TY - JOUR
T1 - Obesity Variants in the GIPR Gene Are not Associated With Risk of Fracture or Bone Mineral Density
AU - Styrkarsdottir, Unnur
AU - Tragante, Vinicius
AU - Stefansdottir, Lilja
AU - Thorleifsson, Gudmar
AU - Oddsson, Asmundur
AU - Sørensen, Erik
AU - Erikstrup, Christian
AU - Schwarz, Peter
AU - Jørgensen, Henrik Løvendahl
AU - Lauritzen, Jes Bruun
AU - Brunak, Søren
AU - Knowlton, Kirk U
AU - Nadauld, Lincoln D
AU - Ullum, Henrik
AU - Pedersen, Ole Birger Vesterager
AU - Ostrowski, Sisse Rye
AU - Holm, Hilma
AU - Gudbjartsson, Daniel F
AU - Sulem, Patrick
AU - Stefansson, Kari
N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.
PY - 2024/7/12
Y1 - 2024/7/12
N2 - CONTEXT: It is not clear if antagonizing the GIP (glucose-dependent insulinotropic polypeptide) receptor (GIPR) for treatment of obesity is likely to increase the risk of fractures, or to lower bone mineral density (BMD) beyond what is expected with rapid weight loss.OBJECTIVE: The objective of this study was to investigate the risk of fracture and BMD of sequence variants in GIPR that reduce the activity of the GIP receptor and have been associated with reduced body mass index (BMI).METHODS: We analyzed the association of 3 missense variants in GIPR, a common variant, rs1800437 (p.Glu354Gln), and 2 rare variants, rs139215588 (p.Arg190Gln) and rs143430880 (p.Glu288Gly), as well as a burden of predicted loss-of-function (LoF) variants with risk of fracture and with BMD in a large meta-analysis of up to 1.2 million participants. We analyzed associations with fractures at different skeletal sites in the general population: any fractures, hip fractures, vertebral fractures and forearm fractures, and specifically nonvertebral and osteoporotic fractures in postmenopausal women. We also evaluated associations with BMD at the lumbar spine, femoral neck, and total body measured with dual-energy x-ray absorptiometry (DXA), and with BMD estimated from heel ultrasound (eBMD).RESULTS: None of the 3 missense variants in GIPR was significantly associated with increased risk of fractures or with lower BMD. Burden of LoF variants in GIPR was not associated with fractures or with BMD measured with clinically validated DXA, but was associated with eBMD.CONCLUSION: Missense variants in GIPR, or burden of LoF variants in the gene, are not associated with risk of fractures or with lower BMD.
AB - CONTEXT: It is not clear if antagonizing the GIP (glucose-dependent insulinotropic polypeptide) receptor (GIPR) for treatment of obesity is likely to increase the risk of fractures, or to lower bone mineral density (BMD) beyond what is expected with rapid weight loss.OBJECTIVE: The objective of this study was to investigate the risk of fracture and BMD of sequence variants in GIPR that reduce the activity of the GIP receptor and have been associated with reduced body mass index (BMI).METHODS: We analyzed the association of 3 missense variants in GIPR, a common variant, rs1800437 (p.Glu354Gln), and 2 rare variants, rs139215588 (p.Arg190Gln) and rs143430880 (p.Glu288Gly), as well as a burden of predicted loss-of-function (LoF) variants with risk of fracture and with BMD in a large meta-analysis of up to 1.2 million participants. We analyzed associations with fractures at different skeletal sites in the general population: any fractures, hip fractures, vertebral fractures and forearm fractures, and specifically nonvertebral and osteoporotic fractures in postmenopausal women. We also evaluated associations with BMD at the lumbar spine, femoral neck, and total body measured with dual-energy x-ray absorptiometry (DXA), and with BMD estimated from heel ultrasound (eBMD).RESULTS: None of the 3 missense variants in GIPR was significantly associated with increased risk of fractures or with lower BMD. Burden of LoF variants in GIPR was not associated with fractures or with BMD measured with clinically validated DXA, but was associated with eBMD.CONCLUSION: Missense variants in GIPR, or burden of LoF variants in the gene, are not associated with risk of fractures or with lower BMD.
KW - Adult
KW - Aged
KW - Body Mass Index
KW - Bone Density/genetics
KW - Female
KW - Fractures, Bone/genetics
KW - Genetic Predisposition to Disease
KW - Humans
KW - Male
KW - Middle Aged
KW - Mutation, Missense
KW - Obesity/genetics
KW - Receptors, Gastrointestinal Hormone/genetics
KW - Risk Factors
U2 - 10.1210/clinem/dgad734
DO - 10.1210/clinem/dgad734
M3 - Article
C2 - 38118020
SN - 0021-972X
VL - 109
SP - e1608-e1615
JO - The Journal of clinical endocrinology and metabolism
JF - The Journal of clinical endocrinology and metabolism
IS - 8
ER -