Type 2 Diabetes Risk Alleles Near BCAR1 and in ANK1 Associate With Decreased ß-Cell Function Whereas Risk Alleles Near ANKRD55 and GRB14 Associate With Decreased Insulin Sensitivity in the Danish Inter99 Cohort

Marie N Harder; Rasmus Ribel-Madsen; Johanne M Justesen; Thomas Sparsø; Ehm Astrid Andersson Galijatovic; Niels Grarup; Torben Jørgensen; Allan Linneberg; Torben Hansen; Oluf Pedersen

doi:10.1210/jc.2012-4169

Type 2 Diabetes Risk Alleles Near BCAR1 and in ANK1 Associate With Decreased ß-Cell Function Whereas Risk Alleles Near ANKRD55 and GRB14 Associate With Decreased Insulin Sensitivity in the Danish Inter99 Cohort

Marie N Harder, Rasmus Ribel-Madsen, Johanne M Justesen, Thomas Sparsø, Ehm Astrid Andersson Galijatovic, Niels Grarup, Torben Jørgensen, Allan Linneberg, Torben Hansen, Oluf Pedersen

40 Citationer (Scopus)

Abstract

Context: Recently, 10 novel type 2 diabetes (T2D) susceptibility single nucleotide polymorphisms (SNPs) in ZMIZ1, ANK1, KLHDC5, TLE1, ANKRD55, CILP2, MC4R, BCAR1, HMG20A, and GRB14 loci were discovered in MetaboChip-genotyped populations of European ancestry. Objective: The aim of the present study was to characterize prediabetic quantitative traits underlying these SNP associations and to calculate the amount of interindividual variation in glycemic traits explained by these and previous T2D susceptibility variants. Design and Participants: A total of 5739 Danish individuals naive to glucose-lowering medication were included in quantitative trait studies, and case-control analyses were performed in 1892 patients with T2D and 6603 normoglycemic control subjects. Participants without known T2D underwent an oral glucose tolerance test, and measures of insulin release and sensitivity were estimated from insulinogenic, disposition, BIGTT, and Matsuda indexes. Results: We confirmed associations of ZMIZ1, KLHDC5, CILP2, HMG20A, ANK1, ANKRD55, and BCAR1 withT2D. The risk T allele of BCAR1 rs7202877 associated with decreased disposition index (P = .02). The C allele of ANK1 rs516946 associated with decreased insulinogenic (P = .005) and disposition (P = .002) indexes. The G allele of ANKRD55 rs459193 associated with decreased Matsuda index (P = .02) adjusted for waist circumference. The C allele of GRB14rs13389219 associated with both increased insulinogenic (P = .04) and decreased Matsuda (P = .05) indexes. All validated European T2D variants still only explained a few percentage points of glycemic trait variation. Conclusions: BCAR1 rs7202877 may mediate its diabetogenic impactthrough impaired β-cell function, but this finding needs to be replicated in independent studies. In addition, we substantiated previous evidence that ANK1 rs516946 confers impaired insulin release and that ANKRD55 rs459193 and GRB14 rs13389219 associate with insulin resistance.

Originalsprog	Engelsk
Tidsskrift	Journal of Clinical Endocrinology and Metabolism
Vol/bind	98
Udgave nummer	4
Sider (fra-til)	801-806
ISSN	0021-972X
DOI	https://doi.org/10.1210/jc.2012-4169
Status	Udgivet - 1 apr. 2013

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10.1210/jc.2012-4169

https://academic.oup.com/jcem/article-pdf/98/4/E801/9050273/jcemE801.pdf

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Citationsformater

Harder, M. N., Ribel-Madsen, R., Justesen, J. M., Sparsø, T., Galijatovic, E. A. A., Grarup, N., Jørgensen, T., Linneberg, A., Hansen, T., & Pedersen, O. (2013). Type 2 Diabetes Risk Alleles Near BCAR1 and in ANK1 Associate With Decreased ß-Cell Function Whereas Risk Alleles Near ANKRD55 and GRB14 Associate With Decreased Insulin Sensitivity in the Danish Inter99 Cohort. Journal of Clinical Endocrinology and Metabolism, 98(4), 801-806. https://doi.org/10.1210/jc.2012-4169

Type 2 Diabetes Risk Alleles Near BCAR1 and in ANK1 Associate With Decreased ß-Cell Function Whereas Risk Alleles Near ANKRD55 and GRB14 Associate With Decreased Insulin Sensitivity in the Danish Inter99 Cohort. / Harder, Marie N; Ribel-Madsen, Rasmus; Justesen, Johanne M et al.

