Journal Article

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

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

2024

Overview

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.

• Publisher: Oxford University Press
• Subject: Adult / Aged / Biotechnology industry / Body Mass Index / Body weight loss / Bone density / Bone Density - genetics / Bone mass / Bone mineral density / Bones / Care and treatment / Density / Dual energy X-ray absorptiometry / Ethylenediaminetetraacetic acid / Female / Fractures / Fractures, Bone - epidemiology / Fractures, Bone - genetics / Genes / Genetic Predisposition to Disease / GIP protein / Glutamine / Glycine / Humans / Male / Middle Aged / Mutation, Missense / Obesity / Obesity - genetics / Osteoporosis / Post-menopause / Postmenopausal women / Receptor density / Receptors, Gastrointestinal Hormone - genetics / Risk Factors / Spine (lumbar) / Type 2 diabetes / Vertebrae / Weight control