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.
BACKGROUND
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.


METHODS
This was a prospective, comprehensive, cohort study (number NCT00252408).


METHODS
A total of 1686 perimenopausal women were included.


METHODS
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.


CONCLUSIONS
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.
Department of Biomedical Sciences and NNF Center for Basic Metabolic Research (S.S.T., T.Han., O.P., J.J.H.), Faculty of Health and Medical Sciences (P.E.), University of Copenhagen, DK-2200 Copenhagen, Denmark; Department of Endocrinology and Metabolism (T.Har., L.R., B.L.L.), Aarhus University Hospital, DK-8000 C Aarhus, Denmark; Department of Cardiology, Nephrology, and Endocrinology (P.E.), Hillerød Hospital, DK-3400 Hillerød, Denmark; Department of Endocrinology (J.B.J.), Hvidovre University Hospital, DK-2650 Hvidovre, Denmark; and Department of Endocrinology M (A.P.H.), Odense University Hospital, DK-5000 Odense, Denmark.
S S
SS
Torekov
T
T
Harsløf
L
L
Rejnmark
P
P
Eiken
J B
JB
Jensen
A P
AP
Herman
T
T
Hansen
O
O
Pedersen
J J
JJ
Holst
B L
BL
Langdahl
D000483:Alleles; D019943:Amino Acid Substitution; D015519:Bone Density / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005272:Femur Neck; D050723:Fractures, Bone / Q000453:epidemiology*; D005787:Gene Frequency; D056726:Genetic Association Studies; D006801:Humans; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000453:epidemiology / Q000235:genetics; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics*
D011964:Receptors, Gastrointestinal Hormone; C041086:gastric inhibitory polypeptide receptor