NPHS2 gene, nephrotic syndrome and focal segmental glomerulosclerosis: a HuGE review.

Nephrotic syndrome, characterized by edema, proteinuria, hyperlipidemia and low serum albumin, is a manifestation of kidney disease involving the glomeruli. Nephrotic syndrome may be caused by primary kidney disease such as focal segmental glomerulosclerosis. Mutations in the podocin gene, NPHS2, have been shown in familial and sporadic forms of steroid-resistant nephrotic syndrome, including focal segmental glomerulosclerosis. Podocin is an integral membrane protein located at the slit diaphragm of the glomerular permeability barrier. Complete information is lacking for the population frequency of some NPHS2 variants for all racial and ethnic groups. The most frequently reported variant, R229Q, is more common among European-derived populations than African-derived populations. We calculated crude odds ratios and 95% confidence intervals of childhood nephrotic syndrome and focal segmental glomerulosclerosis associated with R229Q heterozygosity using data from five studies. The R229Q variant is not associated with focal segmental glomerulosclerosis in the US population of African descent. In contrast, the R229Q variant is associated with a trend toward increased focal segmental glomerulosclerosis risk in European-derived populations, with an estimated increased risk of 20-40%. Our insight into the association between NPHS2 variants and nephrotic disease is hampered by the limitations of the existing studies, including small numbers of affected individuals and suboptimal control groups. Nevertheless, the available data suggest that large epidemiological case-control studies to examine the association between NPHS2 variants and nephrotic syndrome are warranted.     

Association between the angiotensin I-converting enzyme gene insertion/deletion polymorphism and endurance running speed in Japanese runners

We investigated the association between the angiotensin I-converting enzyme (ACE) gene insertion (I)/deletion (D) polymorphism and endurance running performance in Japanese elite runners, including several Olympic athletes. The frequency of the I/I genotype was not significantly higher and the frequency of the D/D genotype was not significantly lower in elite runners compared with non-athletes. However, the frequency of the I/D genotype tended to be lower in elite runners than in non-athletes. The best performance was significantly higher for runners with the D/D genotype than for those with the I/I genotype, and the average running speed was significantly higher for those with the combined D/D + I/D genotypes than for those with the I/I genotype. There were no I/I genotypes among the five fastest marathon runners. These results suggest that the D allele of the ACE gene I/D polymorphism is associated with a high level of human endurance.     

Polymorphisms in the Angiotensin Converting Enzyme Gene and Growth in the First Year of Life

Abnormal patterns of fetal and infant growth have been associated with an increased risk of cardiovascular disease in adulthood. Catch‐up growth during the first year of life has been associated with a higher prevalence of type 2 diabetes mellitus, whereas a lack of catch‐up growth tracks with a risk of hypertension. The role of genetic factors influencing both growth and blood pressure have not been explored. We genotyped cord blood samples from 530 singleton, Caucasian, uncomplicated pregnancies, drawn from a larger cohort of 1650 pregnancies, and related polymorphism in the angiotensin converting enzyme (ACE) gene (alleles insertion (I) or deletion (D)) with measures of size at birth and at age of 1 year. ACE genotype did not significantly influence size at birth, although there was a greater proportion of individuals with the D/D genotype born with a birth weight less than the 10^th centile (P = 0.004). The ACE I/I genotype was significantly associated with higher weight (p = 0.001), body mass index (p = 0.001) and mid arm circumference (p = 0.001) at 1 year of age compared to the ACE D/D and I/D genotypes. Individuals with the I/I genotype displayed catch‐up (gain from birth size of ≥0.6 Standard Deviation Score) in weight (p = 0.04), body mass index (p = 0.03) and mid arm circumference (p = 0.03) compared to the D/D group, the majority of which showed no change or catch‐down. The I/D genotype was distributed equally across the catch up/catch down/no change categories. The effect was more marked in males, but ACE genotype and sex of the infant contributed independently to mid arm circumference measurements and there was no interaction between the two. There was no effect of maternal or paternal ACE genotype on birth size. In a multiple linear regression model ACE genotype, socioeconomic status and sex of the infant explained 10.9% of the variance in body mass index SDS at 1 year of age. We conclude that the ACE I/I genotype is associated with a higher weight and body mass index SDS at 1 year of age, along with catch‐up in terms of these measures from birth to 1 year. The D/D genotype is associated with a greater proportion of babies, born at term, that at small for gestational age. These results suggest that due consideration should be given to the underlying genotype of an individual when evaluating the association of early human growth with the development of risk factors for cardiovascular disease. The observation of independent effects of genotype, sex of the individual and socioeconomic status on postnatal growth suggests the need to develop methodologies for the integration of genetic and environmental factors in causality modelling.     

