Effect of Adiposity on Bone Mineral Density in Adults
Objective The causal effect of adipose tissue on bone mass and the direction of its net influence have not been directly assessed in adult humans. Using the Mendelian randomization analysis, we assessed the causality of adiposity in measurements of bone mass in adult males and females.
Design and Methods Subjects consisted of 2154 adults aged 25–54 years from a cross-sectional cohort of the employees of the Electricity Generating Authority of Thailand. Body composition was determined after at least 3 h of fasting using multifrequency bioelectrical impedance analysis. Bone mineral density (BMD) was assessed by dual energy X-ray absorptiometry. A polymorphism in the fat mass and obesity-associated gene (FTO rs9939609) was used as an instrument in the Mendelian randomization analysis.
Results The genotype distribution of the FTO rs9939609 polymorphism was 61·1% TT, 33·9% AT and 5·0% AA. The average body mass index (BMI), body fat mass and percentage body fat were 23·9 kg/m (SD = 3·6), 17·9 kg (SD = 6·6) and 26·8% (SD = 7·2), respectively. The FTO rs9939609 polymorphism was significantly correlated with BMI (coefficient = 0·673 kg/m, P < 0·001), body fat mass (coefficient = 0·948 kg, P < 0·001) and percentage body fat (coefficient = 0·759%, P < 0·01). An instrumental variable (IV) regression model, using BMI as the intermediate phenotype, suggested that FTO was a strong IV. Also, the FTO-BMI polymorphism was significantly associated with total hip and femoral neck BMD but was not correlated with total spine BMD, with estimated correlation coefficients of 0·0189 (95% CI: 0·0046, 0·0332), 0·0149 (95% CI: 0·0030, 0·0268) and 0·0025 (95% CI: −0·0131, 0·0136) g/cm, respectively. The variances of BMDs explained by the FTO-BMI were 19·0%, 21·3% and 1·1%, respectively. Similar trends were also observed for the FTO-body fat mass and FTO-percentage body fat correlations.
Conclusions Mendelian randomization analysis suggests that adiposity might be causally related to BMD at the femur but not at the spine.
Osteoporosis is a health problem worldwide. A number of risk factors are related to susceptibility to osteoporosis, including oestrogen deficiency, sedentary lifestyle and reduced adiposity. Adipose tissue is now considered an endocrine organ. In addition to its conventional role in energy storage, adipose tissue secretes a number of bioactive proteins, which influence a variety of biological processes, including energy homoeostasis and inflammation. As far as bone is concerned, leptin, an adipokine secreted from adipose tissue, has been shown to diminish bone formation through a central nervous system delay in animal models. In humans, a number of adipokines, including leptin, adiponectin and omentin-1, have been shown in observational studies to be variably related to bone mineral density (BMD).
Although results from animal models and observational studies in humans suggest that adiposity influences bone mass, the effects of adipokines on bone mass are different. Results from observational studies can be confounded by factors, which influence both adiposity and bone mass, such as body size and weight. Moreover, the causality of adipose tissue on bone mass and the direction of net influence have not been directly assessed in adult humans.
The fat mass and obesity-associated (FTO) locus on chromosome 16 (16q12.2) has been identified from genome-wide association studies as a major candidate gene for obesity in children and adults. The FTO rs9939609 polymorphism is of particular interest, as it was found to be associated with obesity in different ethnic groups. The finding of common genetic variants of FTO, which have been consistently associated with adiposity, provided an opportunity to conduct a Mendelian randomization study of obesity and bone outcomes. Therefore, utilizing the Mendelian randomization analysis, we assessed the causality of adiposity in the attainment of BMD in adults.
Abstract and Introduction
Abstract
Objective The causal effect of adipose tissue on bone mass and the direction of its net influence have not been directly assessed in adult humans. Using the Mendelian randomization analysis, we assessed the causality of adiposity in measurements of bone mass in adult males and females.
Design and Methods Subjects consisted of 2154 adults aged 25–54 years from a cross-sectional cohort of the employees of the Electricity Generating Authority of Thailand. Body composition was determined after at least 3 h of fasting using multifrequency bioelectrical impedance analysis. Bone mineral density (BMD) was assessed by dual energy X-ray absorptiometry. A polymorphism in the fat mass and obesity-associated gene (FTO rs9939609) was used as an instrument in the Mendelian randomization analysis.
Results The genotype distribution of the FTO rs9939609 polymorphism was 61·1% TT, 33·9% AT and 5·0% AA. The average body mass index (BMI), body fat mass and percentage body fat were 23·9 kg/m (SD = 3·6), 17·9 kg (SD = 6·6) and 26·8% (SD = 7·2), respectively. The FTO rs9939609 polymorphism was significantly correlated with BMI (coefficient = 0·673 kg/m, P < 0·001), body fat mass (coefficient = 0·948 kg, P < 0·001) and percentage body fat (coefficient = 0·759%, P < 0·01). An instrumental variable (IV) regression model, using BMI as the intermediate phenotype, suggested that FTO was a strong IV. Also, the FTO-BMI polymorphism was significantly associated with total hip and femoral neck BMD but was not correlated with total spine BMD, with estimated correlation coefficients of 0·0189 (95% CI: 0·0046, 0·0332), 0·0149 (95% CI: 0·0030, 0·0268) and 0·0025 (95% CI: −0·0131, 0·0136) g/cm, respectively. The variances of BMDs explained by the FTO-BMI were 19·0%, 21·3% and 1·1%, respectively. Similar trends were also observed for the FTO-body fat mass and FTO-percentage body fat correlations.
Conclusions Mendelian randomization analysis suggests that adiposity might be causally related to BMD at the femur but not at the spine.
Introduction
Osteoporosis is a health problem worldwide. A number of risk factors are related to susceptibility to osteoporosis, including oestrogen deficiency, sedentary lifestyle and reduced adiposity. Adipose tissue is now considered an endocrine organ. In addition to its conventional role in energy storage, adipose tissue secretes a number of bioactive proteins, which influence a variety of biological processes, including energy homoeostasis and inflammation. As far as bone is concerned, leptin, an adipokine secreted from adipose tissue, has been shown to diminish bone formation through a central nervous system delay in animal models. In humans, a number of adipokines, including leptin, adiponectin and omentin-1, have been shown in observational studies to be variably related to bone mineral density (BMD).
Although results from animal models and observational studies in humans suggest that adiposity influences bone mass, the effects of adipokines on bone mass are different. Results from observational studies can be confounded by factors, which influence both adiposity and bone mass, such as body size and weight. Moreover, the causality of adipose tissue on bone mass and the direction of net influence have not been directly assessed in adult humans.
The fat mass and obesity-associated (FTO) locus on chromosome 16 (16q12.2) has been identified from genome-wide association studies as a major candidate gene for obesity in children and adults. The FTO rs9939609 polymorphism is of particular interest, as it was found to be associated with obesity in different ethnic groups. The finding of common genetic variants of FTO, which have been consistently associated with adiposity, provided an opportunity to conduct a Mendelian randomization study of obesity and bone outcomes. Therefore, utilizing the Mendelian randomization analysis, we assessed the causality of adiposity in the attainment of BMD in adults.
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