Association of the distal region of the ectonucteotide pyrophosphatase/phosphodiesterase 1 gene with type 2 diabetes in an African-American population enriched for nephropathy
ABSTRACT Variants in the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene have shown positive associations with diabetes and related phenotypes, including insulin resistance, metabolic syndrome, and type 1 diabetic nephropathy. Additionally, evidence for linkage for type 2 diabetes in African Americans was observed at 6q24-27, with the proximal edge of the peak encompassing the ENPP1 gene. Our objective was to comprehensively evaluate variants in ENPP1 for association with type 2 diabetic end-stage renal disease (ESRD).
Forty-nine single nucleotide polymorphisms (SNPs) located in the coding and flanking regions of ENPP1 were genotyped in 577 African-American individuals with type 2 diabetic ESRD and 596 African-American control subjects. Haplotypic association and genotypic association for the dominant, additive, and recessive models were tested by calculating a chi(2) statistic and corresponding P value.
Nine SNPs showed nominal evidence for association (P < 0.05) with type 2 diabetic ESRD in one or more genotypic model. The most significant associations were observed with rs7754586 (P = 0.003 dominant model, P = 0.0005 additive, and P = 0.007 recessive), located in the 3' untranslated region, and an intron 24 SNP (rs1974201: P = 0.004 dominant, P = 0.0005 additive, and P = 0.005 recessive). However, the extensively studied K121Q variant (rs1044498) did not reveal evidence for association with type 2 diabetic ESRD in this African-American population.
This study was the first to comprehensively evaluate variants of the ENPP1 gene for association in an African-American population with type 2 diabetes and ESRD and suggests that variants in the distal region of the ENPP1 gene may contribute to diabetes or diabetic nephropathy susceptibility in African Americans.
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ABSTRACT: Les complications cardiovasculaires (CCV) sont les causes les plus fréquentes de mortalité chez les patients ayant le diabète de type 2 (DT2). Cependant, les déterminants physiopathologiques et les mécanismes moléculaires impliqués dans la progression des CCV liées au DT2 sont mal compris. Nous avons entrepris de cerner quelques déterminants génétiques et cliniques des CCV par une approche multidisciplinaire unique impliquant des investigateurs canadiens et finlandais. Nous étudions les nouveaux modèles animaux combinant l’athérosclérose, l’obésité induite par l’alimentation et le DT2 pour comprendre les bases moléculaires des CCV du DT2 lié à l’obésité. Nous menons également des études cliniques pour cerner les principaux déterminants des CCV chez les patients ayant le DT2 et pour déterminer si un programme de modification du mode de vie ciblant la perte de tissu adipeux viscéral et de graisse ectopique pourrait être associée à des avantages cliniques chez ces patients. Ensemble, nous croyons fermement que nous pourrons combler certaines lacunes en matière de compréhension de la pathogenèse des CCV liées au DT2 et trouver de nouvelles cibles thérapeutiques, et nous espérons que ces nouvelles connaissances pourront mener à l’élaboration d’interventions cliniques efficaces destinées à réduire de manière optimale le risque cardiovasculaire chez les sujets ayant le DT2.Canadian Journal of Diabetes 10/2013; 37(5):351–358. DOI:10.1016/j.jcjd.2013.08.262 · 0.46 Impact Factor
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ABSTRACT: MicroRNAs (miRNAs) are important endogenous regulators in eukaryotic gene expression and a broad range of biological processes. MicroRNA-related genetic variations have been proved to be associated with human diseases such as type 2 diabetes mellitus (T2DM). Polymorphisms in microRNA genes (primary microRNAs, precursor microRNAs, mature microRNAs and microRNA regulatory regions) may be involved in the development of T2DM by changing the expression and structure of microRNAs and target gene expression. The genetic polymorphisms of 3'untranslated region (UTR) in microRNA target genes may destroy putative microRNA binding sites or create new microRNA binding sites, which affect the binding of untranslated region with microRNAs, finally result in the susceptibility and development of T2DM. Therefore, focusing on studies on genetic polymorphisms in microRNAs or microRNA binding sites are helpful for understanding the pathophysiology mechanism of T2DM development and better health management. Here, we will review the association of genetic polymorphisms in microRNA and microRNA targets genes with T2DM development.Journal of Diabetes 03/2014; DOI:10.1111/1753-0407.12143 · 2.35 Impact Factor
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ABSTRACT: Computational identification of phylogenetic motifs helps to understand the knowledge about known functional features that includes catalytic site, substrate binding epitopes, and protein-protein interfaces. Furthermore, they are strongly conserved among orthologs, indicating their evolutionary importance. The study aimed to analyze five candidate genes involved in type II diabetic nephropathy and to predict phylogenetic motifs from their corresponding orthologous protein sequences. AKR1B1, APOE, ENPP1, ELMO1 and IGFBP1 are the genes that have been identified as an important target for type II diabetic nephropathy through experimental studies. Their corresponding protein sequences, structures, orthologous sequences were retrieved from UniprotKB, PDB, and PHOG database respectively. Multiple sequence alignments were constructed using ClustalW and phylogenetic motifs were identified using MINER. The occurrence of amino acids in the obtained phylogenetic motifs was generated using WebLogo and false positive expectations were calculated against phylogenetic similarity. In total, 17 phylogenetic motifs were identified from the five proteins and the residues such as glycine, leucine, tryptophan, aspartic acid were found in appreciable frequency whereas arginine identified in all the predicted PMs. The result implies that these residues can be important to the functional and structural role of the proteins and calculated false positive expectations implies that they were generally conserved in traditional sense. The prediction of phylogenetic motifs is an accurate method for detecting functionally important conserved residues. The conserved motifs can be used as a potential drug target for type II diabetic nephropathy.Iranian Journal of Public Health 07/2012; 41(7):24-33. · 0.58 Impact Factor