Abstract
Chronic low-grade inflammation is strongly related to the etiology of diabetes mellitus type 2 (T2DM), and the expression of inflammatory cytokines may be modulated by polymorphisms located in the regulatory regions of the NFκβ, IL-1β, IL-6, TNFα, and LPL genes. We considered it particularly important to investigate the relationship of gene polymorphisms involved in chronic inflammation with the risk of T2DM or uncontrolled biochemical parameters. Methods: We included 199 individuals with a T2DM diagnosis and 213 individuals without a T2DM diagnosis. Restriction fragment length polymorphism (RFLP) analyses were used to assess polymorphisms. Results: We found a risk association between T2DM and uncontrolled biochemical parameters in a Mexican population for the genotypes del/del of NFκβ, -174 and -572 of IL-6, C/C of IL-1β, -308 and -238 of TNFα, and T/T of LPL. In subjects without diabetes (controls), we found an association between the G/C genotype of the -572 polymorphism and the G/C and C/C genotypes of the -597 polymorphism of IL-6 with the risk of glucose levels > 131 mg/dL. Genotype C/C of polymorphism -174 of the IL-6 gene was associated with high triglyceride levels, and levels > 5.8% of HbA1c were associated with the G/A genotype of TNFα -308. Conclusion: Here, we describe for the first time the relationship of T2DM risk and uncontrolled biochemical parameters with polymorphisms in the NFκβ, IL-6, TNFα, IL-1β, and LPL genes in a Mexican population. We also showed that for the population included in this study, there is an additive effect of the polymorphisms of the studied genes that considerably increases the risk of developing T2DM.We also showed that there are interactions between genes related to chronic inflammation that affect the risk of T2DM.
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References
Achyut BR, Srivastava A, Bhattacharya S, Mittal B (2007) Genetic association of interleukin-1β (- 511C/T) and interleukin-1 receptor antagonist (86 bp repeat) polymorphisms with Type 2 diabetes mellitus in North Indians. Clin Chim Acta 377(1–2):163–169. https://doi.org/10.1016/j.cca.2006.09.012
American Diabetes Association (ADA) (2017) 2. Classification and diagnosis of diabetes. American Diabetes Care Association 40:S11–S24. https://doi.org/10.2337/dc17-S005
Basto-Abreu A, Barrientos-Gutiérrez T, Rojas-Martínez R, Aguilar-Salinas CA, López-Olmedo N, De la Cruz-Góngora V et al (2020) Prevalencia de diabetes y descontrol glucemico en Mexico: Resultados de la Ensanut 2016. Salud Publica Mex 62(1):50–59
Behera S, Lamare AA, Rattan R, Patnaik B, Das S (2020) Association of NFkB1 gene polymorphism with inflammatory markers in patients of Type 2 Diabetes mellitus with or without renal involvement in Eastern India. J Diabetes Mellitus 10(03):169–181. https://doi.org/10.4236/jdm.2020.103014
Bhat IA, Naykoo NA, Qasim I, Ganie FA, Yousuf Q, Bhat BA et al (2014) Association of interleukin 1 beta (IL-1β) polymorphism with mRNA expression and risk of non small cell lung cancer. Meta Gene 2(1):123–133. https://doi.org/10.1016/j.mgene.2013.12.002