I: Journal of Clinical Endocrinology and Metabolism, Bind 98, Nr. 4, 01.04.2013, s. 801-806.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Harder, MN, Ribel-Madsen, R, Justesen, JM, Sparsø, T, Galijatovic, EAA, Grarup, N, Jørgensen, T, Linneberg, A , Hansen, T & Pedersen, O 2013, 'Type 2 Diabetes Risk Alleles Near BCAR1 and in ANK1 Associate With Decreased ß-Cell Function Whereas Risk Alleles Near ANKRD55 and GRB14 Associate With Decreased Insulin Sensitivity in the Danish Inter99 Cohort', Journal of Clinical Endocrinology and Metabolism, bind 98, nr. 4, s. 801-806. https://doi.org/10.1210/jc.2012-4169

Harder MN, Ribel-Madsen R, Justesen JM, Sparsø T, Galijatovic EAA, Grarup N et al. Type 2 Diabetes Risk Alleles Near BCAR1 and in ANK1 Associate With Decreased ß-Cell Function Whereas Risk Alleles Near ANKRD55 and GRB14 Associate With Decreased Insulin Sensitivity in the Danish Inter99 Cohort. Journal of Clinical Endocrinology and Metabolism. 2013 apr. 1;98(4):801-806. doi: 10.1210/jc.2012-4169

Harder, Marie N ; Ribel-Madsen, Rasmus ; Justesen, Johanne M et al. / Type 2 Diabetes Risk Alleles Near BCAR1 and in ANK1 Associate With Decreased ß-Cell Function Whereas Risk Alleles Near ANKRD55 and GRB14 Associate With Decreased Insulin Sensitivity in the Danish Inter99 Cohort. I: Journal of Clinical Endocrinology and Metabolism. 2013 ; Bind 98, Nr. 4. s. 801-806.

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title = "Type 2 Diabetes Risk Alleles Near BCAR1 and in ANK1 Associate With Decreased {\ss}-Cell Function Whereas Risk Alleles Near ANKRD55 and GRB14 Associate With Decreased Insulin Sensitivity in the Danish Inter99 Cohort",

abstract = "Context: Recently, 10 novel type 2 diabetes (T2D) susceptibility single nucleotide polymorphisms (SNPs) in ZMIZ1, ANK1, KLHDC5, TLE1, ANKRD55, CILP2, MC4R, BCAR1, HMG20A, and GRB14 loci were discovered in MetaboChip-genotyped populations of European ancestry. Objective: The aim of the present study was to characterize prediabetic quantitative traits underlying these SNP associations and to calculate the amount of interindividual variation in glycemic traits explained by these and previous T2D susceptibility variants. Design and Participants: A total of 5739 Danish individuals naive to glucose-lowering medication were included in quantitative trait studies, and case-control analyses were performed in 1892 patients with T2D and 6603 normoglycemic control subjects. Participants without known T2D underwent an oral glucose tolerance test, and measures of insulin release and sensitivity were estimated from insulinogenic, disposition, BIGTT, and Matsuda indexes. Results: We confirmed associations of ZMIZ1, KLHDC5, CILP2, HMG20A, ANK1, ANKRD55, and BCAR1 withT2D. The risk T allele of BCAR1 rs7202877 associated with decreased disposition index (P = .02). The C allele of ANK1 rs516946 associated with decreased insulinogenic (P = .005) and disposition (P = .002) indexes. The G allele of ANKRD55 rs459193 associated with decreased Matsuda index (P = .02) adjusted for waist circumference. The C allele of GRB14rs13389219 associated with both increased insulinogenic (P = .04) and decreased Matsuda (P = .05) indexes. All validated European T2D variants still only explained a few percentage points of glycemic trait variation. Conclusions: BCAR1 rs7202877 may mediate its diabetogenic impactthrough impaired β-cell function, but this finding needs to be replicated in independent studies. In addition, we substantiated previous evidence that ANK1 rs516946 confers impaired insulin release and that ANKRD55 rs459193 and GRB14 rs13389219 associate with insulin resistance.",

author = "Harder, {Marie N} and Rasmus Ribel-Madsen and Justesen, {Johanne M} and Thomas Spars{\o} and Galijatovic, {Ehm Astrid Andersson} and Niels Grarup and Torben J{\o}rgensen and Allan Linneberg and Torben Hansen and Oluf Pedersen",

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month = apr,

day = "1",

doi = "10.1210/jc.2012-4169",

language = "English",

volume = "98",

pages = "801--806",

journal = "Journal of Clinical Endocrinology and Metabolism",

issn = "0021-972X",

publisher = "Oxford University Press",

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TY - JOUR

T1 - Type 2 Diabetes Risk Alleles Near BCAR1 and in ANK1 Associate With Decreased ß-Cell Function Whereas Risk Alleles Near ANKRD55 and GRB14 Associate With Decreased Insulin Sensitivity in the Danish Inter99 Cohort

