ATP2C1 gene mutations in Hailey-Hailey disease and possible roles of SPCA1 isoforms in membrane trafficking.

ATP2C1 gene codes for the secretory pathway Ca(2+)/Mn(2+)-ATPase pump type 1 (SPCA1) localizing at the golgi apparatus. Mutations on the human ATP2C1 gene, causing decreased levels of the SPCA1 expression, have been identified as the cause of the Hailey-Hailey disease, a rare skin disorder. In the last few years, several mutations have been described, and here we summarize how they are distributed along the gene and how missense mutations affect protein expression. SPCA1 is expressed in four different isoforms through alternative splicing of the ATP2C1 gene and none of these isoforms is differentially affected by any of these mutations. However, a better understanding of the tissue specific expression of the isoforms, their localization along the secretory pathway, their specific binding partners and the role of the C-terminal tail making isoforms different from each other, will be future goals of the research in this field.

Rare diseases in clinical endocrinology: a taxonomic classification system.

PURPOSE: Rare endocrine-metabolic diseases (REMD) represent an important area in the field of medicine and pharmacology. The rare diseases of interest to endocrinologists involve all fields of endocrinology, including rare diseases of the pituitary, thyroid and adrenal glands, paraganglia, ovary and testis, disorders of bone and mineral metabolism, energy and lipid metabolism, water metabolism, and syndromes with possible involvement of multiple endocrine glands, and neuroendocrine tumors. Taking advantage of the constitution of a study group on REMD within the Italian Society of Endocrinology, consisting of basic and clinical scientists, a document on the taxonomy of REMD has been produced. METHODS AND RESULTS: This document has been designed to include mainly REMD manifesting or persisting into adulthood. The taxonomy of REMD of the adult comprises a total of 166 main disorders, 338 including all variants and subtypes, described into 11 tables. CONCLUSIONS: This report provides a complete taxonomy to classify REMD of the adult. In the future, the creation of registries of rare endocrine diseases to collect data on cohorts of patients and the development of common and standardized diagnostic and therapeutic pathways for each rare endocrine disease is advisable. This will help planning and performing intervention studies in larger groups of patients to prove the efficacy, effectiveness, and safety of a specific treatment.

Vitamin D levels and bone mineral density: are LH levels involved in the pathogenesis of bone impairment in hypogonadal men?

BACKGROUND: Osteoporosis is a major public health problem also in men and it recognizes hypogonadism as a major cause. AIMS: To investigate the possible pathogenetic mechanisms on bone impairment in male hypogonadism and on its improvement in response to testosterone replacement treatment (TRT). METHODS: We retrospectively investigated the hormonal profile and bone mineral density (BMD), evaluated by DXA, in 17 middle-aged hypogonadal men treated for at least 5 years with TRT, compared with 21 recently diagnosed untreated hypogonadal males and 18 age- and BMI-matched healthy subjects. RESULTS: No significant differences in clinical, biochemical and densitometric parameters were found among the three groups, with the exception of 25-OH vitamin D levels that were significantly higher in healthy subjects compared with hypogonadal patients. Untreated patients affected by central hypogonadism, despite similar hormonal levels, displayed significantly lower BMD and decreased LH and 25-OH vitamin D levels, compared with patients with primary hypogonadism. Among the treated patients, BMD parameters were similar regardless of the formulation of TRT. CONCLUSIONS: A recent history of central hypogonadism, compared with primary hypogonadism, appears to adversely affect bone health independently of gonadal steroids levels. This could be due to lower LH levels and consequent reduction of vitamin D 25-hydroxylation in the testis.

Primary aldosteronism and essential hypertension: assessment of cardiovascular risk at diagnosis and after treatment.

BACKGROUND AND AIMS: Primary aldosteronism (PA), the most frequent form of secondary hypertension, is characterized by a higher rate of cardiovascular (CV) events than essential hypertension (EH). Aim of the study was to evaluate the cardiovascular risk according to the ESH/ESC 2007 guidelines, in patients with PA and with EH, at diagnosis and after treatment. METHODS AND RESULTS: We prospectively studied 102 PA patients (40 with aldosterone producing adenoma-APA and 62 with idiopathic hyperaldosteronism-IHA) and 132 essential hypertensives at basal and after surgical or medical treatment (mean follow-up period 44 months for PA and 42 months for EH). At baseline evaluation the stratification of CV risk was significantly different: the predominant risk category was the high CV risk (50% in total PA, 53% in PA matched for blood pressure values and 55% in EH), but the very high risk category was twice in PA than in EH patients (36% in total PA and 33% in matched PA vs. 17% in EH, p < 0.05). The worse risk profile of PA was due to a higher prevalence of glycemic alterations, metabolic syndrome and left ventricular hypertrophy (LVH) (p < 0.05). After adequate treatment, the CV risk was significantly reduced becoming comparable in PA and in EH patient due to a reduction of hypertension grading, prevalence of metabolic syndrome, hypertension persistence and LVH (p < 0.05). CONCLUSION: Patients with PA present a high CV risk, which is in part reversible after specific treatment, due both to the reduced blood pressure values and to the improvement of end-organ damage.

