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Biomedical subjects

A M Sharma

Publications and source records attributed to A M Sharma.

At least 91 records · Page 5Linked to original sources
PubMed1999

Worldwide ethnic distribution of the G protein beta3 subunit 825T allele and its association with obesity in Caucasian, Chinese, and Black African individuals.

Recently, it was demonstrated that one allele (825T) of the gene encoding the G protein beta3 subunit (GNB3) is associated with hypertension in Germans. This study investigates a possible association with obesity in young male Germans, Chinese, and black South Africans with low, intermediate, and high 825T allele frequencies, respectively. In each of these three distinct cohorts, the 825T allele frequency was increased significantly in overweight (body mass index [BMI] > or =25 kg/m2) and obese individuals (BMI >27 kg/m2) compared to those with normal weight. The 825T allele frequencies in these three BMI groups were, respectively, 29.5, 39.3, and 47.7% in Germans, 46.8, 53.9, and 58.6% in Chinese, and 83.1, 87.7, and 90.9% in South Africans. In each of these three distinct groups, the 825T allele was significantly associated with obesity with odds ratios between 2 and 3. More urban than rural black Africans were overweight despite similar 825T allele frequencies in both populations, which underscores the role of both genetic and environmental factors. BP values in young male whites increased significantly with increasing BMI values but were independent of the C825T polymorphism, suggesting that hypertension associated with the 825T allele could be a consequence of obesity. Genotyping of 5254 individuals from 55 native population samples from Africa, the Americas, Europe, Asia, Australia, and New Guinea demonstrated highest 825T allele frequencies in black Africans (82%) and intermediate values in east Asians (47%). It is anticipated that high frequencies of the 825T allele in Africans and Asians may contribute to an obesity and hypertension epidemic if Westernization of lifestyles continues.

Adolescent↗
PubMed1999

[Emotional irritability and anxiety in salt-sensitive persons at risk for essential hypertension].

Personality traits such as anxiety and anger have long been associated with essential hypertension. However, the results of past studies have been criticised for selection bias, and it has not been clarified whether psychological traits are causes or consequences of high blood pressure. We studied emotional state and trait patterns and reactivity to mental stress in 16 healthy salt-sensitive volunteers at genetic risk of developing hypertension, and a well-matched control group. We have previously reported increased blood pressure reactivity to mental stress in those individuals. In this paper, we present the results of several standardized psychological questionnaires in which salt-sensitive individuals displayed increased anxiety (p < 0.01), emotional irritation (p < 0.01) and a lower level of anger control (p < 0.01). Thus, an elevated level of anxiety and irritation, as well as an increased blood-pressure response to mental stress may play a role in the development of salt-sensitive hypertension.

Adult↗
PubMed1998

The thrifty-genotype hypothesis and its implications for the study of complex genetic disorders in man.

According to the "thrifty-genotype" hypothesis proposed by Neel, diseases of civilization such as non-insulin-dependent diabetes mellitus and hypertension result from a discordance between certain features of our present-day environment and our genetic make-up which evolved to fit the life of Paleolithic humans. This concept implies that while "affected" individuals harbor the "original" ancestral version of the relevant genes, healthy or "unaffected" individuals have picked up recent mutations leading to a "loss of thriftiness" of these genes. Support for this concept now comes from recent studies of the angiotensinogen gene, where an ancestral variant of the gene (AGT 235T), also present in primates, has now been associated with hypertension whereas a neomorphic variant (AGT 235M) apparently reduces the risk of high blood pressure. The implications of these findings for our understanding and approach to the study of complex genetic diseases is discussed.

Angiotensinogen↗
PubMed1998

Angiotensin II receptor blockade and renal protection.

It is now well-established that inhibition of the angiotensin-converting enzyme (ACE) can retard the progression of chronic renal failure in a variety of experimental and clinical settings. The recent introduction of highly specific angiotensin receptor type 1 (AT1) antagonists has raised the issue whether these compounds produce comparable beneficial effects on the natural progression of chronic renal injury. Currently, a large body of experimental and clinical evidence indicates that both ACE inhibition and AT1 blockade lead to similar changes in renal hemodynamics and proteinuria. Animal studies have also shown that AT1 blockade effectively attenuates the development and progression of renal injury caused by a variety of mechanisms ranging from unilateral ureteric obstruction to renal ablation or immune-mediated acute glomerular injury. These findings make it likely that AT1 blockade may ultimately prove to be a promising new therapy for slowing the progression of renal injury in patients with kidney disease.

