on October 6, 2003
Published online before print October 6, 2003, doi: 10.1161/01.HYP.0000095615.83724.82
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Submitted on May 7, 2003
From the Endocrine-Hypertension Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (N.K., R.M.M., G.H.W.), Boston, Mass; the Department of Medicine, University of Utah (S.C.H., P.N.H., R.R.W.), Salt Lake City; the Department of Medicine, Centre d'Investigation Clinique, Hopital Broussais and INSERM U College de France (X.J., P.C.), Paris; Department of Internal Medicine and Public Health, Università di L'Aquila (C.F.), L'Aquila, Italy; and the Department of Radiology, Brigham and Women's Hospital and Harvard Medical School (N.K.H.), Boston, Mass. * To whom correspondence should be addressed. E-mail: gwilliams{at}partners.org.
Abstract--We sought to determine whether genes of the renin-angiotensin-aldosterone system can predict the nonmodulating intermediate phenotype in essential hypertension. Aldosterone responses to angiotensin II were assessed in 298 subjects with hypertension. Subjects were genotyped at the angiotensinogen M235T, angiotensin-converting enzyme I/D, aldosterone synthase C-344 T, renin, angiotensin II type 1 receptor, and adducin loci. The data were analyzed by Student t test, ANOVA, stepwise linear regression and general linear model or GENMOD regression techniques, and
Revised on May 28, 2003
Genetic Determinants of Nonmodulating Hypertension
Natapong Kosachunhanun;
2 analysis odds ratios (ORs). Aldosterone response varied by genotype for angiotensin and aldosterone synthase but not for the other loci. The combination of angiotensinogen 235 TT and angiotensin-converting enzyme DD showed further reduction (P=0.0377) when compared with angiotensinogen 235 TT alone, an example of genetic epistasis. When the subject was required also to possess the CYP11B2 -344 TT genotype, there was a further substantial reduction. Of these 3 loci, only angiotensinogen 235 TT significantly increased the OR of predicting the nonmodulating hypertensive phenotype (OR, 2.00; 95% confidence interval, 1.152 to 3.51). However, when angiotensin-converting enzyme DD was combined with angiotensinogen 235 TT, the OR nearly doubled to 3.74, with a further increase to 5.36-fold when the subject possessed all 3 genotypes. Thus, the angiotensinogen, angiotensin-converting enzyme, and aldosterone synthase genotypes identified individuals with the nonmodulating phenotype with an increasing degree of fidelity. For this subclass of essential hypertension, it is likely that genotyping can be substituted for complex phenotyping for therapeutic and preventive decision making.
Key words: hypertension, genetic • hypertension, nonmodulating • aldosterone • genetics • gene expression
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