A variant in CDKAL1 influences insulin response and risk of type 2 diabetes

Valgerdur Steinthorsdottir; Gudmar Thorleifsson; Inga Reynisdottir; Rafn Benediktsson; Thorbjorg Jonsdottir; G Bragi Walters; Unnur Styrkarsdottir; Solveig Gretarsdottir; Valur Emilsson; Shyamali Ghosh; Adam Baker; Steinunn Snorradottir; Hjordis Bjarnason; Maggie C Y Ng; Torben Hansen; Yu Bagger; Robert L Wilensky; Muredach P Reilly; Adebowale Adeyemo; Yuanxiu Chen; Jie Zhou; Vilmundur Gudnason; Guanjie Chen; Hanxia Huang; Kerrie Lashley; Ayo Doumatey; Wing-Yee So; Ronald C Y Ma; Gitte Andersen; Knut Borch-Johnsen; Torben Jorgensen; Jana V van Vliet-Ostaptchouk; Marten H Hofker; Cisca Wijmenga; Claus Christiansen; Daniel J Rader; Charles Rotimi; Mark Gurney; Juliana C N Chan; Oluf Pedersen; Gunnar Sigurdsson; Jeffrey R Gulcher; Unnur Thorsteinsdottir; Augustine Kong; Kari Stefansson

doi:10.1038/ng2043

A variant in CDKAL1 influences insulin response and risk of type 2 diabetes

Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Inga Reynisdottir, Rafn Benediktsson, Thorbjorg Jonsdottir, G Bragi Walters, Unnur Styrkarsdottir, Solveig Gretarsdottir, Valur Emilsson, Shyamali Ghosh, Adam Baker, Steinunn Snorradottir, Hjordis Bjarnason, Maggie C Y Ng, Torben Hansen, Yu Bagger, Robert L Wilensky, Muredach P Reilly, Adebowale Adeyemo, Yuanxiu ChenJie Zhou, Vilmundur Gudnason, Guanjie Chen, Hanxia Huang, Kerrie Lashley, Ayo Doumatey, Wing-Yee So, Ronald C Y Ma, Gitte Andersen, Knut Borch-Johnsen, Torben Jorgensen, Jana V van Vliet-Ostaptchouk, Marten H Hofker, Cisca Wijmenga, Claus Christiansen, Daniel J Rader, Charles Rotimi, Mark Gurney, Juliana C N Chan, Oluf Pedersen, Gunnar Sigurdsson, Jeffrey R Gulcher, Unnur Thorsteinsdottir, Augustine Kong, Kari Stefansson

752 Citations (Scopus)

Abstract

We conducted a genome-wide association study for type 2 diabetes (T2D) in Icelandic cases and controls, and we found that a previously described variant in the transcription factor 7-like 2 gene (TCF7L2) gene conferred the most significant risk. In addition to confirming two recently identified risk variants, we identified a variant in the CDKAL1 gene that was associated with T2D in individuals of European ancestry (allele-specific odds ratio (OR) = 1.20 (95% confidence interval, 1.13-1.27), P = 7.7 x 10(-9)) and individuals from Hong Kong of Han Chinese ancestry (OR = 1.25 (1.11-1.40), P = 0.00018). The genotype OR of this variant suggested that the effect was substantially stronger in homozygous carriers than in heterozygous carriers. The ORs for homozygotes were 1.50 (1.31-1.72) and 1.55 (1.23-1.95) in the European and Hong Kong groups, respectively. The insulin response for homozygotes was approximately 20% lower than for heterozygotes or noncarriers, suggesting that this variant confers risk of T2D through reduced insulin secretion.

Original language	English
Journal	Nature Genetics
Volume	39
Issue number	6
Pages (from-to)	770-5
Number of pages	6
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng2043
Publication status	Published - 2007

Keywords

Adult
Blood Glucose
Carrier Proteins
Case-Control Studies
Cross-Sectional Studies
Diabetes Mellitus, Type 2
Female
Gene Frequency
Genome, Human
Humans
Insulin
Insulin Resistance
Intracellular Signaling Peptides and Proteins
Linkage Disequilibrium
Male
Middle Aged
Nerve Tissue Proteins
Polymorphism, Single Nucleotide
TCF Transcription Factors
Transcription Factor 7-Like 1 Protein
Transcription Factor 7-Like 2 Protein

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng2043

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Steinthorsdottir, V., Thorleifsson, G., Reynisdottir, I., Benediktsson, R., Jonsdottir, T., Walters, G. B., Styrkarsdottir, U., Gretarsdottir, S., Emilsson, V., Ghosh, S., Baker, A., Snorradottir, S., Bjarnason, H., Ng, M. C. Y., Hansen, T., Bagger, Y., Wilensky, R. L., Reilly, M. P., Adeyemo, A., ... Stefansson, K. (2007). A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nature Genetics, 39(6), 770-5. https://doi.org/10.1038/ng2043

