Current Diabetes Reports

, Volume 10, Issue 6, pp 467–475 | Cite as

Genetics of Diabetes Complications

  • Alessandro DoriaEmail author


A large body of evidence indicates that the risk for developing chronic diabetic complications is under the control of genetic factors. Previous studies using a candidate gene approach have uncovered a number of genetic loci that may shape this risk, such as the VEGF gene for retinopathy, the ELMO1 gene for nephropathy, and the ADIPOQ gene for coronary artery disease. Recently, a new window has opened on identifying these genes through genome-wide association studies. Such systematic approach has already led to the identification of a major locus for coronary artery disease on 9p21 as well three potential genes for nephropathy on 7p, 11p, and 13q. Further insights are expected from a broader application of this strategy. It is anticipated that the identification of these genes will provide novel insights on the etiology of diabetic complications, with crucial implications for the development of new drugs to prevent the adverse effects of diabetes.


Diabetic nephropathy Diabetic retinopathy Coronary artery disease Atherosclerosis Polymorphisms Candidate genes Genome-wide association studies 

Clinical Trial Acronyms


Diabetes Control and Complications Trial


Epidemiology of Diabetes Interventions and Complications


Genetics of Kidneys in Diabetes



Results of the author’s work described in this article were supported by National Institutes of Health grants HL73168, HL71981, and DK36836.


