- Email: [email protected]
Is white-coat effect a uniform phenomenon?
82A
POSTERS: Genetics/Gene Therapy
defined as PDH. All patients had their pulse pressure pattern confirmed by ambulatory blood pressure monitoring (ABPM). The II, ID and DD genotype variants of ACE were characterized by the triple primer nested-PCR method. Results were compared to 36 normotensive controls individuals. Statistical significance was assessed by Chi square method. Hypertensive patients (31 males, mean age: 41⫾8,3; BMI: 25,2⫾ 3,4) had II⫽10 (20%), ID⫽17 (35%), DD⫽22 (45%), while normotensive controls (11 males; mean age: 59⫾9; BMI: 25,1⫾2,1) II⫽14(39%), ID⫽12(33%), DD⫽10(28%). DD vs. ID vs. II (p⬍0,05). ACE allele frequencies in PDH patients and controls were D⫽0,625, I⫽0,375 and D⫽0,55, I⫽0,45, respectively (P⬍0,01). These results are the first to show an association between the DD ACE polymorphism and predominantly diastolic hypertension. Key Words: ACE polymorphism, diastolic blood pressure, genetics
P-120 IMPORTANCE OF SOME GENETIC POLYMORPHISMS OF THE RENIN ANGIOTENSIN SYSTEM ON THE EFFECT OF TELMISARTAN ON BP AND MICROALBUMINURIA OF ESSENTIAL HYPERTENSIVE PATIENTS Josep Redon, Manuel Luque-Otero, Nieves Martell, on behalf the investigators of the POLPRI Study, Spain. The aim of this study is to investigate the impact of several genetic polymorphisms of the components of the renin angiotensin system on the effect of Telmisartan on blood pressure and microalbuminuria of essential hypertensives. Essential hypertensives (EH) of both sexes, aged 20-75 years, with seated BP between 140-180 and/or 90-104 mmHg after a washout period were included in the study. Patients with diabetes, renal insufficiency (serum creatinine ⬎ 1.8 mg/dl), secondary hypertension, major cardiovascular events in the last 6 months and pregnancy will be excluded from the study. At baseline BP was determined in the seated position, two samples of 24-urine were obtained for microalbuminuria (MA) and blood samples were obtained after and overnight period of fasting to determine the lipid profile, creatinine and glucose concentration, and to determine the A-6G (M235T) and T174M angiotensinogen polymorphism, the I/D ACE polymorphism and the A1166C and C573T AT1 receptor polymorphism. The patients were treated with telmisartan 80 mg and other antihypertensive drugs (diuretics and calcium antagonists) were added if necessary to achieve the BP control. The follow-up lasted 12 months, and 81 EH need to be treated with a combination of drugs. Two hundred and four EH (81 female, age) were enrolled in the study. BP was 154 ⫾ 13 / 95 ⫾ 7 mm Hg. MA averaged 32.7 ⫾ 84 mg/g creatinine. After 12 months of treatment BP and MA decreased to 130 ⫾ 11/80 ⫾ 8 mm Hg and 23 ⫾ 68 mg/g respectively (p⬍0.0001). There were no statistically significant relationship between the genotypes studied and either the baseline BP and MA values, the decrease of both parameters observed during the study or the need to associate another drug to telmisartan to achieve the BP control. In conclusion in this population of essential hypertensives treatment with telmisartan reduced significantly BP and microalbuminuria. However we do not find associations of the polymorphisms of the components of the renin angiotensin system with either the BP or microalbuminuria reduction obtained with the treatment. Key Words: Renin angiotensin system polymorphism, angiotensin II receptor antagonists, microalbuminuria
AJH–May 2003–VOL. 16, NO. 5, PART 2
P-121 UCSNP-43 G/A POLYMORPHISM OF CALPAIN-10 GENE IS ASSOCIATED WITH HYPERTENSION AND DYSLIPIDEMIA IN JAPANESE POPULATION Ken Sugimoto, Tomohiro Katsuya, Kazuhiko Ishikawa, Yoshihiro Iwashima, Kouichi Yamamoto, Yuxiao Fu, Akiko Matsuo, Masaharu Motone, Hiromi Rakugi, Toshio Ogihara. Geriatric Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. Background: Previous linkage studies in Mexican-American localized a major susceptibility locus for type 2 diabetes, NIDDM1, to chromosome band 2q37.3. In this locus, recently, a common G/A polymorphism (UCSNP-43) within intron 3 of the CAPN-10 gene (CAPN10) was reported as a major candidate for the cause of NIDDM, and it was also reported that homozygous UCSNP-43 G alleles reduced CAPN10 mRNA expression. The aim of this study was to assess the frequency of G/A polymorphism of CAPN10 in Japanese population and to