Association between PNPLA3 and TM6SF2 gene polymorphisms and non-alcoholic fatty liver disease patients in Kazakhstan
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Medical Center Hospital of President’s Affairs Administration of the Republic of Kazakhstan, Astana, KAZAKHSTAN
NJSC Astana Medical University, Astana, KAZAKHSTAN
Department of Internal Medicine, Nazarbayev University School of Medicine, Astana, KAZAKHSTAN
Tel Aviv Sourasky Medical Center, Tel Aviv, ISRAEL
Online publication date: 2023-09-24
Publication date: 2023-11-01
Electron J Gen Med 2023;20(6):em546
Non-alcoholic fatty liver disease (NAFLD) is a growing burden on a global scale and considered as the most common liver disease of the 21st century, affecting both adults and children. Genome-wide association studies (GWAS) in the field of liver diseases have made a significant contribution to the understanding of genetic background for NAFLD development. Targeted genes like PNPLA3 and TM6SF2 showed some relationship with the steatosis and hepatocellular carcinoma within NAFLD patients. In this study, we tried to analyze the frequency of PNPLA3 and TM6SF2 gene polymorphisms and their relationship to changes in instrumental and laboratory markers, the composition of the gut microbiome, the development and progression of NAFLD stage in Kazakhstan.

Materials and methods:
39 individuals were involved in this study, including 18 men and 21 women: patients with a history of heavy alcohol consumption (>20 g/day) and other specific diseases such as hepatitis B and C virus infection, etc. were excluded. The diagnosis was established based on the results of clinical assessment and laboratory-instrumental results. The microbiome composition of the large intestine was studied by semiconductor sequencing of the bacterial genome using biochips. The degree of steatosis and liver fibrosis were evaluated by fibroscanning on fibroscan touch 502. Genotyping of PNPLA3 and TM6SF2 were carried out by PCR.

According to PNPLA3 genotyping: 21 patients (53.85%) were C/G, 7 (17.95%) were C/C and 11 (28.20%) were G/G. Within analyzed variables, GGT showed statistically significant difference among nucleotide variability with p-value of 0.012. Other parameters within metabolic panel also showed statistically significant difference between groups, namely, total cholesterol (p=0.036) and LDL (p=0.006). Genotyping of TM6SF2 includes 24 patients (61.54%) with C/C, 15 (38.46%) with C/T and 0 with T/T. The relationship between TM6SF2 liver function test results showed no statistically significant differences between groups. All other parameters including gut microbiome analysis are not statistically significant.

In this study, C/G genotype possesses the highest risk and GGT along with LDL were the statistically significant parameter between them in PNPLA3 gene. TM6SF2 and gut microbiome analysis did not reveal any statistically significant differences. Additional studies with larger sample size are recommended to obtain for more detailed and sensitive results.

