Relationship Of Osteoprotegerin,different Types Of Obesity,Lipid Accumulation Product With Osteoporosis

Osteoporosis(OP)is a complex disease caused by a variety of risk factors,and its influencing factors mainly include genetic factors and non-genetic factors.In the term of genetic factors,a number of osteoporosis-related genetic loci have been discovered in genome-wide association scan studies(GWASs),in which osteoprotegerin(OPG)is used as a research hotspot and it is significantly correlated with bone mineral density(BMD)but the related mechanisms of action are very complex and rarely explored.In addition,osteoporosis is affected by non-genetic factors,such as other diseases and physical status.Among them,the relationship between obesity and osteoporosis is very close,but the correlation between obesity and osteoporosis is still unclear,and the results of previous epidemiological analysis are controversial.We have found that this controversy may be due to the different options of mechanical loading adjustment.In addition,we also found that the obesity-related indices used in the study of obesity and osteoporosis are conventional,and some new and diagnostic indicators for obesity have not been studied.Therefore,this study explores the relationship of OPG,different types of obesity,lipid accumulation product index(LAP)with osteoporosis in three chapters,respectively,to further reveal the influencing factors of osteoporosis.Chapter I:The importance of hot spot gene OPG to osteoporosis is determined through integration analysis.Chapter II:Controlling the mechanical loading of weight and fat free mass(FFM)and exploring the effects of different types of obesity on BMD.Chapter III:Exploring the correlation between LAP and osteoporosis,a new obesity-related indicator,the difference in gender,and the ability of LAP to predict osteoporosis risk.Chapter IObjectivePerform integrative analysis to confirm the importance of OPG on osteoporosis.MethodsThe integrative analysis started with gene-based association analysis to evaluate the entire effect of OPG for osteoporosis with the publicly available datasets(The GEnetic Factors for OSteoporosis consortium,GEFOS-2),then performed expression quantitative trait loci(eQTLs)confirmation to test the regulation effect of the studied variants on mRNA expression,and meta-analysis of focused single nucleotide polymorphism(SNP)to combine the existing association results,finally,performed luciferase reporter assays in 293T cells to validate the functions of the focused SNP in vitro.ResultsIn the gene-based association analysis,the gene-based P values for OPG were 6.24×10-13 for femoral neck(FN)and 7.37×10-17 for lumbar spine(LS),which confirmed the importance of OPG for osteoporosis.The eQTL results confirmed 5 SNPs with eQTL effects,exerting cis-regulation effects on OPG at FN and LS.Further analyses found that rs2073617(as known as T950C,located in the promoter region)was the hot SNP and finally 13 other relevant studies have been investigated besides the study offered by GEFOS.Meta-analyses with 7 related studies showed that there were significant differences among TT,TC and CC genotypes in BMD at FN(P=0.047)and LS(P=0.025).LS-BMD and FN-BMD were significantly lower in individuals with TT genotypes than TC or CC genotypes.CC genotypes had significant higher BMD at LS and FN than TC genotypes(P<0.001).Individuals with TT homozygote had lower BMD and CC homozygote had higher BMD at LS and FN than others(P<0.001).Furthermore,luciferase gene expression was significantly higher in the presence of allele C in 293T cell.ConclusionsThis study took OPG as an example,and by integrative analyses provided additional evidence in supporting the importance of OPG and variant(T950C)on osteoporosis.Our results would further increase our understanding on complex relationship between OPG and osteoporosis,and more likely provide useful example for other genes research.Chapter ?ObjectiveExplore the effects of general,central and lower limp obesity on osteoporosis with control of the mechanical loading.MethodsA total of 3,749 community residents aged>65 years were included in this chapter.Each subject was measured for BMD using dual-energy X-ray absorptiometry(DEXA)bone densitometer and for body composition using the bioelectrical impedance analyzer.Linear regression analyses were performed under three conditions(unadjusted,adjusted with weight and adjusted with FFM).ResultsUnder no adjustment of loading,three general obesity parameters,body mass index(BMI),fat mass(FM),and percentage FM(PFM)were significantly(P<0.001)and positively associated with BMD at three skeletal sites.However,after the adjustment with weight,these associations are still significant but reverse i.e.,negatively in direction(e.g.,PFM,?=-0.185,P<0.001 for FN-BMD),except for BMI and BMD at total hip(TH).After the adjustment with FFM,the three parameters are still positively and significantly(P<0.001)associated with BMD but the regression coefficients of these associations were smaller when compared to the unadjusted associations.Similar associations were observed for the study of the central adiposity indices(trunk-PFM and trunk-FM)and lower limb adiposity indices(lower limb-PFM and lower limb-FM).ConclusionsThis study is the first time to explore the complex relationship between different types of obesity and osteoporosis and to evaluate the overall impact of different choices of mechanical loading on their relationship.The results would improve our understanding on their relationship,and provide helpful directions on the adjustment of mechanical loading on association study between obesity and osteoporosis.Chapter ?ObjectiveIn the previous part,we studied several conventional obesity-related indices and osteoporosis.The purpose of this chapter is to analyze the correlation between the new index LAP and osteoporosis,and its differences in gender.Compare the association of LAP with conventional obesity-related indices.Assess whether the newly added index,LAP,increases the ability of predicting the risk of osteoporosis and how much it increases.MethodsThe subjects were from the Osteoporosis Preventive Project implemented in two community health service centers in Suzhou in 2017 and 2018.The two samples included 2,128 and 3,384 permanent residents aged ? 65 years.These participants received anthropometric measurements,questionnaires,bone density measurements,body composition measurements,and blood biochemical tests.Regression and correlation analysis,multiple linear regression analysis and cluster analysis were performed in the two samples to assess the extent of correlation;Receiver operating charac-teristic curve and Area Under the Curv(AUC),Net Reclassification Improvement(NRI)and Integrated Discrimination Improvement(IDI)were calculated to risk prediction capabilities.The above analysis was performed separately in the male and female groups in the two samples.ResultsIn both samples,multiple linear regression analysis showed that LAP and all conventional obesity-related indices were significantly positively correlated with BMD at three sites(P<0.001).The results were the same in different gender groups.Cluster analysis showed LAP and PFM were classified into one category.After the adjustment of PFM,the positive correlation between LAP and BMD in the three sites was still statistically significant(P<0.01).The same results were obtained in the male samples,while in the female samples,2017-LS and 2018-FN were meaningless(P>0.05).The LAP was added to the predictive model including the PFM to form a new model.There was no statistically significant difference between AUCs before and after the addition of LAP in all BMD measurement sites.IDI and NRI were statistically significant(P<0.05),except for 2017-FN-IDI.The results of the two samples were consistent.In the male samples,the AUC differences of 2017-TH,2017-FN,2018-TH and 2018-LS were statistically significant(P<0.05),and the IDI and NRI of all sites were statistically significant(P<0.05).The results in the female sample lack consistency.ConclusionsConsistent with other conventional obesity-related indicators,the new index LAP also demonstrated a positive correlation between obesity and osteoporosis.The correlation between LAP and osteoporosis is not more close than conventional obesity-related indicators,but its correlation is independent of PFM.Furthermore,the addition of LAP improves the accuracy of osteoporosis risk prediction and is more valuable for improving the predictive accuracy of male samples.