Steinthorsdottir, V, Thorleifsson, G, Reynisdottir, I, Benediktsson, R, Jonsdottir, T, Walters, GB, Styrkarsdottir, U, Gretarsdottir, S, Emilsson, V, Ghosh, S, Baker, A, Snorradottir, S, Bjarnason, H, Ng, MCY, Hansen, T, Bagger, Y, Wilensky, RL, Reilly, MP, Adeyemo, A, Chen, Y, Zhou, J, Gudnason, V, Chen, G, Huang, H, Lashley, K, Doumatey, A, So, W-Y, Ma, RCY, Andersen, G, Borch-Johnsen, K, Jorgensen, T, van Vliet-Ostaptchouk, JV, Hofker, MH, Wijmenga, C, Christiansen, C, Rader, DJ, Rotimi, C, Gurney, M, Chan, JCN, Pedersen, O, Sigurdsson, G, Gulcher, JR, Thorsteinsdottir, U, Kong, A & Stefansson, K 2007, 'A variant in CDKAL1 influences insulin response and risk of type 2 diabetes', Nature Genetics, vol. 39, no. 6, pp. 770-5. https://doi.org/10.1038/ng2043

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title = "A variant in CDKAL1 influences insulin response and risk of type 2 diabetes",

abstract = "We conducted a genome-wide association study for type 2 diabetes (T2D) in Icelandic cases and controls, and we found that a previously described variant in the transcription factor 7-like 2 gene (TCF7L2) gene conferred the most significant risk. In addition to confirming two recently identified risk variants, we identified a variant in the CDKAL1 gene that was associated with T2D in individuals of European ancestry (allele-specific odds ratio (OR) = 1.20 (95% confidence interval, 1.13-1.27), P = 7.7 x 10(-9)) and individuals from Hong Kong of Han Chinese ancestry (OR = 1.25 (1.11-1.40), P = 0.00018). The genotype OR of this variant suggested that the effect was substantially stronger in homozygous carriers than in heterozygous carriers. The ORs for homozygotes were 1.50 (1.31-1.72) and 1.55 (1.23-1.95) in the European and Hong Kong groups, respectively. The insulin response for homozygotes was approximately 20% lower than for heterozygotes or noncarriers, suggesting that this variant confers risk of T2D through reduced insulin secretion.",

keywords = "Adult, Blood Glucose, Carrier Proteins, Case-Control Studies, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, Gene Frequency, Genome, Human, Humans, Insulin, Insulin Resistance, Intracellular Signaling Peptides and Proteins, Linkage Disequilibrium, Male, Middle Aged, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, TCF Transcription Factors, Transcription Factor 7-Like 1 Protein, Transcription Factor 7-Like 2 Protein",

author = "Valgerdur Steinthorsdottir and Gudmar Thorleifsson and Inga Reynisdottir and Rafn Benediktsson and Thorbjorg Jonsdottir and Walters, {G Bragi} and Unnur Styrkarsdottir and Solveig Gretarsdottir and Valur Emilsson and Shyamali Ghosh and Adam Baker and Steinunn Snorradottir and Hjordis Bjarnason and Ng, {Maggie C Y} and Torben Hansen and Yu Bagger and Wilensky, {Robert L} and Reilly, {Muredach P} and Adebowale Adeyemo and Yuanxiu Chen and Jie Zhou and Vilmundur Gudnason and Guanjie Chen and Hanxia Huang and Kerrie Lashley and Ayo Doumatey and Wing-Yee So and Ma, {Ronald C Y} and Gitte Andersen and Knut Borch-Johnsen and Torben Jorgensen and {van Vliet-Ostaptchouk}, {Jana V} and Hofker, {Marten H} and Cisca Wijmenga and Claus Christiansen and Rader, {Daniel J} and Charles Rotimi and Mark Gurney and Chan, {Juliana C N} and Oluf Pedersen and Gunnar Sigurdsson and Gulcher, {Jeffrey R} and Unnur Thorsteinsdottir and Augustine Kong and Kari Stefansson",

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doi = "10.1038/ng2043",

language = "English",

volume = "39",

pages = "770--5",

journal = "Nature: New biology",

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T1 - A variant in CDKAL1 influences insulin response and risk of type 2 diabetes

