A GREM1 Gene Variant Associates with Diabetic Nephropathy (original) (raw)
Related papers
Metabolism, 2009
Several novel genes that are up regulated in the kidney in diabetes have been identified including GREM1, which encodes gremlin 1. GREM1 maps to human chromosome 15q12, a region previously found to be linked to albumin to creatinine ratio (ACR) in Mexican Americans. The objective of this study is to investigate whether genetic variants in GREM1, a positional candidate gene, contribute to variation in ACR. By sequencing 32 individuals for both exons and 2 kb putative promoter region of GREM1, we identified 19 genetic variants including 5 in the promoter region and 13 in the 3′UTR. Of 19 polymorphisms identified, 13 polymorphisms were genotyped in the entire cohort (N=670; 39 large families) either by restriction fragment length polymorphism or by TaqMan Assays. Association analyses between the genotypes and ACR, type 2 diabetes and related phenotypes were carried out using a measured genotype approach as implemented in the variance component analytical tools (SOLAR). Of the variants examined for association, none exhibited statistically significant association with ACR after accounting for the effects of covariates such as age, sex, diabetes, duration of diabetes, systolic blood pressure and antihypertensive medications. However, two novel variants at the 3′ UTR showed significant association with estimated glomerular filtration rate (P = 0.010 and P = 0.049) and body mass index (P = 0.013 and P = 0.019) after accounting for trait-specific covariate influences. Also, a novel variant located in the promoter exhibited a significant association with systolic (P = 0.038)
Genetics of diabetic nephropathy
Arquivos Brasileiros de Endocrinologia & Metabologia, 2010
The increasing prevalence of diabetes mellitus has led to a growing number of chronic complications including diabetic nephropathy (DN). In addition to its high prevalence, DN is associated with high morbidity and mortality especially due to cardiovascular diseases. It is well established that genetic factors play a role in the pathogenesis of DN and genetically susceptible individuals can develop it after being exposed to environmental factors. DN is probably a complex, polygenic disease. Two main strategies have been used to identify genes associated to DN: analysis of candidate genes, and more recently genome-wide scan. Great efforts have been made to identify these main genes, but results are still inconsistent with different genes associated to a small effect in specific populations. The identification of the main genes would allow the detection of those individuals at high risk for DN and better understanding of its pathophysiology as well.
Erratum to: Genetic associations in diabetic nephropathy: a meta-analysis
Diabetologia, 2014
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.
Allelic Depletion of grem1 Attenuates Diabetic Kidney Disease
Diabetes, 2009
OBJECTIVE Gremlin (grem1) is an antagonist of the bone morphogenetic protein family that plays a key role in limb bud development and kidney formation. There is a growing appreciation that altered grem1 expression may regulate the homeostatic constraints on damage responses in diseases such as diabetic nephropathy. RESEARCH DESIGN AND METHODS Here we explored whether knockout mice heterozygous for grem1 gene deletion (grem1+/−) exhibit protection from the progression of diabetic kidney disease in a streptozotocin-induced model of type 1 diabetes. RESULTS A marked elevation in grem1 expression was detected in the kidneys and particularly in kidney tubules of diabetic wild-type mice compared with those of littermate controls. In contrast, diabetic grem1+/− mice displayed a significant attenuation in grem1 expression at 6 months of diabetes compared with that in age- and sex-matched wild-type controls. Whereas the onset and induction of diabetes were similar between grem1+/− and wild-t...
Gene for susceptibility to diabetic nephropathy in type 2 diabetes maps to 18q22.3-23
Kidney International, 2002
Gene for susceptibility to diabetic nephropathy in type 2 diabethy, the diabetes-related loss of kidney function, is one tes maps to 18q22.3-23. of the major complications of diabetes. Diabetic nephrop-Background. Diabetic nephropathy is the major cause of athy is characterized by persistent proteinuria, that is, end-stage renal failure in patients with diabetes mellitus types 1 the presence of protein in the urine. The incidence of and 2. Epidemiological studies have suggested a genetic susceptithis complication peaks during the second decade of bility to diabetic nephropathy. The aim of this study was to localize the gene(s) responsible for susceptibility to diabetic nephropathy. diabetes mellitus type 1 and declines thereafter [2, 3]. Methods. A genetic linkage analysis was performed in 18 Diabetic nephropathy is the major cause of end-stage large Turkish families with type 2 diabetes mellitus and diabetic renal failure in the Western world. nephropathy. The result was checked in 101 affected sibling pairs Despite often poorly controlled blood glucose concenof Pima Indians. Results. A highly significant LOD score of 6.1 on chromotrations, a major subgroup of patients with type 1 [2, 4-6] some 18q22.3-23 between the markers D18S469 and D18S58 or type 2 diabetes mellitus never develops nephropathy was obtained in multipoint analysis. There was no indication [6, 7]. This observation and the clustering of diabetic for locus heterogeneity. In Pima Indians, linkage to the markers nephropathy in families with type 1 [8, 9] and type 2 D18S469 and D18S58 was confirmed (P ϭ 0.033), using the [10, 11] diabetes suggest that only a subset of diabetic affected sib-pair method. The genetic model that fit best was a dominant mode of inheritance with an almost complete penepatients is susceptible to the development of diabetic tration in the Turkish population. nephropathy. Besides a genetic susceptibility to diabetes Conclusions. There is strong evidence for the localization mellitus there may be one or more other (modifier) genes of a gene responsible for diabetic nephropathy in Turkish type 2 for the susceptibility to diabetic nephropathy. Seaquist diabetes mellitus patients. This locus maps to chromosome 18q22.3-23, between D18S43 and D18S50, an interval of 8.5 cM.
Genetics of Diabetic Nephropathy: Lessons From Mice
Seminars in Nephrology, 2007
Although diabetic nephropathy occurs only in a minority of diabetic patients (ϳ30%), it is the major single cause of end-stage renal disease in the United States. Hyperglycemia and hypertension are important factors predisposing patients to nephropathy, however, accumulating evidence points to critical genetic factors that predispose only a subset of diabetic patients to nephropathy. Defining the genes responsible for nephropathy risk in human populations has proven challenging. Comparative genomics using the robust genetic reagents available in the laboratory mouse should provide a complementary approach to defining genes that may predispose to diabetic nephropathy in mice and human beings. In this article we review studies that have started to identify genetic risk factors for diabetic nephropathy in mice and the multiple approaches that may be used to elucidate the genetic pathogenesis of this disorder. Semin Nephrol 27:237-247 . Age-matched controls for MRL/MpJ and FVB/NJ strains were not available (NA) for studying. *P Ͻ .05 (t test) versus age-matched controls; § P Ͻ .05 (ANOVA) versus diabetic C57BL/6J, A/J, and MRL/MpJ strains; ʈ P Ͻ .05 (ANOVA) versus controls in other studied strains.
Diabetes, 2005
To search for a gene(s) conferring susceptibility to diabetic nephropathy (DN), we genotyped over 80,000 genebased single nucleotide polymorphisms (SNPs) in Japanese patients and identified that the engulfment and cell motility 1 gene (ELMO1) was a likely candidate for conferring susceptibility to DN, in view of the significant association of an SNP in this gene with the disease (intron 18؉9170, GG vs. GA؉AA, 2 ؍ 19.9, P ؍ 0.000008; odds ratio 2.67, 95% CI 1.71-4.16). In situ hybridization (ISH) using the kidney of normal and diabetic mice revealed that ELMO1 expression was weakly detectable mainly in tubular and glomerular epithelial cells in normal mouse kidney and was clearly elevated in the kidney of diabetic mice.