AU - Harder, Marie N

AU - Ribel-Madsen, Rasmus

AU - Justesen, Johanne M

AU - Sparsø, Thomas

AU - Galijatovic, Ehm Astrid Andersson

AU - Grarup, Niels

AU - Jørgensen, Torben

AU - Linneberg, Allan

AU - Hansen, Torben

AU - Pedersen, Oluf

PY - 2013/4/1

Y1 - 2013/4/1

N2 - Context: Recently, 10 novel type 2 diabetes (T2D) susceptibility single nucleotide polymorphisms (SNPs) in ZMIZ1, ANK1, KLHDC5, TLE1, ANKRD55, CILP2, MC4R, BCAR1, HMG20A, and GRB14 loci were discovered in MetaboChip-genotyped populations of European ancestry. Objective: The aim of the present study was to characterize prediabetic quantitative traits underlying these SNP associations and to calculate the amount of interindividual variation in glycemic traits explained by these and previous T2D susceptibility variants. Design and Participants: A total of 5739 Danish individuals naive to glucose-lowering medication were included in quantitative trait studies, and case-control analyses were performed in 1892 patients with T2D and 6603 normoglycemic control subjects. Participants without known T2D underwent an oral glucose tolerance test, and measures of insulin release and sensitivity were estimated from insulinogenic, disposition, BIGTT, and Matsuda indexes. Results: We confirmed associations of ZMIZ1, KLHDC5, CILP2, HMG20A, ANK1, ANKRD55, and BCAR1 withT2D. The risk T allele of BCAR1 rs7202877 associated with decreased disposition index (P = .02). The C allele of ANK1 rs516946 associated with decreased insulinogenic (P = .005) and disposition (P = .002) indexes. The G allele of ANKRD55 rs459193 associated with decreased Matsuda index (P = .02) adjusted for waist circumference. The C allele of GRB14rs13389219 associated with both increased insulinogenic (P = .04) and decreased Matsuda (P = .05) indexes. All validated European T2D variants still only explained a few percentage points of glycemic trait variation. Conclusions: BCAR1 rs7202877 may mediate its diabetogenic impactthrough impaired β-cell function, but this finding needs to be replicated in independent studies. In addition, we substantiated previous evidence that ANK1 rs516946 confers impaired insulin release and that ANKRD55 rs459193 and GRB14 rs13389219 associate with insulin resistance.

AB - Context: Recently, 10 novel type 2 diabetes (T2D) susceptibility single nucleotide polymorphisms (SNPs) in ZMIZ1, ANK1, KLHDC5, TLE1, ANKRD55, CILP2, MC4R, BCAR1, HMG20A, and GRB14 loci were discovered in MetaboChip-genotyped populations of European ancestry. Objective: The aim of the present study was to characterize prediabetic quantitative traits underlying these SNP associations and to calculate the amount of interindividual variation in glycemic traits explained by these and previous T2D susceptibility variants. Design and Participants: A total of 5739 Danish individuals naive to glucose-lowering medication were included in quantitative trait studies, and case-control analyses were performed in 1892 patients with T2D and 6603 normoglycemic control subjects. Participants without known T2D underwent an oral glucose tolerance test, and measures of insulin release and sensitivity were estimated from insulinogenic, disposition, BIGTT, and Matsuda indexes. Results: We confirmed associations of ZMIZ1, KLHDC5, CILP2, HMG20A, ANK1, ANKRD55, and BCAR1 withT2D. The risk T allele of BCAR1 rs7202877 associated with decreased disposition index (P = .02). The C allele of ANK1 rs516946 associated with decreased insulinogenic (P = .005) and disposition (P = .002) indexes. The G allele of ANKRD55 rs459193 associated with decreased Matsuda index (P = .02) adjusted for waist circumference. The C allele of GRB14rs13389219 associated with both increased insulinogenic (P = .04) and decreased Matsuda (P = .05) indexes. All validated European T2D variants still only explained a few percentage points of glycemic trait variation. Conclusions: BCAR1 rs7202877 may mediate its diabetogenic impactthrough impaired β-cell function, but this finding needs to be replicated in independent studies. In addition, we substantiated previous evidence that ANK1 rs516946 confers impaired insulin release and that ANKRD55 rs459193 and GRB14 rs13389219 associate with insulin resistance.

U2 - 10.1210/jc.2012-4169

DO - 10.1210/jc.2012-4169

M3 - Journal article

C2 - 23457408

SN - 0021-972X

VL - 98

SP - 801

EP - 806

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 4

ER -