Human genetics illuminates the paths to metabolic disease

Nature

Volumn 462, Issue 7271, 2009, Pages 307-314

  Orahilly, Stephen ^a  

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

INSULIN; LEPTIN; LEPTIN RECEPTOR; MELANOCORTIN 4 RECEPTOR; NEUROPEPTIDE; PROOPIOMELANOCORTIN; PROPROTEIN CONVERTASE 1; SULFONYLUREA DERIVATIVE; TRANSCRIPTION FACTOR; TRIACYLGLYCEROL;

DIABETES; HERITABILITY; MOLECULAR ANALYSIS; OBESITY; PUBLIC HEALTH;

ADIPOSE TISSUE; BARDET BIEDL SYNDROME; DISEASE ASSOCIATION; ENERGY EXPENDITURE; FOOD INTAKE; GENE MUTATION; GENOME; HERITABILITY; HORMONE ACTION; HUMAN; HUMAN GENETICS; HYPERGLYCEMIA; INSULIN BLOOD LEVEL; INSULIN RESISTANCE; LIPID METABOLISM; LIPID STORAGE; METABOLIC DISORDER; NON INSULIN DEPENDENT DIABETES MELLITUS; OBESITY; PANCREAS ISLET BETA CELL; PATHOPHYSIOLOGY; PHYSICAL ACTIVITY; PRADER WILLI SYNDROME; PRIORITY JOURNAL; REVIEW; RISK FACTOR; SINGLE NUCLEOTIDE POLYMORPHISM; TWINS;

DIABETES MELLITUS, TYPE 2; HUMANS; INSULIN; OBESITY;

EID: 70450193472     PISSN: 00280836     EISSN: 14764687     Source Type: Journal    
DOI: 10.1038/nature08532     Document Type: Review

References (108)

