Angiotensin-converting Enzyme Locus Research Articles

Türkiye’nin Doğu Bölgesinde Auralı ve Aurasız Migren Hastalarında Anjiyotensin Konverting Enzim Geninin İnsersiyon/Delesyon Polimorfizmiyle İlişkisi Var mıdır?

Objective: Angiotensin-converting enzyme (ACE) is one of the key enzymes in the renin-angiotensin-aldosterone system which modulates vascular tension and blood pressure. Many authors have reported an association between ACE-D allele and coronary heart disease and other cardiovascular diseases. The mechanism underlying the positive associations between the ACE-D alleles and diseases are not yet clear. Alterations of the renin-angiotensin system have been implicated in the pathogenesis of various diseases. Several angiotensin I converting enzyme inhibitors and an angiotensin II receptor blocker were demonstrated to have a clinically important prophylactic effect in migraine. Previous reports showed an association between migraine without aura and ACE-D allele polymorphism. In this study it is aimed to evaluate whether the DD genotype could also be associated with the frequency and duration of migraine without aura (MoA) and migraine with aura (MwA). Material and Methods: One hundred one migraine patients (37 MoA, 64 MwA) and 101 healthy non-migrainous controls from the region of Eastern Turkey were included in this study. The genotype characteristics were determined by the PCR analysis using DNA extracted from peripheral blood. Results: There was no significant difference in allelic frequency (I and D) and genotype polymorphism (DD, DI and II) of the ACE gene in migraine patients and controls (genotype frequency: p= 0.08). ACE genotype distribution was similar in migraine patients and healthy control groups. Turkish patients MoA and MwA did not show any difference in incidence of the ACE-DD genotype. Conclusion: We conclude that the I/D polymorphism at the ACE locus does not play any role in the pathogenesis and progression of migraine.

Identification of specific angiotensin‐converting enzyme variants and haplotypes that confer risk and protection against type 2 diabetic nephropathy

Cross-sectional and family studies identified angiotensin-converting enzyme (ACE) gene as a risk factor for diabetic nephropathy (DN). The contribution of ACE gene variants to DN development and progression is controversial and varies among different ethnic/racial groups. We investigated the association of three ACE gene variants with DN, rs1799752 insertion/deletion (I/D), rs1800764T/C and rs12449782A/G in 917 Tunisian type 2 diabetic (T2DM) patients: 515 with (DN) and 402 without (DWN) nephropathy. ACE genotyping was done by PCR-based assays; haplotype estimation was performed using H-Plus software (chi(2)-test based). Genotype frequency distributions of the three studied variants were in Hardy-Weinberg equilibrium. Minor allele frequency of rs1800764 was higher in DN patients than DWN patients or healthy controls, and minor allele frequency of rs1799752 was higher in DN than DWN patients. Higher frequency of rs1799752 and rs1800764 homozygous mutant genotypes was seen in DN compared to DWN patients. Of the three variants, only rs1799752 deletion/deletion (D/D) genotype was associated with a significant increase in albumin to creatinine ratios levels, and D/D carriers had elevated low-density lipoprotein, total cholesterol and urea. Three locus haplotype [rs1799752(I/D)/rs1800764(T/C)/rs12449782(A/G)] analysis revealed that the frequency of DCG haplotype was higher, while that of ITG and ICA haplotypes were lower among unselected type 2 diabetic patients. Taking ITA haplotype as reference, multivariate regression analysis confirmed the negative (ITG), and positive (DCG, DTG, DCA and DTA) association of specific ACE haplotypes with DN, after adjusting for potential nephropathy-linked covariates. Our results support the involvement of specific ACE variants in DN pathogenesis and demonstrate the presence of DN-specific haplotypes at the ACE locus.

