Current Diabetes Reports

, Volume 1, Issue 3, pp 275–281 | Cite as

Genetics of diabetic nephropathy in the pima indians

  • Giuseppina Imperatore
  • William C. Knowler
  • Robert G. Nelson
  • Robert L. Hanson
Article

Abstract

Diabetic nephropathy is the leading cause of renal failure in industrialized countries. There is strong evidence that diabetic nephropathy is influenced by genetic factors. Studies in the Pima Indians as well as in other populations demonstrate that diabetic nephropathy aggregates in families. The hypothesis that the familial aggregation reflects the effect of a major gene was formally tested by segregation analysis of diabetic nephropathy in Pima Indians with type 2 diabetes.

The segregation analysis provided strong evidence for a major genetic effect on the prevalence of diabetic nephropathy; this suggests that some of the genetic determinants of diabetic nephropathy may have effects of sufficient magnitude to be detected by linkage analysis. Therefore, we analyzed data from a genome-wide scan to identify susceptibility loci for nephropathy in diabetic Pima Indians. Analyses conducted by both parametric (model-based) and nonparametric methods revealed tentative evidence for nephropathy susceptibility loci on chromosomes 3q, 7q, 18q, and 20p.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    U. S. Renal Data System. 1999 annual data report [no authors listed]. Am J Kidney Dis 1999, 34(2 suppl 1):S9–S19.Google Scholar
  2. 2.
    Ritz E, Orth RS: Nephropathy in patients with type 2 diabetes mellitus. N Engl J Med 2000, 341:1127–1133.CrossRefGoogle Scholar
  3. 3.
    Knowler WC, Pettitt DJ, Hamman RF, Miller M: Diabetes incidence and prevalence in Pima Indians: a 19-fold greater incidence than in Rochester Minnesota. Am J Epidemiol 1978, 108:497–505.PubMedGoogle Scholar
  4. 4.
    Knowler WC, Bennett PH, Bottazzo GF, et al.: Islet cell antibodies and diabetes mellitus in Pima Indians. Diabetologia 1979, 17:161–164.PubMedCrossRefGoogle Scholar
  5. 5.
    Dabelea D, Palmer JP, Bennett PH, et al.: Absence of glutamic acid decarboxylase antibodies in Pima Indian children with diabetes mellitus. Diabetologia 1999, 42:1265–1266.PubMedCrossRefGoogle Scholar
  6. 6.
    Nelson RG, Newman JM, Knowler WC, et al.: Incidence of end-stage renal disease in type 2 (non-insulin-dependent) diabetes mellitus in Pima Indians. Diabetologia 1988, 31:730–736.PubMedCrossRefGoogle Scholar
  7. 7.
    Sievers ML, Nelson RG, Knowler WC, et al.: Impact of non-insulin dependent diabetes mellitus on mortality and causes of death in Pima Indians. Diabetes Care 1992, 15:1541–1549.PubMedCrossRefGoogle Scholar
  8. 8.
    Ginsberg JM, Chang BS, Matarese RS, et al.: Use of single voided urine samples to estimate quantitative proteinuria. N Engl J Med 1983, 309:1543–1546.PubMedCrossRefGoogle Scholar
  9. 9.
    Nelson RG, Knowler WC, Pettitt DJ, et al.: Kidney disease in diabetes. In Diabetes in America, edn 2. Edited by Harris MI. Bethesda, MD: National Institutes of Health; 1995:349–400.Google Scholar
  10. 10.
    Nelson RG, Knowler WC, Pettitt DJ, et al.: Assessment of risk of overt nephropathy in diabetic patients from albumin excretion in untimed urine specimens. Arch Intern Med 1991, 151:1761–1765.PubMedCrossRefGoogle Scholar
  11. 11.
    Nelson RG, Knowler WC, McCance DR, et al.: Determinants of end-stage renal disease in Pima Indians with type 2 (non-insulin-dependent) diabetes mellitus and proteinuria. Diabetologia 1993, 36:1087–1093.PubMedCrossRefGoogle Scholar
  12. 12.
    Nelson RG, Bennett PH, Beck GJ, et al.: Development and progression of renal disease in Pima Indians with noninsulin dependent diabetes mellitus. N Engl J Med 1996, 335:1636–1642.PubMedCrossRefGoogle Scholar
  13. 13.
    Pagtalunan ME, Miller PL, Jumping-Eagle S, et al.: Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest 1997, 99:342–348.PubMedGoogle Scholar
  14. 14.
    Pugh JA, Medina R, Ramirez M: Comparison of the course of end-stage renal disease of type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetic nephropathy. Diabetologia 1993, 36:1094–1098.PubMedCrossRefGoogle Scholar
  15. 15.
