Polymorphisms in the renin-angiotensin system and endothelium-dependent vasodilation in normotensive subjects.

BACKGROUND: Our aim was to test the hypothesis that genes encoding components in the renin-angiotensin system influence endothelial vasodilatory function. METHODS: In 59 apparently healthy, normotensive individuals, endothelium-dependent vasodilation (EDV) and endothelial-independent vasodilation (EIDV) was evaluated by infusing metacholine and sodium nitroprusside into the brachial artery. Forearm blood flow was measured by venous occlusion plethysmography. The ACE insertion (I)/deletion (D) polymorphism, the T174M and M235T angiotensinogen restriction fragments length polymorphisms, the angiotensin II receptor type 1 (AT1R) A1166C, and the aldosterone synthase gene (CYP11B2) C-344T polymorphisms were analysed. RESULTS: When analysing the ACE, the two angiotensinogen and the aldosterone synthase CYP11B2 genotypes independently, no significant association with endothelial vasodilatory function was found. However, a significant reduction in endothelium-dependent vasodilation was observed in the subjects (n=9) with the ACE D allele and the angiotensinogen T174M genotype (P<0.05). Subjects with the AT1R genotype AC showed a reduction in both EDV (P=0.05) and EIDV (P=0.04) when compared with those with the AA genotype. CONCLUSIONS: The subjects with the ACE D allele in combination with the angiotensinogen T174M genotype are associated with a reduced EDV. This together with the observation that the AC AT1R genotype is associated with a reduction in both EDV and EIDV, supports the hypothesis that endothelial vasodilatory function is influenced by genes in the renin-angiotensinogen system.     

血管紧张素系统基因多态性与原发性高血压的相关研究

目的：探讨中国人血管紧张素原（angiotensinogen,AGT)基因的蛋白产物M235T、血管紧张素Ⅱ-I型受体（AT1R)基因的蛋白产物A1166C以及血管紧线素转换酶（angiotensin convertingenzyme,ACE)基因I／D多态性与高血压病（hypertension,HT)的关系。方法：用PCR以及PCR加酶解方法检测了161例HT患者及134名健康人（normotensive controls,NT)ACEI/D基因多态性、AGTM235T及AT1RA1166C突变,并检测了血清ACE活性。结果：HT组ACEI／D基因多态性等位基因频率I为0．571,D为0．429,等位基因频率及基因型频率与NT组比较差异无显著性（P＞0．05）;＜60岁HT组D等位基因频率（0．457)显著高于NT组（0．358,P＜0．05）。HT组与NT组的AGT235T分别为0．813及0．832,两组间差异无显著性。AT1RA1166C的C等位基因频率HT组为0．021,NT组为0．053,两组间差异无显著性;但在＜60岁NT组AGTM235T显著高于NT组。两组中均发现ACE基因型与血清ACE活性相关。HT组DD－TT及ID－TT联合基因型显著高于对照组。结论：D等位基因及AGT235T对于HT早期发病可能有重要意义,DD－TT及ID－TT基因型人群可能是高血压发病的高危人群。     

Association of 3 gene polymorphisms with atopic diseases

BACKGROUND: Various peptidases, including angiotensin-converting enzyme (ACE), inactivate some inflammatory peptides that are considered to influence the pathogenesis of atopic diseases. This enzyme is also involved in the conversion or activation of 2 bronchoconstriction mediators: angiotensin II from angiotensinogen and endothelin (ET), respectively. OBJECTIVE: We tested a hypothesis that asthma or other atopic diseases are associated with insertion/deletion ACE, M235T angiotensinogen, and TaqI ET-1 gene polymorphisms. METHODS: A case-control approach was used in the study. Healthy subjects (141 persons) were used as control subjects, and 231 patients with histories of atopic asthma, allergic rhinitis, atopic dermatitis, or a combination thereof were studied. ACE genotype was determined by PCR, angiotensinogen M235T and ET-1 by PCR, and restriction analysis by AspI and TaqI, respectively. RESULTS: We found the significant association of the insertion/deletion polymorphism of the ACE, as well as that of M235T polymorphism of the angiotensinogen genes, with the group of patients with atopic diseases ( P =.0025 and P =.0204, respectively). No difference was proved for the intron 4 (position 8000) polymorphism in the ET-1 gene when comparing the atopic patients with the control group (P =.1774). A significant difference was found between groups of patients with both asthma and rhinitis and patients without both respiratory atopic diseases (P =.0033). CONCLUSION: It follows that the examined polymorphisms in the genes for ACE, angiotensinogen, and ET-1 could participate in the etiopathogenesis of atopic diseases.     

