Obesity Variants in the GIPR Gene Are not Associated With Risk of Fracture or Bone Mineral Density

Unnur Styrkarsdottir; Vinicius Tragante; Lilja Stefansdottir; Gudmar Thorleifsson; Asmundur Oddsson; Erik Sørensen; Christian Erikstrup; Peter Schwarz; Henrik Løvendahl Jørgensen; Jes Bruun Lauritzen; Søren Brunak; Kirk U Knowlton; Lincoln D Nadauld; Henrik Ullum; Ole Birger Vesterager Pedersen; Sisse Rye Ostrowski; Hilma Holm; Daniel F Gudbjartsson; Patrick Sulem; Kari Stefansson

doi:10.1210/clinem/dgad734

Obesity Variants in the GIPR Gene Are not Associated With Risk of Fracture or Bone Mineral Density

Unnur Styrkarsdottir
, Vinicius Tragante
, Lilja Stefansdottir
, Gudmar Thorleifsson
, Asmundur Oddsson
, Erik Sørensen
, Christian Erikstrup
, Peter Schwarz
, Henrik Løvendahl Jørgensen
, Jes Bruun Lauritzen
, Søren Brunak
, Kirk U Knowlton
, Lincoln D Nadauld
, Henrik Ullum
, Ole Birger Vesterager Pedersen
, Sisse Rye Ostrowski
, Hilma Holm
, Daniel F Gudbjartsson
, Patrick Sulem
, Kari Stefansson^*

^*Corresponding author for this work

Clinical Immunology

Research output: Contribution to journal › Article › Research › peer-review

Abstract

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.

Original language	English
Pages (from-to)	e1608-e1615
Journal	The Journal of clinical endocrinology and metabolism
Volume	109
Issue number	8
Early online date	20 Dec 2023
DOIs	https://doi.org/10.1210/clinem/dgad734
Publication status	Published - 12 Jul 2024

Keywords

Adult
Aged
Body Mass Index
Bone Density/genetics
Female
Fractures, Bone/genetics
Genetic Predisposition to Disease
Humans
Male
Middle Aged
Mutation, Missense
Obesity/genetics
Receptors, Gastrointestinal Hormone/genetics
Risk Factors

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10.1210/clinem/dgad734

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Styrkarsdottir, U., Tragante, V., Stefansdottir, L., Thorleifsson, G., Oddsson, A., Sørensen, E., Erikstrup, C., Schwarz, P., Jørgensen, H. L., Lauritzen, J. B., Brunak, S., Knowlton, K. U., Nadauld, L. D., Ullum, H., Pedersen, O. B. V., Ostrowski, S. R., Holm, H., Gudbjartsson, D. F., Sulem, P., & Stefansson, K. (2024). Obesity Variants in the GIPR Gene Are not Associated With Risk of Fracture or Bone Mineral Density. The Journal of clinical endocrinology and metabolism, 109(8), e1608-e1615. https://doi.org/10.1210/clinem/dgad734

@article{081723d793874df6b2df10e19a2b9394,

title = "Obesity Variants in the GIPR Gene Are not Associated With Risk of Fracture or Bone Mineral Density",

abstract = "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.",

keywords = "Adult, Aged, Body Mass Index, Bone Density/genetics, Female, Fractures, Bone/genetics, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Mutation, Missense, Obesity/genetics, Receptors, Gastrointestinal Hormone/genetics, Risk Factors",

author = "Unnur Styrkarsdottir and Vinicius Tragante and Lilja Stefansdottir and Gudmar Thorleifsson and Asmundur Oddsson and Erik S{\o}rensen and Christian Erikstrup and Peter Schwarz and J{\o}rgensen, \{Henrik L{\o}vendahl\} and Lauritzen, \{Jes Bruun\} and S{\o}ren Brunak and Knowlton, \{Kirk U\} and Nadauld, \{Lincoln D\} and Henrik Ullum and Pedersen, \{Ole Birger Vesterager\} and Ostrowski, \{Sisse Rye\} and Hilma Holm and Gudbjartsson, \{Daniel F\} and Patrick Sulem and Kari Stefansson",

note = "{\textcopyright} The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.",

year = "2024",

month = jul,

day = "12",

doi = "10.1210/clinem/dgad734",

language = "English",

volume = "109",

pages = "e1608--e1615",

journal = "The Journal of clinical endocrinology and metabolism",

issn = "0021-972X",

publisher = "Endocrine Society",

number = "8",

}

Styrkarsdottir, U, Tragante, V, Stefansdottir, L, Thorleifsson, G, Oddsson, A, Sørensen, E, Erikstrup, C, Schwarz, P, Jørgensen, HL, Lauritzen, JB, Brunak, S, Knowlton, KU, Nadauld, LD, Ullum, H, Pedersen, OBV, Ostrowski, SR, Holm, H, Gudbjartsson, DF, Sulem, P & Stefansson, K 2024, 'Obesity Variants in the GIPR Gene Are not Associated With Risk of Fracture or Bone Mineral Density', The Journal of clinical endocrinology and metabolism, vol. 109, no. 8, pp. e1608-e1615. https://doi.org/10.1210/clinem/dgad734

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 -

Obesity Variants in the GIPR Gene Are not Associated With Risk of Fracture or Bone Mineral Density

Abstract

Keywords

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