Bone health and aldosterone excess.

UNLABELLED: A picture of hyperparathyroidism secondary to increased urinary calcium excretion was found in 116 patients with primary aldosteronism (PA), compared with 110 essential hypertensives. After medical or surgical treatment in 40 PA patients, parathyroid hormone (PTH) levels were significantly reduced and bone mineral density (BMD) significantly increased at the lumbar spine, femoral neck, and total hip. INTRODUCTION: Recent studies have shown that aldosterone induces urinary calcium excretion leading to a reduction of calcemia with consequent secondary hyperparathyroidism and BMD loss. In patients with PA, this picture of hyperparathyroidism is significantly improved by treatment with adrenal surgery or with mineralocorticoid receptor antagonists. On these premises, the aim of the present study was to evaluate calcium and phosphate metabolism parameters in PA patients, compared with patients with essential hypertension (EH) and the effect of treatment of aldosterone excess on bone health in PA patients. METHODS: We studied 226 patients: 116 with PA (46 with an aldosterone-producing adenoma and 70 with bilateral adrenal hyperplasia) and 110 patients with EH. In 40 patients with PA, we evaluated biochemical parameters and bone mass, using the dual-energy X-ray absorptiometry, at baseline and after a mean follow-up of 24 months from treatment. RESULTS: In PA patients, compared with EH, PTH levels and urinary calcium excretion significantly increased while serum calcium significantly decreased with comparable vitamin D levels. At follow-up in PA patients, PTH levels were significantly reduced compared with basal evaluation, despite similar vitamin D amounts. At follow-up, we observed a significant improvement of the Z-score at the lumbar spine, femoral neck, and at total hip sites. CONCLUSIONS: Our results support previous data showing secondary hyperparathyroidism in PA patients, which is reversible after treatment. Moreover, this targeted treatment appears to be able to determine a significant improvement of BMD both at the spine and hip sites.

Prospective appraisal of the prevalence of primary aldosteronism in hypertensive patients presenting with atrial flutter or fibrillation (PAPPHY Study): rationale and study design.

Primary aldosteronism (PA) is the most common endocrine form of hypertension and may carry an increased risk of atrial flutter or fibrillation (AFF). The primary goal of this multicentre cohort study is thus to prospectively establish the prevalence of PA in consecutive hypertensive patients referred for lone (non-valvular), paroxysmal or permanent AFF. Secondary objectives are to determine: (1) the predictors of AFF in patients with PA; (2) the rate of AFF recurrence at follow-up after specific treatment in the patients with PA; (3) the effect of AFF that can increase atrial natriuretic peptide via the atrial stretch and thereby blunt aldosterone secretion, on the aldosterone-to-renin ratio (ARR), and thus the case detection of PA; (4) the diagnostic accuracy of ARR based on plasma renin activity or on the measurement of active renin (DRA) for diagnosing PA in AFF patients. Case detection and subtyping of PA will be performed according to established criteria, including the 'four corners criteria' for diagnosing aldosterone-producing adenoma. Pharmacologic or direct current cardioversion will be undertaken whenever indicated following current guidelines. The hormonal values and ARR will be compared within patient between AFF and sinus rhythm. Organ damage, cardiovascular events and recurrence of AFF will also be assessed during follow-up in patients with PA.

[Gitelman syndrome associated with chondrocalcinosis: description of two cases]. / Sindrome di Gitelman associata con condrocalcinosi: descrizione di due casi.

