Genetic variants in obesity-related genes and the risk of osteoporotic fracture. The Hortega Follow-up Study

Ana B García-García,Felipe J Chaves,Francisco Lara-Hernandez,Javier Martín-Vallejo,Jesica Abadía-Otero,Jose Luis Pérez-Castrillón,Juan Carlos Martín-Escudero,Laisa Briongos-Figuero,Ricardo Usategui-Martín,Soraya García-Sorribes

doi:10.31083/j.fbl2701032

Abstract

Osteoporosis and obesity are major public health problems that are closely correlated, as they share various features, including a genetic predisposition. A genetic correlation between obesity and osteoporosis due to the biological common pathways of bone and fat metabolism, which implies pleiotropic genes regulating has been described. The objective of our study was to analyse whether polymorphisms in obesity-related genes modify the risk of osteoporotic bone fracture.We studied 575 subjects from the Hortega Study. The subjects were followed-up for 12-14 years. 202 subjects were overweight, 143 obese and 221 had bone fractures. The distribution of 39 genetic variants in 22 obesity-related genes were studied.The results showed a relationship between polymorphisms in the FTO and NEGR1 genes and the susceptibility to osteoporotic fracture. The variant genotype of the rs2568958 NEGR1 polymorphism and the rs6499649, rs3751812, and rs8044769 genetic variants in FTO were associated with susceptibility to bone fracture. In the best of our knowledge, this is the first time that these variants in NEGR1 and FTO genes have been associated with the susceptibility to osteoporotic bone fracture, supporting the hypothesis that the NEGR1 and FTO genes might be candidates for osteoporosis and bone fracture.In conclusion, this study associates obesity-related polymorphisms in the NEGR1 and FTO genes with osteoporotic bone fracture, reinforcing the hypothesis that obesity and bone metabolism are closely correlated genetically.

Highlights

Osteoporosis (OMIM: 166710) is a chronic, progressive, silent, and systemic bone metabolism disease caused by reduced bone mineral density (BMD) and alterations in the tissue microarchitecture, increasing the risk of fragility fractures [1,2]
Various studies have summarized that genetic variants in NEGR1 are relationated with human body weight changes [38,53], and we found an association between the variant allele of the rs2568958 NEGR1 SNPs and body mass index (BMI)
The results showed that SNPs in the NEGR1 and FTO genes were associated with the risk of osteoporotic bone fracture

Summary

Introduction

Osteoporosis (OMIM: 166710) is a chronic, progressive, silent, and systemic bone metabolism disease caused by reduced bone mineral density (BMD) and alterations in the tissue microarchitecture, increasing the risk of fragility fractures [1,2]. The underlying pathological mechanism in osteoporosis is an unbalance between bone resorption and bone formation, which leads to increased bone fragility and higher risk of osteoporotic fracture [6]. Studies have shown that 50– 80% of the osteoporotic risk is explained by genetic variants, and multiple genes/loci have been associated with BMD phenotypes and fractures [7,8]. The objective of our study was to analyse whether polymorphisms in obesity-related genes modify the risk of osteoporotic bone fracture. The variant genotype of the rs2568958 NEGR1 polymorphism and the rs6499649, rs3751812, and rs8044769 genetic variants in FTO were associated with susceptibility to bone fracture. Conclusions: In conclusion, this study associates obesity-related polymorphisms in the NEGR1 and FTO genes with osteoporotic bone fracture, reinforcing the hypothesis that obesity and bone metabolism are closely correlated genetically

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Conclusion