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Obesity-dependent association of TNF-LTA locus with type 2 diabetes in North Indians

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Abstract

Six common genetic variants (rs2229094, rs1041981, rs1800630, rs1800629, rs361525, and rs1800610) in the TNF-LTA locus encoding the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and lymphotoxin-α have been shown to be associated with various metabolic traits including susceptibility to type 2 diabetes, metabolic syndrome, insulin resistance, and increased body mass index (BMI) in Caucasians from different geographic locations and have yielded mixed results. We tested for the association of these variants with type 2 diabetes in North Indians by studying 2,115 participants comprising of 1,073 type 2 diabetes patients and 1,042 controls. We report the association of a promoter region variant of TNF: rs1800630 and non-synonymous LTA variant: rs2229094 with type 2 diabetes [OR = 0.83 (95% CI 0.72–0.95), P = 0.005 and OR = 0.86 (95% CI 0.75–0.98), P = 0.02, respectively]. Although these associations were BMI-dependent, no interactive effect of BMI and variants on type 2 diabetes was detectable. Further, the haplotype carrying all the six major alleles conferred susceptibility to type 2 diabetes [OR = 1.23 (95% CI 1.06–1.42), P = 0.005; P permuted = 0.02], with the effect much enhanced in non-obese subjects [OR = 1.45 (95% CI 1.19–1.78), P = 2 × 10−4: P permuted = 3 × 10−4]. The minor allele of rs2229094 was associated with lower hsCRP, BMI, and waist circumference (WC), while the minor allele of rs1800630 showed association with lower BMI and WC (all P < 0.01). This is the first report demonstrating association of rs1800630 and rs2229094 with type 2 diabetes in any population, suggesting an important role of the TNF-LTA locus in type 2 diabetes in North Indians.

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References

  1. Wild S, Roglic G, Green A, Sicree R, King H (2004) Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27:1047–1053

    Article  PubMed  Google Scholar 

  2. Mahajan A, Tabassum R, Chavali S, Dwivedi OP, Bharadwaj M, Tandon N, Bharadwaj D (2009) High-sensitivity C-reactive protein levels and type 2 diabetes in urban North Indians. J Clin Endocrinol Metab 94:2123–2127

    Article  PubMed  CAS  Google Scholar 

  3. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389:610–614

    Article  PubMed  CAS  Google Scholar 

  4. Moller DE (2000) Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol Metab 11:212–217

    Article  PubMed  CAS  Google Scholar 

  5. Aldhahi W, Hamdy O (2003) Adipokines, inflammation, and the endothelium in diabetes. Curr Diab Rep 3:293–298

    Article  PubMed  Google Scholar 

  6. Heijmans BT, Westendorp RG, Droog S, Kluft C, Knook DL, Slagboom PE (2002) Association of the tumour necrosis factor α-308G/A polymorphism with the risk of diabetes in an elderly population-based cohort. Genes Immun 3:225–228

    Article  PubMed  CAS  Google Scholar 

  7. Kubaszek A, Pihlajamäki J, Komarovski V, Lindi V, Lindström J, Eriksson J, Valle TT, Hämäläinen H, Ilanne-Parikka P, Keinänen-Kiukaanniemi S et al (2003) Promoter polymorphisms of the TNF-alpha (G-308A) and IL-6 (C-174G) genes predict the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study. Diabetes 52:1872–1876

    Article  PubMed  CAS  Google Scholar 

  8. Fontaine-Bisson B, Wolever TM, Chiasson JL, Rabasa-Lhoret R, Maheux P, Josse RG, Leiter LA, Rodger NW, Ryan EA, El-Sohemy A (2007) Tumor necrosis factor alpha -238G >A genotype alters postprandial plasma levels of free fatty acids in obese individuals with type 2 diabetes mellitus. Metabolism 56:649–655

    Article  PubMed  CAS  Google Scholar 

  9. Sookoian SC, González C, Pirola CJ (2005) Meta-analysis on the G-308A tumor necrosis factor alpha gene variant and phenotypes associated with the metabolic syndrome. Obes Res 13:2122–2131

    Article  PubMed  Google Scholar 

  10. Zeggini E, Groves CJ, Parkinson JR, Halford S, Owen KR, Frayling TM, Walker M, Hitman GA, Levy JC, O’Rahilly S, Hattersley AT et al (2005) Large-scale studies of the association between variation at the TNF/LTA locus and susceptibility to type 2 diabetes. Diabetologia 48:2013–2017

    Article  PubMed  CAS  Google Scholar 

  11. Lindholm E, Bakhtadze E, Cilio C, Agardh E, Groop L, Agardh CD (2008) Association between LTA, TNF and AGER polymorphisms and late diabetic complications. PLoS ONE 3:e2546

    Article  PubMed  CAS  Google Scholar 

  12. Day CP, Grove J, Daly AK, Stewart MW, Avery PJ, Walker M (1998) Tumour necrosis factor-alpha gene promoter polymorphism and decreased insulin resistance. Diabetologia 41:430–434

    Article  PubMed  CAS  Google Scholar 

  13. Willer CJ, Bonnycastle LL, Conneely KN, Duren WL, Jackson AU, Scott LJ, Narisu N, Chines PS, Skol A, Stringham HM et al (2007) Screening of 134 single nucleotide polymorphisms (SNPs) previously associated with type 2 diabetes replicates association with 12 SNPs in nine genes. Diabetes 56:256–264

    Article  PubMed  CAS  Google Scholar 

  14. Hamid YH, Urhammer SA, Glümer C, Borch-Johnsen K, Jørgensen T, Hansen T, Pedersen O (2005) The common T60N polymorphism of the lymphotoxin-alpha gene is associated with type 2 diabetes and other phenotypes of the metabolic syndrome. Diabetologia 48:445–451

