Abstract
Background
The objective of this study was to investigate the association of polymorphisms in four genes, tumor necrosis factor-α (TNFA), patatin-like phospholipase domain containing 3 (PNPLA3), adiponectin (ADIPOQ) and apolipoprotein C3 (APOC3), with obesity and non-alcoholic fatty liver disease (NAFLD) in Asian Indian adolescents.
Methods
In this case-control study, 218 Asian Indian adolescents with overweight/obesity and 86 lean healthy adults without fatty liver were enrolled. Hepatic steatosis was assessed and graded by ultrasonography (USG). Serum insulin, lipids, alanine aminotransferase (ALT), aspartate aminotransferase (AST), TNF-α, adiponectin and apolipoprotein C3 were measured and genotyping was done. Frequencies of variant and wild genotypes in all adolescents and in the subgroups without steatosis, with grade 1 steatosis and with grade 2 or 3 steatosis were compared to those in the controls. The frequencies were also compared in the overweight adolescents with grade 2 or 3 steatosis and without steatosis.
Results
Variant genotypes of polymorphisms −863 C > A and −1031 T > C of the TNFA gene, 455 T > C of the APOC3 gene and the wild type of +276 G > T of the ADIPOQ gene were associated with obesity with odds ratios (OR, 95% confidence interval [CI]) of 2.5 (1.5–4.4), 2.5 (1.5–4.2), 2.0 (1.1–3.6) and 2.5 (1.4–5.0), respectively. Polymorphisms 455 T > C of APOC3 and rs738409 C > G of PNPLA3 were associated with NAFLD. Fasting insulin and triglycerides (TG) were higher in the adolescents with homozygous variant polymorphisms −1031 T > C of TNFA and 455 T > C of APOC3 genes, respectively.
Conclusions
Several polymorphisms were noted to have a significant association with obesity and NAFLD in Asian Indian adolescents.
Acknowledgments
The help provided by Ms. Babita Upadhyaya, project dietician, in recruitment of subjects and controls is acknowledged.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission. VJ conceptualized and designed the study; AK, NA, OJ and BK conducted the genetic investigations; MK conducted the statistical analysis; SS and MK supervised the genetic investigations; MJ conducted the ultrasonography for all patients; and VJ and AK drafted the paper. All authors gave their critical inputs and approved the final manuscript. VJ will act as the guarantor.
Research funding: This study was funded by a research grant from the Indian Council of Medical Research, New Delhi, India, Grant Number: 5/4/3-1/TF/2012/NCD-II.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: No competing financial interests exist. The funding organization played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Enas EA, Mohan V, Deepa M, Farooq S, Pazhoor S, et al. The metabolic syndrome and dyslipidemia among Asian Indians: a population with high rates of diabetes and premature coronary artery disease. J Cardiometab Syndr 2007;2:267–75.10.1111/j.1559-4564.2007.07392.xSearch in Google Scholar PubMed
2. Misra A, Chowbey P, Makkar BM, Vikram NK, Wasir JS, et al. Consensus statement for diagnosis of obesity, abdominal obesity and the metabolic syndrome for Asian Indians and recommendations for physical activity, medical and surgical management. J Assoc Physicians India 2009;57:163–70.Search in Google Scholar
3. Mulukutla SR, Venkitachalam L, Marroquin OC, Kip KE, Aiyer A, et al. Population variations in atherogenic dyslipidemia: a report from the HeartSCORE and IndiaSCORE studies. J Clin Lipidol 2008;2:410–7.10.1016/j.jacl.2008.10.005Search in Google Scholar PubMed
4. Das MK, Bhatia V, Sibal A, Gupta A, Gopalan S, et al. Prevalence of non-alcoholic fatty liver disease in normal-weight and overweight preadolescent children in Haryana, India. Indian Pediatr 2017;54:1012–6.10.1007/s13312-017-1202-3Search in Google Scholar PubMed
5. Pawar SV, Zanwar VG, Choksey AS, Mohite AR, Jain SS, et al. Most overweight and obese Indian children have nonalcoholic fatty liver disease. Ann Hepatol 2016;15:853–61.Search in Google Scholar
6. Jain V, Jana M, Upadhyay B, Ahmad N, Jain O, et al. Prevalence, clinical and biochemical correlates of non-alcoholic fatty liver disease in overweight Indian adolescents. Indian J Med Res 2018;148:291–301.10.4103/ijmr.IJMR_1966_16Search in Google Scholar PubMed PubMed Central
