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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 Staiger¹, Alena Stanáková², Jone Zilinskaite², Markku Vänttinen², Torben Hansen³, Maria Adelaide Marini⁴, Ann Hammarstedt⁵, Per-Anders Jansson⁵, Giorgio Sesti⁶, Ulf Smith⁵, Oluf Pedersen³, Markku Laakso², Norbert Stefan¹, Andreas Fritsche¹, and Hans-Ulrich Häring¹

¹ Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Tübingen University Hospital, Tübingen, Germany
² Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, Finland
³ Steno Diabetes Center, Copenhagen, Denmark
⁴ Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy
⁵ The Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
⁶ Department of Experimental and Clinical Medicine, Polyclinic Mater Domini, University Magna Graecia of Catanzaro, Catanzaro, Italy

Address correspondence and reprint requests to Hans-Ulrich Häring, MD, Internal Medicine IV, Medical Clinic Tübingen, Otfried-Müller-Str. 10, D-72076 Tübingen, Germany. E-mail: hans-ulrich.haering{at}med.uni-tuebingen.de

Abbreviations: HOMA-IR, homeostasis model assessment of insulin resistance; OGTT, oral glucose tolerance test; IVGTT, intravenous glucose tolerance test; SNP, single nucleotide polymorphism

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 β-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 β-cell dysfunction and, thus, might confer increased susceptibility of β-cells toward adverse environmental factors.

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