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Examination of association with candidate genes for diabetic nephropathy in a Mexican American population.

ABSTRACT: Diabetic nephropathy (DN) is a multifactorial complication characterized by persistent proteinuria in susceptible individuals with type 1 and type 2 diabetes. Disease burden in people of Mexican-American descent is particularly high, but there are only a few studies that characterize genes for DN in this ethnic group. Two genes, carnosine dipeptidase 1 (CNDP1) and engulfment and cell motility 1 (ELMO1) previously showed association with DN in other ethnic groups. CNDP1 and ELMO1 were examined along with eight other genes that are less well characterized for DN in a new study of Mexican-Americans.The target sample was patients of Mexican-American ancestry collected from three centers: 455 patients with DN and 437 controls with long-term diabetes but no incident nephropathy. Forty-two, 227, and 401 single nucleotide polymorphisms (SNPs) in CNDP1, ELMO1, and the other eight genes, respectively, were examined.No region in CNDP1 or ELMO1 showed significant P values. Of the other eight candidate genes, an association of DN with a SNP pair, rs2146098 and rs6659783, was found in hemicentin 1 (HMCN1) (unadjusted P = 6.1 x 10(-5)). Association with a rare haplotype in this region was subsequently identified.The associations in CNDP1 or ELMO1 were not replicable; however, an association of DN with HMCN1 was found. Additional work at this and other loci will enable refinement of the genetic hypotheses regarding DN in the Mexican-American population to find therapies for this debilitating disease.

SUBMITTER: Kim S

PROVIDER: S-EPMC2879299 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Examination of association with candidate genes for diabetic nephropathy in a Mexican American population.

Kim Sulgi S Abboud Hanna E HE Pahl Madeleine V MV Tayek John J Snyder Susan S Tamkin James J Alcorn Harry H Ipp Eli E Nast Cynthia C CC Elston Robert C RC Iyengar Sudha K SK Adler Sharon G SG

Clinical journal of the American Society of Nephrology : CJASN 20100318 6

<h4>Background and objectives</h4>Diabetic nephropathy (DN) is a multifactorial complication characterized by persistent proteinuria in susceptible individuals with type 1 and type 2 diabetes. Disease burden in people of Mexican-American descent is particularly high, but there are only a few studies that characterize genes for DN in this ethnic group. Two genes, carnosine dipeptidase 1 (CNDP1) and engulfment and cell motility 1 (ELMO1) previously showed association with DN in other ethnic groups ...[more]

PMID: 20299368

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Project description:Type 1 diabetes (T1D) increases risk of the development of microvascular complications and cardiovascular disease (CVD). Dyslipidemia is a common risk factor in the pathogenesis of both CVD and diabetic nephropathy (DN), with CVD identified as the primary cause of death in patients with DN. In light of this commonality, we assessed single nucleotide polymorphisms (SNPs) in thirty-seven key genetic loci previously associated with dyslipidemia in a T1D cohort using a case-control design. SNPs (n = 53) were genotyped using Sequenom in 1467 individuals with T1D (718 cases with proteinuric nephropathy and 749 controls without nephropathy i.e. normal albumin excretion). Cases and controls were white and recruited from the UK and Ireland. Association analyses were performed using PLINK to compare allele frequencies in cases and controls. In a sensitivity analysis, samples from control individuals with reduced renal function (estimated glomerular filtration rate<60 ml/min/1.73 m(2)) were excluded. Correction for multiple testing was performed by permutation testing. A total of 1394 samples passed quality control filters. Following regression analysis adjusted by collection center, gender, duration of diabetes, and average HbA1c, two SNPs were significantly associated with DN. rs4420638 in the APOC1 region (odds ratio [OR] = 1.51; confidence intervals [CI]: 1.19-1.91; P = 0.001) and rs1532624 in CETP (OR = 0.82; CI: 0.69-0.99; P = 0.034); rs4420638 was also significantly associated in a sensitivity analysis (P = 0.016) together with rs7679 (P = 0.027). However, no association was significant following correction for multiple testing. Subgroup analysis of end-stage renal disease status failed to reveal any association. Our results suggest common variants associated with dyslipidemia are not strongly associated with DN in T1D among white individuals. Our findings, cannot entirely exclude these key genes which are central to the process of dyslipidemia, from involvement in DN pathogenesis as our study had limited power to detect variants of small effect size. Analysis in larger independent cohorts is required.