examine the interaction between CAPN10 genotype and hypertension. Methods: This study population was consecutive in- or out-patients of Osaka University Hospital. The subjects who gave the informed consent for the study protocol and genetic analysis were recruited in this study (n⫽1087). Results: UCSNP-43 G/A polymorphism was clearly determined using the TaqMan PCR method. The distribution of this genotype was as follows: GG 88%, GA 11%, AA ⬍1%. We divided the subjects into two groups: subjects with GG genotype (GG) and those with GA or AA genotypes (A carrier). Among the subjects with BP measurements (n⫽730), GG had significantly higher frequency of prevalence of hypertension (PH) than A carrier, but the significant association disappeared after the adjustment for age, sex and BMI. Among lean subjects (BMI⬍25kg/m2, n⫽570), however, PH was significantly higher in GG than in A carrier even after the adjustment for age and sex (OR⫽1.9 (95%CI 1.1-3.5)). Furthermore, among the lean subjects without antihyperlipidemic drugs (n⫽360), serum total cholesterol (TC) and triglyceride (TG) levels were significantly higher in GG than in A carrier after adjusted for age and sex (TC; 212.5⫾1.8 vs. 197.3⫾5.9 mg/dl, p⬍0.02, TG; 150.3⫾3.5 vs. 120.7⫾11.4 mg/dl, p⬍0.02). In addition, among the subjects with serum insulin level (n⫽188), value of HOMA scale was higher in GG than in A carrier (2.1⫾0.2 vs. 1.4⫾0.5). Conclusion: Our data suggested that UCSNP-43 GG homozygous of calpain-10 gene is a genetic risk for hypertension and dyslipidemia in lean subjects via alteration of insulin sensitivity. Key Words: Polymorphism, calpain-10 gene, hypertension
P-122 IS WHITE-COAT EFFECT A UNIFORM PHENOMENON? Mikolaj Winnicki, Virend K Somers, Michal Hoffmann, Valentina Accurso, Daniele D‘Este, Giuseppe Zanatta, Alessandra Bartolazzi, Ryszard Pawlowski, Andrea Semplicini, Winfried Siffert, Paolo Palatini. Hypertension, Medical University of Gdansk, Gdansk, Poland; Clinical & Experimental Medicine, University of Padova, Padova, Italy; Hypertension, Mayo Clinic, Rochester, MN; Pharmacology, University of Essen, Essen, Germany. White coat hypertensives come from families with higher blood pressure (BP) levels, have high BP readings early in life, and maintain elevated readings from childhood to adulthood. While these features suggest a genetic influence on the white coat effect (WCE), little is known about the specifics of the genetic background of WCE. We therefore studied the relationship between the WCE and angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) M235T and beta3 subunit of G-
AJH–May 2003–VOL. 16, NO. 5, PART 2
protein (GNB3) C825T polymorphisms in 255 never treated mild hypertensives, participanting in the Harvest study. WCE was defined as the difference between office and daytime ambulatory BP and heart rate. None of the polymorphisms was associated with either systolic WCE or heart rate WCE. In univariate analysis, subjects with ACE II (p⫽0.043), AGT MT (p⬍0.0001) and GNB3 CC (p⫽0.08) had a higher diastolic WCE than the rest of the group. In multivariate analysis ACE-II (F⫽3.9,p⬍0.05), GNB3-CC (F⫽3.9,p⬍0.05) and AGT-MT (F⫽9.2,p⬍0.0001) were independently associated with higher diastolic WCE. In addition, a negative family history of hypertension (FH-) (p⬍0.03) and alcohol consumption (p⫽0.025) were also associated with a higher diastolic WCE. There was a strong association between the diastolic WCE and the combined FH-/AGT status (F⫽5.5,p⫽0.004), so that FH- subjects with the AGT-MT allele had higher diastolic WCE than the rest of the group.
POSTERS: Genetics/Gene Therapy
83A
In conclusion, our results suggest that certain alleles of common gene polymorphisms, alcohol consumption and the absence of a family history of hypertension, are associated with a selectively enhanced diastolic WCE in mild hypertensive subjects. None of the polymorphisms, nor family history of hypertension and alcohol consumption, were associated with systolic or heart rate WCE, suggesting that they do not influence these components of WCE. This differential association supports the concept that the evaluation of the pathophysiologic effects of the WCE should be done considering systolic BP, diastolic BP, and heart rate responses individually rather than assuming that they collectively represent a generic or uniform “white-coat effect”.
