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W14.389 Beta2-adrenergic receptor gene polymorphisms and elevated blood pressure
90
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Workshops W14 Genetics of atherosclerosis
Sekuri
ASSOCIATION BETWEEN RENIN-ANGIOTENSIN SYSTEM GENE POLYMORPHISMS AND PREMATURE CORONARY HEART DISEASE IN A TURKISH POPULATION
C. Sekuri, F. Cam, E. Ercan, A. Sagcan, A. Berdeli, E. Ese. Celal Bayar
University, Manisa, Central Hospital, Atakalp Hospital, Ege University, Izmir, Turkey It has been suggested that the renin-angiotensin system (RAS) affects the pathogenesis of atherosclerosis and prognosis of coronat'y heat't (CHD) disease. The aim of this study was to investigate the genotype distribution and the allele fi'equencies of three RAS gene polymorphisms and their effects on premature CHD in a Turkish population. 115 Turkish patients with premature CHD and 128 controls were included into study. ACE, AT1R and AGT gene polymorphisms were analysed by polymerase chain leaction (PCR) and restriction fi'agment length polymorphism (RFLP). The patients group showed an increase fi'equency of the ACE D allele compared to controls (65% versus 35%, p=0.0001). There was a significant association between the DD genotype and premature CHD [ACE DD vs ID and II; OR= 2.82 (CI 95% 1.33-2.91, P=0.002)]. Also, we observed increased premature CHD risk associated with higher fi'equencies of the AGT MM genotype in patients when compat'ed with controls [AGT MM vs TT and MT, OR=1.92 (CI 95% 1.11-3.33, p= 0.018)]. We found a significant association between AT1R AA genotype and decreased risk of premature CHD [AT1R AA vs AC and CC, OR= 0.57 (C195% 0.34-0.95, p=0.03)]. Conclusion: We demonstrated that increased premature CHD risk associated with higher fi'equencies of the ACE DD and AGT MM genotypes. This findings indicate a sinergistic contribution of ACE DD and AGT MM polymolphisms to the development of the premature CHD. Also, our results suggested that family history, smoking, diabetes, hypertension, obesity and ACE DD genotpye were independent risk factors for prematme CHD.
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BETA2-ADRENERGIC RECEPTOR GENE POLYMORPHISMS AND ELEVATED BLOOD PRESSURE
A. Sethi, A. Tybj~erg-Hansen, G. Jensen, B. Nordestgaat'd. Copenhagen
University Hospital, Hvidovre University Hospital, Herlev University Hospital, Copenhagen, Denmark Aim: The beta2-a&'energic receptor plays a pivotal role in signaling in lelation to elevated blood pressure. Fm'thermore, single nucleotide polymol~ phisms (SNPs) in the gene coding for this receptor has been associated with altered response to sympathetic stimulation. We tested the hypothesis that tl~'ee SNPs in the beta2-a&'energic receptor gene were associated or not with elevated blood pressure in 9234 individuals fi'om the general population. Methods: SNPs in the beta-2 adlenergic receptor gene, Gly16Arg, Gln27Glu, and Thr164Ile, were genotyped on NanogenT M microelectronic chips in 9234 individuals. Results: Allele fi'equencies of 16Arg, 27Glu, and 164Ile were 0.38, 0.44, and 0.01, respectively; the 16Arg allele always occurs together with 27Gln and 164Thr. No individuals homozygous for the 164Ile allele were found. Diastolic blood presstn'e was significantly elevated in women cma'ying 164Ile when compat'ed with 164ThrThr women(P=0.02); however, this was not true for men or for Gly16Arg and Gln27Glu examined alone or as combined genotypes for systolic blood presstn'e, diastolic blood pressure, or pulse presstn'e in either gender. On multifactorial logistic regression analysis women heterozygous for Th'164Ile versus non-cma'iers had an odds ratio for elevated blood pressme of 1.93(95 percent confidence intervals, 1.25-2.96) which increased to 2.70(1.27-5.71) if they in addition were non-cata'ier for Gln27Glu and heterozygous for Gly16Arg. This was not found in men or when examining Gly16Arg and Gln27Glu alone or as combined genotypes. Conclusions: Ore" data suggest that heterozygosity for Thr164Ile is associated with increased levels of diastolic blood pressure and is a risk factor for elevated blood presstn'e in women.
