The FTO, PNPLA3 and TM6SF2 Gene Polymorphisms and Genetic Predisposition to NAFLD in Yakut Population

Aleksandra T. Diakonova, Khariton A. Kurtanov, Nadezhda I. Pavlova, Tuyara N. Aleksandrova

 
International Journal of Biomedicine. 2021;11(1):92-95.
DOI: 10.21103/Article11(1)_OA16
Originally published March 5, 2021

Abstract: 

The aim of our research was to study the distribution of alleles and genotypes of the FTO rs9939609 SNP, the PNPLA3 rs738409 SNP, and the TM6SF2 rs58542926 SNP in the Yakut population.
Methods and Results: A total of 85 DNA samples from the population were tested. An analysis of the frequency distribution of alleles and genotypes of the FTO rs9939609 SNP in the study group did not reveal significant differences. An analysis of the frequency distribution of alleles and genotypes of the PNPLA3 rs738409 SNP revealed that in men and women the G allele and the homozygous GG genotype prevailed. The results of the analysis of the frequency distribution of alleles and genotypes of the TM6SF2 rs58542926 SNP showed the predominance of individuals with the C allele (89% in men and 90% in women) with statistical significance in women.
Conclusion: The further studies with a larger sample size are required to detect the features of the distribution of alleles and genotypes of the FTO rs9939609 SNP and the TM6SF2 rs58542926 SNP in that population.

