Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity

A. S. Dimas; V. Lagou; A. Barker; J. W. Knowles; R. Magi; M. F. Hivert; A. Benazzo; D. Rybin; A. U. Jackson; H. M. Stringham; C. Song; A. Fischer-Rosinsky; T. W. Boesgaard; N. Grarup; F. A. Abbasi; T. L. Assimes; K. Hao; X. Yang; C. Lecoeur; I. Barroso; L. L. Bonnycastle; Y. Bottcher; S. Bumpstead; P. S. Chines; M. R. Erdos; J. Graessler; P. Kovacs; M. A. Morken; N. Narisu; F. Payne; A. Stancakova; A. J. Swift; A. Tonjes; S. R. Bornstein; S. Cauchi; P. Froguel; D. Meyre; P. E. H. Schwarz; H. U. Haring; U. Smith; M. Boehnke; R. N. Bergman; F. S. Collins; K. L. Mohlke; J. Tuomilehto; T. Quertemous; L. Lind; Torben Hansen; O. Pedersen; M. Walker; A. F. H. Pfeiffer; J. Spranger; M. Stumvoll; J. B. Meigs; N. J. Wareham; J. Kuusisto; M. Laakso; C. Langenberg; J. Dupuis; R. M. Watanabe; J. C. Florez; E. Ingelsson; M. I. McCarthy; I. Prokopenko; Magic Investigators

doi:10.2337/db13-0949

Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity

A. S. Dimas, V. Lagou, A. Barker, J. W. Knowles, R. Magi, M. F. Hivert, A. Benazzo, D. Rybin, A. U. Jackson, H. M. Stringham, C. Song, A. Fischer-Rosinsky, T. W. Boesgaard, N. Grarup, F. A. Abbasi, T. L. Assimes, K. Hao, X. Yang, C. Lecoeur, I. BarrosoL. L. Bonnycastle, Y. Bottcher, S. Bumpstead, P. S. Chines, M. R. Erdos, J. Graessler, P. Kovacs, M. A. Morken, N. Narisu, F. Payne, A. Stancakova, A. J. Swift, A. Tonjes, S. R. Bornstein, S. Cauchi, P. Froguel, D. Meyre, P. E. H. Schwarz, H. U. Haring, U. Smith, M. Boehnke, R. N. Bergman, F. S. Collins, K. L. Mohlke, J. Tuomilehto, T. Quertemous, L. Lind, Torben Hansen, O. Pedersen, M. Walker, A. F. H. Pfeiffer, J. Spranger, M. Stumvoll, J. B. Meigs, N. J. Wareham, J. Kuusisto, M. Laakso, C. Langenberg, J. Dupuis, R. M. Watanabe, J. C. Florez, E. Ingelsson, M. I. McCarthy, I. Prokopenko, Magic Investigators

KI, Medicinsk Endokrinologi

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

Abstrakt

Patients with established type 2 diabetes display both beta-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 (TCF712, 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.

Originalsprog	Engelsk
Tidsskrift	Diabetes
Vol/bind	63
Udgave nummer	6
Sider (fra-til)	2158-2171
Antal sider	14
ISSN	0046-0192
DOI	https://doi.org/10.2337/db13-0949
Status	Udgivet - 2014

Dokumenter og links

10.2337/db13-0949

Citationsformater

Dimas, A. S., Lagou, V., Barker, A., Knowles, J. W., Magi, 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., ... Investigators, M. (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, A. S. ; Lagou, V. ; Barker, A. ; Knowles, J. W. ; Magi, 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. ; Barroso, I. ; Bonnycastle, L. L. ; Bottcher, Y. ; Bumpstead, S. ; Chines, P. S. ; Erdos, M. R. ; Graessler, J. ; Kovacs, P. ; Morken, M. A. ; Narisu, N. ; Payne, F. ; Stancakova, A. ; Swift, A. J. ; Tonjes, A. ; Bornstein, S. R. ; Cauchi, S. ; Froguel, P. ; Meyre, D. ; Schwarz, P. E. H. ; Haring, H. U. ; Smith, U. ; Boehnke, M. ; Bergman, R. N. ; Collins, F. S. ; Mohlke, K. L. ; Tuomilehto, J. ; Quertemous, T. ; Lind, L. ; Hansen, Torben ; Pedersen, O. ; Walker, M. ; Pfeiffer, A. F. H. ; Spranger, J. ; Stumvoll, M. ; Meigs, J. B. ; Wareham, N. J. ; Kuusisto, J. ; Laakso, M. ; Langenberg, C. ; Dupuis, J. ; Watanabe, R. M. ; Florez, J. C. ; Ingelsson, E. ; McCarthy, M. I. ; Prokopenko, I. ; Investigators, Magic. / Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity. I: Diabetes. 2014 ; Bind 63, Nr. 6. s. 2158-2171.

@article{88a2329e74104d8f84545ea3dc276121,

title = "Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity",

abstract = "Patients with established type 2 diabetes display both beta-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 (TCF712, 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, {A. S.} and V. Lagou and A. Barker and Knowles, {J. W.} and R. Magi and Hivert, {M. F.} and A. Benazzo and D. Rybin and Jackson, {A. U.} and Stringham, {H. M.} and C. Song and A. Fischer-Rosinsky and Boesgaard, {T. W.} and N. Grarup and Abbasi, {F. A.} and Assimes, {T. L.} and K. Hao and X. Yang and C. Lecoeur and I. Barroso and Bonnycastle, {L. L.} and Y. Bottcher and S. Bumpstead and Chines, {P. S.} and Erdos, {M. R.} and J. Graessler and P. Kovacs and Morken, {M. A.} and N. Narisu and F. Payne and A. Stancakova and Swift, {A. J.} and A. Tonjes and Bornstein, {S. R.} and S. Cauchi and P. Froguel and D. Meyre and Schwarz, {P. E. H.} and Haring, {H. U.} and U. Smith and M. Boehnke and Bergman, {R. N.} and Collins, {F. S.} and Mohlke, {K. L.} and J. Tuomilehto and T. Quertemous and L. Lind and Torben Hansen and O. Pedersen and M. Walker and Pfeiffer, {A. F. H.} and J. Spranger and M. Stumvoll and Meigs, {J. B.} and Wareham, {N. J.} and J. Kuusisto and M. Laakso and C. Langenberg and J. Dupuis and Watanabe, {R. M.} and Florez, {J. C.} and E. Ingelsson and McCarthy, {M. I.} and I. Prokopenko and Magic Investigators",

