Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To search for a gene(s) conferring susceptibility to diabetic nephropathy (DN), we genotyped over 80,000 gene-based 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, chi(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. Subsequent in vitro analysis revealed that ELMO1 expression was elevated in cells cultured under high glucose conditions (25 mmol/l) compared with cells cultured under normal glucose conditions (5.5 mmol/l). Furthermore, we identified that the expression of extracellular matrix protein genes, such as type 1 collagen and fibronectin, were increased in cells that overexpress ELMO1, whereas the expression of matrix metalloproteinases was decreased. These results indicate that ELMO1 is a novel candidate gene that both confers susceptibility to DN and plays an important role in the development and progression of this disease.
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PMID:Genetic variations in the gene encoding ELMO1 are associated with susceptibility to diabetic nephropathy. 1579 58

We have previously identified the engulfment and cell motility 1 (ELMO1) as a susceptibility gene for diabetic nephropathy. To elucidate the role of ELMO1 in the pathogenesis of chronic renal injury, we examined the expression of Elmo1 in the kidney of a rat model for chronic glomerulonephritis (uninephrectomy plus anti-Thy1.1 antibody [E30] injection). We found that the expression of the Elmo1 was significantly increased in the renal cortex and glomeruli of uninephrectomized rats injected with E30 compared to controls. By in situ hybridization, the expression of Elmo1 was shown to be elevated in the diseased kidney, especially in glomerular epithelial cells. In COS cells, the overexpression of ELMO1 resulted in a substantial increase in fibronectin expression, whereas the depletion of the ELMO1 by small interfering RNA (siRNA) targeting ELMO1 significantly suppressed the fibronectin expression in ELMO1 overexpressing and control cells. We also found that the expression of integrin-linked kinase (ILK) was significantly increased in ELMO1 overexpressing cells, and the ELMO1-induced increase in fibronectin was partially, but significantly, inhibited by siRNA targeting ILK. Furthermore, we identified that the cell adhesion to ECMs was considerably inhibited in cells overexpressing ELMO1. These results suggest that the ELMO1 contributes to the development and progression of chronic glomerular injury through the dysregulation of ECM metabolism and the reduction in cell adhesive properties to ECMs.
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PMID:ELMO1 increases expression of extracellular matrix proteins and inhibits cell adhesion to ECMs. 1702

Approximately 30% of individuals with type 1 and type 2 diabetes develop persistent albuminuria, lose renal function, and are at increased risk for cardiovascular and other microvascular complications. Diabetes and kidney diseases rank within the top 10 causes of death in Westernized countries and cause significant morbidity. Given these observations, genetic, genomic, and proteomic investigations have been initiated to better define basic mechanisms for disease initiation and progression, to identify individuals at risk for diabetic complications, and to develop more efficacious therapies. In this review we have focused on linkage analyses of candidate genes or chromosomal regions, or coarse genome-wide scans, which have mapped either categorical (chronic kidney disease or end-stage renal disease) or quantitative kidney traits (albuminuria/proteinuria or glomerular filtration rate). Most loci identified to date have not been replicated, however, several linked chromosomal regions are concordant between independent samples, suggesting the presence of a diabetic nephropathy gene. Two genes, carnosinase (CNDP1) on 18q, and engulfment and cell motility 1 (ELMO1) on 7p14, have been identified as diabetic nephropathy susceptibility genes, but these results require authentication. The availability of patient data sets with large sample sizes, improvements in informatics, genotyping technology, and statistical methodologies should accelerate the discovery of valid diabetic nephropathy susceptibility genes.
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PMID:Mining the genome for susceptibility to diabetic nephropathy: the role of large-scale studies and consortia. 1741 89

