A candidate type 2 diabetes polymorphism near the HHEX locus affects acute glucose-stimulated insulin release in European populations: results from the EUGENE2 study

Harald Staiger; Alena Stancáková; Jone Zilinskaite; Markku Vänttinen; Torben Hansen; Maria Adelaide Marini; Ann Hammarstedt; Per-Anders Jansson; Giorgio Sesti; Ulf Smith; Oluf Pedersen; Markku Laakso; Norbert Stefan; Andreas Fritsche; Hans-Ulrich Häring

doi:10.2337/db07-1254

A candidate type 2 diabetes polymorphism near the HHEX locus affects acute glucose-stimulated insulin release in European populations: results from the EUGENE2 study

Harald Staiger, Alena Stancáková, Jone Zilinskaite, Markku Vänttinen, Torben Hansen, Maria Adelaide Marini, Ann Hammarstedt, Per-Anders Jansson, Giorgio Sesti, Ulf Smith, Oluf Pedersen, Markku Laakso, Norbert Stefan, Andreas Fritsche, Hans-Ulrich Häring

Department of Biomedical Sciences

45 Citations (Scopus)

Abstract

OBJECTIVE: In recent genome-wide association studies, two single nucleotide polymorphisms (SNPs) near the HHEX locus were shown to be more frequent in type 2 diabetic patients than in control subjects. Based on HHEX's function during embryonic development of the ventral pancreas in mice, we investigated whether these SNPs affect beta-cell function in humans. RESEARCH DESIGN AND METHODS: A total of 854 nondiabetic subjects, collected from five European clinical centers, were genotyped for the HHEX SNPs rs1111875 and rs7923837 and thoroughly characterized by an oral glucose tolerance test (OGTT). To assess glucose-stimulated insulin release, a subgroup of 758 subjects underwent an intravenous glucose tolerance test (IVGTT). RESULTS: SNPs rs1111875 and rs7923837 were not associated with anthropometric data (age, weight, height, BMI, body fat, and waist and hip circumference). After adjustment for center, family relationship, sex, age, and BMI, both SNPs were also not associated with glucose and insulin concentrations in the fasting state and during the OGTT or with measures of insulin sensitivity. Furthermore, HHEX SNP rs1111875 was not associated with insulin release during the IVGTT. By contrast, the minor A-allele of HHEX SNP rs7923837 was significantly associated with higher IVGTT-derived first-phase insulin release before and after appropriate adjustment (P = 0.013 and P = 0.014, respectively). CONCLUSIONS: A common genetic variation in the 3'-flanking region of the HHEX locus, i.e., SNP rs7923837, is associated with altered glucose-stimulated insulin release. This SNP's major allele represents a risk allele for beta-cell dysfunction and, thus, might confer increased susceptibility of beta-cells toward adverse environmental factors.

Original language	English
Journal	Diabetes
Volume	57
Issue number	2
Pages (from-to)	514-7
Number of pages	3
ISSN	0012-1797
DOIs	https://doi.org/10.2337/db07-1254
Publication status	Published - 2008

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Staiger, H., Stancáková, A., Zilinskaite, J., Vänttinen, M., Hansen, T., Marini, M. A., Hammarstedt, A., Jansson, P-A., Sesti, G., Smith, U., Pedersen, O., Laakso, M., Stefan, N., Fritsche, A., & Häring, H-U. (2008). A candidate type 2 diabetes polymorphism near the HHEX locus affects acute glucose-stimulated insulin release in European populations: results from the EUGENE2 study. Diabetes, 57(2), 514-7. https://doi.org/10.2337/db07-1254

Staiger, H, Stancáková, A, Zilinskaite, J, Vänttinen, M, Hansen, T, Marini, MA, Hammarstedt, A, Jansson, P-A, Sesti, G, Smith, U, Pedersen, O, Laakso, M, Stefan, N, Fritsche, A & Häring, H-U 2008, 'A candidate type 2 diabetes polymorphism near the HHEX locus affects acute glucose-stimulated insulin release in European populations: results from the EUGENE2 study', Diabetes, vol. 57, no. 2, pp. 514-7. https://doi.org/10.2337/db07-1254

