Genes associated with diabetes: Potential for novel therapeutic targets?

Expert Opinion on Therapeutic Targets

Volumn 20, Issue 3, 2016, Pages 255-267

  Hara, Kazuo ^a   Kadowaki, Takashi ^b   Odawara, Masato ^a  

^a TOKYO MEDICAL UNIVERSITY   (Japan)

^b UNIVERSITY OF TOKYO   (Japan)

Author keywords

association; causal variant; genetic variant; GWAS; molecular target; nonsynonymous variant; regulatory variant; type 2 diabetes

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; ADIPONECTIN; ALPHA 2A ADRENERGIC RECEPTOR; DNA; FAT MASS AND OBESITY PROTEIN; FORSKOLIN; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; GLUCOKINASE; GLUCOKINASE REGULATORY PROTEIN; ICOSAPENTAENOIC ACID; INSULIN; LINOLENIC ACID; MELATONIN; MELATONIN RECEPTOR; MELATONIN RECEPTOR 1B; MELATONIN RECEPTOR AGONIST; REGULATOR PROTEIN; SOLUTE LINKED CARRIER 30 MEMBER 8; SULFONYLUREA; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR 7 LIKE 2; UNCLASSIFIED DRUG; YOHIMBINE; ZINC; ZINC TRANSPORTER; ANTIDIABETIC AGENT;

CLINICAL RESEARCH; DIABETIC PATIENT; DRUG DESIGN; EPIDEMIOLOGICAL DATA; FAT MASS; GENE EXPRESSION; GENE FUNCTION; GENE LOCUS; GENE MAPPING; GENE TARGETING; GENETIC ANALYSIS; GENETIC ASSOCIATION; GENETIC VARIABILITY; HISTOPATHOLOGY; HUMAN; INSULIN DEPENDENT DIABETES MELLITUS; INSULIN RESISTANCE; INSULIN TREATMENT; MISSENSE MUTATION; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PATHOGENESIS; PERSONALIZED MEDICINE; REVIEW; RISK FACTOR; VITAMIN SUPPLEMENTATION; ANIMAL; DIABETES MELLITUS, TYPE 2; GENETICS; GENOME-WIDE ASSOCIATION STUDY; MOLECULARLY TARGETED THERAPY; PATHOPHYSIOLOGY;

ANIMALS; DIABETES MELLITUS, TYPE 2; DRUG DESIGN; GENOME-WIDE ASSOCIATION STUDY; HUMANS; HYPOGLYCEMIC AGENTS; MOLECULAR TARGETED THERAPY; PRECISION MEDICINE;

EID: 84958042859     PISSN: 14728222     EISSN: 17447631     Source Type: Journal    
DOI: 10.1517/14728222.2016.1098618     Document Type: Review

References (90)

