Common genetic variants differentially influence the transition from clinically defined states of fasting glucose metabolism

G. A. Walford; T. Green; B. Neale; T. Isakova; J. I. Rotter; S. F A Grant; C. S. Fox; J. S. Pankow; J. G. Wilson; J. B. Meigs; D. S. Siscovick; D. W. Bowden; M. J. Daly; J. C. Florez

doi:10.1007/s00125-011-2353-8

Common genetic variants differentially influence the transition from clinically defined states of fasting glucose metabolism

G. A. Walford, T. Green, B. Neale, T. Isakova, J. I. Rotter, S. F A Grant, C. S. Fox, J. S. Pankow, J. G. Wilson, J. B. Meigs, D. S. Siscovick, D. W. Bowden, M. J. Daly, J. C. Florez

Epidemiology

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38 Scopus citations

Abstract

Aims/hypothesis: Common genetic variants have been associated with type 2 diabetes. We hypothesised that a subset of these variants may have different effects on the transition from normal fasting glucose (NFG) to impaired fasting glucose (IFG) than on that from IFG to diabetes. Methods: We identified 16 type 2 diabetes risk variants from the Illumina Broad Candidate-gene Association Resource (CARe) array genotyped in 26,576 CARe participants. Participants were categorised at baseline as NFG, IFG or type 2 diabetic (n=16,465, 8,017 or 2,291, respectively). Using Cox proportional hazards and likelihood ratio tests (LRTs), we compared rates of progression by genotype for 4,909 (NFG to IFG) and 1,518 (IFG to type 2 diabetes) individuals, respectively. We then performed multinomial regression analyses at baseline, comparing the risk of assignment to the NFG, IFG or diabetes groups by genotype. Results: The rate of progression from NFG to IFG was significantly greater in participants carrying the risk allele at MTNR1B (p=1×10 ^-4), nominally greater at GCK and SLC30A8 (p<0.05) and nominally smaller at IGF2BP2 (p=0.01) than the rate of progression from IFG to diabetes by the LRT. Results of the baseline, multinomial regression model were consistent with these findings. Conclusions/interpretation: Common genetic risk variants at GCK, SLC30A8, IGF2BP2 and MTNR1B influence to different extents the development of IFG and the transition from IFG to type 2 diabetes. Our findings may have implications for understanding the genetic contribution of these variants to the development of IFG and type 2 diabetes.

Original language	English (US)
Pages (from-to)	331-339
Number of pages	9
Journal	Diabetologia
Volume	55
Issue number	2
DOIs	https://doi.org/10.1007/s00125-011-2353-8
State	Published - Feb 2012

Bibliographical note

Funding Information:
Acknowledgements G.A. Walford (Massachusetts General Hospital) received support from NIH training grant DK007028 and from the Scholars in Clinical Science programme of Harvard Catalyst—The Harvard Clinical and Translational Science Center (award UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic healthcare centres). J.B. Meigs (Massachusetts General Hospital) is supported in part by NIDDK K24 DK080140. J.C. Florez (Massachusetts General Hospital) is supported by a Clinical Scientist Development Award from the Doris Duke Charitable Foundation. The authors wish to acknowledge the support of the National Heart, Lung, and Blood Institute and the contributions of the research institutions, study investigators, field staff and study participants involved in creating this resource for biomedical research. Specific funding information for the nine parent studies contributing to CARe can be found in the ESM text. This study was presented in poster form as a late-breaking abstract at the 2010 American Diabetes Association Scientific Sessions in Orlando, FL, USA.

Keywords

Common genetic variants
Diabetes mellitus
Genetics
Glycaemic progression
Impaired fasting glucose
Normal fasting glucose
Single nucleotide polymorphism
Type 2 diabetes

UN SDGs

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Walford, G. A., Green, T., Neale, B., Isakova, T., Rotter, J. I., Grant, S. F. A., Fox, C. S., Pankow, J. S., Wilson, J. G., Meigs, J. B., Siscovick, D. S., Bowden, D. W., Daly, M. J., & Florez, J. C. (2012). Common genetic variants differentially influence the transition from clinically defined states of fasting glucose metabolism. Diabetologia, 55(2), 331-339. https://doi.org/10.1007/s00125-011-2353-8