Effects of long-term and reduced-dose hormone replacement therapy on endothelial function and intima-media thickness in postmenopausal women.

OBJECTIVE: Short-term estrogen therapy improves endothelial function in postmenopausal women. However, there are few reports on its long-term effects on endothelial function and carotid intima-media thickness. Further, we determined whether a reduced dosage of estrogen may maintain its beneficial effects. DESIGN: Eighteen postmenopausal women (53.7+/-1.1 years) who had been diagnosed as having osteoporosis were enrolled. Among them, 11 women were prescribed oral conjugated estrogen 0.625 mg and medroxyprogesterone acetate 2.5 mg per day, and 7 women were prescribed an oral calcium supplement as the control group. Each patient decided whether she would take hormone replacement therapy or a calcium supplement. We performed ultrasound measurement of endothelial function of the brachial artery and carotid intima-media thickness. Examinations were scheduled to be performed pre-therapy and after 3, 6, 12, 18, 24, and 36 months of therapy. RESULTS: After three years of therapy, 6 women in the hormone replacement therapy group agreed to take half the dose of oral conjugated estrogen. Improvement of flow-mediated dilatation was observed at 3 months and the improvement was preserved up to 36 months. A similar improvement was also observed while women were on hormone replacement therapy even at the reduced dosage. Intima-media thickness of the common carotid artery in the control group increased after 12 months, which was not observed in the hormone replacement therapy group. CONCLUSIONS: Our results indicate that even at half the dose of estrogen, hormone replacement therapy may improve endothelial function and prevent the progression of carotid intima-media thickening in postmenopausal women.     

Sequence variants of ACE, AGT, AT1R, and PAI-1 as genetic risk factors for vascular dementia

Sequence variants of angiotensin converting enzyme (ACE) insertion/deletion (I/D), angiotensinogen (AGT) T235M, angiotensin II type 1 receptor (AT1R) A1166C, and plasminogen activator inhibitor-1 (PAI-1) 4G/5G were analyzed to see their genetic associations with vascular dementia as its candidate genetic risk factors involving renin-angiotensin and fibrin systems. While the ACE I/D, AT1R A1166C, and PAI-1 4G/5G did not contribute to the genetic susceptibility to vascular dementia (P>0.05), a significant association with vascular dementia was shown in the T235M polymorphism of AGT. The frequency of the M allele in patients was higher than in controls with the odds ratio (OR) estimate of 1.51 (P<0.05). In a dominant model, the TM+MM genotypes increased the risk of vascular dementia compared to the TT genotype (OR=2.01; P<0.001). The current results suggested that AGT T235M polymorphism might be a risk factor of vascular dementia.     

肾素-血管紧张素系统基因多态性与2型糖尿病脑梗塞的关系

目的研究肾素-血管紧张素系统(renin-angiotensin system,RAS)中血管紧张素Ⅱ的1型受体(type1angiotensin Ⅱ receptor,AT1R)基因A1166C多态及血管紧张素Ⅰ转化酶(angiotensin1-converting enzyme,ACE)基因插入/缺失(I/D)多态与中国汉族2型糖尿病(type 2 diabetes     

Angiotensinogen and angiotensin II type 1 receptor gene polymorphism in patients with autosomal dominant polycystic kidney disease: effect on hypertension and ESRD