@article{ddc0a650ee1f11ddbf70000ea68e967b,

title = "A candidate type 2 diabetes polymorphism near the HHEX locus affects acute glucose-stimulated insulin release in European populations: results from the EUGENE2 study",

abstract = "OBJECTIVE: In recent genome-wide association studies, two single nucleotide polymorphisms (SNPs) near the HHEX locus were shown to be more frequent in type 2 diabetic patients than in control subjects. Based on HHEX's function during embryonic development of the ventral pancreas in mice, we investigated whether these SNPs affect beta-cell function in humans. RESEARCH DESIGN AND METHODS: A total of 854 nondiabetic subjects, collected from five European clinical centers, were genotyped for the HHEX SNPs rs1111875 and rs7923837 and thoroughly characterized by an oral glucose tolerance test (OGTT). To assess glucose-stimulated insulin release, a subgroup of 758 subjects underwent an intravenous glucose tolerance test (IVGTT). RESULTS: SNPs rs1111875 and rs7923837 were not associated with anthropometric data (age, weight, height, BMI, body fat, and waist and hip circumference). After adjustment for center, family relationship, sex, age, and BMI, both SNPs were also not associated with glucose and insulin concentrations in the fasting state and during the OGTT or with measures of insulin sensitivity. Furthermore, HHEX SNP rs1111875 was not associated with insulin release during the IVGTT. By contrast, the minor A-allele of HHEX SNP rs7923837 was significantly associated with higher IVGTT-derived first-phase insulin release before and after appropriate adjustment (P = 0.013 and P = 0.014, respectively). CONCLUSIONS: A common genetic variation in the 3'-flanking region of the HHEX locus, i.e., SNP rs7923837, is associated with altered glucose-stimulated insulin release. This SNP's major allele represents a risk allele for beta-cell dysfunction and, thus, might confer increased susceptibility of beta-cells toward adverse environmental factors.",

author = "Harald Staiger and Alena Stanc{\'a}kov{\'a} and Jone Zilinskaite and Markku V{\"a}nttinen and Torben Hansen and Marini, {Maria Adelaide} and Ann Hammarstedt and Per-Anders Jansson and Giorgio Sesti and Ulf Smith and Oluf Pedersen and Markku Laakso and Norbert Stefan and Andreas Fritsche and Hans-Ulrich H{\"a}ring",

note = "Keywords: Adult; Body Mass Index; Diabetes Mellitus, Type 2; Europe; European Continental Ancestry Group; Female; Glucose; Glucose Intolerance; Homeodomain Proteins; Humans; Insulin; Male; Middle Aged; Polymorphism, Single Nucleotide; Reference Values; Transcription Factors; Waist-Hip Ratio",

year = "2008",

doi = "10.2337/db07-1254",

language = "English",

volume = "57",

pages = "514--7",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association",

number = "2",

}

TY - JOUR

T1 - A candidate type 2 diabetes polymorphism near the HHEX locus affects acute glucose-stimulated insulin release in European populations: results from the EUGENE2 study

AU - Staiger, Harald

AU - Stancáková, Alena

AU - Zilinskaite, Jone

AU - Vänttinen, Markku

AU - Hansen, Torben

AU - Marini, Maria Adelaide

AU - Hammarstedt, Ann

AU - Jansson, Per-Anders

AU - Sesti, Giorgio

AU - Smith, Ulf

AU - Pedersen, Oluf

AU - Laakso, Markku

AU - Stefan, Norbert

AU - Fritsche, Andreas

AU - Häring, Hans-Ulrich

N1 - Keywords: Adult; Body Mass Index; Diabetes Mellitus, Type 2; Europe; European Continental Ancestry Group; Female; Glucose; Glucose Intolerance; Homeodomain Proteins; Humans; Insulin; Male; Middle Aged; Polymorphism, Single Nucleotide; Reference Values; Transcription Factors; Waist-Hip Ratio

