Renal function in relation to three candidate genes.
We recently found that femoral intima media thickness, as well as the incidence of hypertension, is influenced by genes encoding the angiotensin-converting enzyme (ACE; insertion/deletion [I/D]) polymorphism, alpha-adducin (Gly460Trp), and aldosterone synthase (-344C/T). By interfering with blood pressure or sodium homeostasis, these genetic polymorphisms also may change renal function. We therefore investigated serum creatinine level, calculated and measured creatinine clearances, and 24-hour urinary protein excretion in subjects previously genotyped for these three polymorphisms. The 1,454 participants drawn at random from the population (64.3% of those invited) were aged 43.4 years and included 744 women (51.2%). Blood pressure, measured by study nurses at subjects' homes, averaged 123/76 mm Hg. Mean values were 90 micromol/L for serum creatinine; 84 and 88 mL/min/1.73 m(2) for calculated and measured (n = 855) creatinine clearances, respectively; and 90 mg/d of protein for proteinuria (n = 556). The prevalence of mild renal dysfunction (creatinine clearance </= 60 mL/min/1.73 m(2)) was nearly 11%. In single-gene analyses with adjustment for significant covariables, the risk for mild renal dysfunction was positively associated with the ACE D allele. However, multiple-gene analyses showed that these associations were restricted to carriers of the mutated alpha-adducin Trp allele (40.1% of all subjects). Findings remained similar after hypertensive patients and women on hormonal therapy were excluded. In this phenotypically more homogeneous subgroup, serum creatinine level was 3.6 micromol/L (P = 0.02) and relative risks for mild renal dysfunction and proteinuria were 1.7-fold (P < 0.001) and 26% (P = 0.02) greater in ACE D subjects than ACE II homozygotes, respectively. The aldosterone synthase T allele did not strengthen genetic associations with the ACE D allele considered alone or in combination with the alpha-adducin Trp allele. Thus, in the present cross-sectional analysis, renal function was slightly but consistently impaired when both the ACE D and alpha-adducin Trp alleles were present. These findings, together with experimental studies and our previous reports on femoral intima media thickness and the incidence of hypertension, constitute a growing body of evidence delineating a clinical entity genetically determined by the risk-carrying ACE D and alpha-adducin Trp alleles.
Wang
J G
JG
Hypertensie en Cardiovasculaire Revalidatie Eenheid, Departement Moleculair en Cardiovasculair Onderzoek, Katholieke Univsiteit Leuven, Belgium.
Staessen
J A
JA
Tizzoni
L
L
Brand
E
E
Birkenhäger
W H
WH
Fagard
R
R
Herrmann
S M
SM
Bianchi
G
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015220:Calcium Channels / Q000235:genetics; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D002648:Child; D003404:Creatinine / Q000097:blood*; D003430:Cross-Sectional Studies; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D011110:Polymorphism, Genetic; D011507:Proteinuria / Q000235:genetics*; D050052:TRPC Cation Channels; D044465:White People / Q000235:genetics; D000099291:Adducins
D015220:Calcium Channels; D002148:Calmodulin-Binding Proteins; D003404:Creatinine; D007703:Peptidyl-Dipeptidase A; D050052:TRPC Cation Channels; D000099291:Adducins