ORCID Profile
0000-0001-8816-6862
Current Organisation
University of California, San Diego
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Publisher: Springer Science and Business Media LLC
Date: 07-2015
DOI: 10.1038/NATURE14618
Publisher: American Diabetes Association
Date: 17-07-2012
DOI: 10.2337/DB11-0751
Abstract: We formed the GEnetics of Nephropathy–an International Effort (GENIE) consortium to examine previously reported genetic associations with diabetic nephropathy (DN) in type 1 diabetes. GENIE consists of 6,366 similarly ascertained participants of European ancestry with type 1 diabetes, with and without DN, from the All Ireland-Warren 3-Genetics of Kidneys in Diabetes U.K. and Republic of Ireland (U.K.-R.O.I.) collection and the Finnish Diabetic Nephropathy Study (FinnDiane), combined with reanalyzed data from the Genetics of Kidneys in Diabetes U.S. Study (U.S. GoKinD). We found little evidence for the association of the EPO promoter polymorphism, rs161740, with the combined phenotype of proliferative retinopathy and end-stage renal disease in U.K.-R.O.I. (odds ratio [OR] 1.14, P = 0.19) or FinnDiane (OR 1.06, P = 0.60). However, a fixed-effects meta-analysis that included the previously reported cohorts retained a genome-wide significant association with that phenotype (OR 1.31, P = 2 × 10−9). An expanded investigation of the ELMO1 locus and genetic regions reported to be associated with DN in the U.S. GoKinD yielded only nominal statistical significance for these loci. Finally, top candidates identified in a recent meta-analysis failed to reach genome-wide significance. In conclusion, we were unable to replicate most of the previously reported genetic associations for DN, and significance for the EPO promoter association was attenuated.
Publisher: Springer Science and Business Media LLC
Date: 28-06-2022
DOI: 10.1007/S00125-022-05735-0
Abstract: Diabetic kidney disease (DKD) is the leading cause of kidney failure and has a substantial genetic component. Our aim was to identify novel genetic factors and genes contributing to DKD by performing meta-analysis of previous genome-wide association studies (GWAS) on DKD and by integrating the results with renal transcriptomics datasets. We performed GWAS meta-analyses using ten phenotypic definitions of DKD, including nearly 27,000 in iduals with diabetes. Meta-analysis results were integrated with estimated quantitative trait locus data from human glomerular ( N =119) and tubular ( N =121) s les to perform transcriptome-wide association study. We also performed gene aggregate tests to jointly test all available common genetic markers within a gene, and combined the results with various kidney omics datasets. The meta-analysis identified a novel intronic variant (rs72831309) in the TENM2 gene associated with a lower risk of the combined chronic kidney disease (eGFR ml/min per 1.73 m 2 ) and DKD (microalbuminuria or worse) phenotype ( p =9.8×10 −9 although not withstanding correction for multiple testing, p .3×10 −9 ). Gene-level analysis identified ten genes associated with DKD ( COL20A1 , DCLK1 , EIF4E , PTPRN–RESP18 , GPR158 , INIP–SNX30 , LSM14A and MFF p .7×10 −6 ). Integration of GWAS with human glomerular and tubular expression data demonstrated higher tubular AKIRIN2 gene expression in in iduals with vs without DKD ( p =1.1×10 −6 ). The lead SNPs within six loci significantly altered DNA methylation of a nearby CpG site in kidneys ( p .5×10 −11 ). Expression of lead genes in kidney tubules or glomeruli correlated with relevant pathological phenotypes (e.g. TENM2 expression correlated positively with eGFR [ p =1.6×10 −8 ] and negatively with tubulointerstitial fibrosis [ p =2.0×10 −9 ], tubular DCLK1 expression correlated positively with fibrosis [ p =7.4×10 −16 ], and SNX30 expression correlated positively with eGFR [ p =5.8×10 −14 ] and negatively with fibrosis [ p .0×10 −16 ]). Altogether, the results point to novel genes contributing to the pathogenesis of DKD. The GWAS meta-analysis results can be accessed via the type 1 and type 2 diabetes (T1D and T2D, respectively) and Common Metabolic Diseases (CMD) Knowledge Portals, and downloaded on their respective download pages ( ownloads.html ownloads.html ownloads.html ).
Publisher: Springer Science and Business Media LLC
Date: 22-12-2022
DOI: 10.1038/S41467-022-34963-6
Abstract: Type 1 diabetes affects over nine million in iduals globally, with approximately 40% developing diabetic kidney disease. Emerging evidence suggests that epigenetic alterations, such as DNA methylation, are involved in diabetic kidney disease. Here we assess differences in blood-derived genome-wide DNA methylation associated with diabetic kidney disease in 1304 carefully characterised in iduals with type 1 diabetes and known renal status from two cohorts in the United Kingdom-Republic of Ireland and Finland. In the meta-analysis, we identify 32 differentially methylated CpGs in diabetic kidney disease in type 1 diabetes, 18 of which are located within genes differentially expressed in kidneys or correlated with pathological traits in diabetic kidney disease. We show that methylation at 21 of the 32 CpGs predict the development of kidney failure, extending the knowledge and potentially identifying in iduals at greater risk for diabetic kidney disease in type 1 diabetes.