Cyclosporin a treatment in children with minimal change nephrotic syndrome and focal segmental glomerulosclerosis

Summary In a pilot study 23 children with nephrotic syndrome were treated with cyclosporin A (Cs) for 6–45 months. 8 children suffered from steroid dependent minimal change nephrotic syndrome (MCNS) and had experienced at least one course with cytotoxic drugs, but had relapsed thereafter. 2 children had diabetes mellitus type I with nephrotic syndrome and 13 children had steroid resistant focal segmental glomerulosclerosis (FSGS). Cs was started with 100 mg/m2/day in two doses and increased stepwise to obtain a Cs whole blood trough level of 200–400 ng/ml. In steroid dependent MCNS treatment with Cs reduced relapse rate significantly, and prednisone therapy could be stopped completely. After discontinuation of Cs, relapses reoccurred as frequently as before. Renal function remained unimpaired despite repeated Cs treatment courses up to 38 months. In cases of nephrotic syndrome with diabetes type I Cs treatment led to complete remission without changing the insulin requirement. However, after discontinuation of Cs relapses reoccurred. In steroid resistant FSGS 6 children benefited from Cs treatment: 4 went into complete remission, 2 into partial remission. The 2 children with complete remission relapsed but remained Cs responsive. The remaining 7 children with FSGS did not respond to Cs but continued the course of their disease, with two patients rapidly progressing to terminal renal failure. Side-effects of Cs treatment were mild. It is concluded that Cs is an effective agent in steroid dependent MCNS and can be used as an alternative drug in specific cases like steroid toxicity or diabetes mellitus. In steroid resistant FSGS a trial with Cs seems to be warranted since some cases do respond favorably. To avoid nephrotoxicity treatment with Cs should always be monitored closely by determination of blood levels and renal function.Abbreviations MCNS minimal change nephrotic syndrome - FSGS focal segmental glomerulosclerosis - Cs Cyclosporin A     

Relationship between ace genotype and short duration aerobic performance development

We have previously demonstrated that, ACE D allele may be related with a better performance in short duration aerobic endurance in a homogeneous cohort with similar training backgrounds. We aimed to study the variation in the short-duration aerobic performance development amongst ACE genotypes in response to identical training programs in homogeneous populations. The study group consisted of 186 male Caucasian non-elite Turkish army recruits. All subjects had undergone an identical training program with double training session per day and 6 days a week for 6 months. Performances for middle distance runs (2,400 m) were evaluated on an athletics track before and after the training period. ACE gene polymorphisms were studied by PCR analysis. The distribution of genotypes in the whole group was 16.7% II, n = 31; 46.2% ID, n = 86; 37.1% DD, n = 69. Subjects with ACE DD genotype had significantly higher enhancement than the ID (P < 0.01) and II (P < 0.05) genotype groups. Around 2,400 m performance enhancement ratios showed a linear trend as ACE DD > ACE ID > ACE II (P value for Pearson χ² = 0.461 and P value for linear by linear association = 0.001). ACE DD genotype seems to have an advantage in development in short-duration aerobic performance. This data in unison with the data that we have obtained from homogenous cohorts previously is considered as an existence of threshold for initiation of ACE I allele effectiveness in endurance performance. This threshold may be anywhere between 10 and 30 min with lasting maximal exercises.     