AU - Steinthorsdottir, Valgerdur

AU - Thorleifsson, Gudmar

AU - Reynisdottir, Inga

AU - Benediktsson, Rafn

AU - Jonsdottir, Thorbjorg

AU - Walters, G Bragi

AU - Styrkarsdottir, Unnur

AU - Gretarsdottir, Solveig

AU - Emilsson, Valur

AU - Ghosh, Shyamali

AU - Baker, Adam

AU - Snorradottir, Steinunn

AU - Bjarnason, Hjordis

AU - Ng, Maggie C Y

AU - Hansen, Torben

AU - Bagger, Yu

AU - Wilensky, Robert L

AU - Reilly, Muredach P

AU - Adeyemo, Adebowale

AU - Chen, Yuanxiu

AU - Zhou, Jie

AU - Gudnason, Vilmundur

AU - Chen, Guanjie

AU - Huang, Hanxia

AU - Lashley, Kerrie

AU - Doumatey, Ayo

AU - So, Wing-Yee

AU - Ma, Ronald C Y

AU - Andersen, Gitte

AU - Borch-Johnsen, Knut

AU - Jorgensen, Torben

AU - van Vliet-Ostaptchouk, Jana V

AU - Hofker, Marten H

AU - Wijmenga, Cisca

AU - Christiansen, Claus

AU - Rader, Daniel J

AU - Rotimi, Charles

AU - Gurney, Mark

AU - Chan, Juliana C N

AU - Pedersen, Oluf

AU - Sigurdsson, Gunnar

AU - Gulcher, Jeffrey R

AU - Thorsteinsdottir, Unnur

AU - Kong, Augustine

AU - Stefansson, Kari

PY - 2007

Y1 - 2007

N2 - We conducted a genome-wide association study for type 2 diabetes (T2D) in Icelandic cases and controls, and we found that a previously described variant in the transcription factor 7-like 2 gene (TCF7L2) gene conferred the most significant risk. In addition to confirming two recently identified risk variants, we identified a variant in the CDKAL1 gene that was associated with T2D in individuals of European ancestry (allele-specific odds ratio (OR) = 1.20 (95% confidence interval, 1.13-1.27), P = 7.7 x 10(-9)) and individuals from Hong Kong of Han Chinese ancestry (OR = 1.25 (1.11-1.40), P = 0.00018). The genotype OR of this variant suggested that the effect was substantially stronger in homozygous carriers than in heterozygous carriers. The ORs for homozygotes were 1.50 (1.31-1.72) and 1.55 (1.23-1.95) in the European and Hong Kong groups, respectively. The insulin response for homozygotes was approximately 20% lower than for heterozygotes or noncarriers, suggesting that this variant confers risk of T2D through reduced insulin secretion.

AB - We conducted a genome-wide association study for type 2 diabetes (T2D) in Icelandic cases and controls, and we found that a previously described variant in the transcription factor 7-like 2 gene (TCF7L2) gene conferred the most significant risk. In addition to confirming two recently identified risk variants, we identified a variant in the CDKAL1 gene that was associated with T2D in individuals of European ancestry (allele-specific odds ratio (OR) = 1.20 (95% confidence interval, 1.13-1.27), P = 7.7 x 10(-9)) and individuals from Hong Kong of Han Chinese ancestry (OR = 1.25 (1.11-1.40), P = 0.00018). The genotype OR of this variant suggested that the effect was substantially stronger in homozygous carriers than in heterozygous carriers. The ORs for homozygotes were 1.50 (1.31-1.72) and 1.55 (1.23-1.95) in the European and Hong Kong groups, respectively. The insulin response for homozygotes was approximately 20% lower than for heterozygotes or noncarriers, suggesting that this variant confers risk of T2D through reduced insulin secretion.

KW - Adult

KW - Blood Glucose

KW - Carrier Proteins

KW - Case-Control Studies

KW - Cross-Sectional Studies

KW - Diabetes Mellitus, Type 2

KW - Female

KW - Gene Frequency

KW - Genome, Human

KW - Humans

KW - Insulin

KW - Insulin Resistance

KW - Intracellular Signaling Peptides and Proteins

KW - Linkage Disequilibrium

KW - Male

KW - Middle Aged

KW - Nerve Tissue Proteins

KW - Polymorphism, Single Nucleotide

KW - TCF Transcription Factors

KW - Transcription Factor 7-Like 1 Protein

KW - Transcription Factor 7-Like 2 Protein

U2 - 10.1038/ng2043

DO - 10.1038/ng2043

M3 - Journal article

C2 - 17460697

SN - 1061-4036

VL - 39

SP - 770

EP - 775

JO - Nature: New biology

JF - Nature: New biology

IS - 6

ER -

A variant in CDKAL1 influences insulin response and risk of type 2 diabetes

Abstract

Keywords

UN SDGs

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