Angiotensin Receptor Antagonists↗
PubMed1998

Familial hemolytic-uremic syndrome in three generations.

The hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are complex entities characterized by microangiopathic hemolytic anemia, thrombocytopenia, and variable impairment of renal function, occasionally complicated by neurological symptoms. In both syndromes, rare instances of familial forms have been reported. We present the case of a family in which signs and symptoms of HUS/TTP appeared in three generations. We also briefly review the literature on inherited forms of HUS/TTP and discuss the outcome of renal transplantation in adult patients with this syndrome.

Adult↗
PubMed1998

Association of a human G-protein beta3 subunit variant with hypertension.

Hypertension is a common disorder of multifactorial origin that constitutes a major risk factor for cardiovascular events such as stroke and myocardial infarction. Previous studies demonstrated an enhanced signal transduction via pertussis toxin-sensitive G proteins in lymphoblasts and fibroblasts from selected patients with essential hypertension. We have detected a novel polymorphism (C825T) in exon 10 of the gene encoding the beta3 subunit of heterotrimeric G proteins (GNB3). The T allele is associated with the occurrence of a splice variant, GNB3-s (encoding G beta3-s), in which the nucleotides 498-620 of exon 9 are deleted. This in-frame deletion causes the loss of 41 amino acids and one WD repeat domain of the G beta subunit. By western-blot analysis, G beta3-s appears to be predominantly expressed in cells from individuals carrying the T allele. Significant enhancement of stimulated GTPgammaS binding to Sf9 insect cells expressing G beta3-s together with G alpha(i)2 and G gamma5 indicates that this splice variant is biologically active. Genotype analysis of 427 normotensive and 426 hypertensive subjects suggests a significant association of the T allele with essential hypertension.

Alleles↗
PubMed1998

Role of genetic variants of the renin-angiotensin system in chronic renal allograft injury.

In the the vast majority of patients undergoing kidney transplantation, long-term success is markedly limited by a gradual decrease in graft function over time, often termed as "chronic rejection" or "chronic allograft injury." Although there have been no formal studies examining the role of genetic factors other than those related to histocompatibility for the development or progression of chronic allograft rejection, it is likely that genetic factors affecting blood pressure regulation, mesangial or vascular proliferation, or aspects of inflammatory response including thrombosis, chemotaxis, or fibrosis may play an important role in this complex syndrome. There is currently little hope that the responsible genes can be identified through sib-pair or linkage studies in families. Therefore, the study of candidate genes selected on the basis of our current understanding of the pathophysiological mechanisms involved in the chronic rejection response appears the only feasible approach. Thus far, studies have focused mainly on the role of functional genetic variants of the renin-angiotensin system on renal allograft funding. These studies, however, have not identified these variants as important determinants of renal allograft survival. Clearly, future studies will have to address the role of other variants of this system as well as genes encoding for other systems deemed to be of pathophysiological significance for the development and progression of chronic transplant injury.

Angiotensinogen↗
PubMed1998

Angiotensin-converting-enzyme insertion/deletion genotype and long-term renal allograft survival.

