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Is leptin the link between angiotensin-converting enzyme gene polymorphism and body mass index in untreated hypertensives?
AJH–APRIL 2000 –VOL. 13, NO. 4, PART 2
Key Words: Amiloride-sensitive sodium channel; T594M; mutation; ESRD; African Americans D012 ANGIOTENSIN TYPE 1 RECEPTOR ANTISENSE VS ACE ANTISENSE GENE THERAPY IN THE SHR M.J. Katovich*, P.Y. Reaves, H.-W. Wang, C.H. Gelband, and M.K. Raizada*. College of Medicine and College of Pharmacy, University of Florida, Gainesville, FL Previously, we have demonstrated that neonatal delivery of angiotensin type I receptor antisense cDNA (AT1R-AS) by a retroviral vector circumvents the limitations imposed by pharmacological therapy, resulting in the permanent prevention of high blood pressure (BP) in the spontaneously hypertensive rat (SHR). In the current study, our aim was to compare the effects of antisense to the angiotensin I converting enzyme (ACE-AS) to AT1R-AS in both the prevention of the development of hypertension and in the pathophysiological alterations that occur the SHR. A single intracardiac injection of AT1R-AS resulted in a 47% reduction in BP when compared to SHRs treated with control vector alone. However ACE-AS treatment resulted in only a BP reduction of 27% compared to the vector-treated SHRs. In addition to the hypertension the following cardiovascular pathophysiology occurs in the SHR: left ventricular hypertrophy, increased vascular sensitivity to vasoconstrictor agents, endothelial dysfunction, increased levels of vascular smooth muscle (VSM) intracellular calcium, increased VSM calcium current, decreased VSM Kv current, and VSM depolarization. Both AT1R-AS and ACE-AS gene therapy equally prevented all of the above pathophysiological alterations. These results suggest that ACE-AS therapy may have actions on the tissue RAS to protect the vascular and cardiac pathophysiology, since BP changes were much more moderate than that exhibited by AT1R-AS delivery. Key Words: AT1R-AS; ACE-AS; hypertension; SHR; viral vector D013 IS LEPTIN THE LINK BETWEEN ANGIOTENSINCONVERTING ENZYME GENE POLYMORPHISM AND BODY MASS INDEX IN UNTREATED HYPERTENSIVES? M. Winnicki$, V. Accurso, M. Hoffmann$, O. Vriz, L. Mos, K. Narkiewicz, B. Phillips•, B. Krupa-Wojciechowska$, P. Palatini, V. SomersY on behalf of the HARVEST Study Group, Italy. University of Padova, Italy, •University of Iowa, USA, YMayo Clinic, USA and $Medical University of Gdansk, Poland Several studies show that subjects homozygous to deletion (D) allele of the angiotensin converting enzyme (ACE) gene polymorphism have lower body mass index (BMI) than heterozygotes or homozygotes for the insertion (I) allele. BMI is strongly related to the ob gene product, leptin. Leptin levels are elevated in the majority of obese subjects, presumably because of leptin resistance. A recent study also demonstrated that angiotensinogen and the enzymes involved in its conversion are expressed in human adipocytes. Previous studies reported that leptin, angiotensinogen and blood pressure levels are positively correlated in normotensive
POSTERS: Genetics/Gene Therapy
77A
young men. However, little is known about the relation between leptin, ACE gene polymorphism and BMI in young hypertensives. We therefore investigated this relationship in a group of 57 stage I, never treated hypertensive males (mean age 35.7 ⫾ 8 years, mean BMI 26.7 ⫾ 2,9 kg/m2) from the HARVEST study. ACE genotyping was performed by polymerase chain reaction with standard methods. Serum leptin levels were assessed by radioimmunoassay with commercially available kits. We compared subjects homozygous for the D allele (DD) with those subjects in whom an I allele was present (ID and II). ACE I/D allele frequencies were II 22.8%, ID 50,9%, DD 26,3%. In Manova adjusted for physical activity, duration of hypertension, profession and age, BMI was significantly lower in DD group (27.2 ⫾ 0.4 vs 25.2 ⫾ 0.8 kg/m2, p ⫽ 0.027). However, after adjusting for leptin levels, the difference between groups disappeared (F ⫽ 2.145, p ⫽ 0.145). Surprisingly, leptin levels were lower in the DD group. The difference