ACEVariants Interact with the RAS Pathway to Confer Risk and Protection against Type 2 Diabetic Nephropathy

Genetic predisposition has been proposed to be a major determinant in the development of renal complications of diabetes. Among candidate genes examined for susceptibility to diabetic nephropathy, angiotensin-converting enzyme (ACE) gene has been found to be associated with pathogenesis and progression of diabetic nephropathy. However, the role of other renin-angiotensin system (RAS) polymorphisms and their possible interactions with different ACE I/D genotypes are less clearly defined. Recent studies also show that ACE haplotypes may be better predictors to disease susceptibility. Thus, in the present study, we evaluated the association of ACE haplotypes and the interactions of ACE, angiotensinogen (AGT), and angiotensin II receptor type I (AGTR1) gene polymorphisms with DNP in Asian Indians. We genotyped seven variants of the RAS pathway genes (ACE, AGT, and AGTR1) in type 2 diabetic cohorts without nephropathy (DM) and with nephropathy (DNP), using allele-specific oligonucleotide-PCR, and PCR-restriction fragment length polymorphism assays. We studied the interaction of these variants with each other and ACE I/D polymorphism. Frequency of ACE D allele and DD genotype (ACE I/D) was significantly higher in DNP (p < 0.005) and was associated with increased risk of nephropathy. The frequency of T allele, MT/TT genotypes (AGT: M235T), and C allele 1166CC genotype (AGTR1: A1166C) was higher and associated with increased risk of DNP (235T, p < 0.0001; 235TT/MT, p < 0.01; 1166C, p < 0.007; 1166CC, p < 0.0001). The ACE locus revealed a near doubling in the prevalence of T-D-G risk haplotype (odds ratio, 1.76) in DNP (0.13) compared to DM (0.08; p < 0.02). ACE haplotypes carrying the I allele were associated with a lower risk of DNP (C-I-A, p < 0.04; C-I-G, p < 0.008). ACE ID/DD genotypes in combination with ACE rs4311, rs4343, and AGT rs699 mutant genotypes increased the risk of DNP development fourfold (p < 0.01). This study provides the first evidence for a disease haplotype for DNP at the ACE locus in Asian Indians. The study further indicates that ACE D allele individually and in interaction with other RAS single-nucleotide polymorphisms significantly increases the risk of nephropathy in type 2 diabetic patients of Asian Indian origin.

Mice with Enhanced Macrophage Angiotensin-Converting Enzyme Are Resistant to Melanoma

Angiotensin-converting enzyme (ACE) is a peptidase responsible for the cleavage of angiotensin I and several other peptides. Here, gene targeting was used to switch control of the ACE locus from the endogenous promoter to the macrophage-specific c-fms promoter. Challenge of these mice, called ACE 10/10, with the aggressive mouse melanoma cell line B16 showed that they are remarkably resistant to tumor growth. Tumor resistance was seen after challenge with different melanoma cell lines and in mice with different genetic backgrounds. Histological study of the tumors that did grow in ACE 10/10 mice showed an enhanced inflammatory response. ACE 10/10 mice had increased numbers of tumor epitope-specific CD8(+) T cells after challenge with melanoma or lymphoma. ACE 10/10 macrophages showed increased production of interleukin-12 and nitric oxide but reduced interleukin-10. Engraftment of wild-type mice with ACE 10/10 bone marrow transferred B16 tumor resistance. Injection of B16 tumors with ACE 10/10 macrophages also reduced tumor growth. ACE 10/10 mice may define a new means of enhancing the immune response, which may be potentially useful in several human clinical situations.

Sex Differences in the Association of Apolipoprotein E and Angiotensin-Converting Enzyme Gene Polymorphisms With Healthy Aging and Longevity: A Population-Based Study From Southern Italy

We investigated the association of sex and age with the occurrence of apolipoprotein E (apoE) and angiotensin-converting enzyme (ACE) genotypes in healthy aging and longevity in 1344 healthy individuals and 64 centenarians. As compared to participants younger than 60 years, a significant higher frequency of the apoE/epsilon2 was observed in men aged 60-90 years (p <.001) and in centenarians (p <.001). Logistic regression analysis confirmed this outcome in both participants aged 60-90 years (odds ratio [OR] = 1.897; 95% confidence interval [CI], 1.227-2.931) and centenarians (OR = 3.263; 95% CI, 1.860-5.722). A further significant association of ACE/D allele and age was observed in centenarians (OR = 2.135; 95% CI, 1.253-3.636). Heterosis was also observed at the ACE locus. No relationship between apoE and ACE polymorphism was found. These findings suggest a role of sex in the association of apoE and ACE gene polymorphisms with healthy aging and longevity.