1. Joslin EP, Kahn CR. Joslin's diabetes mellitus. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.
2. Hara K, Shojima N, Hosoe J, et al. Genetic architecture of type 2 diabetes. Biochem Biophys Res Commun. 2014;452:213-220.
3. Inagaki N, Gonoi T, Clement JP, et al. Reconstitution of I (KATP): an inward rectifier subunit plus the sulfonylurea receptor. Science. 1995;270:1166-1169.
4. Lehmann JM, Moore LB, Smith-Oliver TA, et al. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995;270:12953-12956.
5. Wessel J, Chu AY, Willems SM, et al. Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Nat Commun. 2015;6:5897.
6. Segre AV, Wei N, Altshuler D, et al. Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk. Diabetes. 2015;64:1470-1483.
7. McCarthy MI, Hirschhorn JN. Genomewide association studies: potential next steps on a genetic journey. Hum Mol Genet. 2008;17:R156-65.
8. Hara K, Okada T, Tobe K, et al. The Pro12Ala polymorphism in PPAR gamma2 may confer resistance to type 2 diabetes. Biochem Biophys Res Commun. 2000;271:212-216.
9. Altshuler D, Hirschhorn JN, Klannemark M, et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet. 2000;26;76-80.
10. Grarup N, Sandholt CH, Hansen T, et al. Genetic susceptibility to type 2 diabetes and obesity: from genome-wide association studies to rare variants and beyond. Diabetologia. 2014;57:1528-1541.
11. Yamauchi T, Hara K, Maeda S, et al. A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B. Nat Genet. 2010;42:864-868.
12. Manolio TA, Collins FS, Cox NJ, et al. Finding the missing heritability of complex diseases. Nature. 2009;461:747-753.
13. Eichler EE, Flint J, Gibson G, et al. Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet. 2010;11:446-450.
14. Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154-156.
15. Cohen JC, Boerwinkle E, Mosley TH Jr., et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264-1272.
16. Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366:1108-1118.
17. Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370:1809-1819.
18. Cicero AF, Tartagni E, Ertek S. Safety and tolerability of injectable lipid-lowering drugs: A review of available clinical data. Expert Opin Drug Saf. 2014;13:1023-1030.
19. Global Lipids Genetics Consortium, Willer CJ, Schmidt EM, et al. Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013;45:1274-1283.
20. Todd JA, Walker NM, Cooper JD, et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet. 2007;39:857-864.
21. Okada Y, Wu D, Trynka G, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014;506:376-381.
22. Endo A, Kuroda M, Tanzawa K. Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity. FEBS Lett. 1976;72:323-326.
23. Kita T, Brown MS, Goldstein JL. Feedback regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in livers of mice treated with mevinolin, a competitive inhibitor of the reductase. J Clin Invest. 1980;66:1094-1100.
24. Do R, Willer CJ, Schmidt EM, et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet. 2013;45:1345-1352.
25. U.K. Prospective Diabetes Study 16. Overview of 6 years' therapy of type II diabetes: A progressive disease. U.K. Prospective Diabetes Study Group. Diabetes. 1995;44:1249-1258.
26. Foti D, Chiefari E, Fedele M, et al. Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice. Nature Med. 2005;11:765-773.
27. Chiefari E, Tanyolac S, Paonessa F, et al. Functional variants of the HMGA1 gene and type 2 diabetes mellitus. JAMA. 2011;305:903-912.
28. Chiefari E, Tanyolaç S, Iiritano S, et al. A polymorphism of HMGA1 is associated with increate risk of metabolic syndrome and related components. Sci Rep. 2013;3:1491.
29. Arcidiacono B, Iiritano S, Chiefari E, et al. Cooperation between HMGA1, PDX-1, and MafA is essential for glucose-induced insulin transcription in pancreatic beta cells. Front Endocrinol. 2015;13:237.
30. Smemo S, Tena JJ, Kim KH, et al. Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature. 2014;507:371-375.
31. Frayling TM, Timpson NJ, Weedon MN, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007;316:889-894.
32. Zeggini E, Weedon MN, Lindgren CM, et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science. 2007;316:1336-1341.
