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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study examined the association between the development of nephropathy in non-insulin-dependent diabetes mellitus (NIDDM) patients and M235T polymorphism in the angiotensinogen gene. White NIDDM patients with diabetic nephropathy (case subjects, n = 117) and patients without any evidence of nephropathy and > or = 10 years of NIDDM (control subjects, n = 125) were selected from among patients of the Joslin Diabetes Center and examined. In addition to a standardized examination, blood was drawn for DNA and determination of M235T genotypes at the angiotensinogen locus. For the angiotensinogen gene, the frequency of the genotype 235T/235T, known to be associated with essential hypertension, was higher among case subjects with nephropathy than in control subjects without this complication. This difference, expressed as the odds ratio for nephropathy among 235T/235T homozygotes in comparison with all other genotypes, was 2.2 (95% confidence interval, 1.1 to 4.4). The difference, however, was confined to men (odds ratio, 4.8; 95% confidence interval, 1.5 to 14.9), with the distribution of genotypes in case and control subjects being equal among women (odds ratio, 1.1). DNA polymorphism M235T in the angiotensinogen gene, which is associated with higher expression of this gene, contributes to the risk of diabetic nephropathy in NIDDM men but not in women.
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PMID:Gender-specific association of M235T polymorphism in angiotensinogen gene and diabetic nephropathy in NIDDM. 953 11

Diabetic nephropathy (DN) clusters in families with type 1 diabetes and the degree of clustering suggests that a major gene having a common disease allele may be responsible. To investigate the chromosomal regions containing genes for the renin-angiotensin system, we performed a linkage study using pairs of siblings with type 1 diabetes who were discordant for DN. Theoretical considerations supported by simulation studies indicated that such discordant pairs, rather than the usual concordant pairs, would be more effective in detecting a major susceptibility gene for DN. We applied this novel strategy to test for linkage between DN and chromosomal regions containing genes for the ACE, angiotensinogen (AGT), and angiotensin II type 1 receptor (AT1). Two polymorphic markers were genotyped in the vicinity of each of the three loci in 66 discordant sib pairs and were analyzed with multipoint methods. The regions containing ACE and AGT loci were not linked with DN, while the region containing the AT1 locus showed linkage with DN. As a result of these positive findings, eight additional polymorphic markers spanning a 63-cM region around AT1 locus were genotyped. Linkage was demonstrated between DN and a 20-cM region that includes AT1 (P = 7.7 x 10(-5)), an obvious candidate gene for DN. To investigate whether AT1 could account for the observed linkage, we sequenced all exons, splicing junctions, and the promoter region and examined the identified polymorphisms/mutations for association with DN using the transmission disequilibrium test. Four new polymorphisms in the gene were found, but neither these nor previously described polymorphisms were associated with DN. Thus, while our study does not implicate AT1 itself in the etiology of DN, it provides very strong evidence that a 20-cM region around AT1 contains a major locus for susceptibility to DN.
Diabetes 1998 Jul
PMID:Major susceptibility locus for nephropathy in type 1 diabetes on chromosome 3q: results of novel discordant sib-pair analysis. 964 45

Two developments in molecular genetics will profoundly influence our understanding and the diagnosis of cardiovascular disorders. First, the identification of genes responsible for monogenic and polygenic traits by analysis of e.g. large pedigrees and affected sib pairs provides invaluable data regarding the role of specific genes in common diseases like arteriosclerosis, hypertension, diabetes, thrombosis/hemostasis and obesity. Besides the insights into the underlying pathophysiology, this knowledge will permit to identify persons at high risk for disease development. These patients can then obtain a targeted intervention. The second development is related to the availability of new analytical tools for molecular biology. New methods such as sequencing by hybridisation (SBH), DNA-array technology or matrix assisted laser desorption/ionisation-time of flight mass spectroscopy (MALDI-TOF) permit sequence analysis of complete genes within hours. Automated PCR-technologies with homogenous amplicon detection formats simplify PCR and permit its use in the routine laboratory setting. Considering cardiovascular diseases there is a number of genes involved in lipid metabolism (apolipoproteins, lipoprotein receptors, lipolytic enzymes), thrombosis/hemostasis (platelet receptors, pro- and anticoagulant proteins, fibrinogen, PAI's), hypertension (angiotensin converting enzyme, angiotensinogen) glucose metabolism (glucose transporters, enzymes) and obesity (hormones, receptors), that are interesting candidates for sophisticated genetic risk assessment. Furthermore, there are also gene candidates involved in processes of early atherogenesis and chronic inflammation such as complement proteins, cell adhesion molecules, and cellular receptors and enzymes. Most of these gene candidates were derived from pathophysiologic knowledge and subsequent epidemiological studies. However, it is foreseeable that in the coming years genes will be identified which were not known so far to be involved in cardiovascular diseases. Genetic studies will be of prime importance in this area, as is exemplified by animal models. In the long term, analysis of these candidate genes before the implementation of therapy will permit a targeted intervention approach towards high risk patients. This will reduce the overall costs of health care without reducing the quality.
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PMID:Recent advances in molecular genetics of cardiovascular disorders. Implications for atherosclerosis and diseases of cellular lipid metabolism. 965 2

