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      Genetic associations in diabetic nephropathy: a meta-analysis

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          Abstract

          Aims/hypothesis

          This meta-analysis assessed the pooled effect of each genetic variant reproducibly associated with diabetic nephropathy.

          Methods

          PubMed, EMBASE and Web of Science were searched for articles assessing the association between genes and diabetic nephropathy. All genetic variants statistically associated with diabetic nephropathy in an initial study, then independently reproduced in at least one additional study, were selected. Subsequently, all studies assessing these variants were included. The association between these variants and diabetic nephropathy (defined as macroalbuminuria/proteinuria or end-stage renal disease [ESRD]) was calculated at the allele level and the main measure of effect was a pooled odds ratio. Pre-specified subgroup analyses were performed, stratifying for type 1/type 2 diabetes mellitus, proteinuria/ESRD and ethnic group.

          Results

          The literature search yielded 3,455 citations, of which 671 were genetic association studies investigating diabetic nephropathy. We identified 34 replicated genetic variants. Of these, 21 remained significantly associated with diabetic nephropathy in a random-effects meta-analysis. These variants were in or near the following genes: ACE, AKR1B1 (two variants), APOC1, APOE, EPO, NOS3 (two variants), HSPG2, VEGFA, FRMD3 (two variants), CARS (two variants), UNC13B, CPVL and CHN2, and GREM1, plus four variants not near genes. The odds ratios of associated genetic variants ranged from 0.48 to 1.70. Additional variants were detected in subgroup analyses: ELMO1 (Asians), CCR5 (Asians) and CNDP1 (type 2 diabetes).

          Conclusions/interpretation

          This meta-analysis found 24 genetic variants associated with diabetic nephropathy. The relative contribution and relevance of the identified genes in the pathogenesis of diabetic nephropathy should be the focus of future studies.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s00125-010-1996-1) contains supplementary material, which is available to authorised users.

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          Most cited references15

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          Genome-wide association studies for complex traits: consensus, uncertainty and challenges.

          Mark McCarthy, Gonçalo R Abecasis, Lon Cardon … (2008)
          The past year has witnessed substantial advances in understanding the genetic basis of many common phenotypes of biomedical importance. These advances have been the result of systematic, well-powered, genome-wide surveys exploring the relationships between common sequence variation and disease predisposition. This approach has revealed over 50 disease-susceptibility loci and has provided insights into the allelic architecture of multifactorial traits. At the same time, much has been learned about the successful prosecution of association studies on such a scale. This Review highlights the knowledge gained, defines areas of emerging consensus, and describes the challenges that remain as researchers seek to obtain more complete descriptions of the susceptibility architecture of biomedical traits of interest and to translate the information gathered into improvements in clinical management.
          Article 0 comments Cited 810 times – based on 0 reviews     Review now
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            Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease.

            Kirk Lohmueller, Celeste Pearce, Malcolm C. Pike … (2003)
            Association studies offer a potentially powerful approach to identify genetic variants that influence susceptibility to common disease, but are plagued by the impression that they are not consistently reproducible. In principle, the inconsistency may be due to false positive studies, false negative studies or true variability in association among different populations. The critical question is whether false positives overwhelmingly explain the inconsistency. We analyzed 301 published studies covering 25 different reported associations. There was a large excess of studies replicating the first positive reports, inconsistent with the hypothesis of no true positive associations (P < 10(-14)). This excess of replications could not be reasonably explained by publication bias and was concentrated among 11 of the 25 associations. For 8 of these 11 associations, pooled analysis of follow-up studies yielded statistically significant replication of the first report, with modest estimated genetic effects. Thus, a sizable fraction (but under half) of reported associations have strong evidence of replication; for these, false negative, underpowered studies probably contribute to inconsistent replication. We conclude that there are probably many common variants in the human genome with modest but real effects on common disease risk, and that studies using large samples will convincingly identify such variants.
            Article 0 comments Cited 310 times – based on 0 reviews     Review now
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              Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy.

              Maria Barbosa, F C Goetz, Elizabeth Seaquist … (1989)
              Diabetic nephropathy develops in less than half of all patients with diabetes. To study heredity as a possible risk factor for diabetic kidney disease, we examined the concordance rates for diabetic nephropathy in two sets of families in which both probands and siblings had diabetes mellitus. In one set, the probands (n = 11) had no evidence of diabetic nephropathy, with normal creatinine clearance and a urinary albumin excretion rate below 45 mg per day. In the other set, the probands (n = 26) had undergone kidney transplantation because of diabetic nephropathy. Evidence of nephropathy was found in 2 of the 12 diabetic siblings of the probands without nephropathy (17 percent). Of the 29 diabetic siblings of probands with diabetic nephropathy, 24 (83 percent) had evidence of nephropathy (P less than 0.001), including 12 with end-stage renal disease. No significant differences were noted between the sibling groups with respect to the duration of diabetes, blood pressure, glycemic control, or glycosylated hemoglobin levels. Logistic regression analysis found nephropathy in the proband to be the only factor significantly predictive of the renal status of the diabetic sibling. We conclude that diabetic nephropathy occurs in familial clusters. This is consistent with the hypothesis that heredity helps to determine susceptibility to diabetic nephropathy. However, this study cannot rule out the possible influences of environmental factors shared by siblings.
              Article 0 comments Cited 121 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                : a.l.mooyaart@lumc.nl
                Journal
                Journal ID (nlm-ta): Diabetologia
                Title: Diabetologia
                Publisher: Springer-Verlag (Berlin/Heidelberg )
                ISSN (Print): 0012-186X
                ISSN (Electronic): 1432-0428
                Publication date (Electronic): 3 December 2010
                Publication date PMC-release: 3 December 2010
                Publication date (Print): March 2011
                Volume: 54
                Issue: 3
                Pages: 544-553
                Affiliations
                [1 ]Department of Pathology, Bldg.1, L1-Q, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands
                [2 ]Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands
                [3 ]Section on Nephrology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC USA
                [4 ]Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
                [5 ]Department of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands
                Article
                Publisher ID: 1996
                DOI: 10.1007/s00125-010-1996-1
                PMC ID: 3034040
                PubMed ID: 21127830
                SO-VID: 803f1375-b2a3-406d-91a5-df674ce639de
                Copyright © © The Author(s) 2010
                History
                Date received : 20 July 2010
                Date accepted : 26 October 2010
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © Springer-Verlag 2011

                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: genetic association studies,meta-analysis,genetic polymorphism,diabetic nephropathy,diabetes mellitus
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: genetic association studies, meta-analysis, genetic polymorphism, diabetic nephropathy, diabetes mellitus

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