A variant in CDKAL1 influences insulin response and risk of type 2 diabetes

Steinthórsdóttir, Valgerður; Þorleifsson, Guðmar; Reynisdóttir, Inga; Benediktsson, Rafn; Jónsdóttir, Þorbjörg; Walters, G. Bragi; Styrkársdóttir, Unnur; Grétarsdóttir, Sólveig; Emilsson, Valur; Ghosh, Shyamali; Baker, Adam; Snorradóttir, Steinunn; Bjarnason, Hjördis; Ng, Maggie; Hansen, Torben; Bagger, Yu Z.; Wilensky, Robert L.; Reilly, Muredach P.; Adeyemo, Adebowale; Chen, Yuanxiu; Zhou, Jie; Gudnason, Vilmundur; Chen, Guanjie; Huang, Hanxia; Lashley, Kerrie; Doumatey, Ayo P.; So, Wing‐Yee; Ronald, C.; Andersen, Gitte; Borch‐Johnsen, Knut; Jørgensen, Torben; Vliet-Ostaptchouk, Jana V. van; Hofker, Marten H.; Wijmenga, Cisca; Christiansen, Claus; Rader, Daniel J.; Rotimi, Charles N.; Gurney, Mark E.; Chan, Juliana C.N.; Pedersen, Oluf; Sigurðsson, Gunnar; Gulcher, Jeffrey R.; Þorsteinsdóttir, Unnur; Kong, Augustine; Stefánsson, Kāri

doi:10.1038/ng2043

Cited by 940 publications

(748 citation statements)

References 25 publications

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“…Especially, they were all located within CDKAL1 gene except for an intergenic variant of rs5015480 near HHEX gene. The association of the CDKAL1 gene concurred with the results from previous studies with American, 1 British, 5 French, 3 Danish, 4 Finnish, 2 Swedish, 1 Icelandic, 4 Korean, 9 Japanese, 10 and Chinese [11][12][13] populations. The significantly associated variants of the gene in the current study were specifically corresponding to those found in previous studies of Horikawa et al 14 and Wu et al 11 for rs7756992 and Zeggini et al 5 and Wu et al 11 for rs9465871 and rs10946398, respectively.…”

Section: Discussionsupporting

confidence: 89%

“…The heterogeneity by gender was a novel finding for T2DM. The larger effect of the CDKAL1 in females concurred with the study of Steinthorsdottir et al, 4 showing a larger association of rs7756992 with insulin secretion in females (Po0.00001) than in males (Po0.001). The differential effect would lead to a deflated association by adding males in the association analysis.…”

Section: Discussionsupporting

confidence: 88%

“…Especially, several genome-wide association studies were recently conducted. [1][2][3][4][5] Nevertheless, their results revealed inconsistencies in associations of many nucleotide sequence variants. 6 A serious publication bias was suspected because a fewer publications with negative results were likely to be reported from candidate gene association analyses.…”

Section: Introductionmentioning

confidence: 99%

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Heterogeneity of genetic associations of CDKAL1 and HHEX with susceptibility of type 2 diabetes mellitus by gender

et al. 2011

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We examined the genetic associations of previously identified sequence variants with type 2 diabetes mellitus (T2DM) and its potentially genetic heterogeneity by gender in a large-scale cohort. A total of 613 T2DM patients and 8221 control subjects from the Korea Association REsource (KARE) cohort were included in the analysis of genetic association of T2DM with 33 nucleotide polymorphic markers identified by previous studies. The association analysis was further conducted with data partitioned by gender. The association analysis resulted in five nucleotide sequence variants associated with the susceptibility of T2DM after Bonferonni correction (Po0.0015). One was located near the gene of hematopoietically expressed homeobox (HHEX), and the others were all in the gene of cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1). Further analysis revealed that the sequence variant (rs5015480) near HHEX and two SNPs (rs7756992 and rs9465871) in CDKAL1 were associated with the susceptibility of T2DM in females (Po0.005), but not in males (P40.005). We suggested heterogeneous genetic associations of the T2DM susceptibility with the CDKAL1 and HHEX genes by gender.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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Heterogeneity of genetic associations of CDKAL1 and HHEX with susceptibility of type 2 diabetes mellitus by gender

