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

TY - JOUR

T1 - 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

AU - Torekov, Signe Sørensen

AU - Harsløf, T

AU - Rejnmark, L

AU - Eiken, P

AU - Jensen, J B

AU - Herman, A P

AU - Hansen, T

AU - Pedersen, O

AU - Holst, J J

AU - Langdahl, B L

PY - 2014/4

Y1 - 2014/4

N2 - 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.

AB - 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.

KW - Alleles

KW - Amino Acid Substitution

KW - Bone Density

KW - Cohort Studies

KW - Female

KW - Femur Neck

KW - Fractures, Bone

KW - Gene Frequency

KW - Genetic Association Studies

KW - Humans

KW - Middle Aged

KW - Osteoporosis, Postmenopausal

KW - Receptors, Gastrointestinal Hormone

U2 - 10.1210/jc.2013-3766

DO - 10.1210/jc.2013-3766

M3 - Journal article

C2 - 24446656

SN - 0021-972X

VL - 99

SP - E729-33

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 4

ER -