Multiple gene approaches to delineate the role of the renin-angiotensin-aldosterone system in nephropathy

Multiple gene approaches to delineate the role of the renin-angiotensin-aldosterone system in nephropathy

ACE gene titration in mice uncovers a new mechanism for ACE on the control of body weight

Mice harboring 1, 2, or 3 copies of the angiotensin-converting enzyme (ACE) gene were used to evaluate the quantitative role of the ACE locus on obesity. Three-copy mice fed with a high-fat diet had lower body weight and peri-epididymal adipose tissue than did 1- and 2-copy mice (P < 0.05). On regular diet, 3-copy mice had to eat more to maintain the same body weight; on a high-fat diet, they ate the same but weighed less than 1- and 2-copy mice (P < 0.05), indicating a higher metabolic rate in 3-copy mice that was not affected by ANG II AT(1) blocker treatment. A catalytically inactive form of thimet oligopeptidase (EC 3.4.24.15; EP24.15) was used to isolate ACE substrates from adipose tissue. Liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) identified 162 peptide peaks; 16 peptides were present in both groups (1- and 3-copy mice fed with a high-fat diet), whereas 58 of the 72 unique peptides were found only in the 3-copy mice. Peptide size distribution was shifted to lower molecular weight in 3-copy mice. Two of the identified peptides, LVVYPWTQRY and VVYPWTQRY, which are ACE substrates, inhibited in vitro protein kinase C phosphorylation in a concentration-dependent manner. In addition, neurolysin (EC 3.4.24.16; EP24.16) activity was lower in fat tissue from 3- vs. 1-copy mice (P < 0.05). Taken together, these results provide evidence that ACE is associated with body weight and peri-epididymal fat accumulation. This response may involve the generation of oligopeptides that inhibit the activity of EP24.16 and other oligopeptidases within the adipose tissue.

Gender Specific Association of Insertion/Deletion Polymorphism of the Human Angiotensin Converting Enzyme Gene with Essential Hypertension

The pattern of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism in the Indian population is poorly known. The population has cultural and linguistic differences and lived in an environment that varied significantly from one region to another. There is controversy regarding the association of the Angiotensin-converting enzyme insertion/deletion polymorphism with essential hypertension and variation in blood pressure. In the present study we examined the importance of ACE (I/D) polymorphism as a determinant of hypertension and to assess the potential modifying effect of gender on ACE gene in Indian population. The ACE I/ D polymorphism was assayed by PCR amplification of ACE gene in 200 hypertension patients and 200 controls. The genotypic and allelic frequencies were observed to be deviated significantly from Hardey-Weinberg equilibrium (p<0.05). The DD and ID genotypes were found to be strongly associated with hypertension in men with an odds ratio 2.25 (95% confidence level (CI), 1.14 to 4.42) and 2.20 (95% CI, 1.27 to 3.80) respectively, (p<0.01). Further, a linear relationship was observed between diastolic pressure and allele D in men but not in women. The data thus provide evidence in favor of an association of I/D polymorphism at the ACE locus (17q23) with essential hypertension. Moreover, these results highlight the potential importance of gender-dependent interactions between genetic background and expression of hypertensive phenotype. It further prompts the need for the confirmatory studies in large population-based samples.

ACE insertion/deletion polymorphism and submaximal exercise hemodynamics in postmenopausal women.

We sought to determine whether the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism is associated with submaximal exercise cardiovascular hemodynamics. Postmenopausal healthy women (20 sedentary, 20 physically active, 22 endurance athletes) had cardiac output (acetylene rebreathing) measured during 40, 60, and 80% VO(2 max) exercise. The interaction of ACE genotype and habitual physical activity (PA) level was significantly associated with submaximal exercise systolic blood pressure, with only sedentary women exhibiting differences among genotypes. No significant effects of ACE genotype or its interaction with PA levels was observed for submaximal exercise diastolic blood pressure. ACE genotype was significantly associated with submaximal exercise heart rate (HR) with ACE II having approximately 10 beats/min higher HR than ACE ID/DD genotype women. ACE genotype did not interact significantly with habitual PA level to associate with submaximal exercise HR. ACE genotype was not independently, but was interactively with habitual PA levels, associated with differences in submaximal exercise cardiac output and stroke volume. For cardiac output, ACE II genotype women athletes had ~25% greater cardiac output than ACE DD genotype women athletes, whereas for stroke volume genotype-dependent differences were observed in both the physically active and athletic women. ACE genotype was not significantly associated, either independently or interactively with habitual PA levels, with submaximal exercise total peripheral resistance or arteriovenous O(2) difference. Thus the common ACE locus polymorphic variation is associated with many submaximal exercise cardiovascular hemodynamic responses.