Walford, GA, Green, T, Neale, B, Isakova, T, Rotter, JI, Grant, SFA, Fox, CS, Pankow, JS, Wilson, JG, Meigs, JB, Siscovick, DS, Bowden, DW, Daly, MJ & Florez, JC 2012, 'Common genetic variants differentially influence the transition from clinically defined states of fasting glucose metabolism', Diabetologia, vol. 55, no. 2, pp. 331-339. https://doi.org/10.1007/s00125-011-2353-8

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abstract = "Aims/hypothesis: Common genetic variants have been associated with type 2 diabetes. We hypothesised that a subset of these variants may have different effects on the transition from normal fasting glucose (NFG) to impaired fasting glucose (IFG) than on that from IFG to diabetes. Methods: We identified 16 type 2 diabetes risk variants from the Illumina Broad Candidate-gene Association Resource (CARe) array genotyped in 26,576 CARe participants. Participants were categorised at baseline as NFG, IFG or type 2 diabetic (n=16,465, 8,017 or 2,291, respectively). Using Cox proportional hazards and likelihood ratio tests (LRTs), we compared rates of progression by genotype for 4,909 (NFG to IFG) and 1,518 (IFG to type 2 diabetes) individuals, respectively. We then performed multinomial regression analyses at baseline, comparing the risk of assignment to the NFG, IFG or diabetes groups by genotype. Results: The rate of progression from NFG to IFG was significantly greater in participants carrying the risk allele at MTNR1B (p=1×10 -4), nominally greater at GCK and SLC30A8 (p<0.05) and nominally smaller at IGF2BP2 (p=0.01) than the rate of progression from IFG to diabetes by the LRT. Results of the baseline, multinomial regression model were consistent with these findings. Conclusions/interpretation: Common genetic risk variants at GCK, SLC30A8, IGF2BP2 and MTNR1B influence to different extents the development of IFG and the transition from IFG to type 2 diabetes. Our findings may have implications for understanding the genetic contribution of these variants to the development of IFG and type 2 diabetes.",

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author = "Walford, {G. A.} and T. Green and B. Neale and T. Isakova and Rotter, {J. I.} and Grant, {S. F A} and Fox, {C. S.} and Pankow, {J. S.} and Wilson, {J. G.} and Meigs, {J. B.} and Siscovick, {D. S.} and Bowden, {D. W.} and Daly, {M. J.} and Florez, {J. C.}",

note = "Funding Information: Acknowledgements G.A. Walford (Massachusetts General Hospital) received support from NIH training grant DK007028 and from the Scholars in Clinical Science programme of Harvard Catalyst—The Harvard Clinical and Translational Science Center (award UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic healthcare centres). J.B. Meigs (Massachusetts General Hospital) is supported in part by NIDDK K24 DK080140. J.C. Florez (Massachusetts General Hospital) is supported by a Clinical Scientist Development Award from the Doris Duke Charitable Foundation. The authors wish to acknowledge the support of the National Heart, Lung, and Blood Institute and the contributions of the research institutions, study investigators, field staff and study participants involved in creating this resource for biomedical research. Specific funding information for the nine parent studies contributing to CARe can be found in the ESM text. This study was presented in poster form as a late-breaking abstract at the 2010 American Diabetes Association Scientific Sessions in Orlando, FL, USA.",

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T1 - Common genetic variants differentially influence the transition from clinically defined states of fasting glucose metabolism

AU - Walford, G. A.

AU - Green, T.

AU - Neale, B.

AU - Isakova, T.

AU - Rotter, J. I.

AU - Grant, S. F A

AU - Fox, C. S.

AU - Pankow, J. S.

AU - Wilson, J. G.

AU - Meigs, J. B.

AU - Siscovick, D. S.

AU - Bowden, D. W.

AU - Daly, M. J.

AU - Florez, J. C.