Key Words: White coat effect, genetics, hypertension
POSTERS: Genetics/Gene Therapy
defined as PDH. All patients had their pulse pressure pattern confirmed by ambulatory blood pressure monitoring (ABPM). The II, ID and DD genotype variants of ACE were characterized by the triple primer nested-PCR method. Results were compared to 36 normotensive controls individuals. Statistical significance was assessed by Chi square method. Hypertensive patients (31 males, mean age: 41⫾8,3; BMI: 25,2⫾ 3,4) had II⫽10 (20%), ID⫽17 (35%), DD⫽22 (45%), while normotensive controls (11 males; mean age: 59⫾9; BMI: 25,1⫾2,1) II⫽14(39%), ID⫽12(33%), DD⫽10(28%). DD vs. ID vs. II (p⬍0,05). ACE allele frequencies in PDH patients and controls were D⫽0,625, I⫽0,375 and D⫽0,55, I⫽0,45, respectively (P⬍0,01). These results are the first to show an association between the DD ACE polymorphism and predominantly diastolic hypertension. Key Words: ACE polymorphism, diastolic blood pressure, genetics
P-120 IMPORTANCE OF SOME GENETIC POLYMORPHISMS OF THE RENIN ANGIOTENSIN SYSTEM ON THE EFFECT OF TELMISARTAN ON BP AND MICROALBUMINURIA OF ESSENTIAL HYPERTENSIVE PATIENTS Josep Redon, Manuel Luque-Otero, Nieves Martell, on behalf the investigators of the POLPRI Study, Spain. The aim of this study is to investigate the impact of several genetic polymorphisms of the components of the renin angiotensin system on the effect of Telmisartan on blood pressure and microalbuminuria of essential hypertensives. Essential hypertensives (EH) of both sexes, aged 20-75 years, with seated BP between 140-180 and/or 90-104 mmHg after a washout period were included in the study. Patients with diabetes, renal insufficiency (serum creatinine ⬎ 1.8 mg/dl), secondary hypertension, major cardiovascular events in the last 6 months and pregnancy will be excluded from the study. At baseline BP was determined in the seated position, two samples of 24-urine were obtained for microalbuminuria (MA) and blood samples were obtained after and overnight period of fasting to determine the lipid profile, creatinine and glucose concentration, and to determine the A-6G (M235T) and T174M angiotensinogen polymorphism, the I/D ACE polymorphism and the A1166C and C573T AT1 receptor polymorphism. The patients were treated with telmisartan 80 mg and other antihypertensive drugs (diuretics and calcium antagonists) were added if necessary to achieve the BP control. The follow-up lasted 12 months, and 81 EH need to be treated with a combination of drugs. Two hundred and four EH (81 female, age) were enrolled in the study. BP was 154 ⫾ 13 / 95 ⫾ 7 mm Hg. MA averaged 32.7 ⫾ 84 mg/g creatinine. After 12 months of treatment BP and MA decreased to 130 ⫾ 11/80 ⫾ 8 mm Hg and 23 ⫾ 68 mg/g respectively (p⬍0.0001). There were no statistically significant relationship between the genotypes studied and either the baseline BP and MA values, the decrease of both parameters observed during the study or the need to associate another drug to telmisartan to achieve the BP control. In conclusion in this population of essential hypertensives treatment with telmisartan reduced significantly BP and microalbuminuria. However we do not find associations of the polymorphisms of the components of the renin angiotensin system with either the BP or microalbuminuria reduction obtained with the treatment. Key Words: Renin angiotensin system polymorphism, angiotensin II receptor antagonists, microalbuminuria
AJH–May 2003–VOL. 16, NO. 5, PART 2
P-121 UCSNP-43 G/A POLYMORPHISM OF CALPAIN-10 GENE IS ASSOCIATED WITH HYPERTENSION AND DYSLIPIDEMIA IN JAPANESE POPULATION Ken Sugimoto, Tomohiro Katsuya, Kazuhiko Ishikawa, Yoshihiro Iwashima, Kouichi Yamamoto, Yuxiao Fu, Akiko Matsuo, Masaharu Motone, Hiromi Rakugi, Toshio Ogihara. Geriatric Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. Background: Previous linkage studies in Mexican-American localized a major susceptibility locus for type 2 diabetes, NIDDM1, to chromosome band 2q37.3. In this locus, recently, a common G/A polymorphism (UCSNP-43) within intron 3 of the CAPN-10 gene (CAPN10) was reported as a major candidate for the cause of NIDDM, and it was also reported that homozygous UCSNP-43 G alleles reduced CAPN10 mRNA expression. The aim of this study was to assess the frequency of G/A polymorphism of CAPN10 in Japanese population and to examine the interaction between CAPN10 