Association of Common Variants of FGF21 Gene Polymorphism Rs499765 and Rs838133 with Type 2 Diabetes Mellitus in Iraqi Population

Authors

  • Majid Kadhum Hussain
  • Abdulhusein A. F. Algenabi
  • Thakra Al-Kashwan
  • Rasha Mohamed Abood

Abstract

SUMMERY  Background: Type 2 diabetes mellitus is a major public health issue. FGF21 is a key endocrine regulating protein factor involved in ontogenesis and metabolism.  Aim: To assess the association of FGF21 gene polymorphism (rs499765 and rs838133) in Iraqi type 2 diabetic patients.  Methods: To assess the relationship between SNPs (rs499765 and rs838133) of the FGF21 gene and T2DM, a case-control study of 200 people (100 T2DM and 100 controls) was undertaken. Tetra ARMS-PCR was used to genotype SNPs (rs499765 and rs838133) using specified primers after extracting DNA from blood. Various statistical analyses were used to analyze the results. Results: The differences in total cholesterol, VLDL, TG and HDL between healthy and diabetic groups are significant. Genotyping of FGF21 gene for rs838133 SNP revealed a significant elevation of the number of the AC carriers in the patient's group versus the controls group under the co-dominant model, the dominant model and the over dominant were significantly increased the risk of T2DM by 1.91, 1.8 and 1.94 folds (OR=1.91, P=0.0320), (OR=1.87, P=0.037) and (OR=1.94, P=0.0270) respectively. The analysis of the rs499765 SNP failed to exhibit a significant variation under all examined inheritance models.   Conclusion: Carriers of the AC genotype of rs838133 SNP in FGF21 gene have a 1.9 folds risk to develop T2DM in comparison to those of the wild genotype, rs499765 (C>G), is not linked to the T2DM in the Iraqi population.

References

- Anon. 2020. “A Polymorphism in the FGF21 Gene Is a Novel Risk Variant for Metabolic-Associated Steatohepatitis Asmaa Elsayed A Thesis Submitted in Fulfilment of the Requirements for the Degree of Master of Philosophy School of Medicine January 2020.” (January).

- Baynest, Habtamu Wondifraw. 2015. “Classification, Pathophysiology, Diagnosis and Management of Diabetes Mellitus.” Journal of Diabetes & Metabolism 06(05). doi: 10.4172/2155-6156.1000541.

- Berglund ED, Kang L, Lee-Young RS, Hasenour CM, Lustig DG, Lynes SE. et al. Glucagon and lipid interactions in the regulation of hepatic AMPK signaling and expression of PPARalpha and FGF21 transcripts in vivo. American journal of physiology Endocrinology and metabolism. 2010;299:E607-14.

- Chatterjee, Sudesna, Kamlesh Khunti, and Melanie J. Davies. 2017. “Type 2 Diabetes.” The Lancet 389(10085):2239–51. doi: 10.1016/S0140-6736(17)30058-2.

- Chu, Audrey Y., Tsegaselassie Workalemahu, Nina P. Paynter, Lynda M. Rose, Franco Giulianini, Toshiko Tanaka, Julius S. Ngwa, Qibin Qi, Gary C. Curhan, Eric B. Rimm, David J. Hunter, Louis R. Pasquale, Paul M. Ridker, Frank B. Hu, Daniel I. Chasman, and Lu Qi. 2013. “Novel Locus Including FGF21 Is Associated with Dietary Macronutrient Intake.” Human Molecular Genetics 22(9):1895–1902. doi: 10.1093/hmg/ddt032.

- Ellis PD. The Essential Guide to Effect Sizes: An Introduction to Statistical Power, Meta-Analysis, and the Interpretation of Research Results. Cambridge University Press, Cambridge. 2010.

- Engineering, Forestry, and Herbivorous Animal Biotechnology. 2021. “FGF21 Polymorphisms of FGF21 Gene and Their Association Analysis with Growth and Carcass Traits in Ovine ( Ovis Arise ) with Different Genders.” 29(02):298–306. doi: 10.3969/j.issn.1674-7968.2021.02.010.

- Epperlein, S.; Gebhardt, C.; Rohde, K.; Chakaroun, R.; Patt, M.; Schamarek, I.; Kralisch, S.; Heiker, J.T.; Scholz, M.; Stumvoll, M.; et al. The Effect of FGF21 and Its Genetic Variants on Food and Drug Cravings, Adipokines and Metabolic Traits. Biomedicines 2021, 9, 345. https:// doi.org/10.3390/biomedicines9040345.

- EVANS, D. M. & PURCELL, S. 2012. Power calculations in genetic studies. Cold Spring Harb Protoc, 2012, 664-74.

- Frayling, Timothy M., Robin N. Beaumont, Samuel E. Jones, Hanieh Yaghootkar, Marcus A. Tuke, Katherine S. Ruth, Francesco Casanova, Ben West, Jonathan Locke, Seth Sharp, Yingjie Ji, William Thompson, Jamie Harrison, Cecilia M. Lindgren, Niels Grarup, Anna Murray, Rachel M. Freathy, Michael N. Weedon, Jessica Tyrrell, and Andrew R. Wood. 2017. “A Common Allele in FGF21 Associated with Preference for Sugar Consumption Lowers Body Fat in the Lower Body and Increases Blood Pressure.” BioRxiv. doi: 10.1101/214700.

