Skip to main content

Advertisement

SpringerLink
Log in

The possible role of 10398A and 16189C mtDNA variants in providing susceptibility toT2DM in two North Indian populations: a replicative study

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

The role of mitochondria in causing diseases is becoming evident as more and more studies are focusing on this organelle of the cell. This is largely attributed to its reactive oxygen species (ROS) production property. In the context of diabetes, ROS is suggested to trigger different forms of insulin resistance involving different mechanisms. The suggestive role of a mtDNA variant G10398A in increasing ROS production and the impaired response to oxidative stress due to T16189C variant is worth addressing as genetic susceptibility factors in type 2 diabetes mellitus (T2DM). A case control study on 312 T2DM cases and ethnically matched 466 controls involving two North Indian populations, referred as cohort 1 and cohort 2 (in a replicative study), was undertaken to test such a genetic association. A statistically significant association was observed for 10398A allele in both the cohorts [cohort1 (OR = 2.67 95% CI 1.77–4.00); cohort2 (OR = 1.76 95%CI 1.12–2.77)]. The analysis of G10398A/T16189C haplotypic combinations revealed that 10398A/16189C haplotype provides a risk in both the cohorts. To sum up the study suggests that 10398A and 16189C alleles provide susceptiblity to T2DM independently as well as together.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–20

    Article  PubMed  CAS  Google Scholar 

  • Canter JA, Kallianpur AR, Parl FF, Millikan RC (2005) Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women. Cancer Res 65:8028–33

    PubMed  CAS  Google Scholar 

  • Deeney JT, Prentki M, Corkey BE (2000) Metabolic control of beta-cell function. Semin Cell Dev Biol 11:267–75

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Ruiz C, Colell A, Mari M, Morales A, Fernandez-Checa JC (1997) Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species. Role of mitochondrial glutathione. J Biol Chem 272:11369–77

    Article  PubMed  CAS  Google Scholar 

  • Giacchetti M, Monticelli A, De Biase I, Pianese L, Turano M, Filla A, De Michele G, Cocozza S (2004) Mitochondrial DNA haplogroups influence the Friedreich’s ataxia phenotype. J Med Genet 41:293–5

    Article  PubMed  CAS  Google Scholar 

  • Hamilton ML, Guo Z, Fuller CD, Van Remmen H, Ward WF, Austad SN, Troyer DA, Thompson I, Richardson A (2001) A reliable assessment of 8-oxo-2-deoxyguanosine levels in nuclear and mitochondrial DNA using the sodium iodide method to isolate DNA. Nucleic Acids Res 29:2117–26

    Article  PubMed  CAS  Google Scholar 

  • Houstis N, Rosen ED, Lander ES (2006) Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 440:944–8

    Article  PubMed  CAS  Google Scholar 

  • Hung JH, Su IJ, Lei HY, Wang HC, Lin WC, Chang WT, Huang W, Chang WC, Chang YS, Chen CC, Lai MD (2004) Endoplasmic reticulum stress stimulates the expression of cyclooxygenase-2 through activation of NF-kappaB and pp38 mitogen-activated protein kinase. J Biol Chem 279:46384–92

    Article  PubMed  CAS  Google Scholar 

  • Ioannidis JP, Trikalinos TA, Ntzani EE, Contopoulos-Ioannidis DG (2003) Genetic associations in large versus small studies: an empirical assessment. Lancet 361:567–71

    Article  PubMed  Google Scholar 

  • Kaftan EJ, Xu T, Abercrombie RF, Hille B (2000) Mitochondria shape hormonally induced cytoplasmic calcium oscillations and modulate exocytosis. J Biol Chem 275:25465–70

    Article  PubMed  CAS  Google Scholar 

  • Kazuno AA, Munakata K, Nagai T, Shimozono S, Tanaka M, Yoneda M, Kato N, Miyawaki A, Kato T (2006) Identification of mitochondrial DNA polymorphisms that alter mitochondrial matrix pH and intracellular calcium dynamics. PLoS Genet 2:e128

