S., Hamesch K., Fischer J., Rosendahl J., Schmelz R., Brueckner S., Brosch M., Heimes C.V., Woditsch V., Scholten D., Nischalke H.D., Janciauskiene S., Mandorfer M., Trauner M., Way M.J., McQuillin A., Reichert M.C., Krawczyk M., Casper M., Lammert F., Braun F., von Schönfels W., Hinz S., Burmeister G., Hellerbrand C., Teufel A., Feldman A., Schattenberg J.M., Bantel H., Pathil A., Demir M., Kluwe J., Boettler T., Ridinger M., Wodarz N., Soyka M., Rietschel M., Kiefer F., Weber T., Marhenke S., Vogel A., Hinrichsen H., Canbay A., Schlattjan M., Sosnowsky K., Sarrazin C, von Felden J., Geier A., Deltenre P., Sipos B., Schafmayer C., Nothnagel M., Aigner E., Datz C., Stickel F., Morgan M.Y., Hampe J., Berg T., Trautwein C. Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis. Gut. 2019; 68 (6): 1099–107. DOI: 10.1136/gutjnl-2018-316228. PMID: 30068662.
  25. Valenti L., Fracanzani A.L., Dongiovanni P., Bugianesi E., Marchesini G., Manzini P., Vanni E., Fargion S. Iron depletion by phlebotomy improves insulin resistance in patients with nonalcoholic fatty liver disease and hyperferritinemia: evidence from a case-control study. Am. J. Gastroenterol. 2007; 102 (6): 1251–8. DOI: 10.1111/j.1572-0241.2007.01192.x. PMID: 17391316.