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Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge

Abstract

Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958–30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, β (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 × 10−15). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 × 10−17; ratio of insulin to glucose area under the curve, P = 1.3 × 10−16) and diminished incretin effect (n = 804; P = 4.3 × 10−4). We also identified variants at ADCY5 (rs2877716, P = 4.2 × 10−16), VPS13C (rs17271305, P = 4.1 × 10−8), GCKR (rs1260326, P = 7.1 × 10−11) and TCF7L2 (rs7903146, P = 4.2 × 10−10) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09–1.15, P = 4.8 × 10−18).

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Figure 1: Regional plots of five genome-wide significant associations for 2 hour glucose based on 2 hour glucose discovery analysis adjusted for age, sex, BMI and study-specific covariates.
Figure 2: Percent incretin effect in the Botnia, Denmark and EUGENE2-Kuopio studies of nondiabetic individuals (n = 804) by GIPR rs10423928 genotype.
Figure 3: mRNA expression in human tissues of the genes located in the GIPR (a) and VPS13C (b) regions.

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Acknowledgements

The authors would like to thank the many colleagues who contributed to collection and phenotypic characterization of the clinical samples, as well as genotyping and analysis of the GWA data. We gratefully acknowledge those who agreed to participate in these studies. A full list of acknowledgments and funding support for each study is described in the Supplementary Note.

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Authors and Affiliations

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Contributions

Writing group: R. Saxena, M.-F.H., C. Langenberg., T. Tanaka, J.S.P., P.V., V.L., N.B.-N., J.C.F., M.I.M., M.B., I.B., R. Sladek, P.F., J.B.M., L.G., N.J.W., R.M.W.

Project design, management and coordination: (Amish) B.D.M., A.R.S.; (ARIC) J.S.P., W.H.L.K., S.J. Bielinski, E. Boerwinkle; (BLSA) A. Singleton, L.F.; (BotniaPPP) L.G., T. Tuomi., B.I.; (CHS) N.L.G., K.R., N.L.S., B.M.P., J.I.R.; (Colaus) P.V., M.F., V. Mayor, G.W., D.M.W., V. Mooser; (Danish) K.B.J., A.S., T. Jørgensen, T.L., T.H., O.P.; (DIAGEN) P. Schwartz, S.R.B.; (DGI) R. Saxena, D.A., L.G.; (Ely) C. Langenberg, N.J.W.; (Fenland) C. Langenberg, N.G.F., R.J.F.L., N.J.W.; (FHS) J.D., J.B.M.; (French) N.B.-N., P.F.; (FUSION) R.N.B., F.S.C., K.L.M., L.J.S., J. Tuomilehto, M.B., R.M.W.; (Hertfordshire) A.A.S., H.S., C.C.; (METSIM) J.K., M.La.; (MPP) P.N.; (Partners/Roche) J.B.M., D.M.N., G.H.W.; (RISC) M.W., L.P.; (Sorbs) A.T., M.S.; (ULSAM) E.I.; (Whitehall II) E. Brunner, A.H., M. Kivimaki, M. Kumari, M.M.

Sample collection and phenotyping: (Amish) A.R.S.; (BLSA) J.M.E.; (BotniaPPP) L.G., V.L., B.I., T. Tuomi; (CHS) B.M.P., D.S.S, N.L.S.; (CoLaus) P.V., G.W.; (Danish) T.W.B., K.B.J, A.S., T. Jørgensen, T.L., T.H., O.P.; (DIAGEN) J.G., P. Schwartz; (DGI) L.G., V.L., B.I., T. Tuomi; (Ely) N.J.W.; (Fenland) N.G.F., R.J.F.L., N.J.W.; (French) P.F., D.M., B.B., C.L.-M., G.C., F. Pattou; (FHS) J.B.M., C.S.F.; (FUSION) R.N.B., T.A.B., J. Tuomilehto, T.T.V.; (Hertfordshire) A.A.S., H.S., C.C.; (METSIM) J.K., M. Laakso; (Partners/Roche) J.B.M., D.M.N., G.H.W.; (Sorbs) P.K., A.T.; (Whitehall II) E. Brunner, M. Kumari, M.M.

Genotyping: (Amish) R.P.; (ARIC) E. Boerwinkle.; (BLSA) A. Singleton; (BotniaPPP) G.J.C.; (CHS) Y.-D.I.C., M.O.G., J.I.R.; (CoLaus) V. Mooser, D.M.W.; (Danish) T.H., T.S., C.H.A., N.G., O.P.; (DGI) D.A., V.L., R. Saxena; (DIAGEN) D.P., A.J.S.; (Ely) I.B., S.J. Bumpstead, F. Payne, N.J.W.; (Fenland) R.J.F.L., N.J.W.; (FHS) J.C.F., J.B.M.; (French) N.B.-N., J.D., R. Sladek, D.M., A.W.; (FUSION) L.L.B., M.R.E., P.S.C.; (FUSION stage 2) P.S.C., A.J.S.; (Hertfordshire) I.B., S.J. Bumpstead, F. Payne, N.J.W.; (METSIM) M.A.M., N.N.; (Partners/Roche) J.C.F., J.B.M.; (Sorbs) Y.B., P.K., K.K.; (ULSAM) A.-C.S.; (Whitehall II) M. Kumari, C. Langenberg, N.J.W.

