High aldosterone-to-renin variants of CYP11B2 and pregnancy outcome.
BACKGROUND
Increased aldosterone concentrations and volume expansion of normal pregnancies are hallmarks of normal pregnancies and blunted in pre-eclampsia. Accordingly, we hypothesized an active mineralocorticoid system to protect from pre-eclampsia.


METHODS
In pregnant women (normotensive n = 44; pre-eclamptic n = 48), blood pressure, urinary tetrahydro-aldosterone excretion and activating polymorphisms (SF-1 site and intron 2) of the aldosterone synthase gene (CYP11B2) were determined; 185 non-pregnant normotensive individuals served as control. Amino acid-changing polymorphisms of the DNA- and agonist-binding regions of the mineralocorticoid receptor were evaluated by RT-PCR, SSCP and sequencing.


RESULTS
Urinary tetrahydro-aldosterone excretion was reduced in pre-eclampsia as compared to normal pregnancy (P < 0.05). It inversely correlated with blood pressure (r = 0.99, P < 0.04). Homozygosity for activating CYP11B2 polymorphisms was preferably present in normotensive as compared to pre-eclamptic pregnancies, identified (intron 2, P = 0.005; SF-1 site, P = 0.016). Two mutant haplotypes decreased the risk of developing pre-eclampsia (RR 0.16; CI 0.05-0.54; P < 0.001). In contrast, intron 2 wild type predisposed to pre-eclampsia (P < 0.0015). No functional mineralocorticoid receptor mutant has been observed.


CONCLUSIONS
High aldosterone availability is associated with lower maternal blood pressure. In line with this observation, gain-of-function variants of the CYP11B2 reduce the risk of developing pre-eclampsia. Mutants of the mineralocorticoid receptor cannot explain the frequent syndrome of pre-eclampsia.
Escher
Geneviève
G
Department of Nephrology/Hypertension, University of Bern, Berne, Switzerland.
Cristiano
Martino
M
Causevic
Maja
M
Baumann
Marc
M
Frey
Felix J
FJ
Surbek
Daniel
D
Mohaupt
Markus G
MG
D000328:Adult; D000450:Aldosterone / Q000031:analogs & derivatives / Q000502:physiology* / Q000652:urine; D001483:Base Sequence; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology; D016022:Case-Control Studies; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007231:Infant, Newborn; D009154:Mutation; D011225:Pre-Eclampsia / Q000235:genetics / Q000503:physiopathology; D011247:Pregnancy; D011256:Pregnancy Outcome; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000502:physiology; D012083:Renin / Q000378:metabolism*
D017931:DNA Primers; D018161:Receptors, Mineralocorticoid; C013282:tetrahydroaldosterone; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; D012083:Renin