BACKGROUND: Increased activity of the renin-angiotensin system has been implicated in decreased long-term survival of renal allografts. Recent studies suggest that a deletion variant of the angiotensin-converting enzyme, associated with increased humoral and tissue activity of this enzyme, may be a risk factor for the development of diabetic nephropathy and the progression of IgA nephropathy. The present study was conducted to determine whether the deletion variant of the angiotensin-converting-enzyme gene influences the long-term outcome in renal-transplant recipients. METHODS: We examined the relationship between recipient angiotensin-converting-enzyme genotype and clinical outcome in patients with a surviving allograft of at least 10 years (median survival 156 months, n= 86). Patients with an allograft survival of less than 3 years served as controls (median survival 10.4 months, n=87). RESULTS: Genotype distribution in long-term renal allograft survivors (II, 18; ID, 41; DD, 27; qD, 0.55) was similar to that in the control group (II, 12; ID, 53; DD, 22; qD, 0.56), and there were no significant differences between the genotypic groups in either cases or controls. Long-term survivors were more often female (58 vs 38%) and less often hypertensive (67 vs 77%). Both recipient and donor age were markedly lower in the long-term survivor group, whereas number of HLA mismatches and cold ischaemia time were comparable between cases and controls. CONCLUSIONS: This study does not support the hypothesis that the angiotensin-converting-enzyme insertion/deletion polymorphism is an important determinant of long-term transplant survival in Caucasian patients undergoing renal transplantation.

Adult↗
PubMed1998

Methylenetetrahydrofolate-reductase gene C677T variant and kidney-transplant survival.

UNLABELLED: BACKGROUND. Hyperhomocysteinaemia, a risk factor for atherosclerosis, is common in haemodialysis and renal-transplant patients. As atherosclerotic lesions in hyperhomocysteinaemia resemble those of chronic allograft injury, we examined the hypothesis that the C677T variant of the methylenetetrahydrofolate reductase (MTHFR) gene, which is linked to elevated plasma homocysteine levels in patients with renal failure, determines renal allograft survival. METHODS: DNA was prospectively collected from 336 patients undergoing renal transplantation in our clinic between 1988 and 1994 and their corresponding donors. Patient and allograft survival was analysed by blinded review of all case records over a follow-up period of 36 months. Additionally, we recruited 83 patients surviving with a functional kidney allograft for at least 10 years (mean: 156, range 120-240 months). MTHFR-C677T genotype was determined by a PCR-RFLP technique. The influence of genotype on transplant survival was analysed by Kaplan-Meyer life-table analysis and two-tailed global log-rank testing. RESULTS: Frequency of the MTHFR-C677T allele in the cohort group was identical in recipients (0.35) and donors (0.34), and comparable to that in the longterm allograft survivors (0.37). Furthermore, life-table analysis revealed a similar allograft survival over 36 months between the genotype groups (CC 74%, CT 69%, TT 75%). Other risk factors including donor and recipient age, hypertension, body-mass index, and number of rejection therapies were evenly distributed between the different genotype groups. CONCLUSIONS: These findings do not support the hypothesis that the C677T variant of the MTHFR gene is an important determinant of renal-transplant survival.

Adult↗
PubMed1998

Relationship between angiotensinogen, leptin and blood pressure levels in young normotensive men.

BACKGROUND AND AIMS: Although the relationship between an increase in adipose tissue and a rise in blood pressure has long been recognized, the mechanism linking these two phenomena has yet to be fully understood. Recently, it has become evident that adipose tissue is a rich source of metabolically active molecules, including free fatty acids, leptin and angiotensinogen, the precursor of angiotensin II. The latter finding has prompted speculation on the possible role of adipocyte-derived angiotensinogen in the relationship between body weight and blood pressure. Therefore we examined the relationship between blood pressure, angiotensinogen, body mass index (BMI) and leptin levels in healthy normotensive subjects who are genetically predisposed to the development of hypertension. SUBJECTS AND METHODS: We studied 40 subjects with a positive family history of hypertension and 51 subjects with a negative family history. After the blood pressure measurements, blood samples were collected for the assessment of angiotensinogen, leptin, glucose, insulin, renin activity and electrolytes. Oral glucose tolerance was studied by an oral glucose tolerance test (75 g glucose). RESULTS: Plasma angiotensinogen was significantly correlated with both BMI (r=0.29, P < 0.01) and plasma leptin (r=0.40, P < 0.001). While plasma angiotensinogen and blood pressure were positively correlated only in subjects with a positive family history of hypertension (r=0.33, P< 0.05), plasma leptin was related to blood pressure in both groups (r=0.26, P=0.01). Furthermore, the insulin response to an oral glucose load was significantly related to both plasma angiotensinogen (r=0.22, P< 0.05) and plasma leptin (r=0.47, P< 0.001). CONCLUSIONS: These findings support the hypothesis that circulating angiotensinogen levels are related to adipose mass in young, normotensive, nonobese men. Further studies on the relationship between adipose tissue and systemic or local renin-angiotensin systems appear warranted.

