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Genetics of diabetes complications

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Abstract

Long-term exposure to the hyperglycemia characteristic of diabetes patients leads to serious and frequently disabling or fatal complications. Emerging evidence suggests that genes are a significant contributor to an individual's risk of developing complications. This evidence is from evaluations of familial aggregation, differences in incidence in racial and ethnic groups, and statistical analysis of family data. Evidence to date suggests that complication genes are distinct from the genes contributing to diabetes.

Molecular geneticists have taken several approaches to identify genes contributing to complications, ranging from relatively simple analysis of specific candidate genes in small case-control comparisons to systematic evaluations of the human genome using genome scans and linkage analysis in large collections of families. Results suggest that genetic contributions to diabetes complications are diverse and complex in nature, presenting a significant challenge to researchers. Diabetes-affected families are frequently enriched for complications such as cardiovascular disease or nephropathy. In addition to their value in the study of diabetes complications, such families may be valuable resources for understanding cardiovascular disease and nephropathy in the nondiabetic population also.

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References and Recommended Reading

  1. National Diabetes Data Group: Diabetes in America, edn 2. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, NIH Publication No. 95-1468; 1995.

    Google Scholar 

  2. U.S. Renal Data System: USRDS 2001 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2001.

    Google Scholar 

  3. Gall MA, Rossing P, Skott P, et al.: Prevalence of micro- and macroalbuminuria, arterial hypertension, retinopathy and large vessel disease in European type 2 (non-insulindependent) diabetic patients. Diabetologia 1991, 34:655–661.

    Article  PubMed  CAS  Google Scholar 

  4. Seaquist ER, Goetz FC, Rich S, Barbosa J: Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 1989, 320:1161–1165.

    Article  PubMed  CAS  Google Scholar 

  5. Borch-Johnsen K, Norgaard K, Hommel E, et al.: Is diabetic nephropathy an inherited complication? Kidney Int 1992, 41:719–722.

    Article  PubMed  CAS  Google Scholar 

  6. The Diabetes Control and Complications Trial Research Group: Clustering of long-term complications in families with diabetes in the diabetes control and complications trial. Diabetes 1997, 46:1829–1839.

    Article  Google Scholar 

  7. Pettitt DJ, Saad MF, Bennett PH, et al.: Familial predisposition to renal disease in two generations of Pima Indians with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1990, 33:438–443.

    Article  PubMed  CAS  Google Scholar 

  8. Freedman BI, Tuttle AB, Spray BJ: Familial predisposition to nephropathy in African-Americans with non-insulindependent diabetes mellitus. Am J Kidney Dis 1995, 25:710–713.

    PubMed  CAS  Google Scholar 

  9. Bergman S, Key BO, Kirk KA, et al.: Kidney disease in the first-degree relatives of African-Americans with hypertensive end-stage renal disease. Am J Kidney Dis 1996, 27:341–346.

    PubMed  CAS  Google Scholar 

  10. Spray BJ, Atassi NG, Tuttle AB, Freedman BI: Familial risk, age at onset, and cause of end-stage renal disease in white Americans. J Am Soc Nephrol 1995, 10:1806–1810.

    Google Scholar 

  11. O'Dea DF, Murphy SW, Hefferton D, Parfrey PS: Higher risk for renal failure in first-degree relatives of white patients with end-stage renal disease: a population-based study. Am J Kidney Dis 1998, 32:794–801.

    PubMed  Google Scholar 

  12. Vijay V, Snehalatha C, Shina K, et al.: Familial aggregation of diabetic kidney disease in type 2 diabetes in south India. Diabetes Res Clin Pract 1999, 43:167–171.

    Article  PubMed  CAS  Google Scholar 

  13. Canani LH, Gerchman F, Gross JL: Familial clustering of diabetic nephropathy in Brazilian type 2 diabetic patients. Diabetes 1999, 48:909–913.