Association of angiotensin converting enzyme and plasminogen activator inhibitor-1 promoter gene polymorphisms with features of the insulin resistance syndrome in patients with premature coronary heart disease

Polymorphisms of the angiotensin-converting enzyme (ACE) (insertion/deletion (I/D) in intron 16) and of the plasminogen activator inhibitor-1 (PAI-1) (promoter 4G/5G) genes have been linked with coronary heart disease (CHD) and/or myocardial infarction (MI). We studied the association of polymorphisms in these genes with CHD with linkage and association analyses in 118 families with premature and severe CHD and in 110 healthy controls. In linkage analysis there was no evidence for a linkage of the ACE or PAI-1 loci with CHD. However, in quantitative linkage analysis the ACE locus was linked with fasting glucose ( P=0. 047) and fasting free fatty acid levels ( P=0.029). In association analysis the ACE genotype frequencies of probands with CHD did not differ from those of healthy controls. Normoglycemic probands with MI and with the ACE polymorphism DD genotype had characteristics of the insulin resistance syndrome. They had higher levels of 1-h glucose ( P=0.008) and 2-h free fatty acids ( P=0.011) in an oral glucose tolerance test and higher levels of total ( P=0.005) and very-low-density lipoprotein triglycerides ( P=0.006) than probands with the ID or the II genotypes. The PAI-1 gene polymorphism was not associated with any of the variables of glucose or lipid metabolism. In conclusion, the ACE and PAI-1 gene polymorphisms are not linked with early-onset CHD. However, the ACE gene polymorphism is associated with features of the insulin resistance syndrome.

Gene polymorphisms and left ventricular hypertrophy in essential hypertension

Hypertensive heart disease results from a complex interaction between haemodynamic factors, neuro-hormonal influences and genetic determinants. In the present study we investigated the association between polymorphic forms at genes of the renin-angiotensin system and the development of left ventricular hypertrophy in a case-control study. The frequency of molecular variants was compared between a group of essential hypertensive patients (stage I-II; n=70) with ventricular involvement and a group of Caucasian healthy control subjects (n=300). After performing a careful clinical and laboratory evaluation, all the enrolled patients (mean age: 49±6 yrs) underwent a 24-h ambulatory blood pressure monitoring in order to obtain a complete blood pressure profile. Left ventricular mass and main parameters of ventricular function were assessed by M-mode/2D/doppler echocardiogram. Subjects were genotyped for M235T polymorphism at the angiotensinogen (AGT) gene, A1166C mutation in the angiotensin II type 1 receptor (AT1R) gene and I/D polymorphism at the angiotensin-converting enzyme (ACE) gene. A statistically significant association was found between allelic variants at AGT, AT1R and ACE loci and essential hypertension (p<0.05). Among cases, there was an overall frequency of 0.47 for 235T allele of the AGT gene, 0.25 for C mutant allele at the AT1R locus and 0.34 for I allele of the ACE gene. AGT and AT1R gene polymorphisms were associated with the occurrence of left ventricular hypertrophy (p<0.05). Patients with D and I alleles at ACE locus did not show significant differences in left ventricular involvement. Obtained results were in accordance with data regarding other Caucasian populations. The observed genotype and allele distribution were in equilibrium as predicted by the Hardy-Weinberg equation. Essential hypertension and related target-organ damage have a multifactorial etiology influenced by multiple genetic and environmental factors. Information on polymorphisms at genes involved in blood pressure regulation will help in identifying patients at higher risk of cardiovascular damage.

