title: Genetic variant of the Renin-Angiotensin system and diabetes influences blood pressure response to Angiotensin receptor blockers.
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.
authors.affiliation: Third Department of Internal Medicine, Fukui University School of Medicine, Eiheiji, Japan. konosita@u-fukui.ac.jp
authors.forename: Tadashi
authors.initials: T
authors.lastname: Konoshita
authors.forename: Norihiro
authors.initials: N
authors.lastname: Kato
authors.forename: Sébastien
authors.initials: S
authors.lastname: Fuchs
authors.forename: Shinichi
authors.initials: S
authors.lastname: Mizuno
authors.forename: Chikako
authors.initials: C
authors.lastname: Aoyama
authors.forename: Makoto
authors.initials: M
authors.lastname: Motomura
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Makino
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Wakahara
authors.forename: Isao
authors.initials: I
authors.lastname: Inoki
authors.forename: Isamu
authors.initials: I
authors.lastname: Miyamori
authors.forename: Florence
authors.initials: F
authors.lastname: Pinet
mesh_terms: D057911:Angiotensin Receptor Antagonists; D001794:Blood Pressure / Q000187:drug effects; D015992:Body Mass Index; D003404:Creatinine / Q000097:blood; D017931:DNA Primers; D003920:Diabetes Mellitus / Q000235:genetics* / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000503:physiopathology; D005260:Female; D017353:Gene Deletion; D014644:Genetic Variation; D005919:Glomerular Filtration Rate; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics*; D012083:Renin / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics*
chemical_list: D057911:Angiotensin Receptor Antagonists; D003404:Creatinine; D017931:DNA Primers; D006442:Glycated Hemoglobin; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012083:Renin