year = "2014",

doi = "10.2337/db13-0949",

language = "English",

volume = "63",

pages = "2158--2171",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association",

number = "6",

}

Dimas, AS, Lagou, V, Barker, A, Knowles, JW, Magi, R, Hivert, MF, 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, Bottcher, Y, Bumpstead, S, Chines, PS, Erdos, MR, Graessler, J, Kovacs, P, Morken, MA, Narisu, N, Payne, F, Stancakova, A, Swift, AJ, Tonjes, A, Bornstein, SR, Cauchi, S, Froguel, P, Meyre, D, Schwarz, PEH, Haring, HU, Smith, U, Boehnke, M, Bergman, RN, Collins, FS, Mohlke, KL, Tuomilehto, J, Quertemous, T, Lind, L, Hansen, T, Pedersen, O, Walker, M, Pfeiffer, AFH, Spranger, J, Stumvoll, M, Meigs, JB, Wareham, NJ, Kuusisto, J, Laakso, M, Langenberg, C, Dupuis, J, Watanabe, RM, Florez, JC, Ingelsson, E, McCarthy, MI, Prokopenko, I & Investigators, M 2014, 'Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity', Diabetes, bind 63, nr. 6, s. 2158-2171. https://doi.org/10.2337/db13-0949

Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity. / Dimas, A. S.; Lagou, V.; Barker, A.; Knowles, J. W.; Magi, 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.; Barroso, I.; Bonnycastle, L. L.; Bottcher, Y.; Bumpstead, S.; Chines, P. S.; Erdos, M. R.; Graessler, J.; Kovacs, P.; Morken, M. A.; Narisu, N.; Payne, F.; Stancakova, A.; Swift, A. J.; Tonjes, A.; Bornstein, S. R.; Cauchi, S.; Froguel, P.; Meyre, D.; Schwarz, P. E. H.; Haring, H. U.; Smith, U.; Boehnke, M.; Bergman, R. N.; Collins, F. S.; Mohlke, K. L.; Tuomilehto, J.; Quertemous, T.; Lind, L.; Hansen, Torben; Pedersen, O.; Walker, M.; Pfeiffer, A. F. H.; Spranger, J.; Stumvoll, M.; Meigs, J. B.; Wareham, N. J.; Kuusisto, J.; Laakso, M.; Langenberg, C.; Dupuis, J.; Watanabe, R. M.; Florez, J. C.; Ingelsson, E.; McCarthy, M. I.; Prokopenko, I.; Investigators, Magic.

I: Diabetes, Bind 63, Nr. 6, 2014, s. 2158-2171.

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

TY - JOUR

T1 - Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity

AU - Dimas, A. S.

AU - Lagou, V.

AU - Barker, A.

AU - Knowles, J. W.

AU - Magi, R.

AU - Hivert, M. F.

AU - Benazzo, A.

AU - Rybin, D.

AU - Jackson, A. U.

AU - Stringham, H. M.

AU - Song, C.

AU - Fischer-Rosinsky, A.

AU - Boesgaard, T. W.

AU - Grarup, N.

AU - Abbasi, F. A.

AU - Assimes, T. L.

AU - Hao, K.

AU - Yang, X.

AU - Lecoeur, C.

AU - Barroso, I.

AU - Bonnycastle, L. L.

AU - Bottcher, Y.

AU - Bumpstead, S.

AU - Chines, P. S.

AU - Erdos, M. R.

AU - Graessler, J.

AU - Kovacs, P.

AU - Morken, M. A.

AU - Narisu, N.

AU - Payne, F.

AU - Stancakova, A.

AU - Swift, A. J.

AU - Tonjes, A.

AU - Bornstein, S. R.

AU - Cauchi, S.

AU - Froguel, P.

AU - Meyre, D.

AU - Schwarz, P. E. H.

AU - Haring, H. U.

AU - Smith, U.

AU - Boehnke, M.

AU - Bergman, R. N.

AU - Collins, F. S.

AU - Mohlke, K. L.

AU - Tuomilehto, J.

AU - Quertemous, T.

AU - Lind, L.

AU - Hansen, Torben

AU - Pedersen, O.

AU - Walker, M.

AU - Pfeiffer, A. F. H.

AU - Spranger, J.

AU - Stumvoll, M.

AU - Meigs, J. B.

AU - Wareham, N. J.

AU - Kuusisto, J.

AU - Laakso, M.

AU - Langenberg, C.

AU - Dupuis, J.

AU - Watanabe, R. M.

AU - Florez, J. C.

AU - Ingelsson, E.

AU - McCarthy, M. I.

AU - Prokopenko, I.

AU - Investigators, Magic

PY - 2014

Y1 - 2014

N2 - Patients with established type 2 diabetes display both beta-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 (TCF712, 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 beta-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 (TCF712, 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

VL - 63

SP - 2158

EP - 2171

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 6

ER -