| Background and Objective: Primary Osteoporosis(OP)is a kind of bone metabolic disease that seriously affects human health.OP is characterized as low bone mineral mass(BMD)and bone microstructure changes,leading to osteoporotic fracture.OP mainly occurred in postmenopausal women.OP susceptibility is affected by genetic factors,environmental factors and gene-environment interactions.Long non-coding RNA(lnc RNA),as an important functional RNA molecule,regulates the differentiation and function of osteoblasts and osteoclasts and affects the occurrence and development of OP.Studies have shown that genetic variations of lnc RNA influence the susceptibility to OP.Our preliminary study has mined out lnc RNA-UC002 yug.2 from the chromosome 21 reported to be related with high susceptibility to OP.We found UC002 yug.2 played an important role in reducing osteoblast proliferation and promoting osteoclast differentiation due to estrogen deficiency.In this study,we explored the association of lnc RNA-UC002 yug.2 genetic variation and its interaction with environmental factors with OP susceptibility.Furthermore,we analyzed the role of the positive genetic variation in UC002 yug.2structure,the interaction between UC002 yug.2-mi RNA and the function of UC002 yug.2,aiming to find out the potential susceptibility gene and provide new ideas for the prevention of OP.Methods: 1.The clinical data and blood samples of 258 OP patients and 168 controls were randomly collected by epidemiological methods.Single nucleotide polymorphisms(SNPs)of lnc RNA-UC002 yug.2,i.e.,rs6517274,rs2246640 and rs2070369,were genotyped by allele-specific PCR.2.The effect of lnc RNA-UC002 yug.2 SNP and environmental factors on OP susceptibility was analyzed by non-conditional logistic regression model.The optimal model of UC002 yug.2-environment factors influencing OP susceptibility was analyzed by general multifactor dimensional reduction(GMDR);the influence of the optimal model on OP susceptibility was assessed by logistic regression model.3.For the positive UC002 yug.2 SNP,its effect on the secondary structure of UC002 yug.2 transcript was analyzed by RNAfold;the interaction between UC002 yug.2-mi RNA influenced by the positive SNP was analyzed by the lnc RNASNP database;the functions of positive UC002 yug.2 SNP was annotated by Regulome DB and Haplo Reg databases.Results: 1.UC002 yug.2 rs2246640(C>T)is associated with OP susceptibility(OR=1.851,95%CI=1.047-3.275,p=0.034),and rs2246640-T is a risk allele for primary OP(OR=1.382,95%CI=1.046-1.826,p=0.023).2.Rs2246640,body mass index(BMI)and physical activity have an interactive effect on OP susceptibility(Testing Bal.Acc.=0.677,CVC=10/10,p=0.001).Low BMI,rs2246640-T allele,and low physical activity are risk factors for OP susceptibility(OR=19.050,95%CI=1.267-86.441,p=0.033).3.UC002 yug.2 rs2246640(C>T)changes the secondary structure of UC002 yug.2 transcript,increasing its stability(rs2246640-C: MFE=-361.40 kcal/mol;rs2246640-T: MFE=-359.70kcal/mol);rs2246640(C>T)enables UC002 yug.2 to acquire hsa-mir-501-5p binding site,but destroyed its binding sites with hsa-mir-3934-3p and hsa-mir-574-3p;The location of rs2246640 in chromosome is the site of transcription factor binding as well as the region of DNA enzyme hypersensitivity,which could affect the binding of transcription factors,including NF-κB and CTCF,with UC002 yug.2,and change the motif of interferon regulatory factor(IRF).Conclusion: 1.UC002 yug.2 rs2246640(C>T)is associated with OP susceptibility,rs2246640-T is a risk allele for primary OP.2.Rs2246640,BMI and physical activity have an interactive effect on OP susceptibility.Low BMI,rs2246640-T allele,and low physical activity are risk factors for OP susceptibility.3.The association of UC002 yug.2 rs2246640 with OP susceptibility may be related to its alteration on the secondary structure of UC002 yug.2 transcript,and its impact on UC002 yug.2-mi RNA interaction as well as the function of UC002 yug.2. |
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