33. Scott LJ, Mohlke KL, Bonnycastle LL, et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science. 2007;316:1341-1345.
34. Cho YS, Go MJ, Kim YJ, et al. A largescale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet. 2009;41:527-34.
35. Fischer J, Koch L, Emmerling C, et al. Inactivation of the Fto gene protects from obesity. Nature. 2009;458:894-898.
36. Church C, Moir L, McMurray F, et al. Overexpression of Fto leads to increased food intake and results in obesity. Nat Genet. 2010;42:1086-1092.
37. Tung YC, Ayuso E, Shan X, et al. Hypothalamic-specific manipulation of Fto, the ortholog of the human obesity gene FTO, affects food intake in rats. PLoS One. 2010;5;e8771.
38. Dekker J, Rippe K, Dekker M, et al. Capturing chromosome conformation. Science. 2002;295:1306-1311.
39. Zhao Z, Tavoosidana G, Sjolinder M, et al. Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra-and interchromosomal interactions. Nat Genet. 2006;38:1341-1347.
40. Yasuda K, Miyake K, Horikawa Y, et al. Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nat Genet. 2008;40:1092-1097.
41. Unoki H, Takahashi A, Kawaguchi T, et al. SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nat Genet. 2008;40:1098-1102.
42. Sladek R, Rocheleau G, Rung J, et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature. 2007;445(7130):881-885.
43. Steinthorsdottir V, Thorleifsson G, Reynisdottir I, et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet. 2007;39:770-775.
44. Horikoshi M, Hara K, Ito C, et al. A genetic variation of the transcription factor 7-like 2 gene is associated with risk of type 2 diabetes in the Japanese population. Diabetologia. 2007;50:747-751.
45. Lyssenko V, Lupi R, Marchetti P, et al. Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest. 2007;117:2155-63.
46. Gaulton KJ, Nammo T, Pasquali L, et al. A map of open chromatin in human pancreatic islets. Nat Genet. 2010;42:255-259.
47. Shu L, Matveyenko AV, Kerr-Conte J, et al. Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP-and GLP-1 receptors and impaired beta-cell function. Hum Mol Genet. 2009;18:2388-2399.
48. Osmark P, Hansson O, Jonsson A, et al. Unique splicing pattern of the TCF7L2 gene in human pancreatic islets. Diabetologia. 2009;52:850-854.
49. Le Bacquer O, Shu L, Marchand M, et al. TCF7L2 splice variants have distinct effects on beta-cell turnover and function. Hum Mol Genet. 2011;20:1906-1915.
50. Takamoto I, Kubota N, Nakaya K, et al. TCF7L2 in mouse pancreatic beta cells plays a crucial role in glucose homeostasis by regulating beta cell mass. Diabetologia. 2014;57:542-53.
51. Chimienti F, Devergnas S, Favier A, et al. Identification and cloning of a beta-cellspecific zinc transporter, ZnT-8, localized into insulin secretory granules. Diabetes. 2004;53:2330-7.
52. Eide DJ. Zinc transporters and the cellular trafficking of zinc. Biochim Biophys Acta. 2006;1763:711-22.
53. Pound LD, Sarkar SA, Benninger RK, et al. Deletion of the mouse Slc30a8 gene encoding zinc transporter-8 results in impaired insulin secretion. Biochem J. 2009;421:371-6.
54. Tamaki M, Fujitani Y, Hara A, et al. The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance. J Clin Invest. 2013;123:4513-24.
55. Pound LD, Sarkar SA, Ustione A, et al. The physiological effects of deleting the mouse SLC30A8 gene encoding zinc transporter-8 are influenced by gender and genetic background. PLoS One. 2012;7: e40972.
56. Flannick J, Thorleifsson G, Beer NL, et al. Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat Genet. 2014;46:357-63.
57. Nicolson TJ, Bellomo EA, Wijesekara N, et al. Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes-associated variants. Diabetes. 2009;58:2070-83.
58. Maruthur NM, Clark JM, Fu M, et al. Effect of zinc supplementation on insulin secretion: interaction between zinc and SLC30A8 genotype in Old Order Amish. Diabetologia. 2015;58:295-303.
59. Bouatia-Naji N, Bonnefond A, Cavalcanti-Proenca C, et al. A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk. Nat Genet. 2009;41:89-94.
60. Prokopenko I, Langenberg C, Florez JC, et al. Variants in MTNR1B influence fasting glucose levels. Nat Genet. 2009;41:77-81.