Autosomal dominant polycystic kidney disease (ADPKD), a common genetic disease, is characterized by the development of hypertension and end stage renal disease. An increase in the activity of the renin-angiotensin system, due to a renal ischemia caused by cyst expansion, contributes to the development of hypertension and renal failure in ADPKD. Recently, the angiotensinogen (AGT) gene, M235T, and angiotensin II type 1 receptor (ATR) gene, A1166C, polymorphisms have been associated with the susceptibility to develop hypertension and renal disease. We hypothesized that the AGT M235T and ATR A1166C polymorphisms could account for some of the variability in the progression of ADPKD. Genotyping was performed in 108 adult patients with ADPKD, and 105 normotensive healthy controls, using PCR and restriction digestion. We analyzed the effects of the AGT M235T and ATR A1166C polymorphisms on hypertension and age at the end stage renal disease (ESRD). Of the 108 patients with ADPKD, 64 (59%) had hypertension and 24 (22%) reached the ESRD. The prevalence of hypertension were; [MM+MT], [TT] genotypes, 60%, 59% (p=1.00); [AA], [AC+CC] genotypes, 60%, 50% respectively (p=0.54). The ages at the onset of ESRD were; [MM+MT], [TT] genotypes, 50 +/- 9 years, 56 +/- 8 years (p=0.07); [AA], [AC+CC] genotypes, 54 +/- 8 years, 52 +/- 14 years, respectively (p=0.07). There were no differences in the prevalence of hypertension and the ages at the ESRD in relation to the AGT M235T and ATR A1166C polymorphisms. We suggest that the AGT and ATR gene polymorphisms would not have an effect on hypertension or the ESRD in ADPKD.     

Association of Angiotensin-converting enzyme and angiotensinogen gene polymorphisms with preeclampsia

We tested the hypothesis that angiotensin-converting enzyme (ACE) and angiotensinogen gene polymorphism influence the incidence, development and outcome of preeclampsia. Subjects were recruited from 90 Korean patients with preeclampsia during pregnancy and 98 age-matched controls. After isolation of DNA, polymerase chain reactions (PCR) were carried out to detect polymorphism of the ACE and angiotensinogen. M235T and T174M genotypes of angiotensinogen were determined by digestion with restriction enzyme endonuclease Tth 111-I and NCo I, respectively. The frequency of DD genotype was significantly greater in preeclampsia (0.36) than in controls (0.14) (p<0.05). The frequency of D allele was 0.55 in preeclampsia and 0.40 in controls (p<0.05). There were no differences in the onset of preeclampsia and pregnancy outcomes according to the ACE genotypes. There was no difference in the frequency of a allele of angiotensinogen M235T between the groups (0.79:0.78 in preeclampsia : controls). The frequency of T allele of angiotensinogen T174M gene was slightly increased, but not significantly, in preeclampsia (0.11) than in controls (0.07). In a multivariate analysis, only ACE genotype was associated with the development of preeclampsia (beta=0.27, p=0.05). In conclusion, a molecular variant of ACE, but not angiotensinogen, gene is associated with preeclampsia in Korean women.     

上海地区汉族人高血压脑卒中与肾素系基因多态性的关系

目的 探讨血管紧张素原（ａｎｇｉｏｔｅｎｓｉｎｏｇｅｍ,ＡＧＴ）和血管紧张素转换酶（ａｎｇｉｏｔｅｎｓｉｎ ｃｏｎｖｅｒｔｉｎｇ ｅｎｚｙｍｅ,ＡＣＥ）基因多态性与高血压性脑卒中的关系。方法 应用聚合酶链反应检测２５７例单纯高血压患者（ｅｓｓｅｎｔｉａｌ ｈｙｐｅｒｔｅｎｓｉｏｎ,ＥＨ）和２１８例高血压性脑卒中患者（其中１３１例出血性脑卒中,８７例制血性脑卒中ＡＧＴ基因Ｍ２３５Ｔ变异多态和ＡＣＥ基     

Does the beneficial effect of HRT on endothelial function depend on lipid changes