remained significant even after adjustment for BMI, physical activity, duration of hypertension, BP level and age (3.9 ⫾ 0.3 vs 2.6 ⫾ 0.5 ng/ml, F ⫽ 4.654, p ⫽ 0.036). We conclude that ACE gene polymorphism influences leptin levels independently of BMI, age, BP level, physical activity and duration of hypertension, such that the DD genotype is accompanied by increased leptin sensitivity. The association of ACE genotype with BMI may be mediated in part through its relationship with leptin levels. Key Words: Leptin; ACE gene polymorphism; BMI; mild hypertensives D014 ANGIOTENSINOGEN GENE MUTATIONS AND HYPERTENSION IN THE GENERAL POPULATION A.A. Sethi, B.G. Nordestgaard, B. Agerholm-Larsen, E. Frandsen, G. Jensen and A. Tybjærg-Hansen. Department of Clinical Biochemistry, Herlev University Hospital, Denmark. Hypertension is linked to the angiotensinogen gene. We tested the hypothesis that the Thr174Met and Met235Thr mutations in this gene increase the risk of hypertension. We genotyped 9100 women and men from the Danish general population, of which 54 percent had hypertension. Twelve and 41 percent carried the 174M and 235T mutations, respectively. The 174M mutation always occurred on the same allele as the 235T mutation. On multifactorial logistic regression analysis, women homozygous for 235T had an odds ratio for hypertension of 1.29 (95 percent confidence interval, 1.05 to 1.58), which increased to 1.50 (95 percent confidence interval, 1.15 to 1.96) if they in addition were homozygous for 174T. Women homozygous for 235T also had increased risk of isolated systolic hypertension (OR, 1.37; 95 percent confidence interval, 1.02 to 1.84), and of mild hypertension (OR, 1.40; 95 percent confidence interval, 1.10 to 1.77). Finally, women homozygous for both 235T and 174T had increased risk of being on antihypertensive medication (OR, 1.53; 95 percent confidence interval, 1.12 to 2.09). We found no effects on risk of hypertension as a function of genotype in men, and no significant differences on systolic- or diastolic blood pressure or pulse pressure as a function of genotype in either gender. The M235T mutation was associated with a 10 percent increase in levels of
Key Words: Amiloride-sensitive sodium channel; T594M; mutation; ESRD; African Americans D012 ANGIOTENSIN TYPE 1 RECEPTOR ANTISENSE VS ACE ANTISENSE GENE THERAPY IN THE SHR M.J. Katovich*, P.Y. Reaves, H.-W. Wang, C.H. Gelband, and M.K. Raizada*. College of Medicine and College of Pharmacy, University of Florida, Gainesville, FL Previously, we have demonstrated that neonatal delivery of angiotensin type I receptor antisense cDNA (AT1R-AS) by a retroviral vector circumvents the limitations imposed by pharmacological therapy, resulting in the permanent prevention of high blood pressure (BP) in the spontaneously hypertensive rat (SHR). In the current study, our aim was to compare the effects of antisense to the angiotensin I converting enzyme (ACE-AS) to AT1R-AS in both the prevention of the development of hypertension and in the pathophysiological alterations that occur the SHR. A single intracardiac injection of AT1R-AS resulted in a 47% reduction in BP when compared to SHRs treated with control vector alone. However ACE-AS treatment resulted in only a BP reduction of 27% compared to the vector-treated SHRs. In addition to the hypertension the following cardiovascular pathophysiology occurs in the SHR: left ventricular hypertrophy, increased vascular sensitivity to vasoconstrictor agents, endothelial dysfunction, increased levels of vascular smooth muscle (VSM) intracellular calcium, increased VSM calcium current, decreased VSM Kv current, and VSM depolarization. Both AT1R-AS and ACE-AS gene therapy equally prevented all of the above pathophysiological alterations. These results suggest that ACE-AS therapy may have actions on the tissue RAS to protect the vascular and cardiac pathophysiology, since BP changes were much more moderate than that exhibited by AT1R-AS delivery. Key Words: AT1R-AS; ACE-AS; hypertension; SHR; viral vector D013 IS LEPTIN THE LINK BETWEEN ANGIOTENSINCONVERTING ENZYME GENE POLYMORPHISM AND BODY MASS INDEX IN UNTREATED