- Hazra, A., Kraft, P., Selhub, J., Giovannucci, E.L., Thomas, G., Hoover, R.N., Chanock, S.J., and Hunter, D.J. (2008). Common variants of FUT2 are associ- ated with plasma vitamin B12 levels. Nat. Genet. 40, 1160–1162.

- International Diabetes Federation. Diabetes Atlas; International Diabetes Federation: Brussels, Belgium, 2019, 9th ed. p. 167. Available online: https://www.diabetesatlas.org/en/resources accessed on 27 July 2020).

- Jiang, Shan, Rong Zhang, Huating Li, Qichen Fang, Feng Jiang, Xuhong Hou, Cheng Hu, and Weiping Jia. 2014. “The Single Nucleotide Polymorphism Rs499765 Is Associated with Fibroblast Growth Factor 21 and Nonalcoholic Fatty Liver Disease in a Chinese Population with Normal Glucose Tolerance.” Journal of Nutrigenetics and Nutrigenomics 7(3):121–29. doi: 10.1159/000367943.

- Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, Sandusky GE, Hammond LJ, Moyers JS, Owens RA, et al. FGF-21 as a novel metabolic regulator. J Clin Invest. 2005;115:1627–1635. doi: 10.1172/JCI23606.

- Kralisch S, Fasshauer M. Fibroblast growth factor 21: effects on carbohydrate and lipid metabolism in health and disease. Curr Opin

Clin Nutr Metab Care 2011; 14(4):354-359.

- Laeger T, Albarado DC, Burke SJ et al (2016) Metabolic responses to dietary protein restriction require an increase in FGF21 that is delayed by the absence ofGCN2. Cell Rep 16:707–716.

- Laeger T, Henagan TM, Albarado DC et al (2014) FGF21 is an endocrine signal ofprotein restriction. J Clin Invest 124:3913–39224.

- McCarthy, Mark I. 2010. “Genomics, Type 2 Diabetes, and Obesity.” New England Journal of Medicine 363(24):2339–50. doi: 10.1056/nejmra0906948.

- Nishimura T, Nakatake Y, Konishi M, Itoh N. Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochim Biophys Acta 2000;1492:203–6.

- Saber-Ayad, Maha, Sarah Hammoudeh, Hadia Radwan, Shaista Manzoor, Hussein Jabbar, Rahaf Wardeh, Ahmed Ashraf, Peter Habib, Alsamman M. Alsamman, and Rifat Hamoudi. 2020. “The FGF-21 Genetic Variants Rs838133 and Rs838145 Are Associated with High Salt Intake in the Emirati Population.” Journal of Advanced Research 24(July):485–94. doi: 10.1016/j.jare.2020.05.020.

- Semba RD, Sun K, Egan JM, Crasto C, Carlson OD, Ferrucci L. Relationship of serum fibroblast growth factor 21 with abnormal glucose metabolism and insulin resistance: the Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2012; 97(4):1375-1382.

- Schnermann, J. 2015. One physiology does not fit all: a path from data variability to "physiogenetics"? Am J Physiol Renal Physiol, 309, F29-32.

- Schumann G,.KLB is associated with alcohol drinking, and its gene product b-Klotho is necessary for FGF21 regulation of alcohol preference. Proc Natl Acad Sci USA. 2016;113(50):14372–14377.

- Søberg, S.; Sandholt, C.H.; Jespersen, N.Z.; Toft, U.; Madsen, A.L.; von Holstein-Rathlou, S.; Grevengoed, T.J.; Christensen, K.B.; Bredie, W.L.P.P.; Potthoff, M.J.; et al. FGF21 Is a Sugar-Induced Hormone Associated with Sweet Intake and Preference in Humans. Cell Metab. 2017, 25, 1045–1053.e6.

- Talukdar, S., et al., A Long-Acting FGF21 Molecule, PF-05231023, Decreases Body Weight and Improves Lipid Profile in Non-human Primates and Type 2 Diabetic Subjects. Cell Metab, 2016. 23(3): p. 427-40.

- Tanaka, T., et al., Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake. Am J Clin Nutr, 2013. 97(6): p. 1395- 402.

- von Holstein-Rathlou, S.; BonDurant, L.D.; Peltekian, L.; Naber, M.C.; Yin, T.C.; Claflin, K.E.; Urizar, A.I.; Madsen, A.N.; Ratner, C.; Holst, B.; et al. FGF21 Mediates Endocrine Control of Simple Sugar Intake and Sweet Taste Preference by the Liver. Cell Metab. 2016, 23, 335–343.

- Y. Panahi1, S. Bonakdaran2, M.A. Yaghoubi.,et al .(2016). Serum levels of fibroblast growth factor 21 in type 2 diabetic patients. General Endocrinology. 10.4183/aeb.2016.257.

- Yu, Weihui, Hong Zhu, Xiong Chen, Xuejiang Gu, Xingxing Zhang, Feixia Shen, Weiping Jia, and Cheng Hu. 2019. “Genetic Variants Flanking the FGF21 Gene Were Associated with Renal Function in Chinese Patients with Type 2 Diabetes.” Journal of Diabetes Research 2019. doi: 10.1155/2019/9387358.

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2022-04-24

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