Adipose Tissue↗
PubMed1998

Transient expression of high molecular weight, heat sensitive, trypsin-resistant form of tyrosinase in B-16 melanoma cells.

High molecular weight forms of tyrosinase have been found to be expressed during spontaneous remelanization of the amelanotic B-16 melanoma cells in culture as well as in melanotic tumors formed from amelanotic melanoma cells grown in C57BL/6J mice. Overnight extraction of the crude melanosomal fractions from such tumors and cultured melanoma cells reveal the presence of an additional DOPA-MBTH positive band well below the stacking gel. This band has been found to be alpha-PEP7 (antibody specific for tyrosinase) positive and alpha-PEP1 (antibody specific for TRP-1) negative on Western blot analysis. Heat treatment at 60 degrees C for 60 min results in the loss of this band and considerable loss of activity of the melanosomal extract. Trypsin treatment of these melanosomal extracts resulted in a minor change in the mobility of the high molecular weight band. SDS-PAGE under reduced conditions followed by Western blotting revealed that the high molecular weight band was lost and not detected by alpha-PEP7 or alpha-PEP1. These findings indicate that high molecular weight, heat sensitive and trypsin resistant forms of tyrosinase are transiently expressed in B-16 melanoma cells and tumors that are initiating remelanization following phenotypic drift towards the amelanotic state.

Animals↗
PubMed1998

Evaluation of the angiotensinogen locus in human essential hypertension: a European study.

Different family and case-control studies support genetic linkage and association at the human angiotensinogen (AGT) locus with essential hypertension. To extend these previous observations, a European collaborative study of nine centers was set up to create a large resource of affected sibling pairs. The AGT locus was studied using a highly polymorphic dinucleotide repeat in the 3'-flanking region of the gene in 350 European families, comprising 630 affected sibling pairs. Statistical analyses using two different methods did not show any evidence for linkage either in the whole panel or in family subsets selected for severity or early onset of disease. Although several arguments from association studies suggest a role of the AGT gene in essential hypertension, this large family study did not replicate the initial linkage reported in smaller studies. Our results highlight the difficulty of identifying susceptibility genes by linkage analysis in complex diseases.

Adult↗
PubMed1998

Association between the angiotensin-converting enzyme-insertion/deletion polymorphism and diabetic nephropathy: a methodologic appraisal and systematic review.

Recent studies have implicated a variant of the angiotensin-converting enzyme gene (ACE), associated with increased activity of this enzyme, in the development and progression of diabetic nephropathy. This study provides a systematic review of all cross-sectional, case-control, and cohort studies in patients with insulin-dependent (IDDM) or non-insulin-dependent (NIDDM) diabetes mellitus of any race, examining the relationship between the ACE-insertion/deletion polymorphism and nephropathy. Nineteen studies in 21 populations published between 1994 and 1997 presenting data on 5336 patients were reviewed. Two investigators independently assessed the studies on methodologic quality, performance of study, and association between the ACE-insertion/deletion polymorphism and nephropathy. Separate analyses of the relationship between genotype and allele frequencies were performed for patients with IDDM and NIDDM by race, using Peto's odds ratio. In Caucasians with IDDM, pooling was not performed due to heterogeneity of the studies, but among the homogeneous studies, no association was detected. Likewise, no association was observed in Caucasian patients with NIDDM (odds ratio [OR], 1.10; 95% confidence interval [95% CI], 0.83 to 1.45). In Asian patients with NIDDM, the risk of nephropathy was increased in the presence of the DD or ID genotype (OR, 1.88; 95% CI, 1.42 to 2.85). Although this analysis fails to confirm an association between the ACE-insertion/deletion genotype and nephropathy in Caucasians with NIDDM or IDDM, a role for this genetic marker in Asian patients cannot be ruled out. However, due to methodologic limitations of individual studies, no definite conclusions can be drawn from this analysis. Clearly, more rigorous methodology needs to be applied in future studies.

Adult↗