Association of variants in the sterol regulatory element-binding factor 1 (SREBF1) gene with type 2 diabetes, glycemia, and insulin resistance: a study of 15,734 Danish subjects

Niels Grarup; Kirstine L Stender-Petersen; Ehm A Andersson; Torben Jørgensen; Knut Borch-Johnsen; Annelli Sandbæk; Torsten Lauritzen; Ole Schmitz; Torben Hansen; Oluf Pedersen

doi:10.2337/db07-1534

Association of variants in the sterol regulatory element-binding factor 1 (SREBF1) gene with type 2 diabetes, glycemia, and insulin resistance: a study of 15,734 Danish subjects

Niels Grarup, Kirstine L Stender-Petersen, Ehm A Andersson, Torben Jørgensen, Knut Borch-Johnsen, Annelli Sandbæk, Torsten Lauritzen, Ole Schmitz, Torben Hansen, Oluf Pedersen

37 Citations (Scopus)

Abstract

OBJECTIVE: We evaluated the association of variants in the sterol regulatory element-binding factor 1 gene (SREBF1) with type 2 diabetes. Due to the previous inconclusive quantitative trait associations, we also did studies of intermediate quantitative phenotypes. RESEARCH DESIGN AND METHODS: We genotyped four variants in SREBF1 in the population-based Inter99 cohort (n = 6,070), the Danish ADDITION study (n = 8,662), and in additional type 2 diabetic patients (n = 1,002). The case-control studies involved 2,980 type 2 diabetic patients and 4,522 glucose-tolerant subjects. RESULTS: The minor alleles of rs2297508, rs11868035, and rs1889018 (linkage disequilibrium R(2) = 0.6-0.8) associated with a modestly increased risk of type 2 diabetes (rs2297508: OR 1.17 [95% CI 1.05-1.30], P = 0.003), which was confirmed in meta-analyses of all published studies (rs2297508 G-allele: 1.08 [1.03-1.14] per allele, P = 0.001). The diabetes-associated alleles also associated strongly with a higher plasma glucose at 30 and 120 min and serum insulin at 120 min during an oral glucose tolerance test (all P < 0.006) and the minor allele of rs1889018 with a surrogate measure of insulin sensitivity (P = 0.03). Furthermore, the diabetes-associated alleles associated with a modestly increased A1C level in the population-based Inter99 of middle-aged subjects and in the ADDITION study of high-risk individuals (P = 0.006 and P = 0.008, respectively). CONCLUSIONS: We associate sequence variation in SREBF1 with a modestly increased predisposition to type 2 diabetes. In the general population, the diabetes-associated alleles are discreetly associated with hyperglycemia presumably due to decreased insulin sensitivity. Because sterol regulatory element-binding protein-1c is a mediator of insulin action, the findings are consistent with the presence of a yet undefined subtle loss-of-function SREBF1 variant.

Original language	English
Journal	Diabetes
Volume	57
Issue number	4
Pages (from-to)	1136-42
Number of pages	6
ISSN	0012-1797
DOIs	https://doi.org/10.2337/db07-1534
Publication status	Published - 2008

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10.2337/db07-1534

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Grarup, N., Stender-Petersen, K. L., Andersson, E. A., Jørgensen, T., Borch-Johnsen, K., Sandbæk, A., Lauritzen, T., Schmitz, O., Hansen, T., & Pedersen, O. (2008). Association of variants in the sterol regulatory element-binding factor 1 (SREBF1) gene with type 2 diabetes, glycemia, and insulin resistance: a study of 15,734 Danish subjects. Diabetes, 57(4), 1136-42. https://doi.org/10.2337/db07-1534

Association of variants in the sterol regulatory element-binding factor 1 (SREBF1) gene with type 2 diabetes, glycemia, and insulin resistance: a study of 15,734 Danish subjects. / Grarup, Niels; Stender-Petersen, Kirstine L; Andersson, Ehm A et al.

In: Diabetes, Vol. 57, No. 4, 2008, p. 1136-42.