Association of essential hypertension in elderly Japanese with I/D polymorphism of the angiotensin-converting enzyme (ACE) gene.

Recent evidence suggests that an insertion/deletion (I/D) polymorphism of the gene encoding angiotensin-converting enzyme (ACE) is associated with myocardial infarction and related cardiovascular diseases. We investigated a possible association of the ACE polymorphism with essential hypertension in a total of 263 cases/controls from among the elderly (age, over 70 years) and middle-aged (age between 30 and 60 years) Japanese population. The frequency of the I/I homozygote was significantly higher in hypertensive subjects than in controls in the elderly age group (33/57 vs 16/46; P = 0.02), but no association was observed in the middle-aged group (25/75 vs 26/85; P = 0.71). Similarly, having at least one insertion allele was associated with essential hypertension in the elderly age group (83/114 vs 46/92 in controls; P = 0.001), but not in the middle-aged group (78/150 vs 94/170; P = 0.524). These data suggest that genetic variation at the ACE locus may be associated with some determinants for blood pressure in elderly persons, and imply the involvement of the ACE insertion/deletion polymorphism in the etiology of age-related essential hypertension in the Japanese population.

The ACE I allele is associated with increased risk for ruptured intracranial aneurysms

Genetic and environmental factors play roles in the aetiology of ruptured intracranial aneurysms. Hypertension has been reported as a risk factor for intracranial aneurysm haemorrhage. We have tested if genotypes...

AGT M235T and ACE ID polymorphisms and exercise blood pressure in the HERITAGE Family Study.

We investigated the association between angiotensinogen (AGT) and angiotensin-converting enzyme (ACE) gene polymorphisms and exercise training responses of resting and exercise blood pressure (BP). BP at rest and during submaximal (50 watts) and maximal exercise tests was measured before and after 20 wk of endurance training in 476 sedentary normotensive Caucasian subjects from 99 families. AGT M235T and ACE insertion/deletion polymorphisms were typed with PCR-based methods. Men carrying the AGT MM and MT genotypes showed 3. 7 +/- 0.6 and 3.2 +/- 0.5 (SE) mmHg reductions, respectively, in diastolic BP at 50 watts (DBP(50)), whereas, in the TT homozygotes, the decrease was 0.4 +/- 1.0 mmHg (P = 0.016 for trend, adjusted for age, body mass index, and baseline DBP(50)). Men with the ACE DD genotype showed a slightly greater decrease in DBP(50) (4.4 +/- 0.6 mmHg) than the II and ID genotypes (2.8 +/- 0.7 and 2.4 +/- 0.5 mmHg, respectively, P = 0.050). Furthermore, a significant (P = 0.022) interaction effect between the AGT and ACE genes was noted for DBP(50); the AGT TT homozygotes carrying the ACE D allele showed no response to training. Men with the AGT TT genotype had greater (P = 0.007) diastolic BP (DBP) response to acute maximal exercise at baseline. However, the difference disappeared after the training period. No associations were found in women. These data suggest that, in men, the genetic variation in the AGT locus modifies the responsiveness of submaximal exercise DBP to endurance training, and interactions between the AGT and ACE loci can alter this response.

Ambulatory blood pressure after acute exercise in older men with essential hypertension

