A review was carried out to check where IL6–174G/Cgene polymorphisms is associated with NAFLD and number of studies were reviewed and found that the 174C genotype is almost absent in African and Asian populations where as it appears that the majority of Asian populations carry the GG genotypes, ranging from 75.0 to 100.0%, whereas Caucasians in the West had a higher frequency of CC genotypes, ranging from 18.0 to 32.0% and it was found that IL-6 –174C polymorphism is associated NAFLD and can be used as a predictor for the metabolic abnormalities in NAFLD and possible progression of the disease and IL6 gene polymorphism could be helpful in identifying individuals at increased risk for developing NAFLD in obese adolescents.

1. Bradbury, M.W. and P.D. Berk, Lipid metabolism in hepatic steatosis. Clinics in Liver Disease, 2004. 8(3): p. 639-671.
2. Sanyal, A.J., et al., Nonalcoholic steatohepatitis: Association of insulin resistance and mitochondrial abnormalities. Gastroenterology, 2001. 120(5): p. 1183-1192.
3. Duvnjak M, T.V., Gomercic M, Duvnjak S, Barsic N, Lerotic I. T, herapy of nonalcoholic fatty liver disease: current status. ;:. J PhysiolPharmaco, 2009. l( 7): p. 57-66.
4. DAN L. DUMITRASCU, M.G.N., NON-ALCOHOLIC FATTY LIVER DISEASE: AN UPDATE ON DIAGNOSIS DOI: 10.15386/cjmed-993, 2018.
5. Arianoff, A.A., E.H. Henrard, and A. van Dessel, R�le et signification du reflux wirsungien dans les pancr�atites recurrentes, in Topical Problems in Pancreatitis, S. Karger AG. p. 105-108.
6. Gariani K, P.J.J.F., Non-alcoholic fatty liver disease and insulin resistance: from bench to bedside. . Diabetes &Metabolism 2013. 39: p. 16-26
7. Chen, S.H., et al., Relationship between nonalcoholic fatty liver disease and metabolic syndrome. Journal of Digestive Diseases. 12(2): p. 125-130.
8. MancoM, B.G., DeVito R, Marcellini M, Mingrone G, NobiliV., Nonalcoholic fatty liver disease in children. j Am Coll Nutr., 2008. 27: p. 667-676.
9. Trombata M, S.G., Zoppini G. Muggeo M. , type 2 diabetes and chronic liver disease in the Verona diabetes study. Aliment pharmaocol Ther, 2005. 22(2): p. 24-7.
10. Falck-Ytter, Y., et al., Clinical Features and Natural History of Nonalcoholic Steatosis Syndromes. Seminars in Liver Disease, 2001. 21(01): p. 017-026.
11. Hill, D.L.B., L.S. Marsano, and C.J. McClain, Increased plasma interleukin-8 concentrations in alcoholic hepatitis. Hepatology, 1993. 18(3): p. 576-580.
12. Kugelmas, M., Cytokines and NASH: A pilot study of the effects of lifestyle modification and vitamin E. Hepatology, 2003. 38(2): p. 413-419.
13. Day, C.P. and O.F.W. James, Steatohepatitis: A tale of two “hits”? Gastroenterology, 1998. 114(4): p. 842-845.
14. Sutterwala, F.S., Y. Ogura, and R.A. Flavell, The inflammasome in pathogen recognition and inflammation. Journal of Leukocyte Biology, 2007. 82(2): p. 259-264.
15. Martinon, F., K. Burns, and J.r. Tschopp, The Inflammasome. Molecular Cell, 2002. 10(2): p. 417-426.
16. Agostini, L., et al., NALP3 Forms an IL-1β-Processing Inflammasome with Increased Activity in Muckle-Wells Autoinflammatory Disorder. Immunity, 2004. 20(3): p. 319-325.
17. Zhou, R., et al., A role for mitochondria in NLRP3 inflammasome activation. 469(7329): p. 221-225.
18. Wong, V.W.S., et al., Metabolic and Adipokine Profile of Chinese Patients With Nonalcoholic Fatty Liver Disease. Clinical Gastroenterology and Hepatology, 2006. 4(9): p. 1154-1161.