The effect of exposure to diabetes on the kidney appears to be modulated by genetic factors determining a variable degree of susceptibility to diabetic nephropathy. Multiple loci are probably involved. Some of them might be found among the genes coding for components of the renin angiotensin system (renin, angiotensinogen, angiotensin I-converting enzyme, angiotensin receptors), some may regulate the way in which cells manage hyperglycemia (e.g. aldose reductase). Various genes have been examined to date, mainly by means of association studies. Positive results have been found for some of them (e.g. ACE, AGTR1, aldose reductase), but have not been confirmed in other populations. Thus, no genetic marker of increased susceptibility to diabetic nephropathy having clinical utility is currently available. New insights are expected from the systematic scanning of the genome for linkage with diabetic nephropathy.
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PMID:Genetic markers of increased susceptibility to diabetic nephropathy. 967 90

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.
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PMID:The thrifty-genotype hypothesis and its implications for the study of complex genetic disorders in man. 969 33

The relationship between coronary artery disease (CAD) and polymorphisms of genes encoding angiotensinogen (AGT) and angiotensin converting enzyme (ACE) was analyzed in Japanese subjects. One hundred and four patients with CAD and 170 healthy subjects were enrolled in the study. CAD was defined as having a luminal diameter stenosis > or =50% in at least one of three major coronary arteries by coronary angiography. The genotypes (determined by polymerase chain reaction) of AGT gene codon 174 were not significantly associated with CAD in the total study population. However, the frequency of T/T homozygotes of AGT codon 174 was significantly higher in CAD patients compared to controls in each of three subgroups: 1) body mass index (BMI) below the median value of 24.1 kg/m2; 2) not more than two CAD risk factors out of five (hypercholesterolemia, hypertension, diabetes mellitus, smoking, and family history of CAD); and 3) the ACE I/I genotype. The M/M genotype of AGT codon 235 was negatively associated, and the ACE D/D genotype was positively associated, with CAD in the total study population. Our results indicate that the T/T genotype of AGT codon 174 may be a risk factor for CAD in Japanese individuals with low BMI, lesser CAD risk factors, or ACE I/I genotype.
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PMID:A polymorphism of angiotensinogen gene codon 174 and coronary artery disease in Japanese subjects. 982 17

Polymorphisms of angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) genes have been reported to be associated with myocardial infarction and coronary artery disease, both of which are closely related to atherosclerosis and insulin resistance. In this study, we investigated the association between ACE and AGT genotypes and insulin sensitivity in a sample of 142 nondiabetic and 64 noninsulin-dependent diabetes mellitus (NIDDM) Japanese subjects, aged 62.7 +/- 9.5 years. The insulin response to the 75-g oral glucose tolerance test (OGTT) was significantly lower in subjects with the ACE D/D genotype compared to those with the I allele (I/D and I/I genotypes) in both nondiabetic (P < 0.05) and NIDDM subjects (P < 0.005). These homozygous D/D subjects also had lower insulin area under the curve of plasma insulin concentrations during OGTT compared to those with the I allele in nondiabetic (P < 0.05) and NIDDM subjects (P < 0.01). However, there was no significant association between AGT genotypes and either insulin response or insulin area under the curve during OGTT, in either nondiabetic or NIDDM subjects. From a viewpoint that insulin response to oral glucose is significantly correlated with insulin sensitivity, these results suggest that polymorphic variations at the ACE gene, but not the AGT gene, may be involved in the genetic regulation of insulin sensitivity in both nondiabetic and NIDDM Japanese subjects.
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PMID:The I/D polymorphism of angiotensin-converting enzyme gene but not the angiotensinogen gene is associated with insulin response to oral glucose in Japanese. 989 68

