ACE gene polymorphism and kidney function in Type 1 paediatric patients

Original title:
Angiotensin I-converting enzyme-gene-polymorphism: relationship to albumin excretion and blood pressure in pediatric patients with type-I-diabetes mellitus.
Pavlovic M, Reile M, Haeberle U et al. Exp Clin Endo-crinol Diabetes 1997; 105: 248-53.

Summary
Angiotensin I-converting enzyme (ACE) insertion/ deletion polymorphism is a candidate gene for predisposition to diabetic nephropathy in Type 1 diabetic patients: subjects homozygous for deletion (D) display the highest ACE values; those homozygous for insertion (I), the lowest ACE values; and those heterozygous (I/D), intermediate values. Because plasma ACE can limit intrarenal angiotensin II production, which can provoke glomerular hypertension in response to diabetic vasodilatation, ACE was the first candidate gene to be tested for its role in diabetic nephropathy.
A cross-sectional study was performed in 247 paediatric Type 1 diabetic patients (age range 3-29 years) to investigate ACE I/D polymorphism in relation to blood pressure and urinary albumin excretion values. No association was found between ACE I/D genotypes and blood pressure or urinary albumin. However, the number of patients with microalbuminuria (incipient nephropathy) was small (n = 12). The authors conclude that the power of their study was too small to rule out a positive association, and intend to follow up their patients for several years to test the predictive value of ACE I/D polymorphism for renal prognosis.

Comment
The ACE I/D polymorphism was the first candidate gene to be tested for its role in predisposition to diabetic nephropathy in Type 1 and Type 2 diabetic patients. Recent meta-analyses confirm that the II genotype (low ACE levels) is associated with a reduced risk of diabetic nephropathy [1, 2]. The practical consequences of this finding are currently unknown, since no prospective follow-up or intervention studies have been carried out into this polymorphism.
In the present study, no association was found between the I/D polymorphism and blood pressure or urinary albumin excretion in young Type 1 diabetic patients. However, the power of the study was too low to detect an association with nephropathy: the patients were divided into those above or below the median urinary albumin excretion value, but very few patients were in fact microalbuminuric. This is not surprising in patients of this age, and it resulted in approximately one case of incipient nephropathy per 20 controls in the study. Also, the lack of association between ACE I/D genotypes and high blood pressure has been well established since the discovery of this polymorphism, which seems implicated in regulating local circulation, i.e. kidney and heart, rather than in systemic pressure. Finally, genotyping paediatric Type 1 diabetic patients is of value for scientific purposes if prospective long-term follow-up is properly organized. Meanwhile, the best strategy for renal prognosis of young Type 1 diabetic patients remains to screen them for microalbuminuria, the earliest sign of nephropathy, for which effective treatments are already well-established.

References
1. 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: 1579-92.
2. 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.

Summary and Comment:
Michel Marre, Angers, France

Authors' reply
Diabetic nephropathy, the major complication in patients with Type 1 diabetes, plays a central role in long-term prognosis and mortality. Earlier studies assumed that genes of the renin-angiotensin system may be involved in susceptibility to diabetic nephropathy.
Since microalbuminuria evolves after many years of diabetes and since few of our patients had microalbuminuria, the power of the study was low. Nevertheless, it may serve as a platform to investigate prospectively our diabetes patients in future years in order to make further comparisons between clinical status and genotype. In addition, the patients will also be screened for other polymorphisms.
Particularly from a paediatric viewpoint, and regarding the intensity of treatment, it would be interesting to define high- and low-risk patient groups. As the development of microalbuminuria takes time, we believe that with well-organized and long-term follow-up, genotyping of patients for the described putative predictive polymorphisms in addition to clinical screening for microalbuminuria is a worthwhile course of study.