Gitelman syndrome is a rare inherited tubulopathy, characterized by hypomagnesemia, hypokalemia, metabolic alkalosis, hypocalciuria and hyperreninemic hyperaldosteronism. The clinical spectrum is wide and includes: cramps, myalgias, muscle weakness, until episodes of carpo-podalic spasm, tetania, rhabdomyolysis and paralysis. Some cases have been described in literature underlining the association of this condition with chondrocalcinosis, as a typical example of hypomagnesemia-induced crystal deposition disease. The therapy of Gitelman syndrome consists on the administration of defective electrolytes, although not always effective. We describe two cases of Gitelman syndrome associated with chondrocalcinosis showing the wide range of presentation of this clinical condition.

Metabolic syndrome in primary aldosteronism and essential hypertension: relationship to adiponectin gene variants.

BACKGROUND AND AIMS: Evidence shows that aldosterone excess is crucial for the development of cardiac and metabolic complications. Among the possible pathogenetic elements of the metabolic syndrome, adiponectin and its polymorphisms seem to confer a genetic risk for metabolic alterations and type 2 diabetes. Aims of the study were to investigate whether metabolic syndrome represents a common feature in patients with primary aldosteronism (PA) compared with essential hypertensives (EH) and to study the impact of two common adiponectin gene variants on the parameters of metabolic syndrome. METHODS AND RESULTS: Metabolic syndrome was defined according to ATPIII criteria. Eighty-nine patients with PA and 164 matched EH were studied. In all patients with PA and in 135 EH two single nucleotide polymorphisms of the adiponectin gene, T45G and G276T, were detected. Patients with PA displayed a higher prevalence of metabolic syndrome compared with EH (45% vs. 30%, p<0.05). In patients with PA, genotypes 45T/G+G/G were associated with significantly lower values of waist circumference, HOMA-IR and serum aldosterone. In both PA patients and EH, the 276T/T genotype was associated with significantly worse metabolic profile and a higher risk for the metabolic syndrome (OR=1.5 for PA and OR=1.3 for EH). CONCLUSIONS: Our data confirm a higher prevalence of metabolic syndrome among patients with PA compared with matched EH. Genetic analysis of T45G and G276T adiponectin gene polymorphisms showed that, while the genotypes 45G/G+G/T seemed to have a protective role on the metabolic complications, the genotype 276T/T defined PA and EH patients with a worse metabolic profile.

Long-term results of laparoscopic adrenalectomy for primary aldosteronism.

BACKGROUND: The management of primary aldosteronism is currently achieved by both medical and surgical treatment. Laparoscopy has in recent years unquestionably become the gold standard in adrenal surgery for benign lesions. This study aims to evaluate our clinical results among patients who underwent laparoscopic adrenalectomy (LA) for primary aldosteronism. METHODS: From January 1994 to January 2006, amid LA series, 59 primary aldosteronism patients were treated in our institution. Patients were 33 males and 26 females with mean age 49.3 yr (19-78). The mean body mass index was 25.9 kg/m2 (20.5-33.3). The mean size of lesion was 2.9 cm (1-5.5). Clinical symptoms were as follows: hypertension and symptomatic/asymptomatic hypokalemia (54), hypokalemia (5). RESULTS: Thirty-five left and 24 right LA were performed. On the left side, 22 procedures were carried out by anterior approach, 9 by anterior submesocolic route, and 4 by means of flank approach. All right procedures were completed by the anterior supine approach. The mean operative time was 103.5 min for left and 92.8 min for right adrenalectomy. There was one major complication, a colonic post-operative fistula, regarding a left adrenalectomy case. The mean post-operative hospital stay was 3 days (1-9). The cure rate of hypertension and hypokalemia was similar to the current literature results. CONCLUSIONS: LA is a safe and effective option in the treatment of primary aldosteronism. Appropriate selection of patients, larger adrenal masses and duration of symptoms are determining factors in the success rate of hypertension management.

Comparison of circulating and local adipose tissue renin-angiotensin system in normotensive and hypertensive obese subjects.

The renin-angiotensin-aldosterone system (RAAS) plays a well-recognized role in the regulation of BP and in salt and water balance. Since hypertension affects a considerable proportion of obese patients, circulating RAAS has been studied in obese subjects with and without hypertension, albeit with conflicting results. Furthermore, attention has recently focused on the expression of the components of the Renin-angiotensin system (RAS) in some organs, including adipose tissue where it seems to be involved in the regulation of growth and differentiation. The aim of our study was to investigate circulating RAAS and adipose tissue RAS in obese patients with and without hypertension and in matched controls. PRA, and plasma and urinary aldosterone levels were measured in 35 obese, 30 hypertensive obese patients and in 20 controls. In addition, the expression of angiotensinogen (AGT) and angiotensin II type 1 receptor (AT1) genes was studied in sc adipose tissue from 8 obese, 6 hypertensive obese and 6 healthy subjects. As previously demonstrated in other studies, there were no significant differences in the levels of circulating RAAS components in the 3 groups. As regards local RAS, interestingly, we found that AT1 gene was significantly more expressed in sc adipose tissue from obese patients with hypertension than in those without hypertension and controls. By contrast, AGT levels were similar in the 3 groups. Our data do not support the hypothesis of an involvement of circulating RAAS in the development of obesity-related hypertension. On the other hand, local RAS seems to be differently regulated in sc adipose tissue from obese patients with hypertension with respect to normotensive obese patients and controls.