We sought to determine whether reductions in blood pressure in hypertensives after acute exercise persist for more than the 2 to 3 h found in controlled laboratory settings. Subjects (n = 11) were obese (32 ± 4% body fat), sedentary (VO 2max 27 ± 4 mL/kg/min) 60 ± 6-year-old men with stage 1 or 2 essential hypertension. Ambulatory blood pressure was recorded on 1 day preceded by 45 min of 70% VO 2max treadmill exercise and on another day not preceded by exercise. Systolic blood pressure was lower by 6 to 13 mm Hg for the first 16 h after exercise ( P < .05) compared to the day without prior exercise. Twenty-four-hour, day, and night average systolic blood pressures were significantly lower on the day after exercise. There was a trend for peak systolic blood pressure to be lower during the entire 24 h and the day portion of the recording; peak systolic blood pressure was significantly lower during the night portion of the recording after exercise. Systolic blood pressure load (percent of systolic blood pressure readings >140 mm Hg) was reduced during the entire 24 h and the day portion of the recording after exercise. Diastolic blood pressure was lower for 12 of the first 16 h after acute exercise (hours 0 to 4, 5 to 8, 13 to 16) ( P < .05) compared to the day without prior exercise. Twenty-four-hour, day, and night average diastolic blood pressure was also significantly lower on the recording after exercise. Peak diastolic blood pressure was lower over the entire 24-h period. Diastolic blood pressure load (percent of diastolic blood pressure readings >90 mm Hg) was lower during the entire 24 h and the day portion of the day after exercise. Preliminary data also suggest that common genetic polymorphisms at the angiotensinogen, lipoprotein lipase, and angiotensin converting enzyme loci may affect the blood pressure-lowering response after acute exercise. Thus, in sedentary, obese hypertensive men a single aerobic exercise session reduced blood pressure enough to result in significantly lower 24-h average systolic, diastolic, and mean arterial blood pressure. This could result in a reduced cardiovascular load during the 24 h after acute exercise in older hypertensive men.

The Angiotensin-Converting Enzyme (ACE) Gene Insertion/Deletion Dimorphism Tracks with Higher Serum ACE Activities in Both Younger and Older Subjects

The absence of a 287 base pair alu sequence in the ACE gene (D allele) is associated with higher ACE levels than its presence (I allele) in adults. We carried out a case-control study of the ACE*I/D dimorphism in relation to circulating ACE activities to evaluate associations between the two variables in adults, compared to younger (18 years or less) individuals. Genotypes of the ACE*I/D dimorphism were determined on DNA samples from a population of 164 random (unrelated) Emirate nationals, composed of two groups: 112 subjects above 18 years of age (range=20-77 years), and 52 subjects of 18 years or less (range=1-18), and analyzed for putative associations with serum ACE activities. ACE*I/D genotypes of the 164 individuals were determined by assays based on polymerase chain reaction. ACE activities were determined on serum samples of these subjects by colorimetric assays. The D allele was associated with increased ACE values in both adult and younger individuals. Mean ACE activity levels associated with II, ID and DD genotypes, however, were 42%-61% higher in the 18 years and under group of subjects. The ACE*I/D marker accounted for 28% of the variance of the phenomenon determining ACE levels in adults, and for 30% among youngsters. The ACE*I/D dimorphism correlated strongly with circulating ACE activities in both adult and young Emirati subjects, and the corresponding mean ACE activities were significantly higher among the youngsters.

Angiotensin I-converting enzyme genotype influences arterial response to injury in normotensive rats.

Two normotensive strains of rat, the Lou and Brown Norway (BN) strains, have contrasting levels of plasma angiotensin-converting enzyme (ACE). To investigate the degree of genetic determination of ACE expression, a polymorphic marker of the ACE gene was analyzed in inbred rats of the two strains. The two inbred strains were shown to bear different alleles for a polymorphic marker at the ACE gene. The segregation of the alleles of this marker and the plasma ACE levels were studied in a group of F2 rats issued from a cross between Lou and BN rats. The degree of genetic determination of plasma ACE activity was estimated to be 94% in the F2 cohort. The ACE locus accounts for 74% of total plasma ACE variance. ACE activity and mRNA expression in lungs were also genetically determined. The difference observed in ACE mRNA accumulation in the lungs between the two strains was due to a difference in the transcriptional rate of the ACE gene, as shown in nuclear run-on experiments. No differences were observed in arterial blood pressure of homozygous F2 progeny. In these animals, ACE genotype did not interfere with the pressor or the depressor responses to ACE-dependent vasoactive peptides. There was a significant effect of strain on constitutive or inducible membrane or soluble ACE activity in primary cultures of vascular cells. Neointima formation in the carotid artery 14 days after balloon injury was also influenced by the genotype in F2 homozygous progeny, whereas the medial area was not. These results demonstrate that there is a close relationship between the genetically determined ACE expression and the inducibility of the ACE gene. The degree of genetic determination of ACE expression in inbred rat strains offers a unique opportunity to study the interaction between genetic and environmental determinants of ACE expression and its involvement in response to experimental cardiovascular and renal injury.

