Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity

Antigone S Dimas; Vasiliki Lagou; Adam Barker; Joshua W Knowles; Reedik Mägi; Marie-France Hivert; Andrea Benazzo; Denis Rybin; Anne U Jackson; Heather M Stringham; Ci Song; Antje Fischer-Rosinsky; Trine Welløv Boesgaard; Niels Grarup; Fahim A Abbasi; Themistocles L Assimes; Ke Hao; Xia Yang; Cécile Lecoeur; Inês Barroso; Lori L Bonnycastle; Yvonne Böttcher; Suzannah Bumpstead; Peter S Chines; Michael R Erdos; Jurgen Graessler; Peter Kovacs; Mario A Morken; Narisu Narisu; Felicity Payne; Alena Stancakova; Amy J Swift; Anke Tönjes; Stefan R Bornstein; Stéphane Cauchi; Philippe Froguel; David Meyre; Peter E H Schwarz; Hans-Ulrich Häring; Ulf Smith; Michael Boehnke; Richard N Bergman; Francis S Collins; Karen L Mohlke; Jaakko Tuomilehto; Thomas Quertemous; Lars Lind; Torben Hansen; Oluf Pedersen; Mark Walker; on behalf of the MAGIC investigators

doi:10.2337/db13-0949

Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity

Antigone S Dimas, Vasiliki Lagou, Adam Barker, Joshua W Knowles, Reedik Mägi, Marie-France Hivert, Andrea Benazzo, Denis Rybin, Anne U Jackson, Heather M Stringham, Ci Song, Antje Fischer-Rosinsky, Trine Welløv Boesgaard, Niels Grarup, Fahim A Abbasi, Themistocles L Assimes, Ke Hao, Xia Yang, Cécile Lecoeur, Inês BarrosoLori L Bonnycastle, Yvonne Böttcher, Suzannah Bumpstead, Peter S Chines, Michael R Erdos, Jurgen Graessler, Peter Kovacs, Mario A Morken, Narisu Narisu, Felicity Payne, Alena Stancakova, Amy J Swift, Anke Tönjes, Stefan R Bornstein, Stéphane Cauchi, Philippe Froguel, David Meyre, Peter E H Schwarz, Hans-Ulrich Häring, Ulf Smith, Michael Boehnke, Richard N Bergman, Francis S Collins, Karen L Mohlke, Jaakko Tuomilehto, Thomas Quertemous, Lars Lind, Torben Hansen, Oluf Pedersen, Mark Walker, on behalf of the MAGIC investigators

194 Citations (Scopus)

Abstract

Patients with established type 2 diabetes display both b-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.

Original language	English
Journal	Diabetes
Volume	63
Issue number	6
Pages (from-to)	2158-2171
Number of pages	14
ISSN	0012-1797
DOIs	https://doi.org/10.2337/db13-0949
Publication status	Published - Jun 2014

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Dimas, A. S., Lagou, V., Barker, A., Knowles, J. W., Mägi, R., Hivert, M-F., Benazzo, A., Rybin, D., Jackson, A. U., Stringham, H. M., Song, C., Fischer-Rosinsky, A., Boesgaard, T. W., Grarup, N., Abbasi, F. A., Assimes, T. L., Hao, K., Yang, X., Lecoeur, C., ... on behalf of the MAGIC investigators (2014). Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity. Diabetes, 63(6), 2158-2171. https://doi.org/10.2337/db13-0949

Dimas, AS, Lagou, V, Barker, A, Knowles, JW, Mägi, R, Hivert, M-F, Benazzo, A, Rybin, D, Jackson, AU, Stringham, HM, Song, C, Fischer-Rosinsky, A, Boesgaard, TW, Grarup, N, Abbasi, FA, Assimes, TL, Hao, K, Yang, X, Lecoeur, C, Barroso, I, Bonnycastle, LL, Böttcher, Y, Bumpstead, S, Chines, PS, Erdos, MR, Graessler, J, Kovacs, P, Morken, MA, Narisu, N, Payne, F, Stancakova, A, Swift, AJ, Tönjes, A, Bornstein, SR, Cauchi, S, Froguel, P, Meyre, D, Schwarz, PEH, Häring, H-U, Smith, U, Boehnke, M, Bergman, RN, Collins, FS, Mohlke, KL, Tuomilehto, J, Quertemous, T, Lind, L, Hansen, T , Pedersen, O, Walker, M & on behalf of the MAGIC investigators 2014, 'Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity', Diabetes, vol. 63, no. 6, pp. 2158-2171. https://doi.org/10.2337/db13-0949