Boeta-Lopez K, Duran J, Elizondo D, Gonzales E, Rentfro A, Schwarzbach AE, Nair S (2018) Association of interleukin-6 polymorphisms with obesity or metabolic traits in young Mexican-Americans. Obesity Sci Pract 4(1):85–96. https://doi.org/10.1002/osp4.138
Braun N, Michel U, Ernst BP, Metzner R, Bitsch A, Weber F, Rieckmann P (1996) Gene polymorphism at position -308 of the tumor-necrosis-factor-α (TNF-α) in Multiple Sclerosis and its influence on the regulation of TNF-α production. Neurosci Lett 215(2):75–78. https://doi.org/10.1016/S0304-3940(96)12920-7
Campbell MJ, Julious SA, Altman DG (1995) Estimating sample sizes for binary, ordered categorical, and continuous outcomes in two group comparisons. BMJ 311(7013):1145–1148. https://doi.org/10.1136/bmj.311.7013.1145
Chen B, Cole JW, Grond-Ginsbach C (2017) Departure from Hardy Weinberg Equilibrium and genotyping error. Front Genet 8:1–6
Chung Y, Lee SY, Elston RC, Park T (2007) Odds ratio based multifactor-dimensionality reduction method for detecting gene–Gene interactions. Bioinformatics 23(1):71–76. https://doi.org/10.1093/bioinformatics/btl557
Compasso S, Richiardi PM, Pociot F, D’Alfonso S, Scorza R (2006) Functional analysis of a new polymorphism in the human TNF alpha Gene Promoter. Scand J Immunol 42(4):501–504. https://doi.org/10.1111/j.1365-3083.1995.tb03686.x
Curti MLR, Pires MM, Barros CR, Siqueira-Catania A, Rogero MME, Ferreira SRG (2012) Associations of the TNF-alpha -308 G/A, IL6 -174 G/C and AdipoQ 45 T/G polymorphisms with inflammatory and metabolic responses to lifestyle intervention in Brazilians at high cardiometabolic risk. Diabetol Metab Syndrome 4(1):1. https://doi.org/10.1186/1758-5996-4-49
Daoud MS, Ataya FS, Fouad D, Alhazzani A, Shehata AI, Al-Jafari AA (2013) Associations of three lipoprotein lipase gene polymorphisms, lipid profiles and coronary artery disease. Biomed Rep 1(4):573–582. https://doi.org/10.3892/br.2013.126
Fishman D, Faulds G, Jeffey R, Mohamed-Ali V, Yudkin JS, Humphries S, Woo P (1998) The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic- onset juvenile chronic arthritis. J Clin Invest 102(7):1369–1376. https://doi.org/10.1172/JCI2629
Gautam A, Gupta S, Mehndiratta M, Sharma M, Singh K, Kalra OP et al (2017) Association of NFKB1 gene polymorphism (rs28362491) with levels of inflammatory biomarkers and susceptibility to diabetic nephropathy in Asian Indians. World J Diabetes 8(2):66. https://doi.org/10.4239/wjd.v8.i2.66
Ghafar MTA, Shalaby KH, Okda HI, Rizk FH (2020) Association of ABCA1 (C69T) gene polymorphism with dyslipidemia and type 2 diabetes among the Egyptian population. Meta Gene 25:100714. https://doi.org/10.1016/j.mgene.2020.100714
Graffelman J, Jain D, Weir B (2017) A genome-wide study of Hardy-Weinberg equilibrium with next generation sequence data. Hum Genet 136(6):727–741. https://doi.org/10.1007/s00439-017-1786-7
Greenberg AS, McDaniel ML (2002) Identifying the links between obesity, insulin resistance and beta-cell function: potential role of adipocyte-derived cytokines in the pathogenesis of type 2 diabetes. Eur J Clin Invest 32(Suppl 3):24–34