Decreased nitric oxide levels and increased calcium content in platelets of hypertensive patients.

Decreased levels of nitric oxide (NO) may contribute to impaired endothelium-dependent vasodilatation in essential hypertension. Moreover, in hypertension, major platelets aggregation and endothelial adhesion, and increased atherogenetic risks are also present. Nitric oxide produced by platelet NO synthase, which is similar to endothelial NO synthase, inhibits platelets aggregation by increasing cytoplasmic cyclic GMP levels and contributes in a major way to the antithrombogenic properties of endothelium. The aim of this study was to investigate platelet NO production and cytosolic Ca2+ levels in patients with essential hypertension and in healthy subjects. We studied NO production in 36 subjects (21 patients had essential hypertension and 15 subjects were normotensive); NO synthase activity was evaluated by measuring nitrite levels by the Griess reaction in the supernatant of sonicated platelets. Cytosolic Ca2+ levels were measured in intact platelets using the fluorescent probe Fura 2-AM. Nitric oxide levels in platelets were found higher in normotensive than in hypertensive patients (P < .0001). Nitric oxide levels in hypertensive women were significantly higher than in hypertensive men (P < .001). Hypertensive women and men had lower levels of nitrite than normotensive women and men (P < .001 and P < .002, respectively). Platelet cytosolic Ca2+ levels were higher in hypertensive patients than in normotensive subjects (P < .001). An inverse correlation was found between platelet cytosolic Ca2+ and NO levels (r = 0.74, P < .002). These data confirm the link between hypertension and altered platelets function and suggest a role for NO in cardiovascular events. Moreover, the higher levels of nitric oxide in child-bearing age women than in men further support the protective effect of estrogens on cardiovascular diseases.

Hypertension due to renal artery occlusion in a patient with antiphospholipid syndrome.

We report an unusual case of renovascular hypertension in a 16-year-old boy with primary antiphospholipid syndrome (PAPS), admitted to our clinic for severe drug-resistant hypertension and hypokalemia. Hormonal investigation revealed secondary aldosteronism and positive captopril test for renovascular disease. Aortography confirmed the occlusion of the left renal artery. After nephrectomy, normalization of blood pressure and secondary aldosteronism occurred. Presently the patient remains in good health, receiving warfarin anticoagulant therapy. PAPS is defined by the presence of antiphospholipid antibodies and recurrent thrombosis. Arterial thrombosis (29%) appears to be less prevalent than venous thrombosis. Thrombotic microangiopathy of the kidney is frequently observed but renal artery occlusion, as seen in our patient, is unusual.

Adipose tissue as an endocrine organ? A review of some recent data.

Recent clinical and experimental data have radically modified the concept of adipose tissue as one solely devoted to energy storage and release. Adipose tissue is a target organ for glucocorticoids. Several studies of the function of the hypothalamic-pituitary-adrenal axis in obese subjects have failed to reach conclusive results. An innovative finding is that adipose tissue produces cortisol from its inactive precursor, cortisone. Identification of leptin, a hormone synthesised by adipose tissue, has ushered in the modern view that it is a true endocrine organ. Leptin is produced by subcutaneous and to a lesser extent by visceral adipose tissue. It has a central role in body weight and especially fat stores regulation, but is also involved in several complex functions, including the physiological processes associated with puberty. Angiotensinogen (AGT), another hormone synthesised in abundance by adipose tissue, is produced in larger amounts by visceral than subcutaneous fat. In addition, in man and animals adipose tissue appears to possess the whole renin-angiotensin system (RAS), suggesting that angiotensin II, the final effector of the system, is locally produced. The function of adipose RAS is not well known; besides participating, together with other hormones and substances, in adipocyte differentiation and fat tissue growth, it could be involved in the pathogenesis of the complications of obesity. All these findings have opened interesting prospects and are expected to yield further stimulating insights into the physiopathology of the adipose organ.