Renin, ANP, ACE polymorphisms, blood pressure and age in American Samoans: Preliminary data.

Molecular studies have identified numerous candidate genes that may influence interindividual variation in physiologically important endpoints. Among these are molecular variants of three proteins associated with blood pressure regulation, renin, atrial natriuretic peptide (ANP), and angiotensin-converting enzyme (ACE). These loci are polymorphic in all populations examined. The purpose of this study was to determine gene and genotype frequencies at these three loci in a sample of American Samoans and to examine associations of the various genotypes with blood pressure, hypertension, and age. Genotype frequencies of a BglI restriction fragment length polymorphisms (RFLP) at the renin locus were slightly out of Hardy-Weinberg expectations (P ⩽ 0.025). Frequencies of a BglI RFLP at the ANP locus and of the insertion/deletion polymorphism at the ACE locus approximated Hardy-Weinberg expectations (P ⩾ 0.10). These frequencies differed from those reported in "Afro-Caribbean" and "Caucasian" samples from London. Neither average blood pressures nor the frequencies of either systolic or diastolic hypertension differed significantly across genotypes at the ANP or ACE loci. However, systolic pressure was elevated among those heterozygous for the renin BglI cut site (P = 0.07). Mean age was 34.4 years among individuals heterozygous for the ANP BglI cut site, while it was 46.0 years for homozygotes without the site (P = 0.04). After dividing the sample at its median age (45 years), 31.8% of younger, but only 8.7% of older participants were ANP BglI heterozygotes (G = 9.48; P = 0.005). Am. J. Hum. Biol. 10:439-449, 1998. © 1998 Wiley-Liss, Inc.

Angiotensin-converting enzyme gene polymorphism in essential hypertensive patients in Japanese population.

Association between angiotensin-converting enzyme (ACE) gene polymorphism and essential hypertension in a Japanese population with the same socioeconomic background was investigated. Insertion-deletion (I/D) polymorphism of the ACE gene located on intron 16 was detected by polymerase chain reaction. Association between ACE gene polymorphism and family history of essential hypertension as well as the development of vascular damage in eye fundi were also investigated. Variation at ACE loci did not contribute to essential hypertension and the vascular damages in eye fundi. These results suggest that the ACE gene was not directly responsible for essential hypertension in this particular Japanese population with the same socioeconomic background.

Absence of association or genetic linkage between the angiotensin-converting-enzyme gene and left ventricular mass.

Homozygous carries of the D allele of the angiotensin-converting-enzyme (ACE) gene have been reported to be at increased risk for various cardiovascular disorders, including left ventricular hypertrophy. We investigated the potential role of the ACE gene in influencing left ventricular mass. Quantitative echocardiographic data and DNA samples were available for 2439 subjects from the Framingham Heart Study. ACE genotypes were determined by an assay based on the polymerase chain reaction. (The D allele of the ACE gene contains a deletion, whereas the I [insertion] allele does not.) Left ventricular mass and the prevalence of left ventricular hypertrophy, adjusted for clinical covariates, were analyzed according to genotype. Genetic linkage between the ACE locus and left ventricular mass was evaluated by quantitative analysis of pairs of siblings. The ACE genotype was associated neither with left ventricular mass nor with the prevalence of left ventricular hypertrophy. Mean (+/-SE) left ventricular mass (adjusted for sex) among subjects carrying the DD, DI, and II genotypes was 165+/-1.6, 165+/-1.3, and 166+/-2.0 g, respectively (P=0.90). The prevalence of left ventricular hypertrophy among the three genotype groups was 15.6 percent, 13.6 percent, and 15.6 percent, respectively (P=0.36), and the adjusted relative risk of left ventricular hypertrophy associated with the DD genotype was 1.10 (95 percent confidence interval, 0.86 to 1.19). Linkage analysis in 759 pairs of siblings using both the ACE D/I marker and a microsatellite polymorphism at the neighboring locus for the human growth hormone gene failed to support any role of ACE in influencing left ventricular mass. The ACE genotype showed no association with echocardiographically determined left ventricular mass, nor did it confer an increased risk of left ventricular hypertrophy. We found no appreciable role of the ACE gene in influencing left ventricular mass.