Genetic Variant of the Renin-Angiotensin System and Diabetes Influences Blood Pressure Response to Angiotensin Receptor Blockers

  1. Tadashi Konoshita, MD, PHD1,
  2. Norihiro Kato, MD, PHD2,
  3. Sébastien Fuchs, MD, PHD3,
  4. Shinichi Mizuno, MD1,
  5. Chikako Aoyama, MD1,
  6. Makoto Motomura, MD1,
  7. Yasukazu Makino, MD1,
  8. Shigeyuki Wakahara, MD, PHD1,
  9. Isao Inoki, MD, PHD1,
  10. Isamu Miyamori, MD, PHD1,
  11. Florence Pinet, PHD4 and
  12. for the Genomic Disease Outcome Consortium (G-DOC) Study Investigators
  1. 1Third Department of Internal Medicine, Fukui University School of Medicine, Eiheiji, Japan;
  2. 2Department of Gene Diagnostics and Therapeutics, Research Institute, International Medical Center of Japan, Tokyo, Japan;
  3. 3Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California;
  4. 4Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 744, Institut Pasteur de Lille, Lille, France.
  1. Corresponding author: Tadashi Konoshita, konosita{at}u-fukui.ac.jp.

Abstract

OBJECTIVE Recent studies have proven the favorable effects of angiotensin receptor blockers (ARBs) on cardiovascular and renal disorders. However, determinants of the response to ARBs remain unclear. We substantiated the hypothesis that genetic variants of the renin-angiotensin system (RAS) have significant impacts on the response to ARBs.

RESEARCH DESIGN AND METHODS Subjects comprised 231 consecutively enrolled hypertensive individuals including 45 type 2 diabetic subjects. Five genetic variants of the RAS, i.e., renin (REN) C-5312T, ACE insertion/deletion, angiotensinogen M235T, angiotensin II type 1 receptor A1166C, and angiotensin II type 2 receptor C3123A were assayed by PCR and restriction fragment-length polymorphism. A dose of 40–160 mg/day of valsartan was administered for 3 months as a monotherapy.

RESULTS Changes in diastolic blood pressure significantly differed between genotypes of REN C-5312T: 10.7-mmHg reduction (from 95.9 ± 12.9 to 85.2 ± 11.4) in CC versus 7.0-mmHg reduction (from 94.7 ± 14.0 to 87.7 ± 12.6) in CT/TT (P = 0.02 for interactive effects of valsartan and genotype). Responder rates also differed between the genotypes: 72.8% in CC versus 58.0% in CT/TT (P = 0.03). Univariate analysis indicated a significant association of response to valsartan with blood pressure, diabetes, plasma aldosterone concentration, and CC homozygotes of REN C-5312T. Finally, multiple logistic regression analysis revealed that systolic blood pressure, CC homozygotes of REN C-5312T, and diabetes were independent predictors for responders with odds ratios (95% CI) of 2.49 (1.41–4.42), 2.03 (1.10–3.74), and 0.48 (0.24–0.96), respectively.

CONCLUSIONS This study provides strong support that a genetic variant of REN C-5312T and diabetes contribute to the effects of ARBs and are independent predictors for responder. Thus, in treatment of hypertension with ARBs, a new possibility for personalized medicine has been shown.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received February 24, 2009.
    • Accepted April 27, 2009.

  • Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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  1. Published online before print June 9, 2009, doi: 10.2337/dc09-0348 Diabetes Care August 2009 vol. 32 no. 8 1485-1490
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