1. Maes, H. H., Neale, M. C. & Eaves, L. J. Genetic and environmental factors in relative body weight and human adiposity. Behav. Genet. 27, 325-351 (1997).
2. Poulsen, P., Kyvik, K. O., Vaag, A. & Beck-Nielsen, H. Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance-a population-based twin study. Diabetologia 42, 139-145 (1999).
3. Wild, S. et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27, 1047-1053 (2004).
4. Wardle, J., Carnell, S., Haworth, C. M. & Plomin, R. Evidence for a strong genetic influence on childhood adiposity despite the force of the obesogenic environment. Am. J. Clin. Nutr. 87, 398-404 (2008).
5. Pearson, E. R. et al. Switching from insulin to oral sulphonylureas in patients with diabetes due to Kir6.2 mutations. N. Engl. J. Med. 355, 467-477 (2006).
6. Farooqi, I. S. et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J. Clin. Invest. 110, 1093-1103 (2002).
7. World Health Organization. Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of a WHO/IDF Consultation. Æhttp:// www.idf.org/webdata/docs/WHO-IDF-definition-diagnosis-of-diabetes.pdfæ (2006).
8. Petersen, K. F. & Shulman, G. I. Etiology of insulin resistance. Am. J. Med. 119, S10-S16 (2006).
9. Reaven, G. M. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37, 1595-1607 (1988).
10. Cline, G. W. et al. Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes. N. Engl. J. Med. 341, 240-246 (1999).
11. Turner, R. C. et al. Pathogenesis of NIDDM-a disease of deficient insulin secretion. Baillieres Clin. Endocrinol. Metab. 2, 327-342 (1988).
12. Tattersall, R. Maturity-onset diabetes of the young: a clinical history. Diabet. Med. 15, 11-14 (1998).
13. Vionnet, N. et al. Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus. Nature 356, 721-722 (1992). Describes first causative mutation to be identified in a familial form of diabetes.).
14. Yamagata, K. et al. Mutations in the hepatocyte nuclear factor-4a gene in maturity-onset diabetes of the young (MODY1). Nature 384, 458-460 (1996). (Pubitemid 26414661)
15. Yamagata, K. et al. Mutations in the hepatocyte nuclear factor-1a gene in maturity-onset diabetes of the young (MODY3). Nature 384, 455-458 (1996). Refs 14 and 15 highlight the importance of mutations in the HNF family of transcription factors in the causation of familial forms of diabetes.). (Pubitemid 26414660)
16. Stoffers, D. A., Ferrer, J., Clarke, W. L. & Habener, J. F. Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nature Genet. 17, 138-139 (1997).
17. Horikawa, Y. et al. Mutation in hepatocyte nuclear factor-1 b gene (TCF2) associated with MODY. Nature Genet. 17, 384-385 (1997).
18. Malecki, M. T. et al. Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Nature Genet. 23, 323-328 (1999).
19. Babenko, A. P. et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N. Engl. J. Med. 355, 456-466 (2006).
20. Gloyn, A. L. et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N. Engl. J. Med. 350, 1838-1849 (2004); erratum 351, 1470 (2004)
21. Støy, J. et al. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc. Natl Acad. Sci. USA 104, 15040-15044 (2007).
22. Gill-Carey, O. & Hattersley, A. T. Genetics and type 2 diabetes in youth. Pediatr. Diabetes 8 (Suppl. 9), 42-47 (2007).
23. Yoshimasa, Y. et al. Insulin-resistant diabetes due to a point mutation that prevents insulin proreceptor processing. Science 240, 784-787 (1988).
24. Accili, D. et al. Insulin resistance due to mutations of the insulin receptor gene: an overview. J. Endocrinol. Invest. 11, 857-864 (1992).
25. George, S. et al. A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science 304, 1325-1328 (2004).
26. Dash, S. et al. A truncation mutation in TBC1D4 in a family with acanthosis nigricans and postprandial hyperinsulinemia. Proc. Natl Acad. Sci. USA 106, 9350-9355 (2009).
27. McGarry, J. D. What if Minkowski had been ageusic? An alternative angle on diabetes. Science 258, 766-770 (1992)
28. Barroso, I. et al. Dominant negative mutations in human PPARc associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 402, 880-883 (1999).
29. Shackleton, S. et al. LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nature Genet. 24, 153-156 (2000).
30. Magré, J. et al. Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nature Genet. 28, 365-370 (2001).
31. Agarwal, A. K. et al. AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nature Genet. 31, 21-23 (2002).
32. Kim, C. A. et al. Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy. J. Clin. Endocrinol. Metab. 93, 1129-1134 (2008).
33. Rubio-Cabezas, O. et al. Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC. EMBO Mol. Med 1, 280-287 (2009).
34. McCarthy, M. I. & Zeggini, E. Genome-wide association studies in type 2 diabetes. Curr. Diab. Rep. 9, 164-171 (2009).