No potential conflict of interest relevant to this article was reported.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Krolewski AS, Warram JH: Epidemiology of late complications of diabetes: a basis for the development and evaluation of preventive program. In Joslin’s Diabetes Mellitus. Edited by Kahn CR, Weir GC, King GL, Jacobson AM, Moses AC, Smith RJ. New York: Lippincott, Williams & Wilkins; 2005:795–808.Google Scholar
  2. 2.
    The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group [no authors listed]. N Engl J Med 1993, 329:977–986.Google Scholar
  3. 3.
    Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group [no authors listed]. Lancet 1998, 352:837–853.Google Scholar
  4. 4.
    Hoerger TJ, Segel JE, Gregg EW, Saaddine JB: Is glycemic control improving in U.S. adults? Diabetes Care 2008, 31:81–86.CrossRefPubMedGoogle Scholar
  5. 5.
    Quinn M, Angelico MC, Warram JH, Krolewski AS: Familial factors determine the development of diabetic nephropathy in patients with IDDM. Diabetologia 1996, 39:940–945.CrossRefPubMedGoogle Scholar
  6. 6.
    Fogarty DG, Rich SS, Hanna L, et al.: Urinary albumin excretion in families with type 2 diabetes is heritable and genetically correlated to blood pressure. Kidney Int 2000, 57:250–257.CrossRefPubMedGoogle Scholar
  7. 7.
    Lange LA, Bowden DW, Langefeld CD et al.: Heritability of carotid artery intima-medial thickness in type 2 diabetes. Stroke 2002, 33:1876–1881.CrossRefPubMedGoogle Scholar
  8. 8.
    Wagenknecht LE, Bowden DW, Carr JJ, et al.: Familial aggregation of coronary artery calcium in families with type 2 diabetes. Diabetes 2001, 50:861–866.CrossRefPubMedGoogle Scholar
  9. 9.
    Arar NH, Freedman BI, Adler SG, et al.: Heritability of the severity of diabetic retinopathy: the FIND-Eye study. Invest Ophthalmol Vis Sci 2008, 49:3839–3845.CrossRefPubMedGoogle Scholar
  10. 10.
    Hietala K, Forsblom C, Summanen P, Groop PH: Heritability of proliferative diabetic retinopathy. Diabetes 2008, 57:2176–2180.CrossRefPubMedGoogle Scholar
  11. 11.
    Greene DA, Lattimer SA, Sima AA: Sorbitol, phosphoinositides, and sodium-potassium-ATPase in the pathogenesis of diabetic complications. N Engl J Med 1987, 316:599–606.CrossRefPubMedGoogle Scholar
  12. 12.
    Ko BC, Lam KS, Wat NM, Chung SS: An (A-C)n dinucleotide repeat polymorphic marker at the 5′ end of the aldose reductase gene is associated with early-onset diabetic retinopathy in NIDDM patients. Diabetes 1995, 44:727–732.CrossRefPubMedGoogle Scholar
  13. 13.
    Heesom AE, Hibberd ML, Millward A, Demaine AG: Polymorphism in the 5′-end of the aldose reductase gene is strongly associated with the development of diabetic nephropathy in type I diabetes. Diabetes 1997, 46:287–291.CrossRefPubMedGoogle Scholar
  14. 14.
    • Abhary S, Hewitt AW, Burdon KP, Craig JE: A systematic meta-analysis of genetic association studies for diabetic retinopathy. Diabetes 2009, 58:2137–2147. This is the first attempt to summarize the findings on the role of aldose reductase gene in shaping susceptibility to diabetic retinopathy.CrossRefPubMedGoogle Scholar
  15. 15.
    So WY, Wang Y, Ng MC, et al.: Aldose reductase genotypes and cardiorenal complications: an 8-year prospective analysis of 1,074 type 2 diabetic patients. Diabetes Care 2008, 31:2148–2153.CrossRefPubMedGoogle Scholar
  16. 16.
    Leung DW, Cachianes G, Kuang WJ, et al.: Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989, 246:1306–1309.CrossRefPubMedGoogle Scholar
  17. 17.
    Jardeleza MS, Miller JW: Review of anti-VEGF therapy in proliferative diabetic retinopathy. Semin Ophthalmol 2009, 24:87–92.CrossRefPubMedGoogle Scholar
  18. 18.
    • Al Kateb H, Mirea L, Xie X, et al.: Multiple variants in vascular endothelial growth factor (VEGFA) are risk factors for time to severe retinopathy in type 1 diabetes: the DCCT/EDIC genetics study. Diabetes 2007, 56:2161–2168. This is a systematic study of genetic variability in VEGF as a determinant of the risk of diabetic retinopathy.CrossRefGoogle Scholar
  19. 19.
    Ng DP, Krolewski AS: Molecular genetic approaches for studying the etiology of diabetic nephropathy. Curr Mol Med 2005, 5:509–525.CrossRefPubMedGoogle Scholar
  20. 20.
    Shimazaki A, Tanaka Y, Shinosaki T, et al.: ELMO1 increases expression of extracellular matrix proteins and inhibits cell adhesion to ECMs. Kidney Int 2006, 70:1769–1776.CrossRefPubMedGoogle Scholar
  21. 21.
    Shimazaki A, Kawamura Y, Kanazawa A, et al.: Genetic variations in the gene encoding ELMO1 are associated with susceptibility to diabetic nephropathy. Diabetes 2005, 54:1171–1178.CrossRefPubMedGoogle Scholar
