Summary
Recent data suggest genetic contributions to the microvascular complications of Type 1 (insulin-dependent) diabetes mellitus. Most research has focused on the HLA region, and the potential role of other genetic loci has not been adequately explored. We examined the possible relationship between DNA polymorphisms in the region 5′ to the insulin gene on chromosome 11 and diabetic nephropathy. This was done by comparison of those diabetic patients homozygous for class 1 alleles at the 5′ insulin gene polymorphism locus to 1/3 heterozygotes in a well-characterized series of 324 insulin-requiring diabetic patients from the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Proteinuria (defined as ≥0.3 g protein/l urine), was used as suggestive evidence for diabetic nephropathy. Hypertension, a frequent associated finding in diabetic patients with nephropathy, was defined as a blood pressure greater than 140/90 or a history of previous treatment of hypertension. The two genotypically defined groups did not differ from each other in regard to sex ratio, age at diagnosis, age at examination, duration of diabetes, body mass, HbAlc or C-peptide. The 1/1 group had a higher prevalence of proteinuria, 29% as compared to 16.2 % in other genotypes (p<0.05). There was no significant difference in the frequency of hypertension between the two genotypic groups. This finding suggests that the 5′ insulin gene polymorphism may be associated with risk for nephropathy, but the pathophysiologic mechanism remains unclear.
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Rotter JI, Vadheim CM, Rimoin DL (1990) Genetics of diabetes mellitus. In: Rifkin H, Porte D (eds) Ellenberg and Rifkin's Diabetes Mellitus, Theory and Practice. Elsevier, New York, pp. 378–413
Barbosa J, Saner B (1984) Do genetic factors play a role in the pathogenesis of diabetic microangiopathy? Diabetologia 27: 487–492
Dornan TL, Ting A, McPherson CK et al. (1982) Genetic susceptibility to the development of retinopathy in insulin-dependent diabetes. Diabetes 31: 226–231
Secchi A, Fabio G, Pontiroli AE et al. (1989) HLA antigens in insulin-dependent diabetes: Their role on development of remission phase and degenerative complications of diabetes. DNM 2: 3–9
Bell GI, Karam JH, Rutter WJ (1981) Polymorphic DNA region adjacent to the 5′ end of the human insulin gene. Proc Natl Acad Sci USA 78: 5759–5763
Bell GI, Horita S, Karam JH (1984) A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes 31: 176–183
Owerbach D, Nerup J (1982) Restriction fragment length polymorphism of the insulin gene in diabetes mellitus. Diabetes 31: 275–277
Hitman GA, Tarn AC, Winter RM et al. (1985) Type 1 (insulindependent) diabetes and a highly variable locus close to the insulin gene on chromosome 11. Diabetologia 28: 218–222
Klein R, Klein BEK, Moss SE, DeMets DL, Kaufman I, Voss PS (1984) Prevalence of diabetes in Southern Wisconsin. Am J Epidemiol 119: 54–61
Klein R, Klein BEK, Moss SE, Davis MD, DeMets DL (1984) The Wisconsin Epidemiologic Study of Diabetic Retinopathy. II: Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol 102: 520–526
Boyum A (1968) Separation of leukocytes from blood and bone marrow. Scand J Clin Invest 21 (Suppl 92): 77–89
Kan YW, Dozy AM, Trecartin R, Todd B (1979) Identification of a nondeletion effect in thalassemia. New Engl J Med 297: 1081–1084
Denaro M, Blanc H, Johnson MJ et al. (1981) Ethnic variation of Hpa I endonuclease cleavage patterns of human mitochondrial DNA. Proc Natl Acad Sci USA 78: 5768–5772
Southern EM (1975) Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Molec Biol 98: 503–517
Wahl GM, Stern M, Stark GR (1979) Efficient transfer of large DNA fragments from agarose gels to diazobenzyloxymethylpaper and rapid hybridization by using dextran sulfate. Proc Natl Acad Sci USA 76: 615–619
Zar JF (1984) Biostatistical Analysis, 2nd edn. Prentice-Hall, Englewood Cliffs, New Jersey
Fleiss JL (1982) Statistical Methods for Rates and Proportions, 2nd edn. John Wiley and Sons, New York