OBJECTIVES: To determine whether improvement in endothelial function of the brachial artery observed in women treated with hormone replacement therapy (HRT) may be explained by changes in lipid profile or blood pressure, information was used obtained in a single-centre, randomised, double blind, placebo-controlled trial. METHODS: Hundred-and-five healthy postmenopausal women, aged 50-65 years, were treated with 0.625 mg conjugated equine estrogens (CEE) combined with 2.5 mg medroxyprogesterone acetate (MPA) (CEE+MPA), 2.5 mg tibolone or placebo for 3 months. At baseline and after 3 months, endothelial function was assessed using flow-mediated dilatation (FMD) and nitro glycerine-mediated dilatation (NMD). Furthermore, lipids were measured. Multivariate linear regression analysis was applied to address the research question. RESULTS: Treatment with CEE+MPA resulted in an improvement in FMD of 2.0% (95% CI: -0.1; 4.1). CEE/MPA reduced total cholesterol with 13% (95% CI: -18%; -7%), LDL-cholesterol with 23% (95% CI: -30%; -15%) and lipoprotein(a) (Lp(a)) with 14% (95% CI: -26%; -2%). The magnitude of the relation of CEE/MPA with endothelial function was attenuated to from 2.0 to 1.6% when change in Lp(a) was taken into account. Adjustments for other lipids or blood pressure did not attenuate the association. CONCLUSIONS: The improvement in endothelial function in postmenopausal women treated with CEE+MPA appears to be partially mediated by change in Lp(a), and apparently not by changes in other lipids.     

Interleukin-6 and flow-mediated dilatation as markers of increased vascular inflammation in women receiving hormone therapy

OBJECTIVE: The lack of a beneficial long-term cardiovascular effect of hormone therapy and the early incidence of cardiovascular adverse events observed in recent randomized studies have been related to a heightened inflammatory effect of hormone therapy. DESIGN: We evaluated the effect of different postmenopause therapies on inflammatory markers and endothelial function in 205 postmenopausal women before and after therapy. RESULTS: all postmenopausal women, estrogens alone increased plasma levels of C-reactive protein (CRP) but decreased all other markers of inflammation including interleukin-6 (IL-6) (CRP: +75% +/- 11%, intracellular adhesion molecule: -21% +/- 4%, vascular cell adhesion molecule: -15% +/- 6%, E-selectin: -18% +/- 4%, s-thrombomodulin -10.5% +/- 3.7%, IL-6 -14% +/- 6%; percent changes, P < 0.01 compared with baseline). Raloxifene and tibolone did not significantly affect the overall inflammatory milieu. In a minority of patients, estrogen-progestogen associations and tibolone increased IL-6 levels and induced unfavorable changes on inflammation markers (CRP: +93% +/- 8%, intracellular adhesion molecule: -3% +/- 2%, vascular cell adhesion molecule: -5% +/- 2%, E-selectin: +6% +/- 2%, s-thrombomodulin: +5% +/- 2%, IL-6: +12% +/- 4%; percent changes compared with baseline). Patients with increased IL-6 levels were older and had a longer time since menopause. In all patients except those with increased IL-6 levels, hormone therapy improved endothelial function, whereas tibolone and raloxifene did not significantly change endothelial function compared with baseline. A worsening of endothelial function was detected in patients with increased IL-6 levels during therapy. CONCLUSIONS: Postmenopausal hormone therapy is associated with decreased vascular inflammation; however, in patients with a longer time since menopause, postmenopause hormone therapy may increase inflammation and worsen endothelial function. These unfavorable vascular effects may be detected by an elevation in IL-6 levels and by a lack of improvement in endothelial function.     

The influence of the alpha-adducin G460W polymorphism and angiotensinogen M235T polymorphism on antihypertensive medication and blood pressure

