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      Endothelin-1 gene polymorphisms and diabetic kidney disease in patients with type 2 diabetes mellitus

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          Abstract

          Background and aims

          Diabetic kidney disease (DKD) is the leading cause of end stage renal disease worldwide and is associated with increased cardiovascular mortality. The endothelin system has been implicated in the pathogenesis of arterial hypertension and renal dysfunction. In the present study, the association of DKD with polymorphisms in ET-1 ( EDN1) and ETRA ( EDNRA) genes was analyzed in patients with type 2 diabetes mellitus (T2DM).

          Methods

          A case–control study was conducted in 548 white T2DM patients. Patients with proteinuria or on dialysis were considered cases and patients with normoalbuminuria were considered controls. Two polymorphisms in the EDN1 gene (rs1800541 and rs57072783) and five in EDNRA gene (rs6842241; rs4835083; rs4639051; rs5333 and rs5343) were genotyped and haplotype analyses were performed.

          Results

          The presence of rs57072783 T allele (TT/TG vs. GG) or rs1800541 G allele (GG/GT vs. TT) protected against DKD (OR = 0.69, 95 % CI 0.48–0.99, P = 0.049; and OR = 0.60, 95 % CI 0.41–0.88, P = 0.009, respectively). However in multivariate analyses, only the rs1800541 G allele remained independently associated with DKD (P = 0.046).

          Conclusions

          The present study shows that ET-1 could be involved in the pathogenesis of DKD in patients with T2DM.

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          Avosentan for overt diabetic nephropathy.

          Giancarlo Viberti, Johannes Mann, Susan Kuranoff … (2010)
          In the short term, the endothelin antagonist avosentan reduces proteinuria, but whether this translates to protection from progressive loss of renal function is unknown. We examined the effects of avosentan on progression of overt diabetic nephropathy in a multicenter, multinational, double-blind, placebo-controlled trial. We randomly assigned 1392 participants with type 2 diabetes to oral avosentan (25 or 50 mg) or placebo in addition to continued angiotensin-converting enzyme inhibition and/or angiotensin receptor blockade. The composite primary outcome was the time to doubling of serum creatinine, ESRD, or death. Secondary outcomes included changes in albumin-to-creatinine ratio (ACR) and cardiovascular outcomes. We terminated the trial prematurely after a median follow-up of 4 months (maximum 16 months) because of an excess of cardiovascular events with avosentan. We did not detect a difference in the frequency of the primary outcome between groups. Avosentan significantly reduced ACR: In patients who were treated with avosentan 25 mg/d, 50 mg/d, and placebo, the median reduction in ACR was 44.3, 49.3, and 9.7%, respectively. Adverse events led to discontinuation of trial medication significantly more often for avosentan than for placebo (19.6 and 18.2 versus 11.5% for placebo), dominated by fluid overload and congestive heart failure; death occurred in 21 (4.6%; P = 0.225), 17 (3.6%; P = 0.194), and 12 (2.6%), respectively. In conclusion, avosentan reduces albuminuria when added to standard treatment in people with type 2 diabetes and overt nephropathy but induces significant fluid overload and congestive heart failure.
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            Gametic disequilibrium measures: proceed with caution.

            Brandon P. Hedrick (1987)
            Five different measures of gametic disequilibrium in current use and a new one based on R. C. Lewontin's D', are examined and compared. All of them, except the measure based on Lewontin's D', are highly dependent upon allelic frequencies, including four measures that are normalized in some manner. In addition, the measures suggested by A. H. D. Brown, M. F. Feldman and E. Nevo, and T. Ohta can have negative values when there is maximum disequilibrium and have rates of decay in infinite populations that are a function of the initial gametic array. The variances were large for all the measures in samples taken from populations at equilibrium under neutrality, with the measure based on D' having the lowest variance. In these samples, three of the measures were highly correlated, D2, D (equal to the correlation coefficient when there are two alleles at each locus) and the measure X(2) of Brown et al. Using frequency-dependent measures may result in mistaken conclusions, a fact illustrated by discussion of studies inferring recombinational hot spots and the effects of population bottlenecks from disequilibrium values.
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              The risk of cardiovascular disease mortality associated with microalbuminuria and gross proteinuria in persons with older-onset diabetes mellitus.