    Article  PubMed  CAS  Google Scholar 

  14. Fioretto P, Steffes MW, Barbosa J, et al.: Is diabetic nephropathy inherited? Studies of glomerular structure in type 1 diabetic sibling pairs. Diabetes 1999, 48:865–869. A unique study in which familial aggregation of diabetic nephropathy was revisited, but in this case combined with pathologic analysis of renal biopsies from the study subjects. The combination of a unique collection of patients and data is unlikely to be duplicated.

    Article  PubMed  CAS  Google Scholar 

  15. Brancati FL, Whittle JC, Whelton PK, et al.: The excess incidence of diabetic end-stage renal disease among blacks. A population-based study of potential explanatory factors. JAMA 1992, 268:3079–3084.

    Article  PubMed  CAS  Google Scholar 

  16. Freedman BI, Spray BJ, Tuttle AB, Buckalew VM Jr: The familial risk of end-stage renal disease in African Americans. Am J Kidney Dis 1993, 21:387–393.

    PubMed  CAS  Google Scholar 

  17. Lei HH, Perneger TV, Klag MJ, et al.: Familial aggregation of renal disease in a population-based case-control study. J Am Soc Nephrol 1998, 9:1270–1276.

    PubMed  CAS  Google Scholar 

  18. Powers DR, Wallin JD: End-stage renal disease in specific ethnic and racial groups: risk factors and benefits of antihypertensive therapy. Arch Intern Med 1998, 158:793–800.

    Article  PubMed  CAS  Google Scholar 

  19. Ball S, Lloyd J, Cairns T, et al.: Why is there so much end-stage renal failure of undetermined cause in UK Indo-Asians? QJM 2001, 94:187–193.

    Article  PubMed  CAS  Google Scholar 

  20. Fogarty DG, Hanna LS, Wantman M, et al.: Segregation analysis of urinary albumin excretion in families with type 2 diabetes. Diabetes 2000, 49:1057–1063. A sophisticated mathematical analysis leading to a quantitative, as opposed to qualitative, measure of the heritability of ACR, a surrogate for renal function.

    Article  PubMed  CAS  Google Scholar 

  21. Imperatore G, Knowler WC, Pettitt DJ, et al.: Segregation analysis of diabetic nephropathy in Pima Indians. Diabetes 2000, 49:1049–1056.

    Article  PubMed  CAS  Google Scholar 

  22. 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.

    Article  PubMed  CAS  Google Scholar 

  23. Rotimi C, Cooper R, Cao G, et al.: Familial aggregation of cardiovascular diseases in African-American pedigrees. Genet Epidemiol 1994, 11:397–407.

    Article  PubMed  CAS  Google Scholar 

  24. Nelson RG, Sievers ML, Knowler WC, et al.: Low incidence of fatal coronary heart disease in Pima Indians despite high prevalence of non-insulin-dependent diabetes. Circulation 1990, 81:987–995.

    PubMed  CAS  Google Scholar 

  25. Banerji MA, Lebovitz HE: Coronary heart disease risk factor profiles in black patients with non-insulin-dependent diabetes mellitus: paradoxic patterns. Am J Med 1991, 91:51–58.

    Article  PubMed  CAS  Google Scholar 

  26. Harris MI: Non-insulin-dependent diabetes mellitus in black and white Americans. Diabetes Care 1990, 6:71–90.

    Article  CAS  Google Scholar 

  27. Persson J, Stavenow L, Wikstrand J, et al.: Noninvasive quantification of atherosclerotic lesions. Reproducibility of ultrasonographic measurement of arterial wall thickness and plaque size. Arterioscler Thromb 1992, 12:261–266.

    PubMed  CAS  Google Scholar 

  28. Pignoli P, Tremoli E, Poli A, et al.: Intimal plus medial thickness of arterial wall: a direct measurement with ultrasound imaging. Circulation 1986, 74:1399–1406.