order to find out any association between the peripheral T cell activities and atherogenic risk factors. Material and Methods: 50 young male healthy volunteers wele enrolled (Age 22.0 2.4 years). Lymphocytes were isolated fi'om the hepatinized venous blood and the proliferative responses to phytohaemaglutinin were measmed fi'om the amount of radioactive thymidine uptake by the lymphocyte DNA. The correlation analyses between basal and stimulated activities of the T cells and Total and LDL cholesterol levels of the patients. The T cell activity responses of patients with family history of coronat'y events were compared with others. Also the activity responses of smokers wele compared with non-smokers. Results: Subjects with positive family history of coronary events had higher PHA stimulated T cell responses (p<0.05). Also, PHA activated T cell responses were positively correlated with total cholesterol and LDL cholesterol levels (p=0.022, r = 0.604, p= 0,015, r= 0,635) in the same group. Conclusion: Peripheral T cell activity lesponses to PHA ate found to be higher in the asymptomatic first degree relatives of patients with coronat'y events. Serum total cholesterol and LDL cholesterol levels were correlated with the T cell responses. The data may indicate a possible familial tendency of the increased peripheral T cell activities of the subjects with positive family history of coronary events. I
Iw14.391 iI GENETIC VARIATION IN THE ZINZ F I N G E R PROTEIN 202 GENE IN INDIVIDUALS FROM THE GENERAL POPULATION WITH EXTREME H D L CHOLESTEROL LEVELS M. Stene, R. Frikke-Schmidt, B. Nordestgaard, A. Tybj~erg-Hansen. Dept.
Clinical Biochemistry, Copenhagen University Hospital, Copenhagen, Dept. Clinical Biochemistry, Herlev University Hospital, Herlev, Denmark Background: The ZNF202 gene resides in a chromosomal region (11q23) linked genetically to low HDL cholesterol (HDL-C). ZNF202 is a transcriptional repressor which binds elements found predominantly in genes pat'ticipating in lipid metabolism. Consequently, ZNF202 is an attractive candidate gene for human dyslipidemia, and especially for modulation of HDL-C in the general population. Aim: To identify genetic variation in ZNF202 associated with variation in HDL-C. Methods: We selected 190 individuals fi'om the Copenhagen City Heat't Study with the 1% highest and 1% lowest HDL-C for age and sex, and screened ZNF202 for genetic vat'iation. Furtherrnore 9,259 individuals fi'om the general population, the Copenhagen City Heart Study, were genotyped for selected SNPs. Results: A total of 17 genetic variants were identified, ten SNPs (allele fi'equency > 1%) and seven mutations (fi'equency < 1%), several situated in highly conserved regulatory and functional important regions of the gene. Of the seven mutations, four were identified only in individuals with low HDL-C, and two were identified only in individuals with high HDL-C. A haplotype, which differed at only one position fi'om the wildtype haplotype AGATCG (1949T>G) tended to be overrepresented in the low HDL cholesterol group. Additionally, 1949G homozygozity showed association with a decrease in HDL cholesterol (p=0.04) and a con'esponding decrease in apoAI (p=0.004) in men (n=4,114). Conclusion: The present screening of ZNF202 identified 17 genetic vat'iants, ten SNPs and seven mutations. A SNP, 1949T>G, showed association with lower HDL-C levels in men, which may suggest a role for common SNPs in ZNF202 in determining HDL-C levels in the general population.
IW14.3921
FAMILIAL HYPOBETALIPOPROTEINEMIA WITH NO TRUNCATED FORMS OF APOLIPOPROTEIN B DETECTABLE IN PLASMA
E Tm'ugi, S. Lancellotti, E. di Leo, S. Calan&'a. University ofModena &
Reggio Emilia, Modena, Italy ~
PERIPHERAL T CELL ACTIVITIES ARE H I G H E R IN THE ASYMPTOMATIC KINDRED OF PATIENTS WITH CORONARY EVENTS
A. Sonmez, M. Yilmaz, G. Uckaya, T. Eyileten, C. Kinalp. Gulhane School
of Medicine and Adana Military Hospital, Ankara, Turkey Introduction: Increased T cell activities ate reported in the pathogenesis of many diseases including atherosclerosis. The study was performed in