Gromerular diseases in Kenya-another look at diseases characterised by nephrotic proteinura

Renal biopsies were evaluated in 422 patients with nephrotic syndrome at the Kenyatta National Hospital between 1982 and 1993. Three hundred and fifty five (84.1%) of the patients were less than 30 years old (range: 7 months to 66 years; mean=SD: 28.4 - 9.2 years). The commonest histological lesions were mesangial proliferative glomerulonephritis (25.1%), minimal change nephropathy (17.5%) and focal segmental glomerulosclerosis (15.2%). Poststreptococcal aetiology was implicated in diffuse proliferative glomerulonephritis while use of skin lightening cosmetics appeared to play a role in the aetiology of minimal change nephrophathy in females. No aetiological role was apparent for hepatitis B virus, human immunodeficiency virus, malarial or schistosomal infection. All patients with minimal change nephropathy, focal segmental glomerulosclerosis and mesangial proliferative glomerulonephritis were treated with steroids and/or cytotoxics with a variable response.     

Second-hand smoke worsens allergies

Glomerular diseases with severe defects in glomerular permeability give rise to heavy proteinuria and can present as nephrotic syndrome. There are many different causes of the nephrotic syndrome and a renal biopsy is nearly always needed to elucidate the underlying disease. During the last decade, substantial advances have occurred in the understanding of the pathophysiological mechanisms involved in immune-mediated glomerular diseases. Here, we review the diagnostic and prognostic implications of recent progress on the understanding of membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, amyloidosis, IgA nephropathy and membranoproliferative glomerulonephritis.     

Rituximab in adult minimal change disease and focal segmental glomerulosclerosis - What is known and what is still unknown?

Primary forms of minimal change disease and focal segmental glomerulosclerosis are rare podocytopathies and clinically characterized by nephrotic syndrome. Glucocorticoids are the cornerstone of the initial immunosuppressive treatment in these two entities. Especially among adults with minimal change disease or focal segmental glomerulosclerosis, relapses, steroid dependence or resistance are common and necessitate re-initiation of steroids and other immunosuppressants. Effective steroid-sparing therapies and introduction of less toxic immunosuppressive agents are urgently needed to reduce undesirable side effects, in particular for patients whose disease course is complex. Rituximab, a B cell depleting monoclonal antibody, is increasingly used off-label in these circumstances, despite a low level of evidence for adult patients. Hence, critical questions concerning drug-safety, long-term efficacy and the optimal regimen for rituximab-treatment remain unanswered. Evidence in the form of large, multicenter studies and randomized controlled trials are urgently needed to overcome these limitations.     

The Place of Cyclosporin in the Management of Primary Nephrotic Syndrome

The 3 main causes of primary nephrotic syndrome are minimal change nephropathy, focal segmental glomerulosclerosis and membranous nephropathy. Corticosteroids result in remission of proteinuria in most patients with minimal change nephropathy. Many patients, however, develop corticosteroid dependency. A course of cytotoxic drugs can also achieve remission but these agents cannot be administered for prolonged periods or in repeated cycles because their toxicity is cumulative. Review of the available literature indicates that cyclosporin may maintain remission of nephrotic syndrome in about 80% of patients with corticosteroid-sensitive disease, indicating an important role for this drug in patients with frequent relapses or corticosteroid dependency. Although cyclosporin is less effective in patients with focal segmental glomerulosclerosis, which is often corticosteroid-resistant, a number of studies indicate that it may be successful both in the few steroid-sensitive patients with frequent relapses and in some corticosteroid-resistant patients. In patients with membranous nephropathy, a 6-month course of corticosteroids and cytotoxic agents may favour remission of nephrotic syndrome and protect renal function. Several studies have shown that cyclosporin can improve proteinuria, and there is a tentative suggestion that it might also protect against renal function deterioration. The risk of nephrotoxicity can be minimised if cyclosporin is used at the correct doses and if renal function is carefully monitored during treatment. In summary, cyclosporin can be considered a useful tool for treating patients with nephrotic syndrome associated with primary glomerulonephritis.     

Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration

Mutations of the novel renal glomerular genes NPHS1 and NPHS2 encoding nephrin and podocin cause two types of severe nephrotic syndrome presenting in early life, Finnish type congenital nephrotic syndrome (CNF) and a form of autosomal recessive familial focal segmental glomerulosclerosis (SRN1), respectively. To investigate the mechanisms by which mutations might cause glomerular protein leak, we analysed NPHS1/NPHS2 genotype/phenotype relationships in 41 non-Finnish CNF patients, four patients with congenital (onset 0 to 3 months) focal segmental glomerulosclerosis and five patients with possible SRN1 (onset 6 months to 2 years). We clarify the range of NPHS1 mutations in CNF, detecting mutation 'hot-spots' within the NPHS1 coding sequence. In addition, we describe a novel discordant CNF phenotype characterized by variable clinical severity, apparently influenced by gender. Moreover, we provide evidence that CNF may be genetically heterogeneous by detection of NPHS2 mutations in some CNF patients in whom NPHS1 mutations were not found. We confirm an overlap in the NPHS1/NPHS2 mutation spectrum with the characterization of a unique di-genic inheritance of NPHS1 and NPHS2 mutations, which results in a 'tri-allelic' hit and appears to modify the phenotype from CNF to one of congenital focal segmental glomerulosclerosis (FSGS). This may result from an epistatic gene interaction, and provides a rare example of multiple allelic hits being able to modify an autosomal recessive disease phenotype in humans. Our findings provide the first evidence for a functional inter-relationship between NPHS1 and NPHS2 in human nephrotic disease, thus underscoring their critical role in the regulation of glomerular filtration.     

Ultrastructure of the non-sclerotic glomeruli in childhood nephrotic syndrome

An electron-microscopic (EM) study of the non-sclerotic glomeruli was made in 96 children with the nephrotic syndrome in whom light microscopy had shown minimal change, focal global glomerulosclerosis or segmental glomerulosclerosis. EM showed a variety of alterations. Foot process fusion, duplication and crenation of the lamina densa, and granular and lucent expansion of lamina rara interna were noted in almost all patients in all three groups. Localised ulceration of the podocytes was noted in some patients in each group. There was no difference in the mean thickness of the glomerular basal lamina but there was an increase with age in minimal change. Curious extracellular curved striated bodies, clusters of electron-dense, round microparticles and microfilaments were found in all three. but most frequently in segmental glomerular sclerosis. Electrondense deposits were seen in all but one of the patients with segmental glomerular sclerosis and usually involved the capillary wall. They were seen in one third of those with minimal change and focal glomerular sclerosis but rarely in the capillary wall. There were no specific features which distinguished segmental glomerular sclerosis although the various types of deposits were more extensive and more frequent than in minimal change and focal glomerular sclerosis. These observations are consistent with common pathogenetic factors operating at different intensities in segmental glomerular sclerosis, focal glomerular sclerosis and minimal change.     

ACE polymorphism and response to electroconvulsive therapy in major depression

The angiotensin I-converting enzyme gene (ACE) has been repeatedly suggested as a major gene affecting affective disorders and their treatment, but the study results have been ambiguous so far. The primary purpose of this study was to compare the effects of the ACE genotype distributions and treatment response to electroconvulsive therapy (ECT) in patients with major depressive disorder (MDD). The association in ACE genotypes and the age at onset of depression was also analyzed and these gene distributions were also compared between patients and healthy controls. The study included 119 treatment-resistant MDD patients who were referred to ECT treatment, and 392 voluntary blood donors as controls. All participants were tested for their ACE genotype, and all study patients were evaluated both before and after treatment. The Montgomery–Åsberg Depression Scale (MADRS) was used as a primary efficacy evaluating method. The ACE genotype was not associated in treatment results for MDD. However, younger onset age of primary depression was associated with the I/D genotype in the whole patient group. The finding was partly gender dependent; in male patients the I allele carried a higher risk of earlier depression onset age, while in female patients the higher risk was seen only in the heterozygous I/D allele carriers. Distributions of these genotypes or alleles did not differ between patients and controls. The studied ACE genotype was not associated with ECT results but may be associated with age of onset of the illness in patients with MDD.     

Does the ACE I/D polymorphism, alone or in combination with the ACTN3 R577X polymorphism, influence muscle power phenotypes in young, non-athletic adults?