genotype and hypertension. Methods: This study population was consecutive in- or out-patients of Osaka University Hospital. The subjects who gave the informed consent for the study protocol and genetic analysis were recruited in this study (n⫽1087). Results: UCSNP-43 G/A polymorphism was clearly determined using the TaqMan PCR method. The distribution of this genotype was as follows: GG 88%, GA 11%, AA ⬍1%. We divided the subjects into two groups: subjects with GG genotype (GG) and those with GA or AA genotypes (A carrier). Among the subjects with BP measurements (n⫽730), GG had significantly higher frequency of prevalence of hypertension (PH) than A carrier, but the significant association disappeared after the adjustment for age, sex and BMI. Among lean subjects (BMI⬍25kg/m2, n⫽570), however, PH was significantly higher in GG than in A carrier even after the adjustment for age and sex (OR⫽1.9 (95%CI 1.1-3.5)). Furthermore, among the lean subjects without antihyperlipidemic drugs (n⫽360), serum total cholesterol (TC) and triglyceride (TG) levels were significantly higher in GG than in A carrier after adjusted for age and sex (TC; 212.5⫾1.8 vs. 197.3⫾5.9 mg/dl, p⬍0.02, TG; 150.3⫾3.5 vs. 120.7⫾11.4 mg/dl, p⬍0.02). In addition, among the subjects with serum insulin level (n⫽188), value of HOMA scale was higher in GG than in A carrier (2.1⫾0.2 vs. 1.4⫾0.5). Conclusion: Our data suggested that UCSNP-43 GG homozygous of calpain-10 gene is a genetic risk for hypertension and dyslipidemia in lean subjects via alteration of insulin sensitivity. Key Words: Polymorphism, calpain-10 gene, hypertension
P-122 IS WHITE-COAT EFFECT A UNIFORM PHENOMENON? Mikolaj Winnicki, Virend K Somers, Michal Hoffmann, Valentina Accurso, Daniele D‘Este, Giuseppe Zanatta, Alessandra Bartolazzi, Ryszard Pawlowski, Andrea Semplicini, Winfried Siffert, Paolo Palatini. Hypertension, Medical University of Gdansk, Gdansk, Poland; Clinical & Experimental Medicine, University of Padova, Padova, Italy; Hypertension, Mayo Clinic, Rochester, MN; Pharmacology, University of Essen, Essen, Germany. White coat hypertensives come from families with higher blood pressure (BP) levels, have high BP readings early in life, and maintain elevated readings from childhood to adulthood. While these features suggest a genetic influence on the white coat effect (WCE), little is known about the specifics of the genetic background of WCE. We therefore studied the relationship between the WCE and angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) M235T and beta3 subunit of G-
AJH–May 2003–VOL. 16, NO. 5, PART 2
protein (GNB3) C825T polymorphisms in 255 never treated mild hypertensives, participanting in the Harvest study. WCE was defined as the difference between office and daytime ambulatory BP and heart rate. None of the polymorphisms was associated with either systolic WCE or heart rate WCE. In univariate analysis, subjects with ACE II (p⫽0.043), AGT MT (p⬍0.0001) and GNB3 CC (p⫽0.08) had a higher diastolic WCE than the rest of the group. In multivariate analysis ACE-II (F⫽3.9,p⬍0.05), GNB3-CC (F⫽3.9,p⬍0.05) and AGT-MT (F⫽9.2,p⬍0.0001) were independently associated with higher diastolic WCE. In addition, a negative family history of hypertension (FH-) (p⬍0.03) and alcohol consumption (p⫽0.025) were also associated with a higher diastolic WCE. There was a strong association between the diastolic WCE and the combined FH-/AGT status (F⫽5.5,p⫽0.004), so that FH- subjects with the AGT-MT allele had higher diastolic WCE than the rest of the group.
POSTERS: Genetics/Gene Therapy
83A
In conclusion, our results suggest that certain alleles of common gene polymorphisms, alcohol consumption and the absence of a family history of hypertension, are associated with a selectively enhanced diastolic WCE in mild hypertensive subjects. None of the polymorphisms, nor family history of hypertension and alcohol consumption, were associated with systolic or heart rate WCE, suggesting that they do not influence these components of WCE. This differential association supports the concept that the evaluation of the pathophysiologic effects of the WCE should be done considering systolic BP, diastolic BP, and heart rate responses individually rather than assuming that they collectively represent a generic or uniform “white-coat effect”.
Key Words: White coat effect, genetics, hypertension