    Article  PubMed  Google Scholar 

  • Kunkel LM, Smith KD, Boyer SH, Borgaonkar DS, Wachtel SS, Miller OJ, Breg WR, Jones HW Jr, Rary JM (1977) Analysis of human Y-chromosome-specific reiterated DNA in chromosome variants. Proc Natl Acad Sci USA 74:1245–9

    Article  PubMed  CAS  Google Scholar 

  • Lamson DW, Plaza SM (2002) Mitochondrial factors in the pathogenesis of diabetes: a hypothesis for treatment. Altern Med Rev 7:94–111

    PubMed  Google Scholar 

  • Lin TK, Chen SD, Wang PW, Wei YH, Lee CF, Chen TL, Chuang YC, Tan TY, Chang KC, Liou CW (2005a) Increased oxidative damage with altered antioxidative status in type 2 diabetic patients harboring the 16189 T to C variant of mitochondrial DNA. Ann NY Acad Sci 1042:64–69

    Article  CAS  Google Scholar 

  • Lin Y, Berg AH, Iyengar P, Lam TK, Giacca A, Combs TP, Rajala MW, Du X, Rollman B, Li W, Hawkins M, Barzilai N, Rhodes CJ, Fantus IG, Brownlee M, Scherer PE (2005b) The hyperglycemia-induced inflammatory response in adipocytes: the role of reactive oxygen species. J Biol Chem 280:4617–26

    Article  CAS  Google Scholar 

  • Lowell BB, Shulman GI (2005). Mitochondrial dysfunction and type 2 diabetes. Science 307:384–7

    Article  PubMed  CAS  Google Scholar 

  • Mancuso M, Conforti FL, Rocchi A, Tessitore A, Muglia M, Tedeschi G, Panza D, Monsurro M, Sola P, Mandrioli J, Choub A, DelCorona A, Manca ML, Mazzei R, Sprovieri T, Filosto M, Salviati A, Valentino P, Bono F, Caracciolo M, Simone IL, La Bella V, Majorana G, Siciliano G, Murri L, Quattrone A (2004) Could mitochondrial haplogroups play a role in sporadic amyotrophic lateral sclerosis? Neurosci Lett 371:158–62

    Article  PubMed  CAS  Google Scholar 

  • McCarthy MI, Froguel P (2002) Genetic approaches to the molecular understanding of type 2 diabetes. Am J Physiol Endocrinol Metab 283:E217–25

    PubMed  CAS  Google Scholar 

  • Mecocci P, MacGarvey U, Beal MF (1994) Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann Neurol 36:747–51

    Article  PubMed  CAS  Google Scholar 

  • Mims MP, Hayes TG, Zheng S, Leal SM, Frolov A, Ittmann MM, Wheeler TM, Prchal JT (2006) Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women. Cancer Res 66:1880

    Article  PubMed  CAS  Google Scholar 

  • Mohlke KL, Jackson AU, Scott LJ, Peck EC, Suh YD, Chines PS, Watanabe RM, Buchanan TA, Conneely KN, Erdos MR, Narisu N, Enloe S, Valle TT, Tuomilehto J,Bergman RN, Boehnke M, Collins FS (2005) Mitochondrial polymorphisms and susceptibility to type 2 diabetes-related traits in Finns. Hum Genet 118:245–5

    Article  PubMed  CAS  Google Scholar 

  • O’Rahilly S, Barroso I, Wareham NJ (2005) Genetic factors in type 2 diabetes: the end of the beginning? Science 307:370–3

    Article  PubMed  CAS  Google Scholar 

  • van den Ouweland JM, Lemkes HH, Ruitenbeek W, Sandkuijl LA, de Vijlder MF, Struyvenberg PA, van de Kamp JJ, Maassen JA (1992) Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat Genet 1:368–71

    Article  PubMed  Google Scholar 

  • Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgun C, Glimcher LH, Hotamisligil GS (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306:457–61