Gene expression of angiotensinogen in adipose tissue of obese patients.

Recently, the genes of components of the renin-angiotensin system (RAS), namely angiotensinogen (AGT), angiotensin converting enzyme and angiotensin II receptor have been described in adipose tissue. In animal models the angiotensinogen in adipose tissue has been implicated in the pathogenesis of metabolic alterations and hypertension associated with obesity. The aim of our study was to evaluate the AGT gene expression both in visceral and subcutaneous adipose tissue in obese patients and lean subjects. AGT mRNA levels were measured by reverse transcriptase polymerase chain reaction (RT-PCR) using specific primers. AGT mRNA was expressed at variable levels in obese patients. It was significantly greater in visceral than in subcutaneous adipose tissue. Positive and significant correlation was found between the expression of AGT in visceral adipose tissue and BMI. These data suggest that angiotensinogen may be determinant of fat distribution and may be involved in the plurimetabolic syndrome of central obesity.

Adrenal incidentaloma.

Incidentally discovered adrenal masses, or adrenal incidentalomas, have become a common clinical problem owing to wide application of radiologic imaging techniques. This definition encompasses a heterogeneous spectrum of pathologic entities, including primary adrenocortical and medullary tumors, benign or malignant lesions, hormonally active or inactive lesions, metastases, and infections. Once an adrenal mass is detected, the clinician needs to address two crucial questions: is the mass malignant, and is it hormonally active? This article provides an overview of the diagnostic clinical approach and management of the adrenal incidentaloma. Mass size is the most reliable variable to distinguish benign and malignant adrenal masses. Adrenalectomy should be recommended for masses greater than 4.0 cm because of the increased risk of malignancy. Adrenal scintigraphy has proved useful in discriminating between benign and malignant lesions. Finally, fine-needle aspiration biopsy is an important tool in the evaluation of oncological patients and it may be useful in establishing the presence of metastatic disease. The majority of adrenal incidentalomas are non-hypersecretory cortical adenomas but an endocrine evaluation can lead to the identification of a significant number of cases with subclinical Cushing's syndrome (5-15%), pheochromocytoma (1.5-13%) and aldosteronoma (0-7%). The first step of hormonal screening should include an overnight low dose dexamethasone suppression test, the measure of urinary catecholamines or metanephrines, serum potassium and, in hypertensive patients, upright plasma aldosterone/plasma renin activity ratio. Dehydroepiandrosterone sulfate measurement may show evidence of adrenal androgen excess.

CA-Repeat polymorphism in intron 1 of HSD11B2 : effects on gene expression and salt sensitivity.

Mutations in the HSD11B2 gene encoding the kidney (11-HSD2) isozyme of 11beta-hydroxysteroid dehydrogenase cause apparent mineralocorticoid excess, a form of familial hypertension. Because the hypertension associated with AME is of the salt-sensitive type, it seemed possible that decreases in 11-HSD2 activity might be associated with salt sensitivity. To examine this, Italians with mild hypertension underwent a protocol consisting of a rapid intravenous saline infusion and subsequent furosemide diuresis. To determine whether there were genetic associations between HSD11B2 and salt sensitivity, 198 Italians were genotyped for a CA repeat polymorphism (11 alleles) in the first intron. Increased differences in mean arterial pressure between the sodium loaded and depleted states were correlated with shorter CA repeat length (R=0.214, P=0. 0025). The effect behaved as a recessive trait. This suggested that decreased HSD11B2 expression was associated with shorter CA repeat length. Furthermore, activity of renal 11-HSD2 as measured by an increase in the ratio of urinary-free cortisol/urinary-free cortisone was lower in 33 salt-sensitive subjects (urinary-free cortisol/urinary-free cortisone 0.89+/-0.04 [mean+/-SE]) compared with 34 salt-resistant subjects (0.71+/-0.04, P<0.001). However, when minigenes containing either 14 or 23 CA repeats were transfected into rabbit or human kidney cortical collecting duct cells, the construct with 14 repeats was instead expressed at levels 50% higher than those of the construct with 23 repeats, as determined by reverse transcription-polymerase chain reaction. We conclude that polymorphisms in HSD11B2 and decreased 11-HSD2 activity are associated with sensitivity to sodium loading, but a functional explanation for these associations remains to be elucidated.

The tissue renin-angiotensin system in rats with fructose-induced hypertension: overexpression of type 1 angiotensin II receptor in adipose tissue.