7. Chesi A, Grant SFA. The genetics of pediatric obesity. Trends Endocrinol Metab 2015;26:711–21.10.1016/j.tem.2015.08.008Search in Google Scholar PubMed PubMed Central
8. Kahali B, Halligan B, Speliotes EK. Insights from genome-wide association analyses of nonalcoholic fatty liver disease. Semin Liver Dis 2015;35:375–91.10.1055/s-0035-1567870Search in Google Scholar PubMed PubMed Central
9. Penke M, Kiess W, Giorgis T. Non-alcoholic fatty liver disease in children and adolescents. J Pediatr Endocrinol Metab 2016;29:1329–30.10.1515/jpem-2016-0415Search in Google Scholar PubMed
10. Bhatt SP, Nigam P, Misra A, Guleria R, Pandey RM, et al. Genetic variation in the patatin-like phospholipase domain-containing protein-3 (PNPLA-3) gene in Asian Indians with nonalcoholic fatty liver disease. Metab Syndr Relat Disord 2013;11:329–35.10.1089/met.2012.0064Search in Google Scholar PubMed
11. Bale G, Steffie AU, Ravi Kanth VV, Rao PN, Sharma M, et al. Regional differences in genetic susceptibility to non-alcoholic liver disease in two distinct Indian ethnicities. World J Hepatol 2017;9:1101–7.10.4254/wjh.v9.i26.1101Search in Google Scholar PubMed PubMed Central
12. Puppala J, Bhrugumalla S, Kumar A, Siddapuram SP, Viswa PD, et al. Apolipoprotein C3 gene polymorphisms in Southern Indian patients with nonalcoholic fatty liver disease. Indian J Gastroenterol 2014;33:524–9.10.1007/s12664-014-0504-9Search in Google Scholar PubMed
13. Gupta V, Gupta A, Jafar T, Gupta V, Agrawal S, et al. Association of TNF-α promoter gene G-308A polymorphism with metabolic syndrome, insulin resistance, serum TNF-α and leptin levels in Indian adult women. Cytokine 2012;57:32.10.1016/j.cyto.2011.04.012Search in Google Scholar PubMed
14. Jamil K, Jayaraman A, Ahmad J, Joshi S, Yerra SK. TNF-alpha -308G/A and -238G/A polymorphisms and its protein network associated with type 2 diabetes mellitus. Saudi J Biol Sci 2017;24:1195–203.10.1016/j.sjbs.2016.05.012Search in Google Scholar PubMed PubMed Central
15. Gupta AC, Misra R, Sakhuja P, Singh Y, Basir SF, et al. Association of adiponectin gene functional polymorphisms (-11377C/G and +45T/G) with nonalcoholic fatty liver disease. Gene 2012;496:63–7.10.1016/j.gene.2011.12.023Search in Google Scholar PubMed
16. Ramya K, Ayyappa KA, Ghosh S, Mohan V, Radha V. Genetic association of ADIPOQ gene variants with type 2 diabetes, obesity and serum adiponectin levels in south Indian population. Gene 2013;532:253–62.10.1016/j.gene.2013.09.012Search in Google Scholar PubMed
17. Lu JF, Zhou Y, Huang GH, Jiang HX, Hu BL, et al. Association of ADIPOQ polymorphisms with obesity risk: a meta-analysis. Hum Immunol 2014;75:1062–8.10.1016/j.humimm.2014.09.004Search in Google Scholar PubMed
18. Johansson LE, Lindblad U, Larsson CA, Råstam L, Ridderstråle M. Polymorphisms in the adiponutrin (PNPLA3) gene are associated with increased insulin secretion and obesity. Eur J Endocrinol 2008;159:577–83.10.1530/EJE-08-0426Search in Google Scholar PubMed
19. Yamada Y, Kato K, Kameyama T, Yokoi K, Matsuo H, et al. Genetic factors forobesity. Int J Mol Med 2006;18:843–51.Search in Google Scholar
20. Johansson LE, Johansson LM, Danielsson P, Norgren S, Johansson S, et al. Genetic variance in the adiponutrin gene family and childhood obesity. PLoS One 2009;4:e5327.10.1371/journal.pone.0005327Search in Google Scholar PubMed PubMed Central
21. Fraga VG, Gomes KB. Adiponectin gene polymorphisms: association with childhood obesity. J Pediatr Genet 2014;3: 17–28.10.3233/PGE-14084Search in Google Scholar PubMed PubMed Central
22. León-Mimila P, Villamil-Ramírez H, Villalobos-Comparán M, Villarreal-Molina T, Romero-Hidalgo S, et al. Contribution of common genetic variants to obesity and obesity-related traits in Mexican children and adults. PLoS One 2013;8:e70640.10.1371/journal.pone.0070640Search in Google Scholar PubMed PubMed Central
23. Ng ZY, Veerapen MK, Hon WM, Lim RL. Association of leptin/receptor and TNF-α gene variants with adolescent obesity in Malaysia. Pediatr Int 2014;56:689–97.10.1111/ped.12336Search in Google Scholar PubMed