European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388-402. https://doi.org/10.1016/j.jhep... PMid:27062661.
Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018; 67(1):328-57. https://doi.org/10.1002/hep.29... PMid:28714183.
Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, et al. Global burden of NAFLD and NASH: Trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15(1):11-20. https://doi.org/10.1038/nrgast... PMid:28930295.
Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, 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. https://doi.org/10.1016/j.cgh.... PMid:24768810 PMCid:PMC4208976.
Lonardo A, Bellentani S, Argo CK, Ballestri S, Byrne CD, Caldwell SH, et al. Epidemiological modifiers of non-alcoholic fatty liver disease: Focus on high-risk groups. Dig Liver Dis. 2015;47(12):997-1006. https://doi.org/10.1016/j.dld.... PMid:26454786.
Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: From steatosis to cirrhosis. Hepatology. 2006;43(S1):S99-112. https://doi.org/10.1002/hep.20... PMid:16447287.
Rinella ME. Nonalcoholic fatty liver disease: A systematic review. JAMA. 2015;313(22):2263-73. https://doi.org/10.1001/jama.2... PMid:26057287.
Anstee QM, Day CP. The genetics of nonalcoholic fatty liver disease: Spotlight on PNPLA3 and TM6SF2. Semin Liver Dis. 2015;35(3):270-90. https://doi.org/10.1055/s-0035... PMid:26378644.
Yoo JJ, Kim W, Kim MY, Jun DW, Kim SG, Yeon JE, et al. Recent research trends and updates on nonalcoholic fatty liver disease. Clin Mol Hepatol. 2019;25(1):1-11. https://doi.org/10.3350/cmh.20... PMid:30086613 PMCid:PMC6435971.
Dongiovanni P, Stender S, Pietrelli A, Mancina RM, Cespiati A, Petta S, et al. Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver. J Intern Med. 2018;283(4):356-70. https://doi.org/10.1111/joim.1... PMid:29280273 PMCid:PMC5900872.
Byrne CD, Targher G. Review NAFLD : A multisystem disease. J Hepatol. 2015;62(1):S47-64. https://doi.org/10.1016/j.jhep... PMid:25920090.
Yki-Järvinen H. Diagnosis of non-alcoholic fatty liver disease (NAFLD). Diabetologia. 2016;59(6):1104-11. https://doi.org/10.1007/s00125... PMid:27091184.
Krawczyk M, Rau M, Schattenberg JM, Bantel H, Pathil A, Demir M, et al. Combined effects of the PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738 variants on NAFLD severity: A multicenter biopsy-based study1. J Lipid Res. 2017;58(1):247-55. https://doi.org/10.1194/jlr.P0... PMid:27836992 PMCid:PMC5234727.
Ching-Yeung Yu B, Kwok D, Wong VWS. Magnitude of nonalcoholic fatty liver disease: Eastern perspective. J Clin Exp Hepatol. 2019;9(4):491-6. https://doi.org/10.1016/j.jceh... PMid:31516265 PMCid:PMC6728533.
Dongiovanni P, Donati B, Fares R, Lombardi R, Mancina RM, Romeo S, et al. PNPLA3 I148M polymorphism and progressive liver disease. World J Gastroenterol. 2013; 19(41):6969-78. https://doi.org/10.3748/wjg.v1... PMid:24222941 PMCid:PMC3819533.
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. https://doi.org/10.1097/MD.000... PMid:30762732 PMCid:PMC6407996.
Kanda T, Goto T, Hirotsu Y, Masuzaki R, Moriyama M, Omata M. Molecular mechanisms: Connections between nonalcoholic fatty liver disease, steatohepatitis and hepatocellular carcinoma. Int J Mol Sci. 2020;21(4):1525. https://doi.org/10.3390/ijms21... PMid:32102237 PMCid:PMC7073210.
Xu M, Li Y, Zhang S, Wang X, Shen J, Zhang S. Interaction of TM6SF2 E167K and PNPLA3 I148M variants in NAFLD in northeast China. Ann Hepatol. 2019;18(3):456-60. https://doi.org/10.1016/j.aohe... PMid:31054977.
Trépo E, Romeo S, Zucman-Rossi J, Nahon P. PNPLA3 gene in liver diseases. J Hepatol. 2016;65(2):399-412. https://doi.org/10.1016/j.jhep... PMid:27038645.
Salari N, Darvishi N, Mansouri K, Ghasemi H, Hosseinian-Far M, Darvishi F, et al. Association between PNPLA3 rs738409 polymorphism and nonalcoholic fatty liver disease: A systematic review and meta-analysis. BMC Endocr Disord. 2021;21(1):125. https://doi.org/10.1186/s12902... PMid:34147109 PMCid:PMC8214766.
Mazo DF, Malta FM, Stefano JT, Salles AP, Gomes-Gouvea MS, Nastri AC, et al. Validation of PNPLA3 polymorphisms as risk factor for NAFLD and liver fibrosis in an admixed population. Ann Hepatol. 2019;18(3):466-71. https://doi.org/10.1016/j.aohe... PMid:31054980.
Lisboa QC, Nardelli MJ, de Araújo Pereira P, Miranda DM, Ribeiro SN, Costa RS, et al. PNPLA3 and TM6SF2 polymorphisms in Brazilian patients with nonalcoholic fatty liver disease. World J Hepatol. 2020; 12(10):792-806. https://doi.org/10.4254/wjh.v1... PMid:33200017 PMCid:PMC7643213.
Lang S, Martin A, Zhang X, Farowski F, Wisplinghoff H, Vehreschild M, et al. Combined analysis of gut microbiota, diet and pnpla3 polymorphism in biopsy-proven non-alcoholic fatty liver disease. Liver Int. 2021;41(7):1576-91. https://doi.org/10.1111/liv.14... PMid:33896117 PMCid:PMC8947846.
Monga Kravetz A, Testerman T, Galuppo B, Graf J, Pierpont B, Siebel S, Richard Feinn, et al. Effect of gut microbiota and PNPLA3 rs738409 variant on nonalcoholic fatty liver disease (NAFLD) in obese youth. J Clin Endocrinol Metab. 2020;105(10):e3575-85. https://doi.org/10.1210/clinem... PMid:32561908 PMCid:PMC7458486.
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