We investigated the association of the angiotensin converting enzyme gene (ACE) insertion/deletion (I/D) polymorphism, alone or in combination with the α-actinin-3 gene (ACTN3) R577X polymorphism, with jumping (vertical squat and counter-movement jump tests) and sprint ability (30 m dash) in non-athletic, healthy young adults [N = 281 (214 male), mean (SD) age 21 (2) years]. We did not observe any effect of the ACE I/D polymorphism on study phenotypes. We repeated the analyses separately in men and women and the results did not materially change. Likewise, the mean estimates of the study phenotypes were similar in subjects with the genotype combinations ACE II + ID and ACTN3 XX or ACE DD and ACTN3 RR + RX. We found no association between the ACE DD and ACTN3 RR + RX genotype combination and performance (≥90th of the sex-specific percentile). In summary, though the ACE I/D polymorphism is a strong candidate to modulate some exercise-related phenotypes or athletic performance status, this polymorphism, alone or in combination with the ACTN3 R577X polymorphism, does not seem to exert a major influence in the muscle ‘explosive’ power of young healthy adults, as assessed during multi-joint exercise tests.     

Cyclosporin in Idiopathic Nephrotic Syndrome

Idiopathic nephrotic syndrome encompasses two main forms of glomerular diseases, minimal change nephropathy and focal segmental glomerulosclerosis. Minimal change nephropathy is a disease of children which generally responds to corticosteroids. After remission, nowever, many patients show frequent relapses or steroid dependency. In these patients, cyclosporine may obtain remission of proteinuria in 80% of cases, although relapse usually occurs when the drug is stopped. Focal glomerulosclerosis is generally resistant to corticosteroids. Under cyclosporine some 40% of patients may attain complete or partial remission of the nephrotic syndrome particularly if low-dose prednisone is associated. Relapse of proteinuria usually occurs after stopping the drug. As cyclosporine may expose to chronic nephrotoxicity some guidelines should be followed to prevent this complication: - the doses should not exceed 5 mg/Kg/day - they should be adjusted whenever an increase in plasma creatinine of ± 30% over the baseline values occurs - treatment should be stopped if there is no response within 3 months - a careful monitoring of patient under the supervision of a clinician trained with the use of cyclosporine is necessary.     

Glomerular morphometry I: nephrotic syndrome in childhood

Glomerular morphometry was performed on needle biopsy specimens from 53 children with the nephrotic syndrome with minimal change (MC), focal global glomerulosclerosis (FGS) and segmental glomerulosclerosis (SGS). There were significantly fewer epithelial cells and more mesangial cells in SGS compared with MC and FGS. The number of epithelial cells decreased with age in MC and FGS, but was constantly low at all ages in SGS. There were no significant differences in differential cellularity between MC, with or without focal glomerular obsolescence or focal tubular atrophy, and FGS. Glomerular diameter increased with age in MC and FGS, but not in SGS. These findings support the view that SGS is a distinct entity rather than a variant of MC.     

CD2相关蛋白在肾病综合征中的表达及意义

目的观察不同病理类型的原发性肾病综合征(nephrotic syndrome,NS)患者肾小球足细胞中CD2相关蛋白(CD2AP)的表达,探讨其与足细胞损伤的关系。方法选取原发性NS患者54例,10例同期肾肿瘤切除患者正常肾组织作为对照。肾活检后常规染色观察肾脏组织病理改变,肾组织行免疫荧光法CD2AP和肾小球上皮细胞蛋白-1(GLEPP1)双重标记,对肾小球CD2AP的表达进行定位;分别用real time PCR和免疫组化SP法检测组织中CD2AP的表达,采用real time PCR检测nephrin的表达,透射电镜观察足细胞的结构变化,并定量测量足突密度。结果 (1)NS患者肾小球中CD2AP的表达及nephrin的表达下调,足细胞足突不同程度融合,足突密度降低。(2)病理表现为微小病变性肾病(minimal change disease,MCD)、局灶性节段性肾小球硬化(focal segmental glomerulosclerosis,FSGS)和膜性肾病(membranous nephropathy,MN)的NS患者CD2AP表达及nephrin表达较对照组明显降低,且CD2AP与nephrin表达呈正相关,病理表现为MCD和FSGS的NS患者CD2AP表达与足突密度呈正相关。结论本研究首次发现原发性NS患者肾小球足细胞中CD2AP的表达降低,且在MCD和FSGS中与足细胞病变程度相关,提示CD2AP低表达在足细胞病变为主的肾小球疾病中发挥重要作用。CD2AP有利于诊断足细胞病变的早期检测,对CD2AP表达减低进行早期干预可能有助于延缓疾病进展。     