35. Stancáková, A. et al. Association of 18 confirmed susceptibility loci for type 2 diabetes with indices of insulin release, proinsulin conversion, and insulin sensitivity in 5,327 non-diabetic Finnish Men. Diabetes 58, 2129-2136 (2009).
36. Pascoe, L. et al. Common variants of the novel type 2 diabetes genes CDKAL1 and HHEX/IDE are associated with decreased pancreatic beta-cell function. Diabetes 56, 3101-3104 (2007).
37. Grarup, N. et al. Studies of association of variants near the HHEX, CDKN2A/B, and IGF2BP2 genes with type 2 diabetes and impaired insulin release in 10,705 Danish subjects: validation and extension of genome-wide association studies. Diabetes 56, 3105-3111 (2007).
38. Palmer, N. D. et al. Association of TCF7L2 gene polymorphisms with reduced acute insulin response in Hispanic Americans. J. Clin. Endocrinol. Metab. 93, 304-309 (2008).
39. Palmer, N. D. et al. Quantitative trait analysis of type 2 diabetes susceptibility loci identified from whole genome association studies in the Insulin Resistance Atherosclerosis Family Study. Diabetes 57, 1093-1100 (2008).
40. Bouatia-Naji, N. et al. A polymorphism within the G6PC2 gene is associated with fasting plasma glucose levels. Science 320, 1085-1088 (2008).
41. Bouatia-Naji, N. et al. A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk. Nature Genet. 41, 89-94 (2009).
42. Prokopenko, I. et al. Variants in MTNR1B influence fasting glucose levels. Nature Genet. 41, 77-81 (2009).
43. Porte, D. Jr & Kahn, S. E. The key role of islet dysfunction in type II diabetes mellitus. Clin. Invest. Med. 18, 247-254 (1995).
44. Tuomilehto, J. et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N. Engl. J. Med. 344, 1343-1350 (2001). (Pubitemid 32378388)
45. Reaven, G. M. The fourth musketeer-from Alexandre Dumas to Claude Bernard. Diabetologia 38, 3-13 (1995).
46. Højlund, K., Mogensen, M., Sahlin, K. & Beck-Nielsen, H. Mitochondrial dysfunction in type 2 diabetes and obesity. Endocrinol. Metab. Clin. North Am. 37, 713-731 (2008).
47. Harding, H. P. & Ron, D. Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes 51 (Suppl. 3), S455-S461 (2002). (Pubitemid 35403430)
48. Shoelson, S. E., Lee, J. & Goldfine, A. B. Inflammation and insulin resistance. J. Clin. Invest. 116, 1793-1801 (2006).
49. van den Ouweland, J. M. et al. Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nature Genet. 1, 368-371 (1992).
50. Inoue, H. et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nature Genet. 20, 143-148 (1998).
51. Sandhu, M. S. et al. Common variants in WFS1 confer risk of type 2 diabetes. Nature Genet. 39, 951-953 (2007).
52. Fonseca, S. G. et al. WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells. J. Biol. Chem. 280, 39609-39615 (2005).
53. Delépine, M. et al. EIF2AK3, encoding translation initiation factor 2-a kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nature Genet. 25, 406-409 (2000)
54. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661-678 (2007).
55. Meigs, J. B. et al. Genotype score in addition to common risk factors for prediction of type 2 diabetes. N. Engl. J. Med. 359, 2208-2219 (2008).
56. Lyssenko, V. et al. Clinical risk factors, DNA variants, and the development of type 2 diabetes. N. Engl. J. Med. 359, 2220-2232 (2008).
57. Hattersley, A. T. & Pearson, E. R. Minireview: pharmacogenetics and beyond: the interaction of therapeutic response, beta-cell physiology, and genetics in diabetes. Endocrinology 147, 2657-2663 (2006).
58. Kopelman, P. G. Obesity as a medical problem. Nature 404, 635-643 (2000).
59. Jéquier, E. Energy expenditure in obesity. Clin. Endocrinol. Metab. 13, 563-580 (1984).
60. Lissner, L. Measuring food intake in studies of obesity. Public Health Nutr. 5, 889-892 (2002).
61. Montague, C. T. et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903-908 (1997).
62. Jackson, R. S. et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nature Genet. 16, 303-306 (1997).
63. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425-432 (1994
64. Huszar, D. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131-141 (1997).
65. O'Rahilly, S. & Farooqi, I. S. Human obesity: a heritable neurobehavioral disorder that is highly sensitive to environmental conditions. Diabetes 57, 2905-2910 (2008).
66. Krakoff, J. et al. Lower metabolic rate in individuals heterozygous for either a frameshift or a functional missense MC4R variant. Diabetes 57, 3267-3272 (2008).
67. Nogueiras, R. et al. The central melanocortin system directly controls peripheral lipid metabolism. J. Clin. Invest. 117, 3475-3488 (2007).
68. Badano, J. L., Mitsuma, N., Beales, P. L. & Katsanis, N. The ciliopathies: an emerging class of human genetic disorders. Annu. Rev. Genomics Hum. Genet. 7, 125-148 (2006).
69. Frayling, T. M. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889-894 (2007).