Hambleton I, Guariguata L, Shaw JE, Linnenkamp U, Beagley J, Whiting DR (2013) Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 103(2):137–149. https://doi.org/10.1016/j.diabres.2013.11.002
Hernández-Ávila M, Gutiérrez JP, Reynoso-Noverón N (2013) Diabetes mellitus en México. El estado de la epidemia. Salud Pública de México 55(1):129–136
Huizinga TWJ, Westendorp RGJ, Bollen ELEM, Keijsers V, Brinkman BMN, Langermans JAM et al (1997) TNF-α promoter polymorphisms, production and susceptibility to multiple sclerosis in different groups of patients. J Neuroimmunol 72(2):149–153. https://doi.org/10.1016/S0165-5728(96)00182-8
Joffe YT, Van Der Merwe L, Carstens M, Collins M, Jennings C, Levitt NS et al (2010) Tumor necrosis factor-α gene -308 G/A polymorphism modulates the relationship between dietary fat intake, serum lipids, and obesity risk in black south African women. J Nutr 140(5):901–907. https://doi.org/10.3945/jn.109.109355
Karban AS, Okazaki T, Panhuysen CIM, Gallegos T, Potter JJ, Bailey-Wilson JE et al (2004) Functional annotation of a novel NFKB1 promoter polymorphism that increases risk for ulcerative colitis. Hum Mol Genet 13(1):35–45. https://doi.org/10.1093/hmg/ddh008
Kirkpatrick G (2007) The good, the bad, the indifferent. Conflict Resolut Q 1988(21):37–45. https://doi.org/10.1002/crq.39019882106
Lahiri DK, Numberger JI (1991) A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res 19(19):5444. https://doi.org/10.1093/nar/19.19.5444
Lara-Gómez RE, Moreno-Cortes ML, Muñiz-Salazar R, Zenteno-Cuevas R (2019) Association of polymorphisms at −174 in IL-6, and −308 and −238 in TNF-α in the development of tuberculosis and type 2 diabetes mellitus in the Mexican population. Gene 702(January):1–7. https://doi.org/10.1016/j.gene.2019.03.050
Lee S, Kasif S, Weng Z, Cantor CR (2008) Quantitative analysis of single nucleotide polymorphisms within copy number variation. PLoS ONE. https://doi.org/10.1371/journal.pone.0003906
Li X, Li J (2012) Statistical. Hum Genet 850:411–421. https://doi.org/10.1007/978-1-61779-555-8
Liu H-L, Yin Y-W, Zeng Y-H, Wang Q, Sun Q-Q, Xu R-J et al (2013) Association between the Interleukin-6 Gene-572 C/G polymorphism and the risk of type 2 diabetes mellitus: a meta-analysis of 11,681 subjects. Ann Hum Genet 77(2):106–114. https://doi.org/10.1111/ahg.12003
McDowell TL, Duff GW, Symons JA, McDevitt HO, Wilson AG (2002) Effects of a polymorphism in the human tumor necrosis factor promoter on transcriptional activation. Proc Natl Acad Sci USA 94(7):3195–3199. https://doi.org/10.1073/pnas.94.7.3195
Meza R, Barrientos T, Rojas R, Reynoso N, Palacio L, Lazcano E, Hernández M (2015) Burden of Type 2 diabetes in Mexico: past, current and future prevalence and incidence rates. Prev Med 81:445–450. https://doi.org/10.1016/j.ypmed.2015.10.015.Burden
Pandaya S, Saleh R, Alam A, Al-amin M, Jain P, Reza HM (2016) Interleukin-6 gene polymorphism (-572 C> G) in Type 2 diabetes of Bangladeshi origin. Adv Biol Res 10(3):167–174. https://doi.org/10.5829/idosi.abr.2016.10.3.102174
Pereira, L. C. V., & , Clara Inés Vargas Castellanos, F. A. S. S. (2016). 28293042. Colombia Médica, 47(29), 189–195.