@article{47424263722d472f89e9e59df02829bd,

title = "Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity",

abstract = "Patients with established type 2 diabetes display both b-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.",

author = "Dimas, {Antigone S} and Vasiliki Lagou and Adam Barker and Knowles, {Joshua W} and Reedik M{\"a}gi and Marie-France Hivert and Andrea Benazzo and Denis Rybin and Jackson, {Anne U} and Stringham, {Heather M} and Ci Song and Antje Fischer-Rosinsky and Boesgaard, {Trine Well{\o}v} and Niels Grarup and Abbasi, {Fahim A} and Assimes, {Themistocles L} and Ke Hao and Xia Yang and C{\'e}cile Lecoeur and In{\^e}s Barroso and Bonnycastle, {Lori L} and Yvonne B{\"o}ttcher and Suzannah Bumpstead and Chines, {Peter S} and Erdos, {Michael R} and Jurgen Graessler and Peter Kovacs and Morken, {Mario A} and Narisu Narisu and Felicity Payne and Alena Stancakova and Swift, {Amy J} and Anke T{\"o}njes and Bornstein, {Stefan R} and St{\'e}phane Cauchi and Philippe Froguel and David Meyre and Schwarz, {Peter E H} and Hans-Ulrich H{\"a}ring and Ulf Smith and Michael Boehnke and Bergman, {Richard N} and Collins, {Francis S} and Mohlke, {Karen L} and Jaakko Tuomilehto and Thomas Quertemous and Lars Lind and Torben Hansen and Oluf Pedersen and Mark Walker and {on behalf of the MAGIC investigators}",

year = "2014",

month = jun,

doi = "10.2337/db13-0949",

language = "English",

volume = "63",

pages = "2158--2171",

journal = "Diabetes",

issn = "0012-1797",

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T1 - Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity

AU - Dimas, Antigone S

AU - Lagou, Vasiliki

AU - Barker, Adam

AU - Knowles, Joshua W

AU - Mägi, Reedik

AU - Hivert, Marie-France

AU - Benazzo, Andrea

AU - Rybin, Denis

AU - Jackson, Anne U

AU - Stringham, Heather M

AU - Song, Ci

AU - Fischer-Rosinsky, Antje

AU - Boesgaard, Trine Welløv

AU - Grarup, Niels

AU - Abbasi, Fahim A

AU - Assimes, Themistocles L

AU - Hao, Ke

AU - Yang, Xia

AU - Lecoeur, Cécile

AU - Barroso, Inês

AU - Bonnycastle, Lori L

AU - Böttcher, Yvonne

AU - Bumpstead, Suzannah

AU - Chines, Peter S

AU - Erdos, Michael R

AU - Graessler, Jurgen

AU - Kovacs, Peter

AU - Morken, Mario A

AU - Narisu, Narisu

AU - Payne, Felicity

AU - Stancakova, Alena

AU - Swift, Amy J

AU - Tönjes, Anke

AU - Bornstein, Stefan R

AU - Cauchi, Stéphane

AU - Froguel, Philippe

AU - Meyre, David

AU - Schwarz, Peter E H

AU - Häring, Hans-Ulrich

AU - Smith, Ulf

AU - Boehnke, Michael

AU - Bergman, Richard N

AU - Collins, Francis S

AU - Mohlke, Karen L

AU - Tuomilehto, Jaakko

AU - Quertemous, Thomas

AU - Lind, Lars

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Walker, Mark

AU - on behalf of the MAGIC investigators

PY - 2014/6

Y1 - 2014/6

N2 - Patients with established type 2 diabetes display both b-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.

AB - Patients with established type 2 diabetes display both b-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.

U2 - 10.2337/db13-0949

DO - 10.2337/db13-0949

M3 - Journal article

C2 - 24296717

SN - 0012-1797

VL - 63

SP - 2158

EP - 2171

JO - Diabetes

JF - Diabetes

IS - 6

ER -

Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity

Abstract

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