Advertisement

Metabolomics study on the association between nicotinamide N-methyltransferase gene polymorphisms and type 2 diabetes

  • Jiang-Hua Li
  • Ya-Hui Wang
  • Xiao-Juan Zhu
  • Qiong Zhou
  • Zu-Hua Xie
  • Teng-Fei Yao
Original Article
  • 74 Downloads

Abstract

Numerous reports have demonstrated that activities of nicotinamide N-methyltransferase (NNMT) are significantly associated with type 2 diabetes (T2D), and more than 200 single nucleotide polymorphisms (SNPs) have been identified across NNMT gene to date. Although two SNPs (rs694539 and rs1941404) have been found significantly associated with a variety of noninfectious chronic diseases, the association between NNMT gene polymorphisms and T2D has not been reported yet. In this paper, 558 T2D patients and 442 healthy controls were recruited from Chinese Han population. After a case-control study on the association between the two SNPs (rs694539 and rs1941404) and T2D, we found that the rs1941404 is significantly associated with T2D and the CC carriers at this locus are T2D susceptible population. The following metabolomics study showed that the rs1941404 variation is able to affect the metabolic pathways of tryptophan, tyrosine, and arginine, which may partly explain why the rs1941404 variation is significantly associated with T2D.

Keywords

Metabolomics Metabolism Nicotinamide N-methyltransferase Polymorphism, single nucleotide Principal component analysis 

Notes

Funding information

This work was supported by the National Natural Science Foundation of China (NSFC 21365013).

Compliance with ethical standards

The investigation was approved by the local ethics committee at Jiangxi Normal University, and all participants provided the written informed consents. This study conforms to the latest revision of the Declaration of Helsinki.

Conflict of interest

The authors declare that there are no conflicts of interest.