N1 - Funding Information: Acknowledgements G.A. Walford (Massachusetts General Hospital) received support from NIH training grant DK007028 and from the Scholars in Clinical Science programme of Harvard Catalyst—The Harvard Clinical and Translational Science Center (award UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic healthcare centres). J.B. Meigs (Massachusetts General Hospital) is supported in part by NIDDK K24 DK080140. J.C. Florez (Massachusetts General Hospital) is supported by a Clinical Scientist Development Award from the Doris Duke Charitable Foundation. The authors wish to acknowledge the support of the National Heart, Lung, and Blood Institute and the contributions of the research institutions, study investigators, field staff and study participants involved in creating this resource for biomedical research. Specific funding information for the nine parent studies contributing to CARe can be found in the ESM text. This study was presented in poster form as a late-breaking abstract at the 2010 American Diabetes Association Scientific Sessions in Orlando, FL, USA.

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N2 - Aims/hypothesis: Common genetic variants have been associated with type 2 diabetes. We hypothesised that a subset of these variants may have different effects on the transition from normal fasting glucose (NFG) to impaired fasting glucose (IFG) than on that from IFG to diabetes. Methods: We identified 16 type 2 diabetes risk variants from the Illumina Broad Candidate-gene Association Resource (CARe) array genotyped in 26,576 CARe participants. Participants were categorised at baseline as NFG, IFG or type 2 diabetic (n=16,465, 8,017 or 2,291, respectively). Using Cox proportional hazards and likelihood ratio tests (LRTs), we compared rates of progression by genotype for 4,909 (NFG to IFG) and 1,518 (IFG to type 2 diabetes) individuals, respectively. We then performed multinomial regression analyses at baseline, comparing the risk of assignment to the NFG, IFG or diabetes groups by genotype. Results: The rate of progression from NFG to IFG was significantly greater in participants carrying the risk allele at MTNR1B (p=1×10 -4), nominally greater at GCK and SLC30A8 (p<0.05) and nominally smaller at IGF2BP2 (p=0.01) than the rate of progression from IFG to diabetes by the LRT. Results of the baseline, multinomial regression model were consistent with these findings. Conclusions/interpretation: Common genetic risk variants at GCK, SLC30A8, IGF2BP2 and MTNR1B influence to different extents the development of IFG and the transition from IFG to type 2 diabetes. Our findings may have implications for understanding the genetic contribution of these variants to the development of IFG and type 2 diabetes.

AB - Aims/hypothesis: Common genetic variants have been associated with type 2 diabetes. We hypothesised that a subset of these variants may have different effects on the transition from normal fasting glucose (NFG) to impaired fasting glucose (IFG) than on that from IFG to diabetes. Methods: We identified 16 type 2 diabetes risk variants from the Illumina Broad Candidate-gene Association Resource (CARe) array genotyped in 26,576 CARe participants. Participants were categorised at baseline as NFG, IFG or type 2 diabetic (n=16,465, 8,017 or 2,291, respectively). Using Cox proportional hazards and likelihood ratio tests (LRTs), we compared rates of progression by genotype for 4,909 (NFG to IFG) and 1,518 (IFG to type 2 diabetes) individuals, respectively. We then performed multinomial regression analyses at baseline, comparing the risk of assignment to the NFG, IFG or diabetes groups by genotype. Results: The rate of progression from NFG to IFG was significantly greater in participants carrying the risk allele at MTNR1B (p=1×10 -4), nominally greater at GCK and SLC30A8 (p<0.05) and nominally smaller at IGF2BP2 (p=0.01) than the rate of progression from IFG to diabetes by the LRT. Results of the baseline, multinomial regression model were consistent with these findings. Conclusions/interpretation: Common genetic risk variants at GCK, SLC30A8, IGF2BP2 and MTNR1B influence to different extents the development of IFG and the transition from IFG to type 2 diabetes. Our findings may have implications for understanding the genetic contribution of these variants to the development of IFG and type 2 diabetes.

KW - Common genetic variants

KW - Diabetes mellitus

KW - Genetics

KW - Glycaemic progression

KW - Impaired fasting glucose

KW - Normal fasting glucose

KW - Single nucleotide polymorphism

KW - Type 2 diabetes

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Common genetic variants differentially influence the transition from clinically defined states of fasting glucose metabolism

Abstract

Bibliographical note

Keywords

UN SDGs

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