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

Research output: Contribution to journalJournal articleResearchpeer-review

Signe Sørensen Torekov, T Harsløf, L Rejnmark, P Eiken, J B Jensen, A P Herman, T Hansen, O Pedersen, J J Holst, B L Langdahl

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/cm(2) vs CG: 747 ± 0.005 g/cm(2); GG: 0.766 ± 0.004 g/cm(2), P < .001). Correspondingly, total hip BMD was significantly lower among C allele carriers (CC: 0.881 ± 0.016 g/cm(2); CG: 0.884 ± 0.005 g/cm(2); and GG: 0.906 ± 0.004 g/cm(2), 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.

Original languageEnglish
JournalThe Journal of clinical endocrinology and metabolism
Volume99
Issue number4
Pages (from-to)E729-33
Number of pages5
ISSN0021-972X
DOIs
Publication statusPublished - Apr 2014

    Research areas

  • Alleles, Amino Acid Substitution, Bone Density, Cohort Studies, Female, Femur Neck, Fractures, Bone, Gene Frequency, Genetic Association Studies, Humans, Middle Aged, Osteoporosis, Postmenopausal, Receptors, Gastrointestinal Hormone

ID: 117418185