  22. 22.
    •• Pezzolesi MG, Katavetin P, Kure M, et al.: Confirmation of genetic associations at ELMO1 in the GoKinD collection supports its role as a susceptibility gene in diabetic nephropathy. Diabetes 2009, 58:2698–2702. This is an extension of the findings of association between variants at the ELMO1 genes and diabetic nephropathy to European whites. The paper shows how information about candidate genes can be extracted from GWAS.CrossRefPubMedGoogle Scholar
  23. 23.
    • Leak TS, Perlegas PS, Smith SG, et al.: Variants in intron 13 of the ELMO1 gene are associated with diabetic nephropathy in African Americans. Ann Hum Genet 2009, 73:152–159. This study extends the finding of association between variants at the ELMO1 genes and diabetic nephropathy to African Americans.CrossRefPubMedGoogle Scholar
  24. 24.
    • Tong Z, Yang Z, Patel S, et al.: Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications. Proc Natl Acad Sci U S A 2008, 105:6998–7003. This study shows that a variant affecting expression of the angiogenic factor EPO may underlie the simultaneous occurrence of diabetic proliferative retinopathy and ESRD.CrossRefPubMedGoogle Scholar
  25. 25.
    Scherer PE, Williams S, Fogliano M, et al.: A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 1995, 270:26746–26749.CrossRefPubMedGoogle Scholar
  26. 26.
    Kadowaki T, Yamauchi T: Adiponectin and adiponectin receptors. Endocr Rev 2005, 26:439–451.CrossRefPubMedGoogle Scholar
  27. 27.
    Qi L, Doria A, Manson JE, et al.: Adiponectin genetic variability, plasma adiponectin, and cardiovascular risk in patients with type 2 diabetes. Diabetes 2006, 55:1512–1516.CrossRefPubMedGoogle Scholar
  28. 28.
    Soccio T, Zhang YY, Bacci S, et al.: Common haplotypes at the adiponectin receptor 1 (ADIPOR1) locus are associated with increased risk of coronary artery disease in type 2 diabetes. Diabetes 2006, 55:2763–2770.CrossRefPubMedGoogle Scholar
  29. 29.
    Zhang YY, Boonyasrisawat W, Xu R, et al.: Polymorphisms at the adiponectin receptor T-Cadherin (CDH13) locus are associated with increased cardiovascular risk in type 2 diabetes. Diabetes 2007, 56:A303.Google Scholar
  30. 30.
    Daly MJ, Rioux JD, Schaffner SF, et al.: High-resolution haplotype structure in the human genome. Nat Genet 2001, 29:229–232.CrossRefPubMedGoogle Scholar
  31. 31.
    Frazer KA, Ballinger DG, Cox DR, et al.: A second generation human haplotype map of over 3.1 million SNPs. Nature 2007, 449:851–861.CrossRefPubMedGoogle Scholar
  32. 32.
    Sapolsky RJ, Hsie L, Berno A, et al.: High-throughput polymorphism screening and genotyping with high-density oligonucleotide arrays. Genet Anal 1999, 14:187–192.PubMedGoogle Scholar
  33. 33.
    •• Pezzolesi MG, Poznik GD, Mychaleckyj JC, et al.: Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes. Diabetes 2009, 58:1403–1410. This is the only GWAS that has been performed to date for diabetic nephropathy.CrossRefPubMedGoogle Scholar
  34. 34.
    • Maeda S, Araki SI, Babazono T, et al.: Replication study for the association between 4 loci identified by a genome-wide association study on European American subjects with type 1 diabetes and susceptibility to diabetic nephropathy in Japanese subjects with type 2 diabetes. Diabetes 2010, 59:2075–2079. This is the first attempt to replicate GWAS findings for diabetic nephropathy in Asians. It provides some evidence of replication for two of the association signals.CrossRefPubMedGoogle Scholar
  35. 35.
    Hoover KB, Bryant PJ: The genetics of the protein 4.1 family: organizers of the membrane and cytoskeleton. Curr Opin Cell Biol 2000, 12:229–234.CrossRefPubMedGoogle Scholar
  36. 36.
    Town M, Jean G, Cherqui S, et al.: A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis. Nat Genet 1998, 18:319–324.CrossRefPubMedGoogle Scholar
  37. 37.
    Riad A, Zhuo JL, Schultheiss HP, Tschope C: The role of the renal kallikrein-kinin system in diabetic nephropathy. Curr Opin Nephrol Hypertens 2007, 16:22–26.CrossRefPubMedGoogle Scholar
  38. 38.
    • Erdmann J, Grosshennig A, Braund PS, et al.: New susceptibility locus for coronary artery disease on chromosome 3q22.3. Nat Genet 2009, 41:280–282. This is one of the most recent GWAS for CAD in the general population.CrossRefPubMedGoogle Scholar
  39. 39.
    •• Helgadottir A, Thorleifsson G, Manolescu A, et al.: A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 2007, 316:1491–1493. This is one of the first two reports of the association between chromosome 9p21 locus and CAD.CrossRefPubMedGoogle Scholar