61. Sparso T, Bonnefond A, Andersson E, et al. G-allele of intronic rs10830963 in MTNR1B confers increased risk of impaired fasting glycemia and type 2 diabetes through an impaired glucose-stimulated insulin release: studies involving 19,605 Europeans. Diabetes. 2009;58:1450-1456.
62. Prasai MJ, George JT, Scott EM. Molecular clocks, type 2 diabetes and cardiovascular disease. Diab Vasc Dis Res. 2008;5:89-95.
63. Dupuis J, Langenberg C, Prokopenko I, et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet. 2010;42:105-116.
64. Bonnefond A, Clement N, Fawcett K, et al. Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes. Nat Genet. 2012;44:297-301.
65. Lyssenko V, Nagorny CL, Erdos MR, et al. Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat Genet. 2009;41:82-88.
66. Peschke E, Bach AG, Muhlbauer E. Parallel signaling pathways of melatonin in the pancreatic beta-cell. J Pineal Res. 2006;40:184-191.
67. Zibolka J, Muhlbauer E, Peschke E. Melatonin influences somatostatin secretion from human pancreatic delta-cells via MT1 and MT2 receptors. J Pineal Res. 2015;58:198-209.
68. Cho YS, Chen CH, Hu C, et al. Metaanalysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians. Nat Genet. 2012;44:67-72.
69. Teo YY, Small KS, Kwiatkowski DP. Methodological challenges of genomewide association analysis in Africa. Nat Rev Genet. 2010;11:149-160.
70. Marchini J, Howie B. Genotype imputation for genome-wide association studies. Nat Rev Genet. 2010;11:499-511.
71. Abecasis GR, Altshuler D, Auton A, et al. A map of human genome variation from population-scale sequencing. Nature. 2010;467:1061-1073.
72. Hara K, Fujita H, Johnson TA, et al. Genome-wide association study identifies three novel loci for type 2 diabetes. Hum Mol Genet. 2014;23:239-246.
73. The ENCODE ProjectConsortium.An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57-74.
74. Pasquali L, Gaulton KJ, Rodriguez-Segui SA, et al. Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. Nat Genet. 2014;46:136-143.
75. Majithia AR, Flannick J, Shahinian P, et al. Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes. Proc Natl Acad Sci USA. 2014;111:13127-13132.
76. Burgess S, Butterworth A, Malarstig A, et al. Use of mendelian randomisation to assess potential benefit of clinical intervention. Bmj. 2012;345:e7325.
77. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: A mendelian randomisation study. Lancet. 2012;380:572-580.
78. Stoffel M, Froguel P, Takeda J, et al. Human glucokinase gene: isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus. Proc Natl Acad Sci USA. 1992;89:7698-7702.
79. Cuesta-Munoz AL, Huopio H, Otonkoski T, et al. Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation. Diabetes. 2004;53:2164-2168.
80. Matschinsky FM, Glaser B, Magnuson MA. Pancreatic beta-cell glucokinase: closing the gap between theoretical concepts and experimental realities. Diabetes. 1998;47:307-315.
81. Matschinsky FM. Glucokinase as glucose sensor and metabolic signal generator in pancreatic beta-cells and hepatocytes. Diabetes. 1990;39:647-652.
82. Lloyd DJ, St Jean DJ Jr., Kurzeja RJ, et al. Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors. Nature. 2013;504:437-440.
83. Anderka O, Boyken J, Aschenbach U, et al. Biophysical characterization of the interaction between hepatic glucokinase and its regulatory protein: impact of physiological and pharmacological effectors. J Biol Chem. 2008;283:31333-31340.
84. Orho-Melander M, Melander O, Guiducci C, et al. Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations. Diabetes. 2008;57:3112-3121.
85. Tang Y, Axelsson AS, Spegel P, et al. Genotype-based treatment of type 2 diabetes with an alpha2A-adrenergic receptor antagonist. Sci Transl Med. 2014;6:257ra139.
86. Kadowaki T, Yamauchi T, Kubota N, et al. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest. 2006;116:1784-1792.
87. Waki H, Yamauchi T, Kamon J, et al. Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin. J Biol Chem. 2003;278:40352-40363.
88. Okada-Iwabu M, Yamauchi T, Iwabu M, et al. A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature. 2013;503:493-499.
89. Tanabe H, Fujii Y, Okada-Iwabu M, et al. Crystal structures of the human adiponectin receptors. Nature. 2015;520:312-316.
90. Yin P, Voight BF. MeRP: A high-throughput pipeline for Mendelian randomization analysis. Bioinformatics. 2015;31:957-959.