Statistical analysis: (Meta-analyses) R. Saxena, J.D., D.R., W.H.L.K., A.U.J.; (Amish) J.O.; (ARIC) W.H.L.K., M.L., A.K., D.J.C.; (BLSA) T. Tanaka; (BotniaPPP) V.L.; (CHS) N.L.G., K.R.; (CoLaus) T. Johnson, K. Song; (Danish) T.S., C.H.A., T.W.B., N.G.; (DGI) R. Saxena; (Ely) C. Langenberg, S.J.S.; (Fenland) C. Langenberg, J.L., J.H.Z.; (French) N.-B.N, C. Lecoeur, C.C-P., A.B., C.D.; (FHS) J.D., A.K.M., D.R., P. Shrader; (FUSION) A.U.J., H.M.S.; (FUSION stage 2) A.U.J., H.M.S.; (Hertfordshire) C. Langenberg, S.J.S.; (Partners/Roche) P.Shr.; (RISC) C. Langenberg, S.J.S.; (Sorbs) I.P.; (ULSAM) E.I.; (Whitehall II) C. Langenberg.

Expression analysis: (Malmo) J. Taneera, V.L., L.G; (French) N.B.-N., O.L.B., F. Patou, P.F.

Type 2 Diabetes association: (DGI) D.A., L.G., R. Saxena, B.F.V., K.A.; (deCODE) V.S., G.T., U.T., K. Stefansson; (EUROSPAN) Y.S.A., J.F.W., M.v.H., E.S., C.v.D.; (French) N.B.-N., J. Deplanque, C. Lecoeur, G.C., P.F.; (Addition-Ely) C. Langenberg, F. Payne, S.J. Bumpstead, I.B., N.J.W.; (Norfolk Diabetes Case-Control Study) C. Langenberg, F. Payne, S.J. Bumpstead, I.B., M.S., N.J.W.; (Cambridgeshire Case-Control Study) C. Langenberg, F. Payne, S.J. Bumpstead, I.B., N.J.W.; (KORA) H.G., W.R., T.I., H.E.W.; (MPP) P.N., V.L., L.G.; (NHS/HPFS) F.B.H. L.Q., M.C.C.; (UKT2D/58BC/OXGN) A.D., C.N.A.P., A.T.H., A.D.M.; T.M.F., M.I.M.; (WTCCC-UKT2D) M.N.W., E.Z.

Corresponding authors

Correspondence to James B Meigs, Leif Groop, Nicholas J Wareham or Richard M Watanabe.

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Competing interests

J.B.M. currently has research grants from GlaxoSmithKline and Sanofi-aventis, and serves on consultancy boards for GlaxoSmithKline, Sanofi-aventis, Interleukin Genetics, Kalypsis, and Outcomes Sciences. J.C.F. has received consulting honoraria from Merck, bioStrategies, XOMA and Publicis Healthcare Communications Group, a global advertising agency engaged by Amylin Pharmaceuticals. deCODE authors are employees at deCODE genetics and own stock or stock options in the company. P.W.F. has received consulting honoraria from Unilever. P.V. and G.W. received financial support from GlaxoSmithKline to build the CoLaus study. V.Mo., K.S. and D.M.W. are all full-time employees at GlaxoSmithKline. I.B. and spouse own stock in GlaxoSmithKline and Incyte. A.S. has research support from GlaxoSmithKline. R.M.W. has received consulting honoraria from Merck & Co. and Vivus Inc., currently has a grant from Merck & Co., and received research material support from Takeda Pharmaceuticals North America.

Additional information

Full membership list of the GIANT consortium is provided in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Figure 1, Supplementary Tables 2–6 and Supplementary Note (PDF 1443 kb)

Supplementary Table 1

Cohort and study characteristics and details of analysis metrics and methods (XLS 81 kb)

Supplementary Table 2

Meta-analysis of association results for 2-hr glucose across discovery and replication cohorts (XLS 59 kb)

Supplementary Table 4

Association of rs10423928 [GIPR], rs17271305 [VPS13C] and rs2877716 [ADCY5] with insulinogenic index, AUC (area under the curve) insulin/glucose, and 2h insulin (adjusted for 2h glucose) within MAGIC and meta-analysis across all studies (XLS 46 kb)

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Saxena, R., Hivert, MF., Langenberg, C. et al. Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat Genet 42, 142–148 (2010). https://doi.org/10.1038/ng.521

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