Alternative titles; symbols
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q23.3 | {Microvascular complications of diabetes 3} | 612624 | 3 | ACE | 106180 |
A number sign (#) is used with this entry because of evidence that susceptibility to microvascular complications of diabetes-3 is associated with variation in the gene encoding angiotensin I-converting enzyme (ACE; 106180) on chromosome 17q23.
For a discussion of genetic heterogeneity of susceptibility to microvascular complications of diabetes, see MVCD1 (603933).
Marre et al. (1994) and Doria et al. (1994) reported that the I/D polymorphism of the ACE gene (106180.0001) was associated with diabetic nephropathy, but this association was disputed by others, e.g., Tarnow et al. (1995) and Schmidt et al. (1995). Marre et al. (1997) performed a large-scale, multicenter study on individuals with insulin-dependent diabetes mellitus (IDDM; 222100) at risk of kidney complications due to long-term exposure to hyperglycemia, i.e., those who had developed proliferative diabetic retinopathy, to test the relationship between genetic factors and renal involvement in IDDM. The degree of renal involvement of the patients was classified according to the genetic polymorphism of ACE and 2 other elements of the renin-angiotensin system, AGT (106150) and AT2R1 (106165). The study concluded that the ACE gene is involved in both the susceptibility to diabetic nephropathy and its progression toward renal failure. Polymorphisms in the other 2 genes were found not to be contributive alone, but an interaction between the ACE I/D and AGT M235T (106150.0001) polymorphisms was found that could account for the degree of renal involvement in the patients studied.
Vleming et al. (1999) studied the contribution of the ACE I/D polymorphism in 79 patients with end-stage renal failure due to diabetic nephropathy and in 82 age-matched controls with 15 years of IDDM but without microalbuminuria and found significant overrepresentation of the DD genotype with a significant increase of the D-allele frequency in the cases compared to controls. The presence of the DD genotype increased the risk of end-stage renal failure compared to other genotypes (odds ratio, 2.1); the presence of 1 D-allele, however, did not increase the risk.
Suehiro et al. (2004) demonstrated that the D allele of the ACE I/D polymorphism leads to higher expression of the ACE mRNA and suggested that this may affect the renin-angiotensin system in local regions.
As indicated by the work of Marre et al. (1994), Doria et al. (1994), and others, nephropathy of type 1 diabetes is associated with the D allele of the insertion/deletion (I/D) polymorphism in intron 16 of the ACE gene. The D allele determines higher enzyme levels. To address causality underlying this association, Huang et al. (2001) induced diabetes in mice having 1, 2, or 3 copies of the Ace gene, normal blood pressure, and an enzyme level range (65-162% of wildtype) comparable to that seen in humans. Twelve weeks later, the 3-copy diabetic mice had increased blood pressure and overt proteinuria. Proteinuria was correlated to plasma ACE level in the 3-copy diabetic mice. Thus, a modest genetic increase in ACE levels was sufficient to cause nephropathy in diabetic mice.
Doria, A., Warram, J. H., Krolewski, A. S. Genetic predisposition to diabetic nephropathy: evidence for a role of the angiotensin I-converting enzyme gene. Diabetes 43: 690-695, 1994. [PubMed: 7909524] [Full Text: https://doi.org/10.2337/diab.43.5.690]
Huang, W., Gallois, Y., Bouby, N., Bruneval, P., Heudes, D., Belair, M.-F., Krege, J. H., Menteton, P., Marre, M., Smithies, O., Alhenc-Gelas, F. Genetically increased angiotensin I-converting enzyme level and renal complications in the diabetic mouse. Proc. Nat. Acad. Sci. 98: 13330-13334, 2001. [PubMed: 11687636] [Full Text: https://doi.org/10.1073/pnas.231476798]
Marre, M., Bernadet, P., Gallois, Y., Savagner, F., Guyene, T.-T., Hallab, M., Cambien, F., Passa, P., Alhenc-Gelas, F. Relationships between angiotensin I converting enzyme gene polymorphism, plasma levels, and diabetic retinal and renal complications. Diabetes 43: 384-388, 1994. [PubMed: 8314010] [Full Text: https://doi.org/10.2337/diab.43.3.384]
Marre, M., Jeunemaitre, X., Gallois, Y., Rodier, M., Chatellier, G., Sert, C., Dusselier, L., Kahal, Z., Chaillous, L., Halimi, S., Muller, A., Sackmann, H., Bauduceau, B., Bled, F., Passa, P., Alhenc-Gelas, F. Contribution of genetic polymorphism in the renin-angiotensin system to the development of renal complications in insulin-dependent diabetes. J. Clin. Invest. 99: 1585-1595, 1997. [PubMed: 9120002] [Full Text: https://doi.org/10.1172/JCI119321]
Schmidt, S., Schone, N., Ritz, E., Giesel, R., Bergis, K., Strojek, K., Greszczak, W., Schroter, W., Willms, B. H. L., Petzold, R., Henrichs, H. R., Rambausek, M., Schwarzbeck, A., Kohr, B., Schneider, P., Bosch, A. Association of ACE gene polymorphism and diabetic nephropathy? Kidney Int. 47: 1176-1181, 1995. Note: Erratum: Kidney Int. 48: 915 only, 1995. [PubMed: 7783416] [Full Text: https://doi.org/10.1038/ki.1995.167]
Suehiro, T., Morita, T., Inoue, M., Kumon, Y., Ikeda, Y., Hashimoto, K. Increased amount of the angiotensin-converting enzyme (ACE) mRNA originating from the ACE allele with deletion. Hum. Genet. 115: 91-96, 2004. [PubMed: 15164285] [Full Text: https://doi.org/10.1007/s00439-004-1136-4]
Tarnow, L., Cambien, F., Rossing, P., Nielsen, F. S., Hansen, B. V., Lecerf, L., Poirier, O., Danilov, S., Parving, H.-H. Lack of relationship between an insertion/deletion polymorphism in the angiotensin I-converting enzyme gene and diabetic nephropathy and proliferative retinopathy in IDDM patients. Diabetes 44: 489-494, 1995. [PubMed: 7729604] [Full Text: https://doi.org/10.2337/diab.44.5.489]
Vleming, L. J., van der Pijl, J. W., Lemkes, H. H. P. J., Westendorp, R. G. J., Maassen, J. A., Daha, M. R., van Es, L. A., van Kooten, C. The DD genotype of the ACE gene polymorphism is associated with progression of diabetic nephropathy to end stage renal failure in IDDM. Clin. Nephrol. 51: 133-140, 1999. [PubMed: 10099885]