Project description:Aims/hypothesisSeveral studies have provided compelling evidence implicating the Wnt signalling pathway in the pathogenesis of diabetic nephropathy. Gene expression profiles associated with renal fibrosis have been attenuated through Wnt pathway modulation in model systems implicating Wnt pathway members as potential therapeutic targets for the treatment of diabetic nephropathy. We assessed tag and potentially functional single nucleotide polymorphisms (SNPs; n = 31) in four key Wnt pathway genes (CTNNB1, AXIN2, LRP5 and LRP6) for association with diabetic nephropathy using a case-control design.MethodsSNPs were genotyped using Sequenom or Taqman technologies in 1351 individuals with type 1 diabetes (651 cases with nephropathy and 700 controls without nephropathy). Cases and controls were white and recruited from the UK and Ireland. Association analyses were performed using PLINK, to compare allele and haplotype frequencies in cases and controls. Adjustment for multiple testing was performed by permutation testing.ResultsFollowing logistic regression analysis adjusted by collection centre, duration of T1D, and average HbA1c as covariates, a single SNP in LRP6 (rs1337791) was significantly associated with DN (OR = 0.74; CI: 0.57-0.97; P = 0.028), although this was not maintained following correction for multiple testing. Three additional SNPs (rs2075241 in LRP6; rs3736228 and rs491347 both in LRP5) were marginally associated with diabetic nephropathy, but none of the associations were replicated in an independent dataset. Haplotype and subgroup analysis (according to duration of diabetes, and end-stage renal disease) also failed to reveal an association with diabetic nephropathy.Conclusions/interpretationOur results suggest that analysed common variants in CTNNB1, AXIN2, LRP5 and LRP6 are not strongly associated with diabetic nephropathy in type 1 diabetes among white individuals. Our findings, however, cannot entirely exclude these genes or other members of the Wnt pathway, from involvement in the pathogenesis of diabetic nephropathy as our study had limited power to detect variants with small effect size.

Project description:BackgroundDiabetic nephropathy (DN), the most intractable complication in diabetes patients, can lead to proteinuria and progressive reduction of glomerular filtration rate (GFR), which seriously affects the quality of life of patients and is associated with high mortality. However, the lack of accurate key candidate genes makes diagnosis of DN very difficult. This study aimed to identify new potential candidate genes for DN using bioinformatics, and elucidated the mechanism of DN at the cellular transcriptional level.MethodsThe microarray dataset GSE30529 was downloaded from the Gene Expression Omnibus Database (GEO), and the differentially expressed genes (DEGs) were screened by R software. We used Gene Ontology (GO), gene set enrichment analysis (GSEA), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to identify the signal pathways and genes. Protein-protein interaction (PPI) networks were constructed using the STRING database. The GSE30122 dataset was selected as the validation set. Receiver operating characteristic (ROC) curves were applied to evaluate the predictive value of genes. An area under curve (AUC) greater than 0.85 was considered to be of high diagnostic value. Several online databases were used to predict miRNAs and transcription factors (TFs) capable of binding hub genes. Cytoscape was used for constructing a miRNA-mRNA-TF network. The online database 'nephroseq' predicted the correlation between genes and kidney function. The serum level of creatinine, BUN, and albumin, and the urinary protein/creatinine ratio of the DN rat model were detected. The expression of hub genes was further verified through qPCR. Data were analyzed statistically using Student's t-test by the 'ggpubr' package.ResultsA total of 463 DEGs were identified from GSE30529. According to enrichment analysis, DEGs were mainly enriched in the immune response, coagulation cascades, and cytokine signaling pathways. Twenty hub genes with the highest connectivity and several gene cluster modules were ensured using Cytoscape. Five high diagnostic hub genes were selected and verified by GSE30122. The MiRNA-mRNA-TF network suggested a potential RNA regulatory relationship. Hub gene expression was positively correlated with kidney injury. The level of serum creatinine and BUN in the DN group was higher than in the control group (unpaired t test, t = 3.391, df = 4, p = 0.0275, r = 0.861). Meanwhile, the DN group had a higher urinary protein/creatinine ratio (unpaired t test, t = 17.23, df = 16, p < 0.001, r = 0.974). QPCR results showed that the potential candidate genes for DN diagnosis included C1QB, ITGAM, and ITGB2.ConclusionsWe identified C1QB, ITGAM and ITGB2 as potential candidate genes for DN diagnosis and therapy and provided insight into the mechanisms of DN development at transcriptome level. We further completed the construction of miRNA-mRNA-TF network to propose potential RNA regulatory pathways adjusting disease progression in DN.

Dataset Information

Examination of association with candidate genes for diabetic nephropathy in a Mexican American population.

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Examination of association with candidate genes for diabetic nephropathy in a Mexican American population.

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