Despite the availability of a variety of effective antihypertensive drugs, inadequate control of blood pressure is common in hypertensive patients. The aim of this study was investigate whether the alpha-adducin G460W polymorphism or angiotensinogen M235T polymorphism has an effect on the mean difference in blood pressure in subjects using antihypertensive drugs. Data from the Rotterdam Study, a population-based prospective cohort study in the Netherlands, was used. This study started in 1990 and included 7983 subjects of 55 years and older. Data from three examination rounds were used. Subjects were included when their blood pressure was elevated at 1 or more examinations and/or a diuretic, beta-blocker, calcium antagonist, or ACE inhibitor was used. A marginal generalized linear model was used to assess the drug-gene interaction. In total, 3025 hypertensives were included. No drug-gene interaction on blood pressure levels was found. The mean difference in systolic blood pressure (SBP) between subjects with the W-allele and GG genotype of the alpha-adducin gene was for diuretic users 1.25 mmHg (95% CI:-2.86 to 5.35), for beta-blockers 0.02 mmHg (95% CI:-3.39 to 3.42), for calcium antagonists -0.70 mmHg (95% CI:-5.61 to 4.21), and for ACE inhibitors -3.50 mmHg (95% CI:-9.02 to 2.02). The mean difference in SBP between subjects with the TT and MM genotype was for diuretic users -2.33 mmHg (95% CI:-8.32 to 3.66), for beta-blocker -0.06 mmHg (95% CI:-4.91 to 4.79), for calcium antagonist 0.59 mmHg (95% CI:-5.95 to 7.13), and for ACE inhibitor -2.33 mmHg (95% CI:-9.66 to 5.01). The G460W polymorphism and the M235T polymorphism did not modify the difference in blood pressure levels among subjects who used diuretics, beta-blockers, calcium antagonists, or ACE inhibitors.     

Relationship of polymorphisms in the renin-angiotensin system and in E-selectin of patients with early severe coronary heart disease

 Previous association studies between angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) polymorphisms and several cardiovascular diseases have reported variable results. Therefore we examined the association of the DNA variants of ACE and AGT with early, severe coronary heart disease (CHD). In addition, we compared the genotypes of both polymorphisms and the recently discovered polymorphism in the E-selectin gene in both patients and an unselected population. This study included 113 patients with severe CHD (50 years old or less) and up to 197 control subjects. The frequencies of the ACE I/D variants were 48% I and 52% D in the controls and 46% I and 54% D in the patients. The frequencies of the AGT-M235T polymorphism were 60.8% M and 39.2% T in controls and 49.1% M and 50.9% T in the patients. The frequencies of the S128R polymorphism of the E-selectin were 91.3% S and 8.7% R in controls and 84.5% S and 15.5% R in the patients. In our studies the DD genotype of ACE was not associated with early severe CHD. We found a correlation between the M235T molecular variant of AGT and the S128R variant of E-selectin to early severe CHD. Received: 15 February 1996 / Accepted: 2 October 1996     

Angiotensin I-converting enzyme gene insertion/deletion polymorphism and endometrial human cancer in normotensive and hypertensive women

Endometrial carcinoma is one of the most common gynecological malignancies. Most cases are diagnosed in older patients with diabetes, hypertension, or obesity. The renin-angiotensin system (RAS) has a central role controlling blood pressure and sodium homeostasis. RAS polymorphisms have been reported as genetic determinants of essential hypertension. The objective of this study was to analyze angiotensin I-converting enzyme gene insertion/deletion polymorphism and endometrial human cancer in normotensive and hypertensive women. The presence of an angiotensin converting enzyme (ACE) polymorphism was analyzed by polymerase chain reaction in DNA isolated from peripheral blood samples of 171 women: 70 cases with endometrial cancer (age, 63.6 +/- 9.5 years) and 101 normal control women (age, 61.3 +/- 6.4 years). We detected DD genotype in 47.5%, ID genotype in 44.3%, and II genotype in 8.2% of cases. The allele frequency was 0.69 for D allele and 0.30 for I allele. In normotensives, we found that the presence of I allele (genotypes ID and II) is significantly associated to an earlier age (56.0 +/- 10.1 versus 65.8 +/- 9.9) of onset of endometrial carcinoma (P=0.029). We observed that normotensive women carriers of an allele I have a higher risk of development of endometrial cancer under the age of 63 years (odds ratio=3.60, 95% confidence interval=1.03-12.56; P=0.037). Our findings suggest that ACE polymorphism may be associated with the development of endometrial carcinoma and with the onset of this tumor in younger women. The definition of a pharmacogenomic profile of human neoplasia may help to identify targets for the development of therapeutic or chemoprevention strategies.     