19. Amal Ahmed Mohamed, W.G.S., Olfat Shaker,Mohamed El-Sayed Mahdy, Eman M. A. Ibrahim, Seham Mohmoud and Ahmed khairalla, Role of Serum Adiponectin, IL-6 and Hs CRP in Nonalcoholic Fatty Liver Egyptian Patients. International Journal of Biochemistry Research & Review, 4, 2014. 4 ((6):): p. 493-50.
20. Tsochatzis, E.A., et al., Insulin resistance and metabolic syndrome in chronic liver diseases: Old entities with new implications. Scandinavian Journal of Gastroenterology, 2009. 44(1): p. 6-14.
21. Bugianesi, E., et al., Plasma Adiponectin in Nonalcoholic Fatty Liver Is Related to Hepatic Insulin Resistance and Hepatic Fat Content, Not to Liver Disease Severity. The Journal of Clinical Endocrinology & Metabolism, 2005. 90(6): p. 3498-3504.
22. Yoon, D., et al., Hypoadiponectinemia and Insulin Resistance are Associated with Nonalcoholic Fatty Liver Disease. Journal of Korean Medical Science, 2005. 20(3): p. 421.
23. Hui JM, H.A., Farrell GC, Kench JG, Kriketos A, George J. , Beyond insulin resistance in NASH: TNF-alpha or adiponectin? . Hepatology, 2004. 40:: p. 46-54.
24. Polyzos, S., J. Kountouras, and C. Zavos, Nonalcoholic Fatty Liver Disease: The Pathogenetic Roles of Insulin Resistance and Adipocytokines. Current Molecular Medicine, 2009. 9(3): p. 299-314.
25. Chang, Y.-H., et al., Association of Interleukin-10 A-592C and T-819C Polymorphisms with Type 2 Diabetes Mellitus. Human Immunology, 2005. 66(12): p. 1258-1263.
26. I, P.J., nflammation and activated innate immunity in the pathogenesis of type 2 diabetes. . Diabetes Care, 2004. 27: p. 813- 823, .
27. Schmidt MI, D.B., Sharrett AR, Lindberg G, Savage PJ, Offenbacher S, Azambuja MI, Tracy RP, Heiss G: , Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study. . Lancet 1999. 353: p. 1649-1652,.
28. Festa A, D.A.R., Tracy RP, Haffner SM: , Elevated levels of acute-phase proteins and plasminogen activator inhibitor- 1 predict the development of type 2 diabetes: the Insulin Resistance Atherosclerosis Study. . Diabetes, 2001. 51: p. 1131-1137.
29. Kopp HP, K.C., Festa A, Krzyzanowska K, Kriwanek S, Minar E, Roka R, Schernthaner G., Impact of weight loss on inflammatory proteins and their association with the insulin resistance syndrome in morbidly obese patients. l Arterioscler Thromb Vasc Bio, 2003. 23(1042-1047).
30. Cai, D., et al., Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB. Nature Medicine, 2005. 11(2): p. 183-190.
31. Hill, D.B., et al., Increased monocyte nuclear factor-κB activation and tumor necrosis factor production in alcoholic hepatitis. Journal of Laboratory and Clinical Medicine, 2000. 135(5): p. 387-395.
32. McClain, C., et al., Cytokines in Alcoholic Liver Disease. Seminars in Liver Disease, 1999. 19(02): p. 205-219.
33. Kishimoto, T., IL-6: from its discovery to clinical applications. International Immunology. 22(5): p. 347-352.
34. Heinrich, P.C., et al., Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochemical Journal, 2003. 374(1): p. 1-20.
35. Yudkin, J.S., et al., Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis, 2000. 148(2): p. 209-214.
36. Wree, A., et al., Obesity Affects the Liver – The Link between Adipocytes and Hepatocytes. 83(1-2): p. 124-133.
37. Terry, C.F., V. Loukaci, and F.R. Green, Cooperative Influence of Genetic Polymorphisms on Interleukin 6 Transcriptional Regulation. Journal of Biological Chemistry, 2000. 275(24): p. 18138-18144.
