Service d'Endocrinologie Diabétologie Métabolisme Nutrition, Centre Hospitalier Universitaire BICHAT Claude BERNARD, Paris, France
Keywords: diabetic nephropathy; glomerular filtration rate; KQ121 polymorphism; PC-1 gene
In the August 2002 issue of this journal, two groups reported discrepant results on the effects of a polymorphism in a candidate gene for nephropathy in type 1 diabetes, i.e. PC-1 [1,2]. A K121Q polymorphism can affect PC1, a membrane glycoprotein known to inhibit insulin signalling. Insulin resistance can affect the risk of nephropathy in type 1 diabetes [3]. The Anglo-Italian group [1] already reported that the rate of decrease in glomerular filtration rate (GFR) in type 1 diabetic patients with nephropathy is conditioned by this polymorphism [4]. Here, they additionally state that the K121Q PC1 polymorphism can interact with the ACE I/D polymorphism in an additive fashion to predict the rate of decline of GFR. Conversely, the Danish group of the Steno Diabetes Center in Copenhagen [2] found no effect of the K121Q PC1 polymorphism on the same parameter in similar type 1 nephropathy patients. They had also reported an effect of ACE I/D polymorphism on GFR course in the same patients [5].
The selection criteria were the same in both studies, and the baseline characteristics of the Anglo-Italian participants were similar to those of the Danish ones [1,2]. The methods used to estimate GFR course were different, but correlated well and were reliable enough in both studies. The treatment strategies used were similar. The median rates of progression of GFR were also similar between the two studies (a loss of 4 ml/min for 1 year). What differences may account for this discrepancy?
The only difference in design is with regard to the location of these two studies: one was multicentric and binational between South Italy and London, UK, and the other was monocentric in Copenhagen, Denmark. There may be differences in genetic backgrounds and environmental conditions between the two studies. Regarding genetic background, all participants were Caucasians. Background ethnicities may have been different, although the Vikings (the ancestors of the Danish people) visited South Italy during the early Middle Ages, but no difference was found between the Londoners and the South Italians for their characteristics and GFR courses within the Anglo-Italian study. In addition, the reported allele frequencies were comparable. From an environmental viewpoint, many factors may have differed. For instance, it is well known that the usual Danish diet differs from the Italian diet, but if diet had been a confounding factor, no deleterious effect of the English diet appeared within the Anglo-Italian study. So what does this mean?
In fact, the two studies share a common flaw in their designs, since they were both retrospective, rather than prospective. This is clearly mentioned in the Anglo-Italian study and is strongly suggested in the Danish study, since values of GFR used to estimate its decline were taken up to 17 years before the current study, whereas the first Danish DNA samples were collected in 1993 [2]. These Anglo-Italian [6] and Danish [7] authors contributed strongly and equally to establishing the link between high albumin excretion rate and premature cardiovascular and renal diseases and mortality in type 1 diabetes. A survival bias and other biases are strongly suspected to have operated to select patients who participated in both studies. A final assessment of the values of PC1 and/or ACE polymorphisms will not be resolved by a joint analysis of these two studies. Rather, it is worth using another strategy, namely to start collecting baseline data and DNA of study patients, and to follow them up prospectively for events, mortality (and drop-out), long enough to have a sufficient power to estimate the putative effects of given genotypes [8].
Notes
Correspondence and offprint requests to: Michel Marre, Service d'Endocrinologie Diabétologie Métabolisme Nutrition, Centre Hospitalier Universitaire BICHAT Claude BERNARD, 46, rue Henri Huchard, 75877 Paris Cedex 18, France. Email: michel.marre{at}bch.ap\|[hyphen]\|hop\|[hyphen]\|paris.fr
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