Genetic susceptibility plays an important role in the pathogenesis of diabetic nephropathy and type II diabetes. To identify the genetic polymorphisms associated with diabetic nephropathy and type II diabetes, we performed a genome-wide association study using single-nucleotide polymorphisms as genetic markers. We also analyzed polymorphisms within the genes encoding for the renin-angiotensin system that were considered as candidate genes for diabetic nephropathy susceptibility and the transcription factor 7-like 2 (TCF7L2) as a candidate for type II diabetes, in a large cohort of a Japanese population. A genome-wide association study identified SLC12A3 and engulfment and cell motility 1 gene as the new candidates for diabetic nephropathy and transcription factor-activating protein 2beta as a novel susceptibility gene for type II diabetes; this observation was based on the significant association between the polymorphisms within the genes and the corresponding diseases (P<0.0001). Further, we discovered that the genes encoding the angiotensin-converting enzyme, angiotensinogen, and angiotensin II type I receptor have a significant combinational effect on conferring susceptibility to diabetic nephropathy. Furthermore, TCF7L2 that has been reported as a convincing susceptibility gene for type II diabetes in Caucasian populations was also shown to be associated with type II diabetes in a Japanese population. These genes could be considered as strong susceptibility genes for diabetic nephropathy and type II diabetes in the Japanese, although the new candidates that have been identified by genome-wide screening need to be examined in greater detail by several replication studies.
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PMID:Genetic variations associated with diabetic nephropathy and type II diabetes in a Japanese population. 1765 10

Variants in the engulfment and cell motility 1 (ELMO1) gene are associated with nephropathy due to type 2 diabetes mellitus (T2DM) in a Japanese cohort. We comprehensively evaluated this gene in African American (AA) T2DM patients with end-stage renal disease (ESRD). Three hundred and nine HapMap tagging SNPs and 9 reportedly associated SNPs were genotyped in 577 AA T2DM-ESRD patients and 596 AA non-diabetic controls, plus 43 non-diabetic European American controls and 45 Yoruba Nigerian samples for admixture adjustment. Replication analyses were conducted in 558 AA with T2DM-ESRD and 564 controls without diabetes. Extension analyses included 328 AA with T2DM lacking nephropathy and 326 with non-diabetic ESRD. The original and replication analyses confirmed association with four SNPs in intron 13 (permutation p-values for combined analyses = 0.001-0.003), one in intron 1 (P = 0.004) and one in intron 5 (P = 0.002) with T2DM-associated ESRD. In a subsequent combined analysis of all 1,135 T2DM-ESRD cases and 1,160 controls, an additional 7 intron 13 SNPs produced evidence of association (P = 3.5 x 10(-5)- P = 0.05). No associations were seen with these SNPs in those with T2DM lacking nephropathy or with ESRD due to non-diabetic causes. Variants in intron 13 of the ELMO1 gene appear to confer risk for diabetic nephropathy in AA.
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PMID:Variants in intron 13 of the ELMO1 gene are associated with diabetic nephropathy in African Americans. 1918 47

Variants in the engulfment and cell motility 1 gene, ELMO1, have previously been associated with kidney disease attributed to type 2 diabetes. The Pima Indians of Arizona have high rates of diabetic nephropathy, which is strongly dependent on genetic determinants; thus, we sought to investigate the role of ELMO1 polymorphisms in mediating susceptibility to this disease in this population. Genotype distributions were compared among 141 individuals with nephropathy and 416 individuals without heavy proteinuria in a family study of 257 sibships, and 107 cases with diabetic ESRD and 108 controls with long duration diabetes and no nephropathy. We sequenced 17.4 kb of ELMO1 and identified 19 variants. We genotyped 12 markers, excluding those in 100% genotypic concordance with other variants or with a minor allele frequency <0.05, plus 21 additional markers showing association with ESRD in earlier studies. In the family study, the strongest evidence for association was with rs1345365 (odds ratio [OR]=2.42 per copy of A allele [1.35-4.32]; P=0.001) and rs10951509 (OR=2.42 per copy of A allele [1.31-4.48]; P=0.002), both of which are located in intron 13 and are in strong pairwise linkage disequilibrium (r(2)=0.97). These associations were in the opposite direction from those observed in African Americans, which suggests that the relationship between diabetic kidney disease and ELMO1 variation may involve as yet undiscovered functional variants or complex interactions with other biological variables.
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PMID:ELMO1 variants and susceptibility to diabetic nephropathy in American Indians. 2082