    PubMed  CAS  Google Scholar 

  29. Carr JJ, Crouse JR, Goff DC, et al.: Burke GL: Evaluation of subsecond gated helical CT for quantification of coronary artery calcium and comparison with electron beam CT. Am J Roentgenol 2000, 174:915–921.

    CAS  Google Scholar 

  30. Raggi P, Callister TQ, Cooil B, et al.: Identification of patients at increased risk of first unheralded acute myocardial infarction by electron-beam computed tomography. Circulation 2000, 101:850–855.

    PubMed  CAS  Google Scholar 

  31. Edmonds ME: Medial arterial calcification and diabetes mellitus. Z Kardiol 2000, 89(suppl 2):101–104

    Article  PubMed  Google Scholar 

  32. Narayan KM, Pettitt DJ, Hanson RL, et al.: Familial aggregation of medial arterial calcification in Pima Indians with and without diabetes. Diabetes Care 1996, 19:968–971.

    Article  PubMed  CAS  Google Scholar 

  33. 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. This is an initial report from the first study focused specifically on genetics of diabetes-associated CVD. This study uses state-of-the-art diagnostic technology for evaluation of subclinical atherosclerosis and analytical approaches for evaluating heritability.

    Article  PubMed  CAS  Google Scholar 

  34. Schurgin S, Rich S, Mazzone T: Increased prevalence of significant coronary artery calcification in patients with diabetes. Diabetes Care 2001, 24:335–338. The clearest report to date comparing CAC in diabetic and nondiabetic populations and demonstrating the dramatic enrichment for CAC, a measure of subclinical atherosclerosis, of individuals with diabetes.

    Article  PubMed  CAS  Google Scholar 

  35. Harris EL, Sherman SH, Georgopoulos A: Black-white differences in risk of developing retinopathy among individuals with type 2 diabetes. Diabetes Care 1999, 22:779–783.

    Article  PubMed  CAS  Google Scholar 

  36. Daly MJ, Rioux JD, Schaffner SF, et al.: High-resolution haplotype structure in the human genome. Nat Genet 2001, 29:229–232. A key study for designing and interpreting association data from case-control studies. This report summarizes the variable amount of linkage disequilibrium that can be observed in the human genome.

    Article  PubMed  CAS  Google Scholar 

  37. Skoog T, van't Hooft FM, Kallin B, et al.: A common functional polymorphism (CÆA substitution at position -863) in the promoter region of the tumour necrosis factor-alpha (TNF-alpha) gene associated with reduced circulating levels of TNF-alpha. Hum Mol Genet 1999, 8:1443–1449.

    Article  PubMed  CAS  Google Scholar 

  38. Shimajiri S, Arima N, Tanimoto A, et al.: Shortened microsatellite d(CA)21 sequence down-regulates promoter activity of matrix metalloproteinase 9 gene. FEBS Lett 1999, 455:70–74.

    Article  PubMed  CAS  Google Scholar 

  39. Maeda S, Haneda M, Guo B, et al.: Dinucleotide repeat polymorphism of matrix metalloproteinase-9 gene is associated with diabetic nephropathy. Kidney Int 2001, 60:1428–1434.

    Article  PubMed  CAS  Google Scholar 

  40. Staessen JA, Wang JG, Ginocchio G, et al.: The deletion/ insertion polymorphism of the angiotensin converting enzyme gene and cardiovascular-renal risk. J Hypertens 1997, 15:1579–1592.

    Article  PubMed  CAS  Google Scholar 

  41. Fujisawa T, Ikegami H, Kawaguchi Y, et al.: Meta-analysis of association of insertion/deletion polymorphism of angiotensin I-converting enzyme gene with diabetic nephropathy and retinopathy. Diabetologia 1998, 41:47–53.

    Article  PubMed  CAS  Google Scholar 

  42. Kunz R, Bork JP, Fritsche L, et al.: Association between the angiotensin- converting enzyme-insertion/deletion polymorphism and diabetic nephropathy: a methodologic appraisal and systematic review. J Am Soc Nephrol 1998, 9:1653–1663.

