Genetic Variant of the Renin-Angiotensin System and Diabetes Influences Blood Pressure Response to Angiotensin Receptor Blocker
- Tadashi Konoshita, MD, PhD (konosita{at}u-fukui.ac.jp)1,
- Norihiro Kato, MD, PhD2,
- Sébastien Fuchs, MD, PhD3,
- Shinichi Mizuno, MD1,
- Chikako Aoyama, MD1,
- Makoto Motomura, MD1,
- Yasukazu Makino, MD1,
- Shigeyuki Wakahara, MD, PhD1,
- Isao Inoki, MD, PhD1,
- Isamu Miyamori, MD, PhD1,
- Florence Pinet, PhD4 and
- the Genomic Disease Outcome Consortium (G-DOC) Study Investigators
- 1Third Department of Internal Medicine, Fukui University School of Medicine, Eiheiji, Japan
- 2Department of Gene Diagnostics and Therapeutics, Research Institute, International Medical Center of Japan, Tokyo, Japan
- 3Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- 4 INSERM UMR744, Institut Pasteur de Lille, Lille, France
Abstract
Objective- Recent studies have proven favorable effects of angiotensin receptor blocker (ARB) on cardiovascular and renal disorders. However, determinants of response to ARB remain unclear. We substantiated the hypothesis that genetic variants of the renin angiotensin system (RAS) have significant impacts on the response to ARB.
Research design and methods- Subjects comprised 231 hypertensives including 45 cases of type 2 diabetics consecutively enrolled. Five genetic variants of the RAS, i.e., renin (REN) C-5312T, ACE Insertion/Deletion, angiotensinogen M235T, AT1 A1166C and AT2 C3123A were assayed by PCR and RFLP. A dosage 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; 10.7mmHg reduction (95.9±12.9 to 85.2±11.4) in CC versus 7.0mmHg reduction (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 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 the responder, with odds ratio (95% confidential interval) being 2.49(1.41-4.42), 2.03(1.10-3.74) and 0.48(0.24-0.96), respectively.
Conclusions- This study provides a strong support that a genetic variant of REN C-5312T and diabetes contribute to effects of ARB and is independent predictors for the responder. Thus in treatment of hypertension with ARB, a new possibility for personalized medicine has been shown.
Footnotes
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- Received February 24, 2009.
- Accepted April 27, 2009.
- Copyright © American Diabetes Association