References

  1. 1.
    Li JH, Chen W, Zhu XJ, Lin YJ, Qiu LQ, Cai CX, et al. Associations of nicotinamide N-methyltransferase Gene single nucleotide polymorphisms with sport performance and relative maximal oxygen uptake. J Sports Sci. 2017;35(22):2185–90.  https://doi.org/10.1080/02640414.2016.1261176.
  2. 2.
    Li JH, Qiu LQ, Zhu XJ, Cai CX. Influence of exercises using different energy metabolism systems on NNMT expression in different types of skeletal muscle fibers. Sci Sports. 2017;32(1):27–32.  https://doi.org/10.1016/j.scispo.2016.06.004.CrossRefGoogle Scholar
  3. 3.
    Liu M, Li L, Chu J, Zhu B, Zhang Q, Yin X, et al. Serum N(1)-Methylnicotinamide is associated with obesity and diabetes in Chinese. J Clin Endocrinol Metab. 2015;100(8):3112–7.  https://doi.org/10.1210/jc.2015-1732.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Salek RM, Maguire ML, Bentley E, Rubtsov DV, Hough T, Cheeseman M, et al. A metabolomic comparison of urinary changes in type 2 diabetes in mouse, rat, and human. Physiol Genomics. 2007;29(2):99–108.  https://doi.org/10.1152/physiolgenomics.00194.2006.CrossRefPubMedGoogle Scholar
  5. 5.
    Kraus D, Yang Q, Kong D, Banks AS, Zhang L, Rodgers JT, et al. Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature. 2014;508(7495):258–62.  https://doi.org/10.1038/nature13198.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Yaguchi H, Togawa K, Moritani M, Itakura M. Identification of candidate genes in the type 2 diabetes modifier locus using expression QTL. Genomics. 2005;85(5):591–9.  https://doi.org/10.1016/j.ygeno.2005.01.006.CrossRefPubMedGoogle Scholar
  7. 7.
    Souto JC, Blanco-Vaca F, Soria JM, Buil A, Almasy L, Ordoñez-Llanos J, et al. A genomewide exploration suggests a new candidate gene atchromosome 11q23 as the majorde terminant of plasma homocysteine levels: results from the GAIT project. Am J Hum Genet. 2005;76(6):925–33.  https://doi.org/10.1086/430409.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    van Driel LM, Smedts HP, Helbing WA, et al. Eight-fold increased risk for congenital heart defects in children carrying the nicotinamide N-methyltransferase polymorphism and exposed to medicines and low nicotinamide. Eur Heart J. 2008;29(11):1424–31.  https://doi.org/10.1093/eurheartj/ehn170.CrossRefPubMedGoogle Scholar
  9. 9.
    Giusti B, Saracini C, Bolli P, Magi A, Sestini I, Sticchi E, et al. Genetic analysis of 56 polymorphisms in 17 genes involved in methionine metabolism in patients with abdominal aortic aneurysm. J Med Genet. 2008;45(11):721–30.  https://doi.org/10.1136/jmg.2008.057851.CrossRefPubMedGoogle Scholar
  10. 10.
    Sazci A, Sazci G, Sazci B, Ergul E, Idrisoglu HA. Nicotinamide-N-Methyltransferase gene rs694539 variant and migraine risk. J Headache Pain. 2016;17(1):93.  https://doi.org/10.1186/s10194-016-0688-8.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Sazci A, Ozel MD, Ergul E, Aygun C. Association of nicotinamide-N-methyltransferase gene rs694539 variant with patients with nonalcoholic steatohepatitis. Genet Test Mol Biomarkers. 2013;17(11):849–53.  https://doi.org/10.1089/gtmb.2013.0309.CrossRefPubMedGoogle Scholar
  12. 12.
    Sazci A, Ozel MD, Ergul E, Onder ME. Association of nicotinamide-N-methyltransferase (NNMT) gene rs694539 variant with bipolar disorder. Gene. 2013;532(2):272–5.  https://doi.org/10.1016/j.gene.2013.08.077.CrossRefPubMedGoogle Scholar
  13. 13.
    Sazci G, Sazci B, Sazci A, Idrisoglu HA. Association of nicotinamide-N-methyltransferase gene rs694539 variant with epilepsy. Mol Neurobiol. 2016;53(6):4197–200.  https://doi.org/10.1007/s12035-015-9364-2.CrossRefPubMedGoogle Scholar
  14. 14.
    Bromberg A, Lerer E, Udawela M, Scarr E, Dean B, et al. Nicotinamide-N-methyltransferase (NNMT) in schizophrenia: genetic association and decreased frontal cortex mRNA levels. Int J Neuro Psycho Pharmacol. 2012;15(6):727–37.Google Scholar
  15. 15.
    Zhu XJ, Lin YJ, Chen W, Wang YH, Qiu LQ, et al. Physiological study on association between nicotinamide N-methyltransferase gene polymorphisms and hyperlipidemia. Biomed Res Int. 2016;2016:7521942.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Goldberg RB, Mather K. Targeting the consequences of the metabolic syndrome in the Diabetes Prevention Program. Arterioscler Thromb Vasc Biol. 2012;32(9):2077–90.  https://doi.org/10.1161/ATVBAHA.111.241893.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Bromberg A, Levine J, Belmaker R, Agam G. Hyperhomocysteinemia does not affect global DNA methylation and nicotinamide N-methyltransferase expression in mice. J Psychopharmacol. 2011;25(7):976–81.  https://doi.org/10.1177/0269881110388328.CrossRefPubMedGoogle Scholar
  18. 18.
    Trammell SA, Brenner C. NNMT: a bad actor in fat makes good in liver. Cell Metab. 2015;22(2):200–1.  https://doi.org/10.1016/j.cmet.2015.07.017.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Belenky P, Bogan KL, Brenner C. NAD+ metabolism in health and disease. Trends Biochem Sci. 2007;32(1):12–9.  https://doi.org/10.1016/j.tibs.2006.11.006.CrossRefPubMedGoogle Scholar
  20. 20.
    Williams AC, Hill LJ, Ramsden DB. Nicotinamide, NAD(P)(H), and methyl-group homeostasis evolved and became a determinant of ageing diseases: hypotheses and lessons from pellagra. Curr Gerontol Geriatr Res. 2012;2012:302–5.CrossRefGoogle Scholar
  21. 21.