肾素-血管紧张素系统基因多态性与糖尿病及合并肾病的关系

目的探讨血管紧张素I转换酶(ACE)基因及血管紧张素原(AGT)基因与2型糖尿病(DM)及合并糖尿病肾病(DN)的相关性。方法分别用PCR、突变基因分离聚合酶链反应(MS-PCR)技术对195例2型DM患者和136例正常对照者的ACEI/D与AGTM235T多态性进行检测。结果(1)DM组ACE-DD基因型和D等位基因频率均比对照组显著增高(P<0.001)。(2)DN(+)组ACE基因型和等位基因频率与DN(-)组比较无显著性差异。(3)AGT基因型分布与等位基因频率在3组中均无显著性差异。(4)联合分析ACE-DD型及AGT-TT型对DN(+)、DN(-)的OR分别为4.17和3.16;均高于单基因DD型及TT型的OR值。结论(1)ACEDD基因型和D等位基因可能是广西地区人群2型DM的易感因素。(2)未发现ACEI/D或AGTM235T多态性单一因素与2型DM患者中DN的发生有关联。(3)ACE-DD基因型与AGTM235T-TT基因型在2型DM及DN发生中有协同作用。     

Angiotensin-converting enzyme and angiotensin II type 1 receptor gene polymorphisms in children with subacute sclerosing panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is a progressive, debilitating, and fatal brain disorder caused by mutant measles virus infection. Although both viral and host factors seem to be involved in SSPE, the exact pathogenesis remains to be determined. Autoimmune demyelination is characteristic of SSPE. The blood angiotensin-converting enzyme (ACE) activity and angiotensin II (Ang II) levels are associated with the ACE gene polymorphism. Proinflammatory effects of Ang II may contribute to the development of SSPE. The aim of this study was to investigate whether the ACE and Ang II type 1 receptor (AT1R) (A1166C) gene polymorphisms were associated with SSPE. The polymorphisms were investigated by polymerase chain reaction (PCR) in 43 patients with SSPE and 100 healthy controls. The genotype distribution of the SSPE children and healthy controls were as follows: DD 58.1% versus 34.0, ID 37.2% versus 48.0%, and II 4.7% versus 18.0, respectively (P = 0.012). Allele frequencies of patients and controls were D 76.7% versus 58.0%, and I 23.3% versus 42.0%, respectively (P = 0.004). The frequency of DD genotype and D allele were significantly higher in SSPE children compared with controls (P < 0.05). AT1R gene polymorphism distribution was found to be similar in SSPE children and control subjects: AA 55.8% versus 60.7%, AC 37.2% versus 32.1%, and CC 7.0% versus 7.2%, respectively (P > 0.05). In conclusion, the results of this study suggest that the DD genotype of ACE I/D polymorphism may be related to SSPE. Due to small size of this study, further studies with more patients are needed to confirm these results.     

非酒精性脂肪性肝炎的ACE-ID与AT1R-A1166C多态性研究

目的:研究血管紧张素转化酶(ACE)基因ID多态性和血管紧张素Ⅱ1型受体(AT1R)基因A1166C多态性与日本高知地区非酒精性脂肪性肝炎(NASH)易感性的相关性,从基因学角度探讨NASH的发生发展机制,为NASH的预防、诊断和治疗提供一定的理论依据。方法:应用聚合酶链反应-限制性片段长度多态性(PCR-PFLP)方法对日本高知地区104例NASH患者和150例正常人ACE-ID基因和AT1R-A1166C基因多态性进行分析。结果:NASH病例组D等位基因频率显著高于正常对照组(P0.01);NASH病例组的DD基因型频率显著高于正常对照组(P0.01);NASH病例组A等位基因频率与正常对照组相比差异无显著(P(0.05)。NASH病例组AA基因型频率与正常对照组相比差异无显著(P(0.05)。结论:ACE-ID基因位于内含子16上D等位基因与DD基因型与NASH的发生发展显著相关,可能是促进NASH发生的原因之一;AT1R-A1166C基因多态性与NASH的发生发展尚未显示相关性。     

Angiotensin-related genes in patients with panic disorder.