24. Santoro N, Kursawe R, D’Adamo E, Dykas DJ, Zhang CK, et al. A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents. Hepatology 2010;52:1281–90.10.1002/hep.23832Search in Google Scholar PubMed PubMed Central
25. Ramírez-López G, Morán-Villota S, Mendoza-Carrera F, Portilla-de Buen E, Valles-Sánchez V, et al. Metabolic and genetic markers’ associations with elevated levels of alanine aminotransferase in adolescents. J Pediatr Endocrinol Metab 2018;31:407–14.10.1515/jpem-2017-0217Search in Google Scholar PubMed
26. Agarwal KN, Saxena A, Bansal AK, Agarwal DK. Physical growth assessment in adolescence. Indian Pediatr 2001;38: 1217–35.Search in Google Scholar
27. Webb M, Yeshua H, Zelber-Sagi S, Santo E, Brazowski E, et al. Diagnostic value of a computerized hepatorenal index for sonographic quantification of liver steatosis. Am J Roentgenol 2009;192:909–14.10.2214/AJR.07.4016Search in Google Scholar PubMed
28. Singh D, Das CJ, Baruah MP. Imaging of non alcoholic fatty liver disease: a road less travelled. Indian J Endocrinol Metab 2013;17:990–5.10.4103/2230-8210.122606Search in Google Scholar PubMed PubMed Central
29. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16:1215.10.1093/nar/16.3.1215Search in Google Scholar PubMed PubMed Central
30. Hedayati M, Sharifi K, Rostami F, Daneshpour MS, Zarif Yeganeh M, et al. Association between TNF-α promoter G-308A and G-238A polymorphisms and obesity. Mol Biol Rep 2012;39:825–9.10.1007/s11033-011-0804-4Search in Google Scholar PubMed PubMed Central
31. Wang JK, Feng ZW, Li YC, Li QY, Tao XY. Association of tumor necrosis factor-α gene promoter polymorphism at sites -308 and -238 with non-alcoholic fatty liver disease: a meta-analysis. J Gastroenterol Hepatol 2012;27:670–6.10.1111/j.1440-1746.2011.06978.xSearch in Google Scholar PubMed
32. Chowdhury SD, Ramakrishna B, Eapen CE, Goel A, Zachariah UG, et al. Fibrosis in non-alcoholic fatty liver disease: correlation with simple blood indices and association with tumor necrosis factor-alpha polymorphisms. Trop Gastroenterol 2013;34:31–5.10.7869/tg.2012.88Search in Google Scholar PubMed
33. Tokushige K, Takakura M, Tsuchiya-Matsushita N, Taniai M, Hashimoto E, et al. Influence of TNF gene polymorphisms in Japanese patients with NASH and simple steatosis. J Hepatol 2007;46:1104–10.10.1016/j.jhep.2007.01.028Search in Google Scholar PubMed
34. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40:146–1465.10.1038/ng.257Search in Google Scholar PubMed PubMed Central
35. Wu J, Liu Z, Meng K, Zhang L. Association of adiponectin gene (ADIPOQ) rs2241766 polymorphism with obesity in adults: a meta-analysis. PLoS One 2014;9:e95270.10.1371/journal.pone.0095270Search in Google Scholar PubMed PubMed Central
36. Wang BF, Wang Y, Ao R, Tong J, Wang BY. AdipoQ T45 G and G276 T polymorphisms and susceptibility to nonalcoholic fatty liver disease among Asian populations: a meta-analysis and meta-regression. J Clin Lab Anal 2016;30:47–57.10.1002/jcla.21814Search in Google Scholar PubMed PubMed Central
37. Valenti L, Nobili V, Al-Serri A, Rametta R, Leathart JB, et al. The APOC3 T-455C and C-482T promoter region polymorphisms are not associated with the severity of liver damage independently of PNPLA3 I148M genotype in patients with nonalcoholic fatty liver. J Hepatol 2011;55:1409–14.10.1016/j.jhep.2011.03.035Search in Google Scholar PubMed
38. Sentinelli F, Romeo S, Maglio C, Incani M, Burza MA, et al. Lack of effect of apolipoprotein C3 polymorphisms on indices of liver steatosis, lipid profile and insulin resistance in obese Southern Europeans. Lipids Health Dis 2011;10:93.10.1186/1476-511X-10-93Search in Google Scholar PubMed PubMed Central
39. Pollex RL, Ban MR, Young TK, Bjerregaard P, Anand SS, et al. Association between the -455T>C promoter polymorphism of the APOC3 gene and the metabolic syndrome in a multi-ethnic sample. BMC Med Genet 2007;8:80.10.1186/1471-2350-8-80Search in Google Scholar PubMed PubMed Central
Supplementary Material
The online version of this article offers supplementary material (https://doi.org/10.1515/jpem-2018-0543).
©2019 Walter de Gruyter GmbH, Berlin/Boston
