Assuntos
Doença de Alzheimer , Glicoproteínas de Membrana , Receptores Imunológicos , Idoso , Feminino , Humanos , Masculino , Doença de Alzheimer/etnologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Apolipoproteínas E/metabolismo , LDL-Colesterol/metabolismo , Clusterina/metabolismo , Predisposição Genética para Doença/genética , Homozigoto , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Mutação de Sentido Incorreto , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismoRESUMO
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.
Assuntos
Densidade Óssea , Fraturas Ósseas , Obesidade , Receptores dos Hormônios Gastrointestinais , Humanos , Densidade Óssea/genética , Feminino , Receptores dos Hormônios Gastrointestinais/genética , Fraturas Ósseas/genética , Fraturas Ósseas/epidemiologia , Obesidade/genética , Pessoa de Meia-Idade , Masculino , Idoso , Adulto , Mutação de Sentido Incorreto , Predisposição Genética para Doença , Índice de Massa Corporal , Fatores de RiscoRESUMO
Musculoskeletal research should synergistically investigate bone and muscle to inform approaches for maintaining mobility and to avoid bone fractures. The relationship between sarcopenia and osteoporosis, integrated in the term 'osteosarcopenia', is underscored by the close association shown between these two conditions in many studies, whereby one entity emerges as a predictor of the other. In a recent workshop of Working Group (WG) 2 of the EU Cooperation in Science and Technology (COST) Action 'Genomics of MusculoSkeletal traits Translational Network' (GEMSTONE) consortium (CA18139), muscle characterization was highlighted as being important, but currently under-recognized in the musculoskeletal field. Here, we summarize the opinions of the Consortium and research questions around translational and clinical musculoskeletal research, discussing muscle phenotyping in human experimental research and in two animal models: zebrafish and mouse.