PY - 2008

Y1 - 2008

N2 - OBJECTIVE: In recent genome-wide association studies, two single nucleotide polymorphisms (SNPs) near the HHEX locus were shown to be more frequent in type 2 diabetic patients than in control subjects. Based on HHEX's function during embryonic development of the ventral pancreas in mice, we investigated whether these SNPs affect beta-cell function in humans. RESEARCH DESIGN AND METHODS: A total of 854 nondiabetic subjects, collected from five European clinical centers, were genotyped for the HHEX SNPs rs1111875 and rs7923837 and thoroughly characterized by an oral glucose tolerance test (OGTT). To assess glucose-stimulated insulin release, a subgroup of 758 subjects underwent an intravenous glucose tolerance test (IVGTT). RESULTS: SNPs rs1111875 and rs7923837 were not associated with anthropometric data (age, weight, height, BMI, body fat, and waist and hip circumference). After adjustment for center, family relationship, sex, age, and BMI, both SNPs were also not associated with glucose and insulin concentrations in the fasting state and during the OGTT or with measures of insulin sensitivity. Furthermore, HHEX SNP rs1111875 was not associated with insulin release during the IVGTT. By contrast, the minor A-allele of HHEX SNP rs7923837 was significantly associated with higher IVGTT-derived first-phase insulin release before and after appropriate adjustment (P = 0.013 and P = 0.014, respectively). CONCLUSIONS: A common genetic variation in the 3'-flanking region of the HHEX locus, i.e., SNP rs7923837, is associated with altered glucose-stimulated insulin release. This SNP's major allele represents a risk allele for beta-cell dysfunction and, thus, might confer increased susceptibility of beta-cells toward adverse environmental factors.

AB - OBJECTIVE: In recent genome-wide association studies, two single nucleotide polymorphisms (SNPs) near the HHEX locus were shown to be more frequent in type 2 diabetic patients than in control subjects. Based on HHEX's function during embryonic development of the ventral pancreas in mice, we investigated whether these SNPs affect beta-cell function in humans. RESEARCH DESIGN AND METHODS: A total of 854 nondiabetic subjects, collected from five European clinical centers, were genotyped for the HHEX SNPs rs1111875 and rs7923837 and thoroughly characterized by an oral glucose tolerance test (OGTT). To assess glucose-stimulated insulin release, a subgroup of 758 subjects underwent an intravenous glucose tolerance test (IVGTT). RESULTS: SNPs rs1111875 and rs7923837 were not associated with anthropometric data (age, weight, height, BMI, body fat, and waist and hip circumference). After adjustment for center, family relationship, sex, age, and BMI, both SNPs were also not associated with glucose and insulin concentrations in the fasting state and during the OGTT or with measures of insulin sensitivity. Furthermore, HHEX SNP rs1111875 was not associated with insulin release during the IVGTT. By contrast, the minor A-allele of HHEX SNP rs7923837 was significantly associated with higher IVGTT-derived first-phase insulin release before and after appropriate adjustment (P = 0.013 and P = 0.014, respectively). CONCLUSIONS: A common genetic variation in the 3'-flanking region of the HHEX locus, i.e., SNP rs7923837, is associated with altered glucose-stimulated insulin release. This SNP's major allele represents a risk allele for beta-cell dysfunction and, thus, might confer increased susceptibility of beta-cells toward adverse environmental factors.

U2 - 10.2337/db07-1254

DO - 10.2337/db07-1254

M3 - Journal article

C2 - 18039816

SN - 0012-1797

VL - 57

SP - 514

EP - 517

JO - Diabetes

JF - Diabetes

IS - 2

ER -

A candidate type 2 diabetes polymorphism near the HHEX locus affects acute glucose-stimulated insulin release in European populations: results from the EUGENE2 study

Abstract

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