    Gall MA, Rossing P, Skøtt P, et al.: Prevalence of microalbuminuria, arterial hypertension, retinopathy, and large vessel disease in European type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1991, 34:655–661.PubMedCrossRefGoogle Scholar
  16. 16.
    Nelson RG, Kunzelman CL, Pettitt DJ, et al.: Albuminuria in type 2 (non-insulin-dependent) diabetes mellitus and impaired glucose tolerance in Pima Indians. Diabetologia 1989, 32:870–876.PubMedCrossRefGoogle Scholar
  17. 17.
    Ravid M, Brosh D, Ravid-Safran D, et al.: Main risk factors for nephropathy in type 2 diabetes mellitus are plasma cholesterol levels, mean blood pressure and hyperglycemia. Arch Intern Med 1998, 158:998–1004.PubMedCrossRefGoogle Scholar
  18. 18.
    Nelson RG, Knowler WC, Pettitt DJ, et al.: Incidence and determinants of elevated urinary albumin excretion in Pima Indians with NIDDM. Diabetes Care 1995, 18:182–187.PubMedCrossRefGoogle Scholar
  19. 19.
    Seaquist ER, Goetz FC, Rich S, et al.: Familial clustering of diabetic kidney disease: evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 1989, 320:1161–1165.PubMedCrossRefGoogle Scholar
  20. 20.
    Freedman BI, Tuttle AB, Spary BJ: Familial predisposition to nephropathy in African-Americans with non-insulindependent diabetes mellitus. Am J Kidney Dis 1995, 25:710–713.PubMedGoogle Scholar
  21. 21.
    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.PubMedGoogle Scholar
  22. 22.
    Faronato PP, Maioli M, Tonolo G, et al.: Clustering of albumin excretion rate abnormalities in Caucasian patients with NIDDM. Diabetologia 1997, 40:816–823.PubMedCrossRefGoogle Scholar
  23. 23.
    Canani LH, Gerchman F, Gross JL: Familial clustering of diabetic nephropathy in Brazilian type 2 diabetic patients. Diabetes 1999, 48:909–913.PubMedCrossRefGoogle Scholar
  24. 24.
    Forsblom CM, Kanninen T, Lehtovirta M, et al.: Heritability of albumin excretion rate in families of patients with type II diabetes. Diabetologia 1999, 42:1359–1366.PubMedCrossRefGoogle Scholar
  25. 25.
    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.PubMedCrossRefGoogle Scholar
  26. 26.
    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.PubMedCrossRefGoogle Scholar
  27. 27.
    Imperatore G, Knowler WC, Pettitt DJ, et al.: Segregation analysis of diabetic nephropathy in Pima Indians. Diabetes 2000, 49:1049–1056. Shows that the familial aggregation of nephropathy in diabetic Pima Indians is consistent with the action of at least one major gene.PubMedCrossRefGoogle Scholar
  28. 28.
    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.PubMedCrossRefGoogle Scholar
  29. 29.
    Elston RC: Linkage and association. Genet Epidemiol 1998, 15:565–576.PubMedCrossRefGoogle Scholar
  30. 30.
    Knowler WC: Approaches to studying the genetics of type 2 diabetes. In Current Topics in Diabetes Research. Front Diabetes. Edited by Belfiore F et al. Basel, Switzerland: Kanger Press; 1993:1–11.Google Scholar
  31. 31.
    Durner M, Vieland VJ, Greenberg DA: Further evidence for the increased power of LOD scores compared with nonparametric methods. Am J Hum Genet 1999, 64:281–289.PubMedCrossRefGoogle Scholar
  32. 32.
    Dizier MH, Babron MC, Clerget-Darpoux F: Conclusion of LOD-score analysis for family data generated under two-locus models. Am J Hum Genet 1996, 58:1338–1346.PubMedGoogle Scholar
  33. 33.
    Rogus JJ, Krolewski AS: Using discordant sib pairs to map loci for qualitative traits with high sibling recurrence risk. Am J Hum Genet 1996, 59:1376–1381.PubMedGoogle Scholar
  34. 34.
    Terwilliger JD, Ott J: Parametric analysis of complex diseases. In Handbook of Human Genetic Linkage. Edited by Terwilliger JD, Ott J. Baltimore, MD: The Johns Hopkins University Press; 1994:211–226.Google Scholar
  35. 35.
    Hanson RL, Ehm MG, Pettitt DJ, et al.: An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians. Am J Hum Genet 1998, 63:1130–1138. Represents a large genomic scan to identify loci influencing susceptibility to diabetes and obesity in the Pima Indians. A diabetessusceptibility locus was identified on chromosome 1q and a diabetesobesity locus on chromosome 11q.PubMedCrossRefGoogle Scholar
  36. 36.