The range of known actions of amylin are reviewed together with the proposal that an important role for amylin may be the hormonal integration of diverse physiological systems activated with feeding. Major targets for the action of amylin are found within the kidney. Components of the amylin system (AS) have been shown to influence the activity of components of the renin-angiotensin system (RAS), and vice versa, in normal, hypertensive and diabetic models. For instance, amylin injected into humans and rats elicits a rapid rise in plasma renin activity. Furthermore, in two models of hypertension (the spontaneously hypertensive rat (SHR) and the model with subtotal nephrectomy (STNx)), the density of amylin-binding sites in the renal cortex associated with the proximal tubules, was associated with elevation of blood pressure. In normotensive controls and in the STNx model, but not in the SHR model, treatment with angiotensin-converting enzyme (ACE) inhibitors reduced blood pressure and the density of amylin binding in the renal cortex. In Sprague-Dawley rats, angiotensin II (Ang II) infusion was associated with increased density of amylin-binding sites as well as elevated blood pressure. Thus, there appears to be a direct relationship between the activity of Ang II and the binding sites for amylin in the renal cortex. From these studies it has been postulated that the activation of the AS in the kidney may play a role in the genesis and/or development of hypertension in certain contexts. The transient expression of amylin mRNA has been detected perinatally, using in situ hybridization, in the subnephrogenic zone of the metanephros and is associated with proximal tubules of the developing nephron. These cells situated close to the glomeruli, represent a subset of brush border epithelial cells. Amylin immunoreactivity (IR) is also found in these cells and colocalizes with angiotensinogen IR. Thus a second important role for amylin is described in which it plays a role as a growth factor in the developing kidney and in renal regrowth in the adult kidney. In a model of IDDM (streptozotocin diabetes), amylin and angiotensinogen IR are both restricted to a subset of brush border epithelial cells close to glomeruli which, in the developing kidney, expressed amylin mRNA. Thus in this IDDM model, we hypothesize that amylin mRNA transcription which is normally downregulated in the adult, is upregulated in this subset of these brush border epithelial cells, and that it stimulates the activity of a local RAS by an intracellular mechanism, leading to the biosynthesis of Ang II. It remains to be determined that if amylin is playing a role in stimulating local Ang II production at these sites, this provides a mechanism for activation of TGF-beta, ultimately leading to interstitial fibrosis.
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PMID:Interaction of the renal amylin and renin-angiotensin systems in animal models of diabetes and hypertension. 993 Mar 78

The prevalence of diabetic nephropathy is greater in nonwhite patients with type II diabetes, including the Chinese, and genetic variation appears to have a role. We examined angiotensin-converting enzyme (ACE) DD/II and angiotensinogen (Atg) M235T polymorphism in a cohort of Chinese patients with type II diabetes with an average duration of diabetes of 14 years. Group A (n = 88) did not have significant diabetic nephropathy (creatinine levels </= 130 micromol/L [</=1.48 mg/L], without macroalbuminuria), and group B (n = 80) had significant diabetic nephropathy (macroalbuminuria or creatinine level >130 micromol/L [>1.48 mg/d], and those undergoing dialysis). The two groups were matched in different aspects, including age, duration of diabetes, blood pressure, and glycemic control. The results showed: (1) no difference of genotype distribution between groups A and B (DD:DI:II, 14%:45%:41% v 8%:38%:54%; P = 0.20; TT:TM/MM, 70%:30% v 76%:24%; P = 0.43), (2) no evidence of synergistic effect of ACE (DD/II) and Atg M235T gene polymorphisms, (3) no difference of allele frequencies between groups A and B (D:I, 36%:64% v 27%:73%; P = 0.20 and T:M, 86%:16% v 86%:14%; P = 0.73), and (4) ACE activity was greatest in patients with DD genotype and least in those with II genotype (DD:DI:II = 66. 9 +/- 13.3 U/L:61.5 +/- 19.9 U/L:45.0 +/- 17.0 U/L; P < 0.005). The data do not support a role of ACE (DD/II) or Atg M235T polymorphism in the development of diabetic nephropathy in Chinese patients with type II diabetes, and no synergistic effect was found between them. Greater ACE activity was associated with DD genotype, and its role in diabetic nephropathy remains to be elucidated.
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PMID:Lack of association of angiotensin-converting enzyme (DD/II) and angiotensinogen M235T gene polymorphism with renal function among Chinese patients with type II diabetes. 1035 94

We determined the relationship between the gene polymorphism of angiotensinogen (AGT), angiotensin-converting enzyme (ACE), or angiotensin II receptor (AT1R) and the progression of diabetic nephropathy in a multicenter trial of ethnically homogeneous Japanese patients with non-insulin-dependent diabetes (NIDDM). Gene polymorphism of ACE I/D, AGT M235T and AT1R A1166C was determined by polymerase chain reaction amplification using allele-specific primers. Japanese NIDDM patients (n = 1,152) were selected from several diabetic clinics. All patients were divided into three groups as follows: (1) group I (n = 407): normoalbuminuric patients; (2) group II (n = 327): microalbuminuric patients, and (3) group III (n = 418): overt albuminuric patients. Clinical factors for investigation in all patients were the date of birth, gender, levels of urinary albumin excretion, findings of the ocular fundus, duration of diabetes, hemoglobin A1c and blood pressure. It appears that genetic polymorphisms in the renin-angiotensin systems, i.e. ACE or AT1R, may affect the progression to renal failure of patients (especially females) with NIDDM.
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PMID:Relationship between polymorphism in the angiotensinogen, angiotensin-converting enzyme or angiotensin II receptor and renal progression in Japanese NIDDM patients. 1036 6


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