Enhanced respiratory variability and decreased heart rate variability have repeatedly been observed in patients with panic disorder. Prompted by the notion that angiotensin may be involved in the control of respiration, heart rate variability, and anxiety-like behavior, we investigated the putative association between polymorphisms in three angiotensin-related genes and panic disorder-angiotensinogen (AGT), angiotensin converting enzyme (ACE), and angiotensin II (ANG II) receptor type 1 (ATr1) in 72 patients with panic disorder and 504 controls. Allele and genotype distribution of the ATr1 A1166C allele and the AGT M235T did not differ between patients and controls. With respect to the ACE I/D polymorphism, the I allele was found to be more frequent in male (chi(2) = 8.042, df = 1, P = 0.005), but not female, panic disorder patients than in controls. The results of this investigation provide preliminary evidence for the suggestion that angiotensin-related genes may be associated with panic disorder in men.     

Angiotensin-converting enzyme gene polymorphism in patients with systemic lupus

The renin-angiotensin-aldosterone system (RAAS) has been considered one of the probable pathophysiologic mechanisms involved in disease progression. Genetic polymorphism of the RAAS has been associated with the clinical course of renal disease. One of the genetic polymorphisms is a deletion or insertion of a 287 base pair fragment in intron 16 of the angiotensin-converting enzyme (ACE) gene. It is known that ACE gene polymorphism is present in humans and that it is associated with an increased risk of cardiovascular diseases, renal disease progression and sarcoidosis. In this study, the potential significance of ACE gene polymorphism in patients with systemic lupus erythematosus (SLE) was investigated. ACE gene polymorphism was determined in 18 patients with SLE and in 21 healthy volunteers as a control group. The mean age of patients was 38.5 years. All patients had a mean follow-up of 30.7 +/- 20.2 months (range 5-95 months). ACE genotypes were determined by the method of polymerase chain reaction. Proteinuria and creatinine were also followed. The frequency of DD, ID and II genotypes was 50%, 28% and 22% in SLE patients and 25%, 50% and 25% in healthy controls, respectively. DD genotype was more common in SLE patients than in the control group. The patients with II genotype had lower proteinuria and creatinine level than those with DD genotype (p < 0.05). The time to disease remission was shorter in patients with II genotype (p < 0.05). Study results indicated an increased frequency of D allele in SLE patients. The increased ACE activity in these patients pointed to the need of further studies of ACE gene polymorphism in SLE.     

Estrogen receptor alpha and beta polymorphisms: is there an association with bone mineral density, plasma lipids, and response to postmenopausal hormone therapy?

OBJECTIVE AND DESIGN: A cross-sectional segregation analysis of polymorphisms in the estrogen receptor (ER) genes (Pvull and Xbal in ERalpha, and Alul in ERAbeta with bone mineral density in the lumbar spine and forearm and with lipid profile was performed in 1098 postmenopausal women. Additionally, in a subpopulation of 280 women, who completed 1 year of treatment with estrogen plus progestin, the association between genotypes and the response to treatment in both plasma lipids and bone was investigated. In another untreated subpopulation of 443 women, genotype influence on the prevalence of vertebral fractures and on annual rate of bone loss during a mean follow-up period of 11 years was estimated. RESULTS: Baseline plasma lipids, bone mineral density, annual rate of bone loss and prevalence of spinal fractures were not significantly associated with polymorphisms in the ERbeta gene. The ERA polymorphism was significantly associated with bone loss from the distal forearm (P = 0.04) but not with bone loss from the spine. After 1 year of treatment with hormone therapy there was also a significant association between the ERbeta polymorphism and the response in total cholesterol (P = 0.02); while the ERalpha gene polymorphisms did not significantly influence the response to hormone therapy. CONCLUSIONS: In a large white population of postmenopausal women, ERalpha gene polymorphisms were not associated with bone mineral density or lipid profile at baseline or after hormone therapy. Conversely, the ERbeta genotype appeared to segregate with bone loss from the forearm and to modulate the decrease in total cholesterol during hormone therapy.