              John Klein, Marina Klein, S Moss … (2000)
              Despite the numerous studies on the relation of albuminuria with increased risk of all-cause mortality in type 2 diabetes mellitus, it remains uncertain whether microalbuminuria and/or gross proteinuria are independent risk factors for cardiovascular mortality. Moreover, the association of albuminuria with cardiovascular mortality in people with type 2 diabetes mellitus has not been well described in US populations. To estimate the relative risks (RRs) for the associations of microalbuminuria and gross proteinuria with cardiovascular disease mortality among persons with older-onset diabetes mellitus. We conducted a prospective cohort study of 840 people with older-onset diabetes mellitus who provided urine samples in the 1984-1986 examination of a population-based study of diabetic persons. The presence of microalbuminuria was determined by an agglutination inhibition assay and gross proteinuria by a reagent strip. The main outcome was time to mortality from cardiovascular disease, as determined from death certificates. Of the 840 older-onset diabetic persons, 54.8% had normoalbuminuria, while 24.8% had microalbuminuria and 20.5% had gross proteinuria. During the 12-year follow-up (6127 person-years), we identified 364 deaths from cardiovascular disease. Compared with persons with normoalbuminuria, those with microalbuminuria and gross proteinuria had significantly higher risks of cardiovascular mortality. The RR as controlled for age, sex, glycemic control, insulin use, alcohol intake, physical activity, cardiovascular disease history, antihypertensive use, and retinopathy severity, was 1.84 (95% confidence interval [CI], 1.42-2.40) for those with microalbuminuria and 2.61 (95% CI, 1.99-3.43) for those with gross proteinuria. Further adjustment for other factors did not change the relations we found. When the end point used was mortality from coronary heart disease, stroke, or all causes, the increased risks were significant for both microalbuminuria (adjusted RRs [95% CIs], 1.96 [1.42-2.72], 2.20 [1.29-3.75], and 1.68 [1.35-2.09], respectively) and gross proteinuria (adjusted RRs [95% CIs], 2.73 [1.95-3.81], 2.33 [1.28-4.24], and 2.47 [1.97-3.10], respectively). Results from our population-based study strongly suggest that both microalbuminuria and gross proteinuria were significantly associated with subsequent mortality from all causes and from cardiovascular, cerebrovascular, and coronary heart diseases. These associations were independent of known cardiovascular risk factors and diabetes-related variables.
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                Author and article information

                Contributors
                Claudete M. Zanatta: claudetemz@hotmail.com
                Daisy Crispim: dcmoreira@hcpa.edu.br
                Denise A. Sortica: denisefarm@hotmail.com
                Lucas P. Klassmann: lucaspk@hotmail.com
                Jorge L. Gross: jorgeluizgross@gmail.com
                Fernando Gerchman: fgerchman@gmail.com
                Luís H. Canani: +55 51 33598127 , luiscanani@yahoo.com , luishenriquecanani@gmail.com
                Journal
                Journal ID (nlm-ta): Diabetol Metab Syndr
                Journal ID (iso-abbrev): Diabetol Metab Syndr
                Title: Diabetology & Metabolic Syndrome
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1758-5996
                Publication date (Electronic): 19 November 2015
                Publication date PMC-release: 19 November 2015
                Publication date Collection: 2015
                Volume: 7
                Electronic Location Identifier: 103
                Affiliations
                [ ]Federal University of Rio Grande do Sul, Porto Alegre, Brazil
                [ ]Endocrine Division, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, RS Brazil
                Article
                Publisher ID: 93
                DOI: 10.1186/s13098-015-0093-5
                PMC ID: 4653842
                PubMed ID: 26594247
                SO-VID: 8bf14df9-f7ec-4ef1-9efb-d07f8e660706
                Copyright © © Zanatta et al. 2015
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 8 April 2015
                Date accepted : 2 November 2015
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2015

                ScienceOpen disciplines: Nutrition & Dietetics
                Keywords: endothelin-1,diabetic kidney disease,diabetes mellitus type 2
                Data availability:
                ScienceOpen disciplines: Nutrition & Dietetics
                Keywords: endothelin-1, diabetic kidney disease, diabetes mellitus type 2

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