Allelic frequencies at the ACE and LRPAP1 loci suggest age-related relationships in a Northern Italian population

The present work attempts to determine the distribution of ACE and LRPAP1 genotypes and allele frequencies in a sample of the population of north-western Italy and to examine the age-related association of these polymorphisms. ACE D allele frequency found in this work further confirms data obtained in previous studies of Northern Italian populations. Regarding the LRPAP1 gene, high frequencies of the deleted allele in European populations were also confirmed. In order to analyse the relationship between ACE and LRPAP1 gene polymorphisms and age, the sample was subdivided into four age groups: 1–30 (n?=?99), 31–50 (n?=?165), 51–79 (n?=?146) and 80–100 years old (n?=?57). For the ACE gene, significant difference in D/D genotype frequency was found only between the younger and the 51–79 age groups (p?<?0.05), the latter showing the lower frequency value. Significant differences were found, for both the I/D and D/D LRPAP1 genotypes, between the first and the second age group (p?<?0.02) and between the first and the third age group (p?<?0.01), with the 51–79 age group showing the higher D/D and the lower I/D genotype frequency values.     

Insertion/deletion polymorphism in the angiotensin-converting enzyme gene associated with macroangiopathy and blood pressure in patients with non-insulin-dependent diabetes mellitus

In the search for new risk factors for diabetic macroangiopathy the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene was studied in 237 consecutive patients (125 men and 112 women) with non-insulin-dependent diabetes. The female population showed an excess of ischemic electro-cardiographic changes or definite myocardial infarctions in the patients homozygous for the deletion [D/D; odds ratio (OR) 2.8; 95% confidence interval (CI) 1.4–5.3] and in the insertion/deletion heterozygotes (I/D; OR 1.8; CI 1.1–3.1) compared with the patients homozygous for the insertion (I/I). In the total series coronary heart disease, cerebrovascular disease, and claudication were more often observed in the patients with I/D (OR 1.5; CI 1.0–2.2) or the D/D genotype patients (OR 1.7; CI 1.1–2.6) than in those with the genotype I/I. The systolic blood pressure was lower in patients with genotype I/I (138±19 mmHg) than in those with the genotype I/D (149±22 mmHg) or D/D (150±21 mmHg; P<0.02). The prevalence of hypertension and the median urinary albumin excretion rate also tended to be lowest in the I/I genotype patients. Multiple logistic analysis revealed that in women the angiotensin-converting enzyme D/D genotype is independently associated with coronary heart disease. Our findings suggest that variation at the angiotensin-converting enzyme gene locus is one of the factors involved in the predisposition of diabetic patients to the development of arterial disease and hypertension.Abbreviations ACE Angiotensin-converting enzyme - CHD Coronary heart disease - NIDDM Non-insulin-dependent diabetes mellitus     

Focal glomerular sclerosis and sarcoidosis

Idiopathic nephrotic syndrome occurred in a patient with sarcoidosis. Typical features of focal segmental glomerulosclerosis were present on kidney biopsy. A unique finding was the occurrence of IgA in blood vessels of the skin and lymph node. Whereas the sarcoid hilar adenopathy responded to steroid therapy, the nephrotic syndrome was resistant to steroids and immunosuppression. Evaluation of humoral and cellular immune responsiveness showed no abnormalities except cutaneous anergy. Glomerulonephritis is uncommon in sarcoidosis, and a brief outline of this association is included. This patient is of importance in view of the unexplained relationship between idiopathic nephrotic syndrome and T lymphocyte abnormalities.     

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. Received: April 18, 2000 / Accepted: July 25, 2000