et al. 2011

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“…The pancreatic β cells were stimulated to secrete insulin to regulate the homoeostasis of the blood glucose by the postprandial high levels of blood glucose [5]. Until now, hundreds of genetic variations related with T2D or glucose/insulin have been identified by GWAS (Genome Wide Association Studies) [6-9]. Most T2D risk genes identified in GWAS performs the biological processes which affect the number or function of the pancreatic β cells, emphasizing the important effect of β cells in the occurrence and development of T2D [10].…”

Section: Introductionmentioning

confidence: 99%

Detection of type 2 diabetes related modules and genes based on epigenetic networks

et al. 2014

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BackgroundType 2 diabetes (T2D) is one of the most common chronic metabolic diseases characterized by insulin resistance and the decrease of insulin secretion. Genetic variation can only explain part of the heritability of T2D, so there need new methods to detect the susceptibility genes of the disease. Epigenetics could establish the interface between the environmental factor and the T2D Pathological mechanism.ResultsBased on the network theory and by combining epigenetic characteristics with human interactome, the weighted human DNA methylation network (WMPN) was constructed, and a T2D-related subnetwork (TMSN) was obtained through T2D-related differentially methylated genes. It is found that TMSN had a T2D specific network structure that non-fatal metabolic disease causing genes were often located in the topological and functional periphery of network. Combined with chromatin modifications, the weighted chromatin modification network (WCPN) was built, and a T2D-related chromatin modification pattern subnetwork was obtained by the TMSN gene set. TCSN had a densely connected network community, indicating that TMSN and TCSN could represent a collection of T2D-related epigenetic dysregulated sub-pathways. Using the cumulative hypergeometric test, 24 interplay modules of DNA methylation and chromatin modifications were identified. By the analysis of gene expression in human T2D islet tissue, it is found that there existed genes with the variant expression level caused by the aberrant DNA methylation and (or) chromatin modifications, which might affect and promote the development of T2D.ConclusionsHere we have detected the potential interplay modules of DNA methylation and chromatin modifications for T2D. The study of T2D epigenetic networks provides a new way for understanding the pathogenic mechanism of T2D caused by epigenetic disorders.

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“…La cartographie détaillée et les études fonctionnelles sauront, on l'espère, distinguer lequel des deux gènes est en cause. Parallèlement à nos travaux, quatre autres équipes concurrentes, qui participent à cette course internationale, viennent de publier des études semblables qui confirment ces deux associations et en mettent en évidence six autres [5][6][7][8]. Ensemble, ces nouvelles associations, additionnées à celles qui étaient déjà détermination simultanée du génotype de centaines de milliers de polymorphismes d'un nucléotide (SNP) à haut débit.…”

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Du nouveau dans la génétique du diabète de type 2

Polychronakos

2008

Med Sci (Paris)

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A variant in CDKAL1 influences insulin response and risk of type 2 diabetes

Abstract: A variant in CDKAL1 influences insulin response and risk of type 2 diabetes Steinthorsdottir, V.; Thorleifsson, G.; Reynisdottir, I.; Benediktsson, R.; Jonsdottir, T.; Walters, G.B.; Styrkarsdottir, U.; Gretarsdottir, S.; Emilsson, V.; Ghosh, S.

Cited by 940 publications

References 25 publications

Heterogeneity of genetic associations of CDKAL1 and HHEX with susceptibility of type 2 diabetes mellitus by gender

Heterogeneity of genetic associations of CDKAL1 and HHEX with susceptibility of type 2 diabetes mellitus by gender

Detection of type 2 diabetes related modules and genes based on epigenetic networks

Du nouveau dans la génétique du diabète de type 2

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