Sequence variation in IGF1R is associated with differences in insulin levels in nondiabetic Old Order Amish

Background: Insulin growth factor-1 receptor (IGF1R) encodes the insulinlike growth factor 1 receptor, a transmembrane tyrosine kinase receptor located on chromosome 15q26.3, in a region of linkage (LOD = 2.53, P = 0.00032) to Insulin30 on an OGTT in the Old Order Amish. Mouse models with beta-cell-specific deficiency of IGF1R demonstrate defects in glucose-stimulated insulin secretion. Methods: To test the hypothesis that genetic variation in IGF1R is associated with impaired insulin secretion, we genotyped 54 SNPs in 778 nondiabetic subjects from the AFDS who had undergone OGTTs and tested them for association with ln Insulin30 and ISI. Results: No individual SNPs were significantly associated with ln Insulin30 or ISI using a multiple hypothesis testing adjusted P < 0.002. Tests of association of 4-SNP haplotypes constructed by a windowing approach revealed an association of the CTTG-variant of a 4-SNP haplotype found in intron 20 (rs1784195-rs2715439-rs8034284- rs12440962) with lower ISI levels (β = 0.18, SE(β) = 0.05, P = 0.001). Conclusions: Sequence variation in IGF1R may influence insulin secretory function, although further studies in other populations will be needed to confirm these findings.