    Article  PubMed  Google Scholar 

  • Poulton J, Luan J, Macaulay V, Hennings S, Mitchell J, Wareham NJ (2002) Type 2 diabetes is associated with a common mitochondrial variant: evidence from a population-based case–control study. Hum Mol Genet 11:1581–1583

    Article  PubMed  CAS  Google Scholar 

  • Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Diabetes Care. 1997 20:1183–97

    Google Scholar 

  • Ross OA, McCormack R, Curran MD, Duguid RA, Barnett YA, Rea IM, Middleton D (2001) Mitochondrial DNA polymorphism: its role in longevity of the Irish population. Exp Gerontol 36:1161–78

    Article  PubMed  CAS  Google Scholar 

  • Shoffner JM, Brown MD, Torroni A, Lott MT, Cabell MF, Mirra SS, Beal MF, Yang CC, Gearing M, Salvo R (1993) Mitochondrial DNA variants observed in Alzheimer disease and Parkinson disease patients. Genomics 17:171–84

    Article  PubMed  CAS  Google Scholar 

  • Smeitink J, van den Heuvel L (1999) Human mitochondrial complex I in health and disease. Am J Hum Genet 64:1505–10

    Article  PubMed  CAS  Google Scholar 

  • Tang DL, Zhou X, Li X, Zhao L, Liu F (2006) Variation of mitochondrial gene and the association with type 2 diabetes mellitus in a Chinese population. Diabetes Res Clin Pract 73:77–82

    Article  PubMed  CAS  Google Scholar 

  • Torroni A, Huoponen K, Francalacci P, Petrozzi M, Morelli L, Scozzari R, Obinu D, Savontaus ML, Wallace DC (1996) Classification of European mtDNAs from an analysis of three European populations. Genetics 144:1835–50

    PubMed  CAS  Google Scholar 

  • van der Walt JM, Nicodemus KK, Martin ER, Scott WK, Nance MA, Watts RL, Hubble JP, Haines JL, Koller WC, Lyons K, Pahwa R, Stern MB, Colcher A, Hiner BC, Jankovic J, Ondo WG, Allen FH Jr, Goetz CG, Small GW, Mastaglia F, Stajich JM, McLaurin AC, Middleton LT, Scott BL, Schmechel DE, Pericak-Vance MA, Vance JM (2003) Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease. Am J Hum Genet 72:804–11

    Article  PubMed  Google Scholar 

  • van der Walt JM, Dementieva YA, Martin ER, Scott WK, Nicodemus KK, Kroner CC, Welsh-Bohmer KA, Saunders AM, Roses AD, Small GW, Schmechel DE, Murali Doraiswamy P, Gilbert JR, Haines JL, Vance JM, Pericak-Vance MA (2004) Analysis of European mitochondrial haplogroups with Alzheimer disease risk. Neurosci Lett 365:28–32

    Article  PubMed  Google Scholar 

  • Zimmet P, Alberti KG, Shaw J (2001) Global and societal implications of the diabetes epidemic. Nature 414:782–7

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors acknowledge the support provided by UGC, India to NCAHG and to the Centre for Advanced Studies, School of Life Sciences, JNU. We also acknowledge the fellowship of CSIR to A. K. Bhat.

Author information

Authors and Affiliations

  1. National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India

    Audesh Bhat, Anil Koul, Swarkar Sharma, Ekta Rai, S. I. A. Bukhari & R. N. K. Bamezai

  2. Department of Biotechnology, University of Jammu, Jammu, India

    Audesh Bhat & M. K. Dhar

Authors
  1. Audesh Bhat
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anil Koul
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Swarkar Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ekta Rai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. I. A. Bukhari
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. K. Dhar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R. N. K. Bamezai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. N. K. Bamezai.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bhat, A., Koul, A., Sharma, S. et al. The possible role of 10398A and 16189C mtDNA variants in providing susceptibility toT2DM in two North Indian populations: a replicative study. Hum Genet 120, 821–826 (2007). https://doi.org/10.1007/s00439-006-0272-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-006-0272-4

Keywords

Search

Navigation