    Li F, Chong ZZ, Maiese K. Cell Life versus cell longevity: the mysteries surrounding the NAD+ precursor nicotinamide. Curr Med Chem. 2006;13(8):883–95.  https://doi.org/10.2174/092986706776361058.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature. 2007;445(7130):881–5.  https://doi.org/10.1038/nature05616.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical Research, Saxena R, Voight BF, Lyssenko V, et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007;316(5829):1331–6.  https://doi.org/10.1126/science.1142358.CrossRefGoogle Scholar
  24. 24.
    Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H, et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science. 2007;316(5829):1336–41.  https://doi.org/10.1126/science.1142364.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Steinthorsdottir V, Thorleifsson G, Reynisdottir I, Benediktsson R, Jonsdottir T, Walters GB, et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet. 2007;39(6):770–5.  https://doi.org/10.1038/ng2043.CrossRefPubMedGoogle Scholar
  26. 26.
    Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, et al. A genomewide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science. 2007;316(5829):1341–5.  https://doi.org/10.1126/science.1142382.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, et al. Metaanalysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet. 2008;40(5):638–45.  https://doi.org/10.1038/ng.120.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Unoki H, Takahashi A, Kawaguchi T, Hara K, Horikoshi M, Andersen G, et al. SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nat Genet. 2008;40(9):1098–102.  https://doi.org/10.1038/ng.208.CrossRefPubMedGoogle Scholar
  29. 29.
    Yasuda K, Miyake K, Horikawa Y, Hara K, Osawa H, Furuta H, et al. Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nat Genet. 2008;40(9):1092–7.  https://doi.org/10.1038/ng.207.CrossRefPubMedGoogle Scholar
  30. 30.
    Kong A, Steinthorsdottir V, Masson G, Thorleifsson G, Sulem P, Besenbacher S, et al. Parental origin of sequence variants associated with complex diseases. Nature. 2009;462(7275):868–74.  https://doi.org/10.1038/nature08625.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Rung J, Cauchi S, Albrechtsen A, Shen L, Rocheleau G, Cavalcanti-Proença C, et al. Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia. Nat Genet. 2009;41(10):1110–5.  https://doi.org/10.1038/ng.443.CrossRefPubMedGoogle Scholar
  32. 32.
    Saxena R, Hivert MF, Langenberg C, Tanaka T, Pankow JS, Vollenweider P, et al. Genetic variation in gastric inhibitory polypeptide receptor (GIPR) impacts the glucose and insulin responses to an oral glucose challenge. Nat Genet. 2010;42(2):142–8.  https://doi.org/10.1038/ng.521.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU, et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet. 2010;42(2):105–16.  https://doi.org/10.1038/ng.520.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Cui B, Zhu X, Xu M, et al. A genome-wide association study confirms previously reported loci for type 2 diabetes in Han Chinese. PLoS One. 2011;6(7):e022353.Google Scholar
  35. 35.
    Li JH, Wang ZH, Zhu XJ, Deng ZH, Cai CX, Qiu LQ, et al. Health effects from swimming training in chlorinated pools and the corresponding metabolic stress pathways. PLoS One. 2015;10(3):e0119241.  https://doi.org/10.1371/journal.pone.0119241.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Shi YY, He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res. 2005;15(2):97–8.  https://doi.org/10.1038/sj.cr.7290272.CrossRefPubMedGoogle Scholar
  37. 37.
    Matchett WH. Inhibition of tryptophan synthetase by indoleacrylic acid. J Bacteriol. 1972;110(1):146–54.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Watała C, Kaźmierczak P, Dobaczewski M, Przygodzki T, Bartuś M, Łomnicka M, et al. Anti-diabetic effects of 1-methylnicotinamide (MNA) in streptozocin-induced diabetes in rats. Pharmacol Rep. 2009;61(1):86–98.  https://doi.org/10.1016/S1734-1140(09)70010-6.CrossRefPubMedGoogle Scholar
  39. 39.
    Jongkees BJ, Hommel B, Kühn S, Colzato LS. Effect of tyrosine supplementation on clinical and healthy populations under stress or cognitive demands—a review. J Psychiatr Res. 2015;70:50–7.  https://doi.org/10.1016/j.jpsychires.2015.08.014.CrossRefPubMedGoogle Scholar
  40. 40.
    Xia N, Horke S, Habermeier A, Closs EI, Reifenberg G, Gericke A, et al. Uncoupling of endothelial nitric oxide synthase in perivascular adipose tissue of diet-induced obese mice. Arterioscler Thromb Vasc Biol. 2016;36(1):78–85.  https://doi.org/10.1161/ATVBAHA.115.306263.CrossRefPubMedGoogle Scholar
  41. 41.
    Hambrecht R, Hilbrich L, Erbs S, Gielen S, Fiehn E, Schoene N, et al. Correction of endothelial dysfunction in chronic heart failure: additional effects of exercise training and oral L-arginine supplementation. J Am Coll Cardiol. 2000;35(3):706–13.  https://doi.org/10.1016/S0735-1097(99)00602-6.CrossRefPubMedGoogle Scholar
  42. 42.
    Kaneto H, Fujii J, Seo HG, Suzuki K, Matsuoka T, Nakamura M, et al. Apoptotic cell death triggered by nitric oxide in pancreatic beta-cells. Diabetes. 1995;44(7):733–8.  https://doi.org/10.2337/diab.44.7.733.CrossRefPubMedGoogle Scholar

Copyright information

© Research Society for Study of Diabetes in India 2018

Authors and Affiliations

  1. 1.Key Laboratory of Functional Small Organic Molecule, Ministry of EducationJiangxi Normal UniversityNanchangChina
  2. 2.Institute of Physical EducationJiangxi Normal UniversityNanchangChina

Personalised recommendations