risk of publication bias. If no publication bias exists, urinary albumin ..... gene in normalcy and among diabetics with vascular complica- ated with coronary heart ...
Nephrol Dial Transplant (1998) 13: 1125–1130
Nephrology Dialysis Transplantation
Meta analysis
Diabetic nephropathy and the insertion/deletion polymorphism of the angiotensin-converting enzyme gene Lise Tarnow, Christian Gluud1 and Hans-Henrik Parving Steno Diabetes Center, Gentofte and 1The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Institute of Preventive Medicine, H5S Kommunehospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Introduction
Methods
Diabetic nephropathy is a leading cause of end-stage renal failure in the Western world, and the number of diabetic patients needing dialysis or kidney transplantation is increasing steadily [1]. While the possibilities for treatment of these patients have improved substantially by introduction of antihypertensive therapy and, perhaps particularly, angiotensinconverting enzyme (ACE) inhibitors, our knowledge of the mechanisms involved in the development of this devastating microvascular complication is still sparse. Studies of familial clustering [2–4] and genetic predisposition [5,6 ] suggest that genetic factors are involved in the pathogenesis of diabetic nephropathy. One candidate gene is the gene coding for ACE in which an insertion/deletion polymorphism (ACE/ID) has been described [7]. Based on the presence [insertion (I )] or absence [deletion (D)] of a 287 bp sequence in intron 16, three genotypes are found (DD and II homozygotes and ID heterozygotes). The DD subjects (diabetic [8,9] or non-diabetic [7]) are characterized by a mean plasma/serum ACE level approximately double that of II subjects, with ID subjects having intermediate values. Furthermore, this polymorphism has been associated with an increased risk of coronary heart disease both in non-diabetic [10] and diabetic populations [11,12]. In diabetes, the initial report from Marre et al. [8] proposed a protective effect of the II genotype against development of diabetic nephropathy in insulindependent diabetes (IDDM ). Since then, a substantial number of association studies have been conducted to investigate the possible relationships between elevated urinary albumin excretion rate and the ACE/ID polymorphism in patients with either IDDM or noninsulin-dependent diabetes (NIDDM ). The aim of this review is to evaluate the prevalence of ACE/ID genotypes in diabetic patients with and without an elevated urinary albumin excretion rate.
Identification of studies
Correspondence and offprint requests to: Lise Tarnow, Steno Diabetes Center, Niels Steensens Vej 2, DK-2820 Gentofte, Denmark.
Studies with a case–control and/or cross-sectional design were considered, without language limitations, provided that they were published as original articles. All studies were included which contained sufficient information to allow a comparison of ACE/ID genotype distributions between adult cases (with IDDM/NIDDM and elevated urinary albumin excretion rate, as defined by the authors) and diabetic controls without an elevated urinary albumin excretion rate. Where studies on the same cases and control subjects had been reported more than once, only one study was included. Abstracts were excluded and unpublished studies were not sought. Studies were identified by an electronic search performed on Current Contents and MEDLINE (1993–1997) using the search terms: angiotensinconverting enzyme gene and diabetes. The last electronic search was conducted on November 24, 1997. Further studies were sought by reading through the reference lists of the identified studies.
Statistical analysis The following items were extracted from the included studies: number of cases and controls, ethnic background, criteria and methods for classification of cases and controls, ACE/ID genotype frequencies and duration of diabetes. Before data analysis, it was decided to analyse IDDM and NIDDM studies separately and to stratify analyses further according to ethnic background, since ACE/ID genotype distribution varies considerably with race [13,14]. Funnel plots comparing sample size with the odds ratio of individual studies were drawn to estimate the risk of publication bias. If no publication bias exists, the points scatter around the pooled value of the odds ratio, with the scatter narrowing as sample size increases. The linear regression approach was used to measure the degree of funnel plot asymmetry by the
© 1998 European Renal Association–European Dialysis and Transplant Association
1126
L. Tarnow et al.
intercept from regression of odds ratio/standard error against precision (1/standard error) [15]. Depending on the absence or presence of study result variability (significant heterogeneity tested by the x2 test defined as P
