Genomic Study On The Effect Of Resistance Exercise On Individual Differences In Bone Mineral Density Of Postmenopausal Women

Objective:Osteoporosis(OP)is one of the main diseases that seriously affect the quality of life of postmenopausal women.The golden standard bone density of OP is determined by genetic and environmental factors.Resistance exercise can effectively improve bone density,but there are large individual differences in intervention effects.In this study,we selected gene combinations(panel)associated with OP to analyze single nucleotide polymorphisms(SNPs)and methylation sites associated with bone density to construct a prediction model of the individual effects of bone density resistance exercise intervention.Through bioinformatics analysis,exploring the potential functions of SNPs and methylation in the improvement of bone density by resistance exercise.To provide a theoretical basis for postmenopausal women to choose personalized and precise exercise and fitness guidance programs.Methods:Study 1:A total of 441 postmenopausal women(age:62±5 years,BMI:25.2±3.3 kg/m~2)were recruited in this study.Dual-energy X-ray bone densitometer(GE-Lunar Prodigy)was used to test the bone density of femoral neck and lumbar spine.2ml of venous blood was collected,and the whole blood DNA was extracted using a medium-volume whole blood genomic DNA extraction kit(Bio Te Ke).Massarray technology was used for SNP typing of 90 candidate gene loci.The genetic predisposition score(GPS)was calculated using the positively associated SNPs.GTEx database was used to analyze the expression of positive sites in various tissues of the human body.Massarray mass spectrometry DNA methylation technology was used to detect DNA methylation of genes related to bone mineral density.Study 2:A total of 65 postmenopausal women volunteered to participate in resistance exercise intervention(age:65±5 years,BMI:24.8±2.9 kg/m~2).The resistance exercise program is 2 times a week,60 minutes each time(5-10 minutes for warm-up,40-45 minutes for training,5-10 minutes for cool-down),the training cycle is 16 weeks.Gene combination(panel)and bioinformatics analysis methods are the same as research 1.0.PLINK and SPSS23.0 software were used to analyze the data.Results:Study 1:1)At the initial value,6 SNPs(OPG rs3102735,rs3134069;RANK rs884205;DKK1 rs11001553;RSPO3 rs13209747;ESR1 rs2228480)were significantly associated with femoral neck bone mineral density(all p<0.05),2 SNPs(ESR1 rs1801132;SOST rs851054)were significantly associated with lumbar bone mineral density(both p<0.05).2)At the initial value,GPS was significantly positively correlated with femoral neck and lumbar bone mineral density(both p<0.01).Each additional"favorable"allele in GPS increased the femoral neck and lumbar bone mineral density by 0.011g/cm~2 and 0.024 g/cm~2,respectively.GPS can explain the difference between 4.7%and 2.2%of the initial values of femoral neck and lumbar spine bone mineral density(R~2=0.047,0.022,both p<0.01).3)The e QTL results showed that the minor allele(T)of rs851054 was significantly related to the low expression level of SOST in arteries(p<0.05).4)At the initial value,there was no significant correlation between the DNA methylation level and the bone mineral density of the femoral neck and lumbar vertebrae(all p>0.05).5)Only the GPS model can explain 0.5%and 0.3%of individual differences in femoral neck and lumbar bone mineral density.Only the MS model can explain 2.4%and 4.6%of the individual differences in femoral neck and lumbar bone mineral density.The combined GPS and MS model can explain 4.1%and 7.7%of the individual differences in femoral neck and lumbar bone mineral density,but no statistical significance exists.Study 2:1)After intervention of 16 weeks,6 SNPs(OPG rs1023968,rs2073618;DKK1 rs1896367;SFRP4 rs1052981;RSPO3 rs13209747;MEF2C rs34316)were significantly associated with?femoral neck bone mineral density(%)(all p<0.05),8SNPs(ESR1 rs1062577,rs3798577,rs3798758;OPG rs2073617;SOST rs865429;Wnt5B rs2010851,rs3803164;SFRP4 rs1802074)were significantly associated with?lumbar bone mineral density(%)(all p<0.05).2)After intervention of 16 weeks,GPS was significantly positively correlated with?femoral neck and lumbar bone mineral density(%)(both p<0.01).As one"favorable"allele in GPS increased,the bone mineral density(%)of the femoral neck and lumbar spine increased by 0.8%and 0.786%,respectively.GPS can explain 36.5%and 21.8%of the difference in the training effect of femoral neck and lumbar bone mineral density(R~2=0.365,0.218,both p<0.01).3)Compared with the GPS<6(n=31)group,the bone mineral density(%)of the femoral neck and lumbar spine increased significantly(-1.37%vs.0.88%,-3.56%vs.0.05%,both p<0.05)in the GPS?6(n=34)group after intervention of 16weeks.4)The e QTL results showed that the sub-allelic(T)of rs1896367 was significantly correlated with the low expression level of DKK1 in the adrenal gland(p<0.05);the sub-allelic(C)of rs34316 was related to the low expression of MEF2C in the bone-muscle significantly(p<0.05);the minor allele(T)of rs1802074 was significantly correlated with the low expression level of SFRP4 in arteries(p<0.05).5)There were significant differences in DNA methylation levels of ESR1 and SOST genes before and after exercise intervention(91.03±2.01%vs.90.07±2.51%;81.95±3.85%vs.83.29±2.91%,both p<0.05).6)After intervention of 16 weeks,?DKK1 methylation(%)and?femoral neck bone mineral density(%)were positively correlated significantly(both p<0.05).For every increase in?DKK1 methylation(%),?femur Neck bone density(%)increased by 0.025%.?DKK1 methylation(%)can explain the individual difference of 6.1%(R~2=0.061,p<0.05)?femoral neck bone mineral density(%).7)Only the GPS model can explain 3.4%and 6.9%of the difference in the training effect of femoral neck and lumbar spine bone mineral density.Only the MS model can explain 2.5%and 4.8%of the training effect difference in bone mineral density between the femoral neck and lumbar spine.The combined GPS and MS model can explain 4.8%and 7.4%of the individual training effect differences in femoral neck and lumbar bone mineral density,but but no statistical significance exists.Conclusions:Study 1:GPS can predict the individual difference of initial bone mineral density of femoral neck and lumbar spine.The higher the GPS of postmenopausal women,the higher bone mineral density of femoral neck and lumbar spine in the initial values.Study 2:1)GPS can significant predictive the increase of bone mineral density of femoral neck and lumbar spine after exercise.Subjects with GPS?6 can improve bone mineral density through resistance exercise,indicating that the effect of resistance exercise on bone mineral density may be related to genotype.2)DKK1 gene methylation can be used as an epigenetic marker to predict the difference in the training effect of femoral neck bone mineral density.