Keywords: 
nonalcoholic fatty liver disease • single nucleotide polymorphism • genome-wide association study • Yakuts
References: 
  1. Kumar A, Shalimar, Walia GK, Gupta V, Sachdeva MP. Genetics of nonalcoholic fatty liver disease in Asian populations. J Genet. 2019 Mar;98:29. PMID: 30945694.
  2. Bellentani S, Scaglioni F, Marino M, Bedogni G. Epidemiology of non-alcoholic fatty liver disease. Dig Dis. 2010;28(1):155-61. doi: 10.1159/000282080. 
  3. Blachier M, Leleu H, Peck-Radosavljevic M, Valla DC, Roudot-Thoraval F. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol. 2013 Mar;58(3):593-608. doi: 10.1016/j.jhep.2012.12.005. 
  4. Kawaguchi T, Sumida Y, Umemura A, Matsuo K, Takahashi M, Takamura T, Yasui K, Saibara T, Hashimoto E, Kawanaka M, Watanabe S, Kawata S, Imai Y, Kokubo M, Shima T, Park H, Tanaka H, Tajima K, Yamada R, Matsuda F, Okanoue T; Japan Study Group of Nonalcoholic Fatty Liver Disease. Genetic polymorphisms of the human PNPLA3 gene are strongly associated with severity of non-alcoholic fatty liver disease in Japanese. PLoS One. 2012;7(6):e38322. doi: 10.1371/journal.pone.0038322. 
  5. Amarapurkar D, Kamani P, Patel N, Gupte P, Kumar P, Agal S, Baijal R, Lala S, Chaudhary D, Deshpande A. Prevalence of non-alcoholic fatty liver disease: population based study. Ann Hepatol. 2007 Jul-Sep;6(3):161-3. PMID: 17786142.
  6. Gu Z, Bi Y, Yuan F, Wang R, Li D, Wang J, Hu X, He G, Zhang L, Liu BC. FTO Polymorphisms are Associated with Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) Susceptibility in the Older Chinese Han Population. Clin Interv Aging. 2020 Aug 11;15:1333-1341. doi: 10.2147/CIA.S254740.
  7. Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J, Najjar S, Nagaraja R, Orrú M, Usala G, Dei M, Lai S, Maschio A, Busonero F, Mulas A, Ehret GB, Fink AA, Weder AB, Cooper RS, Galan P, Chakravarti A, Schlessinger D, Cao A, Lakatta E, Abecasis GR. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet. 2007 Jul;3(7):e115. doi: 10.1371/journal.pgen.0030115. 
  8. Andreasen CH, Stender-Petersen KL, Mogensen MS, Torekov SS, Wegner L, Andersen G, Nielsen AL, Albrechtsen A, Borch-Johnsen K, Rasmussen SS, Clausen JO, Sandbaek A, Lauritzen T, Hansen L, Jørgensen T, Pedersen O, Hansen T. Low physical activity accentuates the effect of the FTO rs9939609 polymorphism on body fat accumulation. Diabetes. 2008 Jan;57(1):95-101. doi: 10.2337/db07-0910. 
  9. Do R, Bailey SD, Desbiens K, Belisle A, Montpetit A, Bouchard C, Pérusse L, Vohl MC, Engert JC. Genetic variants of FTO influence adiposity, insulin sensitivity, leptin levels, and resting metabolic rate in the Quebec Family Study. Diabetes. 2008 Apr;57(4):1147-50. doi: 10.2337/db07-1267. 
  10. Grant SF, Li M, Bradfield JP, Kim CE, Annaiah K, Santa E, Glessner JT, Casalunovo T, Frackelton EC, Otieno FG, Shaner JL, Smith RM, Imielinski M, Eckert AW, Chiavacci RM, Berkowitz RI, Hakonarson H. Association analysis of the FTO gene with obesity in children of Caucasian and African ancestry reveals a common tagging SNP. PLoS One. 2008 Mar 12;3(3):e1746. doi: 10.1371/journal.pone.0001746. 
  11. Hinney A, Nguyen TT, Scherag A, Friedel S, Brönner G, Müller TD, Grallert H, Illig T, Wichmann HE, Rief W, Schäfer H, Hebebrand J. Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants. PLoS One. 2007 Dec 26;2(12):e1361. doi: 10.1371/journal.pone.0001361. 
  12. Hubacek JA, Bohuslavova R, Kuthanova L, Kubinova R, Peasey A, Pikhart H, Marmot MG, Bobak M. The FTO gene and obesity in a large Eastern European population sample: the HAPIEE study. Obesity (Silver Spring). 2008 Dec;16(12):2764-6. doi: 10.1038/oby.2008.421. 
  13. Hunt SC, Stone S, Xin Y, Scherer CA, Magness CL, Iadonato SP, Hopkins PN, Adams TD. Association of the FTO gene with BMI. Obesity (Silver Spring). 2008 Apr;16(4):902-4. doi: 10.1038/oby.2007.126. 
  14. Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V, Hewitson KS, Yeo GS, McDonough MA, Cunliffe S, McNeill LA, Galvanovskis J, Rorsman P, Robins P, Prieur X, Coll AP, Ma M, Jovanovic Z, Farooqi IS, Sedgwick B, Barroso I, Lindahl T, Ponting CP, Ashcroft FM, O'Rahilly S, Schofield CJ. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science. 2007 Nov 30;318(5855):1469-72. doi: 10.1126/science.1151710. 
  15. Speakman JR, Rance KA, Johnstone AM. Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure. Obesity (Silver Spring). 2008 Aug;16(8):1961-5. doi: 10.1038/oby.2008.318. Epub 2008 Jun 12. 