    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. Diabetes 1998, 47:821–830. Depicts to our knowledge the first genomic scan to identify diabetic nephropathy susceptibility genes. Tentative evidence for linkage was seen on chromosomes 3q, 7q, and 20p.PubMedCrossRefGoogle Scholar
  37. 37.
    Elston RC: Genetic analysis workshop II: sib-pair screening tests for linkage. Genet Epidemiol 1984, 1:175–178.PubMedCrossRefGoogle Scholar
  38. 38.
    Fogarty DG, Moczulski DK, Makita Y, et al.: Evidence for a susceptibility locus for diabetic nephropathy on chromosome 7q in Caucasian families with type 2 diabetes [abstract]. Diabetes 1999, 48(suppl 1):A47.Google Scholar
  39. 39.
    Cottingham RW, Idury RM, Schäffer AA: Faster sequential genetic linkage computations. Am J Hum Genet 1993, 53:252–263.PubMedGoogle Scholar
  40. 40.
    Lathrop GM, Lalouel JM, Julier C, Ott J: Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci U S A 1984, 81:3443–3446.PubMedCrossRefGoogle Scholar
  41. 41.
    Curtis D, Gurling H: A procedure for combining two-point lod scores into a summary multipoint map. Hum Hered 1993, 43:173–185.PubMedCrossRefGoogle Scholar
  42. 42.
    Lander ES, Kruglyak L: Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995, 11:241–247.PubMedCrossRefGoogle Scholar
  43. 43.
    Davis S, Weeks DE: Comparison of nonparametric statistics for detection of linkage in nuclear families: single-marker evaluation. Am J Hum Genet 1997, 61:1431–1444.PubMedCrossRefGoogle Scholar
  44. 44.
    Greenwood CMT, Bull SB: Down-weighting of multiple affected sib pairs leads to biased likelihood-ratio test, under the assumption of no linkage. Am J Hum Genet 1999, 64:1248–1252.PubMedCrossRefGoogle Scholar
  45. 45.
    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.PubMedCrossRefGoogle Scholar
  46. 46.
    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.PubMedCrossRefGoogle Scholar
  47. 47.
    Moczulski DK, Burak W, Doria A, et al.: The role of aldose reductase gene in the susceptibility to diabetic nephropathy in type II (non-insulin-dependent) diabetes mellitus. Diabetologia 1999, 42:94–97.PubMedCrossRefGoogle Scholar
  48. 48.
    Moczulski DK, Scott L, Antonellis A, et al.: Aldose reductase gene polymorphisms and susceptibility to diabetic nephropathy in type 1 diabetes mellitus. Diabet Med 2000, 17:111–118.PubMedCrossRefGoogle Scholar
  49. 49.
    Zanchi A, Moczulski DK, Hanna LS, et al.: Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism. Kidney Int 2000, 57:405–413.PubMedCrossRefGoogle Scholar
  50. 50.
    Neugebauer S, Baba T, Watanabe T: Association of the nitric oxide synthase gene polymorphism with an increased risk for progression to diabetic nephropathy in type 2 diabetes. Diabetes 2000, 49:500–503.PubMedCrossRefGoogle Scholar
  51. 51.
    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.PubMedCrossRefGoogle Scholar
  52. 52.
    Bond JS, Rojas K, Overhauser J, et al.: The structural genes, MEP1A and MEP1B, for the alpha and beta subunits of the metalloendopeptidase meprin map to human chromosomes 6p and 18q, respectively. Genomics 1995, 25:300–303.PubMedCrossRefGoogle Scholar
  53. 53.
    Bond JS, Marchand P, Tang J, et al.: Structure and membrane association of mouse and rat meprins. In The Astacins: Structure and Function of a New Protein Family. Edited by Zwilling R, Stocker W. Heidelberg, Germany: Springer-Verlag Publishers; 1997:45–55.Google Scholar
  54. 54.
    Wolz RL, Bond JS: Meprins A and B. Methods Enzymol 1995, 248:325–345.PubMedCrossRefGoogle Scholar
  55. 55.
    The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993, 329:977–986.CrossRefGoogle Scholar
  56. 56.
    Lewis EJ, Hunsisker LG, Bain RP, et al.: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993, 329:1456–1462.PubMedCrossRefGoogle Scholar
  57. 57.
    Gaede P, Vedel P, Parving HH, Pedersen O: Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. Lancet 1999, 353:617–622.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2001

Authors and Affiliations

  • Giuseppina Imperatore
    • 1
  • William C. Knowler
  • Robert G. Nelson
  • Robert L. Hanson
  1. 1.Division of Diabetes TranslationNational Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and PreventionAtlantaUSA

Personalised recommendations