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Human Molecular Genetics Advance Access published online on July 7, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi238
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received May 6, 2005
Revised June 29, 2005
Accepted June 29, 2005

Article

Angiotensin-converting enzyme (ACE)-haplotypes and cyclosporine-A (CsA) response: a model of the complex relationship between ACE quantitative trait locus and pathological phenotypes

Paolo Catarsi 1*, Roberto Ravazzolo 2, Francesco Emma 3, Doriana Fruci 4, Livio Finos 5, Andrea Frau 6, Giacomo Morreale 6, Alba Carrea 6, and GianMarco Ghiggeri 7

1 Laboratory on Pathophysiology of Uremia, G.Gaslini Institute, Genova; Laboratory on Pathophysiology of Uremia, G. Gaslini Institute, Largo Gaslini 5, 16147 Genova, Italy
2 Laboratory of Molecular Genetics, G. Gaslini Institute, Genova
3 Division of Nephrology and Dialysis, Bambin Gesù Hospital, Roma
4 Laboratory of Cell Biology, Bambin Gesù Hospital, Roma
5 Faculty of Medicine - D.S.B.T.A. Section of Human Physiology, University of Ferrara, Ferrara
6 Laboratory on Pathophysiology of Uremia, G.Gaslini Institute, Genova
7 Department of Nephrology, G.Gaslini Institute, Genova; Laboratory on Pathophysiology of Uremia, G.Gaslini Institute, Genova

* To whom correspondence should be addressed.
Paolo Catarsi, E-mail: pcatarsi{at}libero.it


  Abstract

Defining the role of angiotensin-converting enzyme polymorphisms in essential hypertension is highly controversial. We studied a group of patients in which hypertension was the major side effect of treatment by cyclosporine A (CsA). This study cohort consisted of 227 Italian patients with nephrotic syndrome, 103 of which were treated with CsA and had different outcome. Forty-nine developed serious hypertension that was reversed after drug withdraw. ACE haplotypes were determined by a combination of molecular and statistical methods after verifying genotypes of six intragenic SNPs in 304 Italian blood donors and assembling them in clades (A, B, C) that include 95% of observed haplotypes. The study of association between ACE clade combinations and serum enzymatic levels confirmed previous results about a role of an unidentified genetic variant at the 5' of the intragenic recombination site located near intron 7. ACE clades were subsequently determined in patients and regression methods were used to analyze variables associated with CsA responsivity and progression to renal failure. ACE genotype and responsiveness to CsA were strictly associated since homozygosis for ACE B clade was able to influence CsA sensitivity. This highlights the role of 5' variants that differentiate clades B and C.

Other genetic markers were tested to search for possible additive effects. We found that PAI-1 4G allele was associated with progression to renal failure in the group of CsA treated patients. Our results are in agreement with the hypothesis, raised after experimental results obtained in mouse models, that the effect of ACE polymorphisms on blood pressure is detectable once environmental factors, such as CsA treatment in our case, overcome physiological homeostatic mechanisms.


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