  16. Wardle J, Llewellyn C, Sanderson S, Plomin R. The FTO gene and measured food intake in children. Int J Obes (Lond). 2009 Jan;33(1):42-5. doi: 10.1038/ijo.2008.174.
  17. den Hoed M, Westerterp-Plantenga MS, Bouwman FG, Mariman EC, Westerterp KR. Postprandial responses in hunger and satiety are associated with the rs9939609 single nucleotide polymorphism in FTO. Am J Clin Nutr. 2009 Nov;90(5):1426-32. doi: 10.3945/ajcn.2009.28053. 
  18. Tanofsky-Kraff M, Han JC, Anandalingam K, Shomaker LB, Columbo KM, Wolkoff LE, Kozlosky M, Elliott C, Ranzenhofer LM, Roza CA, Yanovski SZ, Yanovski JA. The FTO gene rs9939609 obesity-risk allele and loss of control over eating. Am J Clin Nutr. 2009 Dec;90(6):1483-8. doi: 10.3945/ajcn.2009.28439. 
  19. Cecil JE, Tavendale R, Watt P, Hetherington MM, Palmer CN. An obesity-associated FTO gene variant and increased energy intake in children. N Engl J Med. 2008 Dec 11;359(24):2558-66. doi: 10.1056/NEJMoa0803839.
  20. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, Cohen JC, Hobbs HH. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008 Dec;40(12):1461-5. doi: 10.1038/ng.257. 
  21. Xu R, Tao A, Zhang S, Deng Y, Chen G. Association between patatin-like phospholipase domain containing 3 gene (PNPLA3) polymorphisms and nonalcoholic fatty liver disease: a HuGE review and meta-analysis. Sci Rep. 2015 Mar 20;5:9284. doi: 10.1038/srep09284.
  22. He S, McPhaul C, Li JZ, Garuti R, Kinch L, Grishin NV, Cohen JC, Hobbs HH. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem. 2010 Feb 26;285(9):6706-15. doi: 10.1074/jbc.M109.064501. 
  23. Pirazzi C, Adiels M, Burza MA, Mancina RM, Levin M, Ståhlman M, Taskinen MR, Orho-Melander M, Perman J, Pujia A, Andersson L, Maglio C, Montalcini T, Wiklund O, Borén J, Romeo S. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J Hepatol. 2012 Dec;57(6):1276-82. doi: 10.1016/j.jhep.2012.07.030. 
  24. Petit JM, Guiu B, Masson D, Duvillard L, Jooste V, Buffier P, Terriat B, Bouillet B, Brindisi MC, Loffroy R, Robin I, Hillon P, Cercueil JP, Verges B. Specifically PNPLA3-mediated accumulation of liver fat in obese patients with type 2 diabetes. J Clin Endocrinol Metab. 2010 Dec;95(12):E430-6. doi: 10.1210/jc.2010-0814. 
  25. Cox AJ, Wing MR, Carr JJ, Hightower RC, Smith SC, Xu J, Wagenknecht LE, Bowden DW, Freedman BI. Association of PNPLA3 SNP rs738409 with liver density in African Americans with type 2 diabetes mellitus. Diabetes Metab. 2011 Nov;37(5):452-5. doi: 10.1016/j.diabet.2011.05.001. 
  26. Dongiovanni P, Donati B, Fares R, Lombardi R, Mancina RM, Romeo S, Valenti L. PNPLA3 I148M polymorphism and progressive liver disease. World J Gastroenterol. 2013 Nov 7;19(41):6969-78. doi: 10.3748/wjg.v19.i41.6969. 
  27. Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH, Tybjærg-Hansen A, Vogt TF, Hobbs HH, Cohen JC. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2014 Apr;46(4):352-6. doi: 10.1038/ng.2901. 
  28. Chen LZ, Xia HH, Xin YN, Lin ZH, Xuan SY. TM6SF2 E167K Variant, a Novel Genetic Susceptibility Variant, Contributing to Nonalcoholic Fatty Liver Disease. J Clin Transl Hepatol. 2015 Dec 28;3(4):265-70. doi: 10.14218/JCTH.2015.00023. 
  29. Li Y, Liu S, Gao Y, Ma H, Zhan S, Yang Y, Xin Y, Xuan S. Association of TM6SF2 rs58542926 gene polymorphism with the risk of non-alcoholic fatty liver disease and colorectal adenoma in Chinese Han population. BMC Biochem. 2019 Feb 6;20(1):3. doi: 10.1186/s12858-019-0106-3. 
  30. Kurtanov KA, Sydykova LA, Pavlova NI, Filippova NP, Dodokhov VV, Apsolikhova GA, Solov'eva NA, D'yakonova AT, Neustroeva LM, Varlamova MA, Borisova NV. [Polymorphism of the adiponutrin gene (PNPLA3) in the indigenous inhabitants of the Republic of Sakha (Yakutia) with type 2 diabetes mellitus]. Almanac of Clinical Medicine. 2018;46 (3):258-263. doi: 10.18786/2072-0505-2018-46-3-258-263. [Article in Russian].
  31. Kurtanov KA, Pavlova NI, Diakonova AT, Sydykova LA, Aleksandrova TN, Borisova YP, Dodokhov VV. The structure of Haplotypes and Diplotypes in the PNPLA3 gene in the Yakut Population International Journal of Biomedicine. 2020; 10(4):433-437.

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Received October 31, 2020.
Accepted February 21, 2021.
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