| The carriage of risk variants of CDKAL1 impairs beta-cell function in both diabetic and non-diabetic patients and reduces response to non-sulfonylurea and sulfonylurea agonists of the pancreatic KATP channel. | |
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MedLine Citation:
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PMID: 21611789 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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On chromosome 6q22.3, a cluster of single-nucleotide polymorphisms located in intron 5 of the cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 1-like 1 (CDKAL1) gene were shown to confer susceptibility to type 2 diabetes in multiple ethnic groups. The diabetogenic role of CDKAL1 variants is suggested to consist in lower insulin secretion probably due to the insufficient inhibition of the CDK5 activity. In this study, we assessed the association of several SNPs of CDKAL1 with T2D in 772 Russian affected patients and 773 normoglycemic controls using a Taqman-based allelic discrimination assay. We showed association of the minor allele C of rs10946398 (Odds Ratio (OR) = 1.21, 95% CI = 1.04-1.4, P = 0.016), allele C of rs7754840 (OR = 1.18, 95% CI = 1.01-1.37, P = 0.038), and allele G of rs7756992 (OR = 1.21, 95% CI = 1.04-1.42, P = 0.017) with higher diabetes risk thereby replicating the predisposing role of CDKAL1 in etiology of T2D. These alleles contribute to three haplotypes (CCA, CGG, and CCG) related to higher diabetes risk (OR = 1.48, 2.12, and 1.95). Combinations of these haplotypes between each other form the group of high-risk haplogenotypes whose carriers had decreased HOMA-β compared to other CDKAL1 variants in both diabetic (38.6 ± 19.3 vs. 48.2 ± 21.2, P (adjusted) = 0.019-0.044) and non-diabetic (91.8 ± 42.1 vs. 108 ± 47.2, P (adjusted) = 0.0054-0.01) patients. The carriage of the risk haplogenotypes of CDKAL1 was associated with reduced response to non-sulfonylurea and sulfonylurea agonists of the pancreatic KATP channel. These data suggest that CDKAL1 is involved in the pathogenesis of T2D through impaired beta-cell function. |
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Authors:
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Dimitry A Chistiakov; V A Potapov; S A Smetanina; L N Bel'chikova; L A Suplotova; V V Nosikov |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-5-25 |
Journal Detail:
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Title: Acta diabetologica Volume: - ISSN: 1432-5233 ISO Abbreviation: - Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-5-25 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9200299 Medline TA: Acta Diabetol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Molecular Diagnostics, National Research Center GosNIIgenetika, 1st Dorozhny Proezd 1, 117545, Moscow, Russia, dimitry.chistiakov@lycos.com. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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