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.
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