Research output: Contribution to journal › Journal article › Research › peer-review

Grarup, N, Stender-Petersen, KL, Andersson, EA, Jørgensen, T, Borch-Johnsen, K, Sandbæk, A, Lauritzen, T, Schmitz, O, Hansen, T & Pedersen, O 2008, 'Association of variants in the sterol regulatory element-binding factor 1 (SREBF1) gene with type 2 diabetes, glycemia, and insulin resistance: a study of 15,734 Danish subjects', Diabetes, vol. 57, no. 4, pp. 1136-42. https://doi.org/10.2337/db07-1534

@article{58bdbf10ee1f11ddbf70000ea68e967b,

title = "Association of variants in the sterol regulatory element-binding factor 1 (SREBF1) gene with type 2 diabetes, glycemia, and insulin resistance: a study of 15,734 Danish subjects",

abstract = "OBJECTIVE: We evaluated the association of variants in the sterol regulatory element-binding factor 1 gene (SREBF1) with type 2 diabetes. Due to the previous inconclusive quantitative trait associations, we also did studies of intermediate quantitative phenotypes. RESEARCH DESIGN AND METHODS: We genotyped four variants in SREBF1 in the population-based Inter99 cohort (n = 6,070), the Danish ADDITION study (n = 8,662), and in additional type 2 diabetic patients (n = 1,002). The case-control studies involved 2,980 type 2 diabetic patients and 4,522 glucose-tolerant subjects. RESULTS: The minor alleles of rs2297508, rs11868035, and rs1889018 (linkage disequilibrium R(2) = 0.6-0.8) associated with a modestly increased risk of type 2 diabetes (rs2297508: OR 1.17 [95% CI 1.05-1.30], P = 0.003), which was confirmed in meta-analyses of all published studies (rs2297508 G-allele: 1.08 [1.03-1.14] per allele, P = 0.001). The diabetes-associated alleles also associated strongly with a higher plasma glucose at 30 and 120 min and serum insulin at 120 min during an oral glucose tolerance test (all P < 0.006) and the minor allele of rs1889018 with a surrogate measure of insulin sensitivity (P = 0.03). Furthermore, the diabetes-associated alleles associated with a modestly increased A1C level in the population-based Inter99 of middle-aged subjects and in the ADDITION study of high-risk individuals (P = 0.006 and P = 0.008, respectively). CONCLUSIONS: We associate sequence variation in SREBF1 with a modestly increased predisposition to type 2 diabetes. In the general population, the diabetes-associated alleles are discreetly associated with hyperglycemia presumably due to decreased insulin sensitivity. Because sterol regulatory element-binding protein-1c is a mediator of insulin action, the findings are consistent with the presence of a yet undefined subtle loss-of-function SREBF1 variant.",

author = "Niels Grarup and Stender-Petersen, {Kirstine L} and Andersson, {Ehm A} and Torben J{\o}rgensen and Knut Borch-Johnsen and Annelli Sandb{\ae}k and Torsten Lauritzen and Ole Schmitz and Torben Hansen and Oluf Pedersen",

note = "Keywords: Cohort Studies; Denmark; Diabetes Mellitus, Type 2; Genetic Variation; Glucose Tolerance Test; Humans; Insulin Resistance; Linkage Disequilibrium; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Sterol Regulatory Element Binding Protein 1",

year = "2008",

doi = "10.2337/db07-1534",

language = "English",

volume = "57",

pages = "1136--42",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association",

number = "4",

}

TY - JOUR

T1 - Association of variants in the sterol regulatory element-binding factor 1 (SREBF1) gene with type 2 diabetes, glycemia, and insulin resistance: a study of 15,734 Danish subjects

AU - Grarup, Niels

AU - Stender-Petersen, Kirstine L

AU - Andersson, Ehm A

AU - Jørgensen, Torben

AU - Borch-Johnsen, Knut

AU - Sandbæk, Annelli

AU - Lauritzen, Torsten

AU - Schmitz, Ole

AU - Hansen, Torben

AU - Pedersen, Oluf

N1 - Keywords: Cohort Studies; Denmark; Diabetes Mellitus, Type 2; Genetic Variation; Glucose Tolerance Test; Humans; Insulin Resistance; Linkage Disequilibrium; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Sterol Regulatory Element Binding Protein 1

