A Functional Amino Acid Substitution in the Glucose-Dependent Insulinotropic Polypeptide Receptor (GIPR) Gene Is Associated With Lower Bone Mineral Density and Increased Fracture Risk

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Abstract
Context: Food ingestion decreases bone resorption, and glucose-dependent insulinotropic polypeptide (GIP) may mediate this effect. Mice overexpressing GIP have increased osteoblast activity and are rescued from age-related bone loss, whereas GIPR knockout mice have decreased cortical bone mass and compromised bone quality. Carriers of the functional variant GIPR Glu354Gln (rs1800437) have higher plasma glucose 2 hours after glucose ingestion, suggesting that the variant encoding GIPR 354Gln decreases the effect of GIP. Objective: The objective of the study was to investigate the effect of GIPR Glu354Gln on bone mineral density (BMD) and fracture risk. Design: This was a prospective, comprehensive, cohort study (number NCT00252408). Participants: A total of 1686 perimenopausal women were included. Main Outcome Measures: Dual-energy X-ray absorptiometry was performed at baseline and after 10 years. Incident fractures were recorded during the follow-up and were obtained from the Danish National Patient Registry, giving a total follow-up time of a minimum 16 years. Results: After 10 years, women with the minor frequency C allele of rs1800437 (354Gln) had significantly lower BMD at the femoral neck compared with carriers of the major G-allele (CC: 0.755 ± 0.015 g/cm2 vs CG: 747 ± 0.005 g/cm2; GG: 0.766 ± 0.004 g/cm2, P < .001). Correspondingly, total hip BMD was significantly lower among C allele carriers (CC: 0.881 ± 0.016 g/cm2; CG: 0.884 ± 0.005 g/cm2; and GG: 0.906 ± 0.004 g/cm2, P < .001). Finally, women homozygous for the variant C allele had an increased risk (hazard ratio 1.6, confidence interval 1.0–2.6, P < .05) of nonvertebral fractures. Conclusion: This study demonstrates an association between a functional GIPR polymorphism Glu354Gln (rs1800437) and BMD and fracture risk. These findings further establish GIP to be involved in the regulation of bone density.

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