70. Dina, C. et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nature Genet. 39, 724-726 (2007).
71. Gerken, T. et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 318, 1469-1472 (2007).
72. Cecil, J. E. et al. An obesity-associated FTO gene variant and increased energy intake in children. N. Engl. J. Med. 359, 2558-2566 (2008).
73. Fischer, J. et al. Inactivation of the Fto gene protects from obesity. Nature 458, 894-898 (2009).
74. Loos, R. J. et al. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nature Genet. 40, 768-775 (2008).
75. Qi, L., Kraft, P., Hunter, D. J. & Hu, F. B. The common obesity variant near MC4R gene is associated with higher intakes of total energy and dietary fat, weight change and diabetes risk in women. Hum. Mol. Genet. 17, 3502-3508 (2008).
76. Willer, C. J. et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nature Genet. 41, 25-34 (2009).
77. Rung, J. et al. Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia. Nature Genet. 41, 1110-1115 (2009).
78. Lindgren, C. M. et al. Genome-wide association scan meta-analysis identifies three loci influencing adiposity and fat distribution. PLoS Genet. 5, e1000508 (2009).
79. Temple, I. K. et al. An imprinted gene(s) for diabetes? Nature Genet. 9, 110-112 (1995).
80. Mackay, D. J. et al. Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nature Genet. 40, 949-951 (2008).
81. Ræder, H. et al. Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nature Genet. 38, 54-62 (2006).
82. Hearn, T. et al. Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alström syndrome. Nature Genet. 31, 79-83 (2002).
83. Collin, G. B. et al. Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alström syndrome. Nature Genet. 31, 74-78 (2002).
84. McCarthy, M. I. & Hattersley, A. T. Learning from molecular genetics: novel insights arising from the definition of genes for monogenic and type 2 diabetes. Diabetes 57, 2889-2898 (2008).
85. Zeggini, E. et al. Meta analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type-2 diabetes. Nature Genet. 40, 638-645 (2008).
86. Deeb, S. S. et al. A Pro12Ala substitution in PPARc2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nature Genet. 20, 284-287 (1998).
87. Saxena, R. et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316, 1331-1336 (2007).
88. Zeggini, E. et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316, 1336-1341 (2007).
89. Scott, L. et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316, 1341-1345 (2007).
90. Steinthorsdottir, V. et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nature Genet. 39, 770-775 (2007).
91. Sladek, R. et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445, 881-885 (2007).
92. Grant, S. F. et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nature Genet. 38, 320-323 (2006).
93. Florez, J. C. Haplotype structure and genotype-phenotype correlations of the sulphonylurea receptor and the islet ATP-sensitive potassium channel gene region. Diabetes 53, 1360-1368 (2004).
94. Gudmundsson, J. et al. Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nature Genet. 39, 977-983 (2007).
95. Clément, K. et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392, 398-401 (1998).
96. Krude, H. et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nature Genet. 19, 155-157 (1998).
97. Vaisse, C., Clement, K., Guy-Grand, B. & Froguel, P. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nature Genet. 20, 113-114 (1998).
98. Yeo, G. S. et al. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nature Genet. 20, 111-112 (1998).
99. Holder, J. L. Jr, Butte, N. F. & Zinn, A. R. Profound obesity associated with a balanced translocation that disrupts the SIM1 gene. Hum. Mol. Genet. 9, 101-108 (2000).
100. Sahoo, T. et al. Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster. Nature Genet. 40, 719-721 (2008).
101. Spiegel, A. Albright's hereditary osteodystrophy and defective G proteins. N. Engl. J. Med. 322, 1461-1462 (1990).
102. Gray, J. et al. Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene. Diabetes 55, 3366-3371 (2006).
103. Han, J. C. et al. Brain-derived neurotrophic factor and obesity in the WAGR syndrome. N. Engl. J. Med. 359, 918-927 (2008); erratum 359, 1414 (2008).
104. Yeo, G. S. et al. A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nature Neurosci. 7, 1187-1189 (2004
105. Beales, P. R., Farooqi, I. S. & O'Rahilly, S. (eds) Genetics of Obesity Syndromes (Oxford Univ. Press, 2009).
106. Thorleifsson, G. et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nature Genet. 41, 18-24 (2009).
107. Benzinou, M. et al. Common nonsynonymous variants in PCSK1 confer risk of obesity. Nature Genet. 40, 943-945 (2008).
108. Meyre, D. et al. Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations. Nature Genet. 41, 157-159 (2009