38. Franceschi, C., et al., Genes involved in immune response/inflammation, IGF1/ insulin pathway and response to oxidative stress play a major role in the genetics of human longevity: the lesson of centenarians. Mechanisms of Ageing and Development, 2005. 126(2): p. 351-361.
39. Nakagawa, H., et al., Serum IL-6 levels and the risk for hepatocarcinogenesis in chronic hepatitis C patients: An analysis based on gender differences. International Journal of Cancer, 2009. 125(10): p. 2264-2269.
40. Wong, V.W.-S., et al., High serum interleukin-6 level predicts future hepatocellular carcinoma development in patients with chronic hepatitis B. International Journal of Cancer, 2009. 124(12): p. 2766-2770.
41. Cressman, D.E., et al., Liver Failure and Defective Hepatocyte Regeneration in Interleukin-6-Deficient Mice. Science, 1996. 274(5291): p. 1379-1383.
42. Zimmers, T., Massive liver growth in mice induced by systemic interleukin 6 administration. Hepatology, 2003. 38(2): p. 326-334.
43. Peters, M., et al., Combined interleukin 6 and soluble interleukin 6 receptor accelerates murine liver regeneration. Gastroenterology, 2000. 119(6): p. 1663-1671.
44. Selzner, M., C.A. Camargo, and P.-A. Clavien, Ischemia impairs liver regeneration after major tissue loss in rodents: Protective effects of interleukin-6. Hepatology, 1999. 30(2): p. 469-475.
45. Camargo, C.A., et al., Interleukin-6 protects liver against warm ischemia/reperfusion injury and promotes hepatocyte proliferation in the rodent. Hepatology, 1997. 26(6): p. 1513-1520.
46. Kovalovich, K., et al., Interleukin-6 Protects against Fas-mediated Death by Establishing a Critical Level of Anti-apoptotic Hepatic Proteins FLIP, Bcl-2, and Bcl-xL. Journal of Biological Chemistry, 2001. 276(28): p. 26605-26613.
47. Streetz, K., Interleukin 6/gp130-dependent pathways are protective during chronic liver diseases. Hepatology, 2003. 38(1): p. 218-229.
48. Blindenbacher, A., Interleukin 6 is important for survival after partial hepatectomy in mice. Hepatology, 2003. 38(3): p. 674-682.
49. Hong, F., et al., Opposing roles of STAT1 and STAT3 in T cell–mediated hepatitis: regulation by SOCS. Journal of Clinical Investigation, 2002. 110(10): p. 1503-1513.
50. Wieckowska A, P.B., Li Z, Lopez R, Zein NN, Feldstein AE., Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. . Am J Gastroenterol, 2008. 103:: p. 1372-1379.
51. Carulli, L., et al., Genetic polymorphisms in non-alcoholic fatty liver disease: Interleukin-6−174G/C polymorphism is associated with non-alcoholic steatohepatitis. Digestive and Liver Disease, 2009. 41(11): p. 823-828.
52. Fernández-Real, J.-M., et al., Interleukin-6 Gene Polymorphism and Lipid Abnormalities in Healthy Subjects. The Journal of Clinical Endocrinology & Metabolism, 2000. 85(3): p. 1334-1339.
53. Hamid, Y.H., et al., Variations of the interleukin-6 promoter are associated with features of the metabolic syndrome in Caucasian Danes. Diabetologia, 2005. 48(2): p. 251-260.
54. Cardellini, M., et al., C-174G Polymorphism in the Promoter of the Interleukin-6 Gene Is Associated With Insulin Resistance. Diabetes Care, 2005. 28(8): p. 2007-2012.
55. Mustafa Cengiz , D.G.Y., Mehmet Ali Ergun,Gulen Akyol,Seren Ozenirler The Role of Interleukin-6 and Interleukin-8 Gene Polymorphisms in Non-Alcoholic Steatohepatitis. Hepat Mon, 2014. 14(12): p. 24635.
