Polymorphism of CYP11B2 determines salt sensitivity in Japanese.
Aldosterone plays essential roles in body fluid and electrolyte homeostasis and blood pressure. However, the association between polymorphisms in the CYP11B2 gene and hypertension is controversial. We resequenced CYP11B1 and CYP11B2 and identified 35 polymorphisms in this region. We performed association studies between the plasma aldosterone concentration and 13 polymorphisms in this region in 1443 subjects. The subjects were all obtained from the Suita Cohort Study. Multiple regression analysis indicated that aldosterone levels were determined by renin activity, age, total cholesterol, and hematocrit. Residuals of the aldosterone levels after adjusting for these confounding factors were nominally associated with the T(-344)C (P=0.0026), C(595)T (P=0.0180), -(4837)C (P=0.0310), and G(4936)A (P=0.0498) polymorphisms. Only the T(-344)C polymorphism was significantly associated with the aldosterone level after a correction for multiple testing (Bonferroni). A significant interaction was observed between the T(-344)C polymorphism and renin activity in determining aldosterone levels. Moreover, a significant interaction was observed in 2063 subjects between urinary sodium excretion, which reflects sodium intake, and the T(-344)C polymorphism in determining systolic blood pressure. Only subjects with the TT genotype showed a positive correlation between urinary sodium excretion and systolic blood pressure. In vitro experiments confirmed the functional significance of this T(-344)C polymorphism in terms of angiotensin II reactivity. Thus, the T(-344)C polymorphism in CYP11B2 appears to affect salt sensitivity in Japanese and to have clinical significance.
Iwai
Naoharu
N
Department of Epidemiology, National Cardiovascular Center, Suita, Osaka, Japan. iwai@ri.ncvc.go.jp
Kajimoto
Kazuaki
K
Tomoike
Hitonobu
H
Takashima
Naoyuki
N
D000368:Aged; D000450:Aldosterone / Q000097:blood; D044466:Asian People / Q000235:genetics*; D001794:Blood Pressure / Q000235:genetics; D015331:Cohort Studies; D003545:Cysteine; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000139:chemically induced* / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009318:Natriuresis / Q000235:genetics; D011110:Polymorphism, Genetic; D012083:Renin / Q000097:blood; D017421:Sequence Analysis; D012965:Sodium Chloride / Q000009:adverse effects*; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics; D013912:Threonine
D013912:Threonine; D012965:Sodium Chloride; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase; D012083:Renin; D003545:Cysteine