Kofoed-Enevoldsen A, Borch-Johnsen K, Kreiner S, Deckert T (1987) Declining incidence of persistent proteinuria in Type 1 (insulin-dependent) diabetic patients in Denmark. Diabetes 36: 205–209
Hasslacher CH, Stech W, Wahl P, Ritz E (1985) Blood pressure and metabolic control as risk factors for nephropathy in Type 1 (insulin-dependent) diabetes. Diabetologia 28: 6–11
Nyberg G, Larsson O, Attman P, Granerus G, Norden G (1985) Time as a risk factor in diabetic nephropathy. Diabetes Care 8: 590–593
Chazan BI, Balodimos MC, Ryan JR, Marble A (1970) Twentyfive to forty-five years of diabetes with and without vascular complications. Diabetologia 6: 565–569
Seaquist ER, Goetz FC, Rich S, Barbosa J (1989) Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 320: 1161–1165
Walton C, Dyer PA, Davidson JA, Harris R, Mallick NP, Oleeksy S (1984) HLA antigens and risk factors fornephropathy inType 1 (insulin-dependent) diabetes mellitus. Diabetologia 27: 3–7
Viberti GC, Walker JD (1988) Diabetic nephropathy: Etiology and prevention. Diabetes Metab Rev 4: 147–162
Mogensen CE, Christensen CK (1984) Predicting diabetic nephropathy in insulin-dependent patients. N Engl J Med 311: 89–93
Owerbach D, Johansen K, Billesbolle P, Poulsen S, Schroll M, Nerup J (1982) Possible association between DNA sequences flanking the insulin gene and atherosclerosis. Lancet ii: 1291–1293
Mandrup-Poulsen T, Owerbach D, Mortensen SA et al. (1984) DNA sequences flanking the insulin gene on chromsome 11 confer risk of atherosclerosis. Lancet i: 250–252
Jowett NI, Rees A, Williams LG et al. (1984) Insulin and apolipoprotein A-l/C-III gene polymorphisms relating to hypertriglyceridaemia and diabetes mellitus. Diabetologia 27: 180–183
Jowett NI, Williams LG, Hitman GA, Galton DJ (1984) Diabetic hypertriglyceridaemia and related 5′ flanking polymorphism of the human insulin gene. Br Med J 288: 96–99
Viberti GC, Keen H, Wiseman MJ (1987) Raised arterial pressure in parents of proteinuric insulin dependent diabetes. Br Med J 295: 515–517
Mangili R, Bending JJ, Scott G, Li LK, Gupta A, Viberti GC (1988) Increased sodium-lithium countertransport activity in red cells of patients with insulin-dependent diabetes and nephropathy. N Engl J Med 318: 146–150
Krolewski AS, Canessa M, Warram JH et al. (1988) Predisposition to hypertension and susceptibility to renal disease in insulindependent diabetes mellitus. N Engl J Med 318: 140–145
Bell GI, Horita S, Karam JH (1984) A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes 31: 176–183
Owerbach D, Nerup J (1982) Restriction fragment length polymorphism of the insulin gene in diabetes mellitus. Diabetes 31: 275–277
Hitman GA, Tarn AC, Winter RM et al. (1985) Type 1 (insulindependent) diabetes and a highly variable locus close to the insulin gene on chromosome 11. Diabetologia 28: 218–222
Cox NJ, Spielman RS (1989) The insulin gene and susceptibility to Type 1 diabetes. Genet Epidemiol 6: 65–69
Dizier M-H, Clerget-Darpoux F, Hochez J (1989) Segregation analysis of two genetic markers in Type 1 diabetes families under two locus models. Genet Epidemiol 6: 71–75
Donald JA, Barendse W, Cooper DW (1989) Linkage studies of HLA and insulin gene restriction fragment length polymorphisms in families with IDDM. Genet Epidemiol 6: 77–81
Fimmers R, Neugebauer M, Dennert J, Wienker T, Baur MP (1989) Association and sibpair analysis for the HLA, Gm, Km, and insulin polymorphisms in multiplex IDDM families. Genet Epidemiol 6: 107–112
Cox NJ, Baker L, Spielman RS (1988) Insulin gene sharing in sib pairs with insulin-dependent diabetes mellitus: No evidence for linkage. Am J Hum Genet 42: 167–172
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Raffel, L.J., Vadheim, C.M., Roth, M.P. et al. The 5′ insulin gene polymorphism and the genetics of vascular complications in Type 1 (insulin-dependent) diabetes mellitus. Diabetologia 34, 680–683 (1991). https://doi.org/10.1007/BF00400999
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DOI: https://doi.org/10.1007/BF00400999