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, Roberto Ravazzolo, Francesco Emma, Doriana Fruci, Livio Finos, Andrea Frau, Giacomo Morreale, Alba Carrea, Gian Marco Ghiggeri

Research output: Contribution to journalArticle

Abstract

It is highly controversial to define the role of angiotensin-converting enzyme (ACE) polymorphisms in essential hypertension. We studied a group of patients in whom hypertension was the major side effect of treatment by cyclosporine A (CsA). This study group comprised 227 Italian patients with nephrotic syndrome, 103 of which were treated with CsA and had different outcome. Forty-nine patients developed serious hypertension that was reversed after withdrawal of drug. ACE haplotypes were determined by a combination of molecular and statistical methods after verifying genotypes of six intragenic single nucleotide polymorphisms in 304 Italian blood donors and assembling them in clades (A, B, C) that include 95% of observed haplotypes. The association between ACE clade combinations and serum enzymatic levels confirmed the 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 then 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, because homozygosis for ACE B clade was able to influence CsA sensitivity. This highlights the role of 5′ variants, which 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, like CsA treatment in our case, overcome physiological homeostatic mechanisms.

Original languageEnglish
Pages (from-to)2357-2367
Number of pages11
JournalHuman Molecular Genetics
Volume14
Issue number16
DOIs
Publication statusPublished - Aug 15 2005

ASJC Scopus subject areas

  • Genetics

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