Familial hypobetalipoproteinemia (FHBL) is a co-dominant disorder characterized by low levels of LDL and apoB due to mutations in apoB gene or in other genes yet to be identified. We recruited 34 FHBL probands and sem'ched first for the presence of U'uncated apoBs detectable in plasma (i.e.apoBs with a size above that of apoB-29). Only 11 probands can'ied U'uncated apoBs detectable in plasma (size range: fi'om apoB-32.38 to apoB-84.04) due to nonsense/fi'ameshift mutations in exon 26 of apoB gene. The complete sequence of apoB gene performed in 18 probands with
74th EAS Congress, 17-20 April 2004, Seville, Spain
•
Workshops W14 Genetics of atherosclerosis
Sekuri
ASSOCIATION BETWEEN RENIN-ANGIOTENSIN SYSTEM GENE POLYMORPHISMS AND PREMATURE CORONARY HEART DISEASE IN A TURKISH POPULATION
C. Sekuri, F. Cam, E. Ercan, A. Sagcan, A. Berdeli, E. Ese. Celal Bayar
University, Manisa, Central Hospital, Atakalp Hospital, Ege University, Izmir, Turkey It has been suggested that the renin-angiotensin system (RAS) affects the pathogenesis of atherosclerosis and prognosis of coronat'y heat't (CHD) disease. The aim of this study was to investigate the genotype distribution and the allele fi'equencies of three RAS gene polymorphisms and their effects on premature CHD in a Turkish population. 115 Turkish patients with premature CHD and 128 controls were included into study. ACE, AT1R and AGT gene polymorphisms were analysed by polymerase chain leaction (PCR) and restriction fi'agment length polymorphism (RFLP). The patients group showed an increase fi'equency of the ACE D allele compared to controls (65% versus 35%, p=0.0001). There was a significant association between the DD genotype and premature CHD [ACE DD vs ID and II; OR= 2.82 (CI 95% 1.33-2.91, P=0.002)]. Also, we observed increased premature CHD risk associated with higher fi'equencies of the AGT MM genotype in patients when compat'ed with controls [AGT MM vs TT and MT, OR=1.92 (CI 95% 1.11-3.33, p= 0.018)]. We found a significant association between AT1R AA genotype and decreased risk of premature CHD [AT1R AA vs AC and CC, OR= 0.57 (C195% 0.34-0.95, p=0.03)]. Conclusion: We demonstrated that increased premature CHD risk associated with higher fi'equencies of the ACE DD and AGT MM genotypes. This findings indicate a sinergistic contribution of ACE DD and AGT MM polymolphisms to the development of the premature CHD. Also, our results suggested that family history, smoking, diabetes, hypertension, obesity and ACE DD genotpye were independent risk factors for prematme CHD.
•
BETA2-ADRENERGIC RECEPTOR GENE POLYMORPHISMS AND ELEVATED BLOOD PRESSURE
A. Sethi, A. Tybj~erg-Hansen, G. Jensen, B. Nordestgaat'd. Copenhagen
University Hospital, Hvidovre University Hospital, Herlev University Hospital, Copenhagen, Denmark Aim: The beta2-a&'energic receptor plays a pivotal role in signaling in lelation to elevated blood pressure. Fm'thermore, single nucleotide polymol~ phisms (SNPs) in the gene coding for this receptor has been associated with altered response to sympathetic stimulation. We tested the hypothesis that tl~'ee SNPs in the beta2-a&'energic receptor gene were associated or not with elevated blood pressure in 9234 individuals fi'om the general population. Methods: SNPs in the beta-2 adlenergic receptor gene, Gly16Arg, Gln27Glu, and Thr164Ile, were genotyped on NanogenT M microelectronic chips in 9234 individuals. Results: Allele fi'equencies of 16Arg, 27Glu, and 164Ile were 0.38, 0.44, and 0.01, respectively; the 16Arg allele always occurs together with 27Gln and 164Thr. No individuals homozygous for the 164Ile allele were found. Diastolic blood presstn'e was significantly elevated in women cma'ying 164Ile when compat'ed with 164ThrThr women(P=0.02); however, this was not true for men or for Gly16Arg and Gln27Glu examined alone or as combined genotypes for systolic blood presstn'e, diastolic blood pressure, or pulse presstn'e in either gender. On multifactorial logistic regression analysis women heterozygous for Th'164Ile versus non-cma'iers had an odds ratio for elevated blood pressme of 1.93(95 percent confidence intervals, 1.25-2.96) which increased to 2.70(1.27-5.71) if they in addition were non-cata'ier for Gln27Glu and heterozygous for Gly16Arg. This was not found in men or when examining Gly16Arg and Gln27Glu alone or as combined genotypes. Conclusions: Ore" data suggest that heterozygosity for Thr164Ile is associated with increased levels of diastolic blood pressure and is a risk factor for elevated blood presstn'e in women.