    Article  PubMed  CAS  Google Scholar 

  15. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW (1997) Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci 94:3195–3199

    Article  PubMed  CAS  Google Scholar 

  16. Kroeger KM, Steer JH, Joyce DA, Abraham LJ (2000) Effects of stimulus and cell type on the expression of the −308 tumour necrosis factor promoter polymorphism. Cytokine 12:110–119

    Article  PubMed  CAS  Google Scholar 

  17. Fong CL, Siddiqui AH, Mark DF (1994) Identification and characterization of a novel repressor site in the human tumor necrosis factor alpha gene. Nucleic Acids Res 22:1108–1114

    Article  PubMed  CAS  Google Scholar 

  18. Ozaki K, Ohnishi Y, Iida A, Sekine A, Yamada R, Tsunoda T, Sato H, Sato H, Hori M, Nakamura Y, Tanaka T (2002) Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction. Nat Genet 32:650–654

    Article  PubMed  CAS  Google Scholar 

  19. Kumaramanickavel G, Sripriya S, Vellanki RN, Upadyay NK, Badrinath SS, Arokiasamy T, Sukumar B, Vidhya A, Joseph B, Sharma T et al (2001) Tumor necrosis factor allelic polymorphism with diabetic retinopathy in India. Diabetes Res Clin Pract 54:89–94

    Article  PubMed  CAS  Google Scholar 

  20. Prasad P, Tiwari AK, Kumar KM, Ammini AC, Gupta A, Gupta R, Thelma BK (2007) Association of TGFbeta1, TNFalpha, CCR2 and CCR5 gene polymorphisms in type-2 diabetes and renal insufficiency among Asian Indians. BMC Med Genet 8:20

    Article  PubMed  CAS  Google Scholar 

  21. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (2003) Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 26:S5–S20

    Article  Google Scholar 

  22. Tabassum R, Chavali S, Dwivedi OP, Tandon N, Bharadwaj D (2008) Genetic variants of FOXA2: risk of type 2 diabetes and effect on metabolic traits in North Indians. J Hum Genet 53:957–965

    Article  PubMed  CAS  Google Scholar 

  23. Tabassum R, Chavali S, Mahajan A, Ghosh S, Madhu SV, Tandon N, Bharadwaj D (2008) Association analysis of TNFRSF1B polymorphisms with type 2 diabetes and its related traits in North India. Genomic Med 2:93–100

    Article  PubMed  Google Scholar 

  24. Shen R, Fan JB, Campbell D, Chang W, Chen J, Doucet D, Yeakley J, Bibikova M, Wickham Garcia E, McBride C et al (2005) High-throughput SNP genotyping on universal bead arrays. Mutat Res 573:70–82

    PubMed  CAS  Google Scholar 

  25. Purcell S, Cherny SS, Sham PC (2003) Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19:149–150

    Article  PubMed  CAS  Google Scholar 

  26. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265

    Article  PubMed  CAS  Google Scholar 

  27. WHO Expert Consultation (2004) Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 363:157–163

    Article  Google Scholar 

  28. Skoog T, van’t Hooft FM, Kallin B, Jovinge S, Boquist S, Nilsson J, Eriksson P, Hamsten A (1999) A common functional polymorphism (C-->A substitution at position -863) in the promoter region of the tumour necrosis factor-alpha (TNF-alpha) gene associated with reduced circulating levels of TNF-alpha. Hum Mol Genet 8:1443–1449

    Article  PubMed  CAS  Google Scholar 

  29. Costa A, Fernández-Real JM, Vendrell J, Broch M, Casamitjana R, Ricart W, Conget I (2003) Lower rate of tumor necrosis factor-alpha -863A allele and higher concentration of tumor necrosis factor-alpha receptor 2 in first-degree relatives of subjects with type 2 diabetes. Metabolism 52:1068–1071

    Article  PubMed  CAS  Google Scholar 

  30. Koch W, Kastrati A, Böttiger C, Mehilli J, von Beckerath N, Schömig A (2001) Interleukin-10 and tumor necrosis factor gene polymorphisms and risk of coronary artery disease and myocardial infarction. Atherosclerosis 159:137–144

    Article  PubMed  CAS  Google Scholar 

  31. Nicaud V, Raoux S, Poirier O, Cambien F, O’Reilly DS, Tiret L (2002) The TNF α/G-308A polymorphism influences insulin sensitivity in offspring of patients with coronary heart disease: the European Atherosclerosis Research Study II. Atherosclerosis 161:317–325

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank all the study participants. This study was supported by “Diabetes mellitus—New drug discovery R&D, molecular mechanisms and genetic & epidemiological factors” (NWP0032-7) funded by Council of Scientific and Industrial Research (CSIR), Government of India. We thank Mr. A. K. Sharma for his help in sample collection and Dr. Abhay Sharma for the critical assessment of the manuscript.

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We report no conflicts of interest.

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Authors and Affiliations

  1. Functional Genomics Unit, Institute of Genomics and Integrative Biology, CSIR, Mall Road, Delhi, 110 007, India

    Anubha Mahajan, Rubina Tabassum, Sreenivas Chavali, Om Prakash Dwivedi, Ganesh Chauhan & Dwaipayan Bharadwaj

  2. Department of Endocrinology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India

    Nikhil Tandon

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  1. Anubha Mahajan
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  2. Rubina Tabassum
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  6. Nikhil Tandon
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  7. Dwaipayan Bharadwaj
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Correspondence to Nikhil Tandon or Dwaipayan Bharadwaj.

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Mahajan, A., Tabassum, R., Chavali, S. et al. Obesity-dependent association of TNF-LTA locus with type 2 diabetes in North Indians. J Mol Med 88, 515–522 (2010). https://doi.org/10.1007/s00109-010-0594-5

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