OBJECTIVE: Fructose feeding induces hypertension, insulin-resistance and hypertriglyceridemia in Sprague-Dawley rats. The mechanisms of fructose-induced hypertension are as yet unknown. Here we investigate the effects of fructose feeding and of varying salt intake on blood pressure, glucose tolerance, plasma renin activity, and tissue angiotensinogen, renin, and AT1 receptor mRNA levels in this model of hypertension. DESIGN AND METHODS: To investigate the role of the renin-angiotensin system in fructose-induced hypertension we measured angiotensinogen, renin and angiotensin II type 1 (AT1) receptor mRNA levels in tissues of Sprague-Dawley rats that were fed either standard rat chow or a diet containing 66% fructose. RESULTS: Blood pressure (P < 0.05) and triglyceride (P < 0.01) levels were significantly greater in the fructose-fed animals. Plasma glucose and insulin responses to an oral glucose load were significantly greater (P< 0.05) in fructose-fed than control rats. Angiotensinogen mRNA levels in liver and fat, and renin mRNA levels in kidney did not differ between fructose-fed and control animals. Levels of AT1 receptor mRNA were significantly greater in the fat obtained from fructose-fed rats than in that from control rats (P< 0.05), but this was not so in the kidney. To determine whether fructose-induced hypertension is dependent on dietary salt content, rats were fed standard rat chow and a fructose-enriched diet with low and high sodium chloride concentrations. Blood pressure increased significantly (P< 0.05) only in the fructose-fed rats receiving the high-salt diet Similarly, increased AT1 receptor mRNA levels were observed only in the fructose-fed rats that were maintained on the high-salt diet CONCLUSIONS: Fructose feeding induces hypertension in normal- or high-salt fed animals and it is associated with an increased expression of the AT1 receptor in adipose tissue. These findings suggest that AT1 receptors might play a role in the pathophysiology of metabolic and hemodynamic abnormalities induced by fructose feeding.

Genotype-phenotype correlations of mutations and polymorphisms in HSD11B2, the gene encoding the kidney isozyme of 11beta-hydroxysteroid dehydrogenase.

Mutations in the HSD11B2 gene encoding the kidney (11-HSD2) isozyme of 11beta-hydroxysteroid dehydrogenase cause the syndrome of apparent mineralocorticoid excess, a form of salt-sensitive hypertension. Enzymatic activities of mutant enzymes measured in cultured cells are correlated with several parameters of clinical severity including urinary steroid product:precursor ratios, age at diagnosis, birth weight and potassium levels, but not with blood pressure. In normals or in subjects with essential hypertension, sensitivity of blood pressure to salt loading is correlated with activity of renal 11-HSD2, as measured by an increase in the ratio of urinary free cortisol/urinary free cortisone (UFF/UFE), and also correlated with length of a CA repeat polymorphism in the first intron of HSD11B2. A functional explanation for these associations remains to be elucidated.

Polymorphisms of angiotensin-converting enzyme and angiotensinogen genes in type 2 diabetic sibships in relation to albumin excretion rate.

Familial clustering of altered albumin excretion and nephropathy risk has been described in both type 1 and type 2 diabetes; moreover, an association of micro-macroalbuminuria and diabetic retinopathy has been recently reported in a large number of white families with type 2 diabetes. Conflicting reports, mainly comparing affected with unaffected unrelated subjects, have suggested a possible role of some genotypes of the renin-angiotensin system in conferring nephropathy risk in type 2 diabetes. To examine the role of genetic factors in influencing albuminuria in families, we studied the relation of angiotensin-converting enzymes (ACE) and angiotensinogen (AGN) genotypes with albumin excretion rate in a population of affected siblings of type 2 diabetic probands. We determined ACE insertion/deletion polymorphism and two polymorphisms of the AGN gene (T174M and M235T) in 160 families with at least one affected member. Defining proband as the patient with the longest known duration of diabetes, we compared the allelic distribution in diabetic probands with and without altered albumin excretion and in their siblings. Allelic distribution of these polymorphisms was similar in the two groups of probands, as well as in their siblings. Identity-by-State (IBS) analysis showed a link between AGN locus and arterial hypertension in these siblings, which was independent from the degree of renal involvement. Thus, our findings suggest that in white families with type 2 diabetes, there is no linkage between the degree of albumin excretion and ACE and AGN polymorphisms, whereas the latter is related to arterial hypertension, as previously found in patients without diabetes but with essential hypertension.