Publisher: Public Library of Science (PLoS)
Date: 20-09-2012
Publisher: Springer Science and Business Media LLC
Date: 05-2021
DOI: 10.1186/S13148-021-01081-X
Abstract: A subset of in iduals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this exploratory investigation was to assess differences in blood-derived DNA methylation patterns between in iduals with T1DM-ESKD and in iduals with long-duration T1DM but no evidence of kidney disease upon repeated testing to identify potential blood-based biomarkers. Blood-derived DNA from in iduals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illumina’s Infinium MethylationEPIC BeadChip arrays ( n = 862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p ≤ × 10 –8 and fold change ± 2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM. Top-ranked genes within which several dmCpGs were located and supported by functional data with methylation look-ups in other cohorts include: AFF3, ARID5B, CUX1, ELMO1 , FKBP5 , HDAC4, ITGAL, LY9 , PIM1, RUNX3, SEPTIN9 and UPF3A . Top-ranked enrichment pathways included pathways in cancer, TGF-β signalling and Th17 cell differentiation. Epigenetic alterations provide a dynamic link between an in idual’s genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped in iduals has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in in iduals with T1DM.
Publisher: Public Library of Science (PLoS)
Date: 31-07-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-09-2019
Abstract: Although studies show that diabetic kidney disease has a heritable component, searches for the genetic determinants of this complication of diabetes have had limited success. In this study, a new international genomics consortium, the JDRF funded Diabetic Nephropathy Collaborative Research Initiative, assembled nearly 20,000 s les from participants with type 1 diabetes, with and without kidney disease. The authors found 16 new diabetic kidney disease–associated loci at genome-wide significance. The strongest signal centers on a protective missense coding variant at COL4A3 , a gene that encodes a component of the glomerular basement membrane that, when mutated, causes the progressive inherited nephropathy Alport syndrome. These GWAS-identified risk loci may provide insights into the pathogenesis of diabetic kidney disease and help identify potential biologic targets for prevention and treatment. Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown. To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function. Our GWAS meta-analysis included association results for up to 19,406 in iduals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain ( COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition ( BMP7) or renal biology ( COLEC11 and DDR1 ). The 16 diabetic kidney disease–associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.
Publisher: American Diabetes Association
Date: 25-08-2015
DOI: 10.2337/DB15-0254
Abstract: Obesity has been posited as an independent risk factor for diabetic kidney disease (DKD), but establishing causality from observational data is problematic. We aimed to test whether obesity is causally related to DKD using Mendelian randomization, which exploits the random assortment of genes during meiosis. In 6,049 subjects with type 1 diabetes, we used a weighted genetic risk score (GRS) comprised of 32 validated BMI loci as an instrument to test the relationship of BMI with macroalbuminuria, end-stage renal disease (ESRD), or DKD defined as presence of macroalbuminuria or ESRD. We compared these results with cross-sectional and longitudinal observational associations. Longitudinal analysis demonstrated a U-shaped relationship of BMI with development of macroalbuminuria, ESRD, or DKD over time. Cross-sectional observational analysis showed no association with overall DKD, higher odds of macroalbuminuria (for every 1 kg/m2 higher BMI, odds ratio [OR] 1.05, 95% CI 1.03–1.07, P & 0.001), and lower odds of ESRD (OR 0.95, 95% CI 0.93–0.97, P & 0.001). Mendelian randomization analysis showed a 1 kg/m2 higher BMI conferring an increased risk in macroalbuminuria (OR 1.28, 95% CI 1.11–1.45, P = 0.001), ESRD (OR 1.43, 95% CI 1.20–1.72, P & 0.001), and DKD (OR 1.33, 95% CI 1.17–1.51, P & 0.001). Our results provide genetic evidence for a causal link between obesity and DKD in type 1 diabetes. As obesity prevalence rises, this finding predicts an increase in DKD prevalence unless intervention should occur.
Publisher: Cold Spring Harbor Laboratory
Date: 19-12-2018
DOI: 10.1101/499616
Abstract: Diabetic kidney disease (DKD) is a heritable but poorly understood complication of diabetes. To identify genetic variants predisposing to DKD, we performed genome-wide association analyses in 19,406 in iduals with type 1 diabetes (T1D) using a spectrum of DKD definitions basedon albuminuria and renal function. We identified 16 genome-wide significant loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM) implicated in heritable nephropathies. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of DKD, including albuminuria and end-stage renal disease. Three other loci are in or near genes with known or suggestive involvement in DKD (BMP7) or renal biology ( COLEC11 and DDR1 ). The 16 DKD-associated loci provide novel insights into the pathogenesis of DKD, identifying potential biological targets for prevention and treatment.
Publisher: Springer Science and Business Media LLC
Date: 21-09-2022
DOI: 10.1038/S41380-022-01776-4
Abstract: Posttraumatic stress disorder (PTSD) is a heritable (h
Publisher: American Diabetes Association
Date: 27-04-2018
DOI: 10.2337/DB17-0914
Abstract: Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication s les, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10−8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased s le sizes will continue to provide more robust inference regarding risk variant discovery for DKD.
Publisher: Springer Science and Business Media LLC
Date: 02-12-2012
DOI: 10.1038/NG.2477
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14177
Publisher: Springer Science and Business Media LLC
Date: 08-04-2012
DOI: 10.1038/NG.2247
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14132
Publisher: Elsevier BV
Date: 04-2022
Location: United States of America
No related grants have been discovered for Rany Salem.