PY - 2008

Y1 - 2008

N2 - OBJECTIVE: We evaluated the association of variants in the sterol regulatory element-binding factor 1 gene (SREBF1) with type 2 diabetes. Due to the previous inconclusive quantitative trait associations, we also did studies of intermediate quantitative phenotypes. RESEARCH DESIGN AND METHODS: We genotyped four variants in SREBF1 in the population-based Inter99 cohort (n = 6,070), the Danish ADDITION study (n = 8,662), and in additional type 2 diabetic patients (n = 1,002). The case-control studies involved 2,980 type 2 diabetic patients and 4,522 glucose-tolerant subjects. RESULTS: The minor alleles of rs2297508, rs11868035, and rs1889018 (linkage disequilibrium R(2) = 0.6-0.8) associated with a modestly increased risk of type 2 diabetes (rs2297508: OR 1.17 [95% CI 1.05-1.30], P = 0.003), which was confirmed in meta-analyses of all published studies (rs2297508 G-allele: 1.08 [1.03-1.14] per allele, P = 0.001). The diabetes-associated alleles also associated strongly with a higher plasma glucose at 30 and 120 min and serum insulin at 120 min during an oral glucose tolerance test (all P < 0.006) and the minor allele of rs1889018 with a surrogate measure of insulin sensitivity (P = 0.03). Furthermore, the diabetes-associated alleles associated with a modestly increased A1C level in the population-based Inter99 of middle-aged subjects and in the ADDITION study of high-risk individuals (P = 0.006 and P = 0.008, respectively). CONCLUSIONS: We associate sequence variation in SREBF1 with a modestly increased predisposition to type 2 diabetes. In the general population, the diabetes-associated alleles are discreetly associated with hyperglycemia presumably due to decreased insulin sensitivity. Because sterol regulatory element-binding protein-1c is a mediator of insulin action, the findings are consistent with the presence of a yet undefined subtle loss-of-function SREBF1 variant.

AB - OBJECTIVE: We evaluated the association of variants in the sterol regulatory element-binding factor 1 gene (SREBF1) with type 2 diabetes. Due to the previous inconclusive quantitative trait associations, we also did studies of intermediate quantitative phenotypes. RESEARCH DESIGN AND METHODS: We genotyped four variants in SREBF1 in the population-based Inter99 cohort (n = 6,070), the Danish ADDITION study (n = 8,662), and in additional type 2 diabetic patients (n = 1,002). The case-control studies involved 2,980 type 2 diabetic patients and 4,522 glucose-tolerant subjects. RESULTS: The minor alleles of rs2297508, rs11868035, and rs1889018 (linkage disequilibrium R(2) = 0.6-0.8) associated with a modestly increased risk of type 2 diabetes (rs2297508: OR 1.17 [95% CI 1.05-1.30], P = 0.003), which was confirmed in meta-analyses of all published studies (rs2297508 G-allele: 1.08 [1.03-1.14] per allele, P = 0.001). The diabetes-associated alleles also associated strongly with a higher plasma glucose at 30 and 120 min and serum insulin at 120 min during an oral glucose tolerance test (all P < 0.006) and the minor allele of rs1889018 with a surrogate measure of insulin sensitivity (P = 0.03). Furthermore, the diabetes-associated alleles associated with a modestly increased A1C level in the population-based Inter99 of middle-aged subjects and in the ADDITION study of high-risk individuals (P = 0.006 and P = 0.008, respectively). CONCLUSIONS: We associate sequence variation in SREBF1 with a modestly increased predisposition to type 2 diabetes. In the general population, the diabetes-associated alleles are discreetly associated with hyperglycemia presumably due to decreased insulin sensitivity. Because sterol regulatory element-binding protein-1c is a mediator of insulin action, the findings are consistent with the presence of a yet undefined subtle loss-of-function SREBF1 variant.

U2 - 10.2337/db07-1534

DO - 10.2337/db07-1534

M3 - Journal article

C2 - 18192539

SN - 0012-1797

VL - 57

SP - 1136

EP - 1142

JO - Diabetes

JF - Diabetes

IS - 4

ER -

Association of variants in the sterol regulatory element-binding factor 1 (SREBF1) gene with type 2 diabetes, glycemia, and insulin resistance: a study of 15,734 Danish subjects

Abstract

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