Pietrani NT, Gomes KB, Sousa MO, Sousa LP, Cruz NG, Fernandes AP (2012) The linkage between inflammation and Type 2 diabetes mellitus. Diabetes Res Clin Pract 99(2):85–92. https://doi.org/10.1016/j.diabres.2012.09.003
Pietrani NT, Sandrim VC, Campos FMF, Bosco AA, Rodrigues KF, Gomes KB (2017) IL-6, TNF-α, and IL-10 levels/polymorphisms and their association with type 2 diabetes mellitus and obesity in Brazilian individuals. Arch Endocrinol Metab 61(5):438–446. https://doi.org/10.1590/2359-3997000000254
Radha V, Vimaleswaran KS, Ayyappa KA, Mohan V (2007) Association of lipoprotein lipase gene polymorphisms with obesity and type 2 diabetes in an Asian Indian population. Int J Obesity 31(6):913–918. https://doi.org/10.1038/sj.ijo.0803547
Rajendiran KS, Rajappa M, Chandrashekar L, Thappa DM, Devaraju P (2020) Association analysis of tumor necrosis factor alpha promoter polymorphisms and vitiligo susceptibility in South Indian Tamils. Dermatology 236(6):554–564. https://doi.org/10.1159/000505544
Rakic M, Petkovic-Curcin A, Struillou X, Matic S, Stamatovic N, Vojvodic D (2015) CD14 and TNFα single nucleotide polymorphisms are candidates for genetic biomarkers of peri-implantitis. Clin Oral Invest 19(4):791–801. https://doi.org/10.1007/s00784-014-1313-3
Rodrigues KF, Pietrani NT, Bosco AA, Campos FMF, Sandrim VC, Gomes KB (2017) IL-6, TNF-α, and IL-10 levels/ polymorphisms and their association with type 2 diabetes mellitus and obesity in Brazilian individuals. Arch Endocrinol Metab 61(5):438–446. https://doi.org/10.1590/2359-3997000000254
Salman BN, Vahabi S, Biglari A, Salavitabar S, Doabsari M (2016) Correlation of interleukin-6-174 GC and interleukin-6-572 GC gene polymorphisms with periodontal disease in an Iranian population. Dent Res J 13(4):354–361. https://doi.org/10.4103/1735-3327.187884
Saxena M, Srivastava N, Banerjee M (2013) Association of IL-6, TNF-α and IL-10 gene polymorphisms with type 2 diabetes mellitus. Mol Biol Rep 40(11):6271–6279. https://doi.org/10.1007/s11033-013-2739-4
Shahsavar F, Varzi AM, Azargoon A (2016) Association between TNF -308G/A polymorphism and susceptibility to pulmonary tuberculosis in the Lur population of Iran. Asian Pac J Trop Biomed 6(1):80–83. https://doi.org/10.1016/j.apjtb.2015.09.017
Sharma A, Singh K, Biswas A, Ranjan R, Kishor K, Pandey H et al (2018) Impact of interleukin 6 promoter polymorphisms (−174 G > C, −572 G > C and −597 G > A) on plasma IL-6 levels and their influence on the development of DVT: a study from India. Hematology 23(10):833–838. https://doi.org/10.1080/10245332.2018.1483546
Singh PK, Chandra G, Bogra J, Gupta R, Kumar V, Jain A et al (2015) Association of interleukin-6 genetic polymorphisms with risk of OSCC in Indian population. Meta Gene 4:142–151. https://doi.org/10.1016/j.mgene.2015.03.002
Tunçdemir M, Yenmiş G, Tombultürk K, Arkan H, Soydaş T, Burak Tek R, Kanıgür-Sultuybek G (2018) NFKB1 rs28362491 and pre-miRNA-146a rs2910164 SNPS on E-cadherin expression in case of idiopathic oligospermia: a case-control study. Int J Reprod BioMed 16(4):247–254
Zuo X, Li M, Yang Y, Liang T, Yang H, Zhao X, Yang D (2018) Interleukin gene polymorphisms in Chinese Han population with breast cancer, a case-control study. Oncotarget 9(26):17994–18001
Acknowledgements
This work was supported in part by the Programa para el Desarrollo Profesional Docente (PRODEP, DSA/103.5/15/3073 to OCM) and Fortalecimiento de Cuerpos Académicos Convocatoria 2017 (25759 to OCM). We thank all our blood donors for their valuable contribution to this project.
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This work was supported in part by the Programa para el Desarrollo Profesional Docente (PRODEP, DSA/103.5/15/3073 to OCM) and Fortalecimiento de Cuerpos Académicos Convocatoria 2017 (25759 to OCM).
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Martínez-Ramírez, O.C., Salazar-Piña, D.A., de Lorena, RG.M. et al. Association of NFκβ, TNFα, IL-6, IL-1β, and LPL Polymorphisms with Type 2 Diabetes Mellitus and Biochemical Parameters in a Mexican Population. Biochem Genet 59, 940–965 (2021). https://doi.org/10.1007/s10528-021-10047-w
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DOI: https://doi.org/10.1007/s10528-021-10047-w