AngiotensinI converting enzyme insertion/deletion

Authors: D P K Ng B C Tai D Koh K W Tan K S Chia

Publish Date: 2005/04/14

Volume: 48, Issue: 5, Pages: 1008-1016

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Abstract

The ACE insertion/deletion polymorphism has been examined for association with diabetic nephropathy over the past decade with conflicting results To clarify this situation we conducted a comprehensive metaanalysis encompassing all relevant studies that were published between 1994 and 2004 and investigated this potential genetic associationA total of 14727 subjects from 47 studies was included in this metaanalysis Cases n=8663 were type 1 or 2 diabetic subjects with incipient microalbuminuria or advanced diabetic nephropathy proteinuria chronic renal failure endstage renal disease Control subjects n=6064 were predominantly normoalbuminuricNo obvious publication bias was detected Using a minimalcase definition based on incipient diabetic nephropathy subjects with the II genotype had a 22 lower risk of diabetic nephropathy than carriers of the D allele pooled odds ratio OR=078 95 CI=069–088 While there was a reduced risk of diabetic nephropathy associated with the II genotype among Caucasians with either type 1 or type 2 diabetes the association was most marked among type 2 diabetic Asians Chinese Japanese Koreans OR=065 95 CI=0 51–083 This OR is significantly different from the OR of 090 95 CI= 078–104 that was obtained for type 2 diabetic Caucasians p=0019 Using a stricter case definition based on advanced diabetic nephropathy a comparable risk reduction of 24–32 was observed among the three subgroups although statistical significance was reached only among AsiansThe results of our metaanalysis support a genetic association of the ACE Ins/Del polymorphism with diabetic nephropathy These findings may have implications for the management of diabetic nephropathy using ACE inhibitors especially among type 2 diabetic AsiansDiabetic nephropathy is the most serious complication of diabetes mellitus and affects approximately a third of diabetic patients Importantly it is the leading cause of endstage renal disease requiring dialysis or transplantation in developed countries 1 as well as in rapidly developing countries in Asia 2 Besides good glycaemic control measures such as the attenuation of the renin–angiotensin system using ACE inhibitors are important in the clinical management of this complication 3 However the efficacy of ACE inhibitors in treating diabetic nephropathy can be influenced by genetic variation at the ACE gene locus 4 5 Specifically a polymorphism termed Ins/Del which results from the insertion/deletion of a 287 bp Alu sequence in intron 16 accounts for half the variance of serum enzyme levels with individuals homozygous for the insertion allele II genotype having significantly lower levels than carriers of the deletion allele ID and DD genotypes 6Studies of familial clustering have consistently demonstrated that genetic susceptibility plays an important role in diabetic nephropathy 7 Regarding ACE investigators have sought to determine if the Ins/Del polymorphism acts as a genetic risk factor for diabetic nephropathy beginning with the initial study by Marre et al in 1994 who reported a protective effect of the II genotype on the development of this complication 8 However metaanalyses published in 1998 did not support this conclusion among Caucasians with either type 1 or type 2 diabetes although the II genotype appeared protective among type 2 diabetic Asians of Japanese and Korean origin 9 10 While genetic susceptibility linked to the ACE locus may be populationspecific an important caveat is that these earlier reviews were conducted on just around 20 studies and comprised about 5000 subjects each This limited data did not allow firm conclusions from such detailed subgroup analyses 9 10 A third metaanalysis did not include the relevant subgroup analyses 11Since 1998 there has been a considerable surge in the number of reports on the association of the ACE Ins/Del polymorphism with diabetic nephropathy Indeed our present literature search indicated that the number of such publications has doubled at least since the previous metaanalyses In light of this significant development we conducted a new metaanalysis based on 47 studies published during the decade starting from 1994 and which comprises 14727 diabetic subjects

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