order to find out any association between the peripheral T cell activities and atherogenic risk factors. Material and Methods: 50 young male healthy volunteers wele enrolled (Age 22.0 2.4 years). Lymphocytes were isolated fi'om the hepatinized venous blood and the proliferative responses to phytohaemaglutinin were measmed fi'om the amount of radioactive thymidine uptake by the lymphocyte DNA. The correlation analyses between basal and stimulated activities of the T cells and Total and LDL cholesterol levels of the patients. The T cell activity responses of patients with family history of coronat'y events were compared with others. Also the activity responses of smokers wele compared with non-smokers. Results: Subjects with positive family history of coronary events had higher PHA stimulated T cell responses (p<0.05). Also, PHA activated T cell responses were positively correlated with total cholesterol and LDL cholesterol levels (p=0.022, r = 0.604, p= 0,015, r= 0,635) in the same group. Conclusion: Peripheral T cell activity lesponses to PHA ate found to be higher in the asymptomatic first degree relatives of patients with coronat'y events. Serum total cholesterol and LDL cholesterol levels were correlated with the T cell responses. The data may indicate a possible familial tendency of the increased peripheral T cell activities of the subjects with positive family history of coronary events. I
Iw14.391 iI GENETIC VARIATION IN THE ZINZ F I N G E R PROTEIN 202 GENE IN INDIVIDUALS FROM THE GENERAL POPULATION WITH EXTREME H D L CHOLESTEROL LEVELS M. Stene, R. Frikke-Schmidt, B. Nordestgaard, A. Tybj~erg-Hansen. Dept.
Clinical Biochemistry, Copenhagen University Hospital, Copenhagen, Dept. Clinical Biochemistry, Herlev University Hospital, Herlev, Denmark Background: The ZNF202 gene resides in a chromosomal region (11q23) linked genetically to low HDL cholesterol (HDL-C). ZNF202 is a transcriptional repressor which binds elements found predominantly in genes pat'ticipating in lipid metabolism. Consequently, ZNF202 is an attractive candidate gene for human dyslipidemia, and especially for modulation of HDL-C in the general population. Aim: To identify genetic variation in ZNF202 associated with variation in HDL-C. Methods: We selected 190 individuals fi'om the Copenhagen City Heat't Study with the 1% highest and 1% lowest HDL-C for age and sex, and screened ZNF202 for genetic vat'iation. Furtherrnore 9,259 individuals fi'om the general population, the Copenhagen City Heart Study, were genotyped for selected SNPs. Results: A total of 17 genetic variants were identified, ten SNPs (allele fi'equency > 1%) and seven mutations (fi'equency < 1%), several situated in highly conserved regulatory and functional important regions of the gene. Of the seven mutations, four were identified only in individuals with low HDL-C, and two were identified only in individuals with high HDL-C. A haplotype, which differed at only one position fi'om the wildtype haplotype AGATCG (1949T>G) tended to be overrepresented in the low HDL cholesterol group. Additionally, 1949G homozygozity showed association with a decrease in HDL cholesterol (p=0.04) and a con'esponding decrease in apoAI (p=0.004) in men (n=4,114). Conclusion: The present screening of ZNF202 identified 17 genetic vat'iants, ten SNPs and seven mutations. A SNP, 1949T>G, showed association with lower HDL-C levels in men, which may suggest a role for common SNPs in ZNF202 in determining HDL-C levels in the general population.
IW14.3921
FAMILIAL HYPOBETALIPOPROTEINEMIA WITH NO TRUNCATED FORMS OF APOLIPOPROTEIN B DETECTABLE IN PLASMA
E Tm'ugi, S. Lancellotti, E. di Leo, S. Calan&'a. University ofModena &
Reggio Emilia, Modena, Italy ~
PERIPHERAL T CELL ACTIVITIES ARE H I G H E R IN THE ASYMPTOMATIC KINDRED OF PATIENTS WITH CORONARY EVENTS
A. Sonmez, M. Yilmaz, G. Uckaya, T. Eyileten, C. Kinalp. Gulhane School
of Medicine and Adana Military Hospital, Ankara, Turkey Introduction: Increased T cell activities ate reported in the pathogenesis of many diseases including atherosclerosis. The study was performed in
Familial hypobetalipoproteinemia (FHBL) is a co-dominant disorder characterized by low levels of LDL and apoB due to mutations in apoB gene or in other genes yet to be identified. We recruited 34 FHBL probands and sem'ched first for the presence of U'uncated apoBs detectable in plasma (i.e.apoBs with a size above that of apoB-29). Only 11 probands can'ied U'uncated apoBs detectable in plasma (size range: fi'om apoB-32.38 to apoB-84.04) due to nonsense/fi'ameshift mutations in exon 26 of apoB gene. The complete sequence of apoB gene performed in 18 probands with
74th EAS Congress, 17-20 April 2004, Seville, Spain