    PubMed  CAS  Google Scholar 

  43. Yu H, Bowden DW, Spray BJ, et al.: Linkage analysis between loci in the renin angiotensin axis and end-stage renal disease in African American. J Am Soc Nephrol 1996, 7:2559–2564.

    PubMed  CAS  Google Scholar 

  44. Freedman BI, Yu H, Rothschild CB, et al.: Genetic linkage analysis of growth factor loci and end-stage renal disease in African Americans. Kidney Int 1997, 51:819–825.

    Article  PubMed  CAS  Google Scholar 

  45. Yu H, Freedman BI, Rich SS, Bowden DW: Human Na+/H+ exchanger genes: identification of polymorphisms by radiation hybrid mapping and analysis of linkage in end-stage renal disease. Hypertension 2000, 35:135–143.

    PubMed  CAS  Google Scholar 

  46. Freedman BI, Yu H, Anderson PJ, et al.: Genetic analysis of nitric oxide and endothelin in end-stage renal disease. Nephrol Dial Transplant 2000, 15:1794–1800.

    Article  PubMed  CAS  Google Scholar 

  47. Yu H, Freedman BI, Spray BJ, et al.: Identification of human plasma kallikrein gene polymorphisms (KLK3) and evaluation of their role in end-stage renal disease. Hypertension 1998, 31:906–911.

    PubMed  CAS  Google Scholar 

  48. Yu H, Anderson PJ, Freedman BI, et al.: Genomic structure of the human plasma prekallikrein gene, identification of allelic variants, and analysis in end-stage renal disease. Genomics 2000, 69:225–234.

    Article  PubMed  CAS  Google Scholar 

  49. Moczulski DK, Rogus JJ, Antonellis A, et al.: Major susceptibility locus for nephropathy in type 1 diabetes on chromosome 3q: results of novel discordant sib-pair analysis. Diabetes 1998, 47:1164–1169.

    Article  PubMed  CAS  Google Scholar 

  50. Imperatore G, Hanson RL, Pettitt DJ, et al.: Sib-pair linkage analysis for susceptibility genes for microvascular complications among Pima Indians with type 2 diabetes. Pima Diabetes Genes Group. Diabetes 1998, 47:821–830.

    Article  PubMed  CAS  Google Scholar 

  51. Vardarli I, Janssen B, Baier LJ, et al.: Modifier gene for diabetic nephropathy (DIANPH) in type 2 diabetes maps to 18q22.3-23. J Am Soc Nephrol 2001, 12:160A.

    Google Scholar 

  52. Yu H, Sale M, Rich SS, et al.: Evaluation of markers on human chromosome 10, including the homologue of the rodent Rf-1 gene, for linkage to ESRD in African Americans. Am J Kidney Dis 1999, 33:294–300.

    PubMed  CAS  Google Scholar 

  53. Brown DM, Provoost AP, Daly MJ, et al.: Renal disease susceptibility and hypertension are under independent genetic control in the fawn-hooded rat. Nat Genet 1996, 12:44–51.

    Article  PubMed  CAS  Google Scholar 

  54. Freedman BI, Bowden DW, Roh BH, et al.: Linkage heterogeneity of end-stage renal disease on human chromosome 10. J Am Soc Nephrol 2001, 12:71A.

    Google Scholar 

  55. Freedman BI: Study design for the Family Investigation of Nephropathy and Diabetes (FIND). J Am Soc Nephrol 2001, 12:202A-203A

    Google Scholar 

  56. Cambien F: Genetics of atherosclerosis and its complications in type 2 diabetes. Lappeenranta, Finland: Proceedings of Atherosclerotic Vascular Diseases in Diabetes, July 25–27, 1997.

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Bowden, D.W. Genetics of diabetes complications. Curr Diab Rep 2, 191–200 (2002). https://doi.org/10.1007/s11892-002-0080-8

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  • DOI: https://doi.org/10.1007/s11892-002-0080-8

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