56. Nozaki, Y., et al., Polymorphisms of Interleukin-1beta and beta3-Adrenergic Receptor in Japanese Patients With Nonalcoholic Steatohepatitis. Alcoholism: Clinical and Experimental Research, 2004. 28(s2): p. 106S-110S.
57. Falleti, E., et al., Genetic polymorphisms of interleukin-6 modulate fibrosis progression in mild chronic hepatitis C. Human Immunology. 71(10): p. 999-1004.
58. Yang, Y.-G., et al., Clinical significance of serum Cathepsin S in patients with hepatocellular carcinoma. World Chinese Journal of Digestology. 21(33): p. 3742.
59. Wolford, J.K., et al., Erratum to “A C-reactive protein promoter polymorphism is associated with type 2 diabetes mellitus in Pima Indians” [Mol. Genet. Metab. 78 (2003) 136–144]. Molecular Genetics and Metabolism, 2003. 79(3): p. 231.
60. Goyenechea, E., D. Parra, and J.A. Martínez, Impact of interleukin 6 −174G>C polymorphism on obesity-related metabolic disorders in people with excess in body weight. Metabolism, 2007. 56(12): p. 1643-1648.
61. Meenagh, A., et al., Frequency of cytokine polymorphisms in populations from western Europe, Africa, Asia, the Middle East and South America. Human Immunology, 2002. 63(11): p. 1055-1061.
62. Riikola, A., et al., Interleukin-6 promoter polymorphism and cardiovascular risk factors: The Health 2000 Survey. Atherosclerosis, 2009. 207(2): p. 466-470.
63. Mendoza-Carrera, F., et al., Influence of CRP, IL6, and TNFA Gene Polymorphisms on Circulating Levels of C-Reactive Protein in Mexican Adolescents. Archives of Medical Research. 41(6): p. 472-477.
64. Gonzalez-Galarza, F.F., et al., Allele frequency net: a database and online repository for immune gene frequencies in worldwide populations. Nucleic Acids Research. 39(Database): p. D913-D919.
65. Nádia Duarte, I.C.C., Rita S. Patarrão, Joana I. Almeida,Carlos Penha-Gonçalves, M. Paula Macedo, How Inflammation Impinges on NAFLD:A Role for Kupffer Cells. BioMed Research International, 2015: p. 11.
66. Fernández RJM, B.M., Vendrell J, Richart C, RicartW. , Interleukin-6 gene polymorphism and lipid abnormalitiesin healthy subjects. J ClinEndocrinolMetab, 2000. 85: p. 1334-1339.
67. Marcos M, P.I., González-Sarmiento R, Laso FJ., Common polymorphisms in interleukin genes (IL4, IL6, IL8 and IL12) are not associated with alcoholic liver disease or alcoholism in Spanish men. Cytokine 2009. 45: p. 158-161.
68. Fan LY, T.X., Zhu Y, Pfeiffer T, Feltens R, Stoecker W, Zhong RQ. , Genetic association of cytokines polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in the Chinese. . World J Gastroenterol, 2005. 11: p. 276.
69. Hong, F., et al., Elevated interleukin-6 during ethanol consumption acts as a potential endogenous protective cytokine against ethanol-induced apoptosis in the liver: involvement of induction of Bcl-2 and Bcl-xL proteins. Oncogene, 2002. 21(1): p. 32-43.
70. Haukeland JW, D.J., Konopski Z, Løberg EM, Haa¬land T, Goverud I, Torjesen PA, Birkeland K, Bjøro K, Auk¬rust P., Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2. . J Hepatol, 2006. 44: p. 1167-1174.
71. Moushira EZ, H.K.N., Wafaa Kandeela, Heba A. El-Maltb,Yasser El-Hossaryc,d, Ramy M. El-Sherbinia and Khalda Amrc, IL-6 - 174G/C polymorphism in obese adolescents with nonalcoholic fatty liver disease and its relation to metabolic and biochemical markers. Middle East Journal of Medical Genetics, 2016.

Syed Irtiza

Department of Biochemistry, Jamia Hamdard New Delhi