Angiotensin-converting enzyme (ACE) haplotypes and cyclosporine A (CsA) response: a model of the complex relationship between ACE quantitative trait locus and pathological phenotypes.
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.
Department of Nephrology, G. Gaslini Institute, Genova, Italy. pcatarsi@libero.it
Paolo
P
Catarsi
Roberto
R
Ravazzolo
Francesco
F
Emma
Doriana
D
Fruci
Livio
L
Finos
Andrea
A
Frau
Giacomo
G
Morreale
Alba
A
Carrea
Gian Marco
GM
Ghiggeri
D000293:Adolescent; D000328:Adult; D001794:Blood Pressure; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000009:adverse effects*; D004791:Enzyme Inhibitors / Q000009:adverse effects*; D005260:Female; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000139:chemically induced* / Q000201:enzymology*; D007223:Infant; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000235:genetics*; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D011110:Polymorphism, Genetic; D040641:Quantitative Trait Loci; D051437:Renal Insufficiency / Q000139:chemically induced / Q000188:drug therapy; D012189:Retrospective Studies; D016896:Treatment Outcome
D004791:Enzyme Inhibitors; D017395:Plasminogen Activator Inhibitor 1; D016572:Cyclosporine; D007703:Peptidyl-Dipeptidase A