HYPERTENSIVES? M. Winnicki$, V. Accurso, M. Hoffmann$, O. Vriz, L. Mos, K. Narkiewicz, B. Phillips•, B. Krupa-Wojciechowska$, P. Palatini, V. SomersY on behalf of the HARVEST Study Group, Italy. University of Padova, Italy, •University of Iowa, USA, YMayo Clinic, USA and $Medical University of Gdansk, Poland Several studies show that subjects homozygous to deletion (D) allele of the angiotensin converting enzyme (ACE) gene polymorphism have lower body mass index (BMI) than heterozygotes or homozygotes for the insertion (I) allele. BMI is strongly related to the ob gene product, leptin. Leptin levels are elevated in the majority of obese subjects, presumably because of leptin resistance. A recent study also demonstrated that angiotensinogen and the enzymes involved in its conversion are expressed in human adipocytes. Previous studies reported that leptin, angiotensinogen and blood pressure levels are positively correlated in normotensive
POSTERS: Genetics/Gene Therapy
77A
young men. However, little is known about the relation between leptin, ACE gene polymorphism and BMI in young hypertensives. We therefore investigated this relationship in a group of 57 stage I, never treated hypertensive males (mean age 35.7 ⫾ 8 years, mean BMI 26.7 ⫾ 2,9 kg/m2) from the HARVEST study. ACE genotyping was performed by polymerase chain reaction with standard methods. Serum leptin levels were assessed by radioimmunoassay with commercially available kits. We compared subjects homozygous for the D allele (DD) with those subjects in whom an I allele was present (ID and II). ACE I/D allele frequencies were II 22.8%, ID 50,9%, DD 26,3%. In Manova adjusted for physical activity, duration of hypertension, profession and age, BMI was significantly lower in DD group (27.2 ⫾ 0.4 vs 25.2 ⫾ 0.8 kg/m2, p ⫽ 0.027). However, after adjusting for leptin levels, the difference between groups disappeared (F ⫽ 2.145, p ⫽ 0.145). Surprisingly, leptin levels were lower in the DD group. The difference remained significant even after adjustment for BMI, physical activity, duration of hypertension, BP level and age (3.9 ⫾ 0.3 vs 2.6 ⫾ 0.5 ng/ml, F ⫽ 4.654, p ⫽ 0.036). We conclude that ACE gene polymorphism influences leptin levels independently of BMI, age, BP level, physical activity and duration of hypertension, such that the DD genotype is accompanied by increased leptin sensitivity. The association of ACE genotype with BMI may be mediated in part through its relationship with leptin levels. Key Words: Leptin; ACE gene polymorphism; BMI; mild hypertensives D014 ANGIOTENSINOGEN GENE MUTATIONS AND HYPERTENSION IN THE GENERAL POPULATION A.A. Sethi, B.G. Nordestgaard, B. Agerholm-Larsen, E. Frandsen, G. Jensen and A. Tybjærg-Hansen. Department of Clinical Biochemistry, Herlev University Hospital, Denmark. Hypertension is linked to the angiotensinogen gene. We tested the hypothesis that the Thr174Met and Met235Thr mutations in this gene increase the risk of hypertension. We genotyped 9100 women and men from the Danish general population, of which 54 percent had hypertension. Twelve and 41 percent carried the 174M and 235T mutations, respectively. The 174M mutation always occurred on the same allele as the 235T mutation. On multifactorial logistic regression analysis, women homozygous for 235T had an odds ratio for hypertension of 1.29 (95 percent confidence interval, 1.05 to 1.58), which increased to 1.50 (95 percent confidence interval, 1.15 to 1.96) if they in addition were homozygous for 174T. Women homozygous for 235T also had increased risk of isolated systolic hypertension (OR, 1.37; 95 percent confidence interval, 1.02 to 1.84), and of mild hypertension (OR, 1.40; 95 percent confidence interval, 1.10 to 1.77). Finally, women homozygous for both 235T and 174T had increased risk of being on antihypertensive medication (OR, 1.53; 95 percent confidence interval, 1.12 to 2.09). We found no effects on risk of hypertension as a function of genotype in men, and no significant differences on systolic- or diastolic blood pressure or pulse pressure as a function of genotype in either gender. The M235T mutation was associated with a 10 percent increase in levels of