  40. 40.
    •• Kathiresan S, Voight BF, Purcell S, et al.: Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet 2009, 41:334–341. This is the largest GWAS effort to date to identify common genetic variants predisposing to early-onset myocardial infarction in the general population.CrossRefPubMedGoogle Scholar
  41. 41.
    •• McPherson R, Pertsemlidis A, Kavaslar N, et al.: A common allele on chromosome 9 associated with coronary heart disease. Science 2007, 316:1488–1491. This is one of the first two reports of the association between chromosome 9p21 and CAD.CrossRefPubMedGoogle Scholar
  42. 42.
    Samani NJ, Erdmann J, Hall AS, et al.: Genomewide association analysis of coronary artery disease. N Engl J Med 2007, 357:443–453.CrossRefPubMedGoogle Scholar
  43. 43.
    • Tregouet DA, Konig IR, Erdmann J, et al.: Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease. Nat Genet 2009, 41:283–285. This is one of the most recent GWAS for CAD in the general population.CrossRefPubMedGoogle Scholar
  44. 44.
    •• Wellcome Trust Case Control Consortium: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007, 447:661–678. This is a landmark report describing the coordinated effort to map genes for several common disorders through the GWAS approach. It is useful to understand how GWAS are designed and analyzed.Google Scholar
  45. 45.
    Abifadel M, Varret M, Rabes JP, et al.: Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003, 34:154–156.CrossRefPubMedGoogle Scholar
  46. 46.
    • Doria A, Wojcik J, Xu R, et al.: Interaction between poor glycemic control and 9p21 locus on risk of coronary artery disease in type 2 diabetes. JAMA 2008, 300:2389–2397. This paper shows that the 9p21 locus has an especially powerful effect on cardiovascular risk among diabetic subjects because of an interaction with the diabetic milieu.CrossRefPubMedGoogle Scholar
  47. 47.
    Meigs JB, Shrader P, Sullivan LM, et al.: Genotype score in addition to common risk factors for prediction of type 2 diabetes. N Engl J Med 2008, 359:2208–2219.CrossRefPubMedGoogle Scholar
  48. 48.
    Broadbent HM, Peden JF, Lorkowski S, et al.: Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p. Hum Mol Genet 2008, 17:806–814.CrossRefPubMedGoogle Scholar
  49. 49.
    • Jarinova O, Stewart AF, Roberts R, et al.: Functional analysis of the chromosome 9p21.3 coronary artery disease risk locus. Arterioscler Thromb Vasc Biol 2009, 29:1671–1677. This paper shows that the 9p21 CVD-associated haplotype is associated with different transcripts of the noncoding gene ANRIL.CrossRefPubMedGoogle Scholar
  50. 50.
    Kamb A, Gruis NA, Weaver-Feldhaus J, et al.: A cell cycle regulator potentially involved in genesis of many tumor types. Science 1994, 264:436–440.CrossRefPubMedGoogle Scholar
  51. 51.
    •• Visel A, Zhu Y, May D, et al.: Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice. Nature 2010, 464:409–412. This is the first experimental demonstration that the 9p21 region where the variants predisposing to CAD are located is involved in the regulation of the CDKN2A/2B genes and controls cell proliferation.CrossRefPubMedGoogle Scholar
  52. 52.
    Natarajan R, Gonzales N, Xu L, Nadler JL: Vascular smooth muscle cells exhibit increased growth in response to elevated glucose. Biochem Biophys Res Commun 1992, 187:552–560.CrossRefPubMedGoogle Scholar
  53. 53.
    Qi L, Parast L, Powers C, et al.: A genetic risk score to improve the prediction of coronary artery disease in type 2 diabetes. Diabetes 2010, 59:A217.Google Scholar
  54. 54.
    Novelli V, Powers C, Gervino EV, et al.: Common genetic variants at the PHACTR1 locus are major determinants of coronary artery disease among individuals with type 2 diabetes. Diabetes 2010, 59:A219.CrossRefGoogle Scholar
  55. 55.
    Reich DE, Lander ES: On the allelic spectrum of human disease. Trends Genet 2001, 17:502–510.CrossRefPubMedGoogle Scholar
  56. 56.
    Fearnhead NS, Wilding JL, Winney B, et al.: Multiple rare variants in different genes account for multifactorial inherited susceptibility to colorectal adenomas. Proc Natl Acad Sci U S A 2004, 101:15992–15997.CrossRefPubMedGoogle Scholar
  57. 57.
    Feuk L, Carson AR, Scherer SW: Structural variation in the human genome. Nat Rev Genet 2006, 7:85–97.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Section on Genetics & EpidemiologyJoslin Diabetes CenterBostonUSA

Personalised recommendations