| Background:Osteoporosis has become a public health problem around the world with the aging of the population. Primary osteoporosis is a complex disease involved in genetic and environmental factors. Domestic and foreign scholars have carried out a lot of researches about its genetic mechanism. Recently, the pharmacogenetics studies exploring the association between the genetic variation of the candidate genes and the effect of anti-osteoporosis drugs have been paid more attention to. However, the pharmacogenetics study in Chinese patients with osteoporosis is limited. Alendronate is one of the most widely used anti-osteoporosis drugs. While, little is known about the association between the candidate genes of osteoporosis and the efficacy of alendronate in women with postmenopausal osteoporosis.Objective:Nitrogen-containing bisphosphonates inhibit osteoclast function through interfering the mevalonate pathway, and geranylgeranyl diphosphate synthase1(GGPS1) is a key enzyme of this pathway. This prospective, multi-center, large sample pharmacogenetics study tried to explore the association between GGPS1polymorphisms and response of nitrogen-containing bisphosphonate alendronate treatment in Chinese women with postmenopausal osteoporosis.Subjects and Methods:632postmenopausal osteoporotic or osteopenia women from seven cities of Beijing, Shanghai, Changsha, Chengdu, Xi’an, Guangzhou, Harbin were enrolled and randomly assigned to low dose (70mg/2w) or conventional dose group (70mg/w) with alendronate (produced by Shijiazhuang Ouyi Pharmaceutical Co., Ltd.) in the1-year study. All the patients took1Caltrate D tablet (produced by Wyeth, containing600mg elemental calcium and125international units vitamin D3) daily. Before and after treatment, serum calcium, phosphate, and bone turnover biochemical markers (alkaline phosphatase, ALP; cross linked C-telopeptide of type I collagen, CTX) levels were measured. Serum CTX level is measured using electrochemiluminescence immunoassay (the kit is produced by Roche Diagnostics Co.,LTD., Germany), and the coefficient of variation (CV) of intra-assay and inter-assay were2.2-4.6%,2.5-4.7%, respectively. Serum25(OH)D concentration before treatment is also measured using electrochemiluminescence immunoassay (the kit is produced by Roche Diagnostics Co.,LTD., Germany), and the coefficient of variation (CV) of intra-assay and inter-assay were4.1-5.7%,6.6-9.9%, respectively. Bone mineral density (BMD) at lumbar spine and proximal femur were measured by dual energy x-ray absorptiometry (DXA) before and after treatment. Lunar and Hologic scanners were used in different research centers. The six tag single nucleotide polymorphisms of GGPS1(rs2803851、rs2789367、rs10802624、rs1092553、 rs3840452、rs2789366) were genotyped using TaqMan SNP Genotyping Assays and short tandem repeat (STR) respectively. The accuracy of genotyping was confirmed by direct sequencing of PCR products. Then we studied the association between the six SNPs and the baseline BMD, serum bone turnover biochemical markers (ALP, CTX),25(OH)D levels. We further studied the association between the six SNPs and the change percentage of bone turnover biochemical markers and BMD after alendronate treatment in Chinese women with postmenopausal osteoporosis.Results:1. The genotype frequencies of A/A, A/-,-/-of rs3840452in this population were58.4%,35.6%,6.0%, and the frequencies of alleles A,-were76.2%,23.8%, which were similar to those of Korean. The genotype frequencies of AA, AG, GG of rs2803851were65.5%,30.5%,4.0%, and the frequencies of alleles A, G were80.7%,19.3%. The genotype frequencies of CC, CG, GG of rs2789367were58.2%,35.1%,6.7%, and the frequencies of alleles C, G were75.7%,24.3%. The genotype frequencies of AA, AG, GG of rs10802624were61.9%,32.9%,5.2%, and the frequencies of alleles A, G were78.4%,21.6%. The genotype frequencies of TT, TC, CC of rs10925503were31.5%,45.5%,23.0%, and the frequencies of alleles T, C were54.2%,45.8%. The genotype frequencies of rs2803851, rs2789367, rs10802624, rs10925503in this population were consistent with those of Han nationality population in Beijing from HapMap database, but different from those in populations of Japan, Europe and Africa, and the differences with the European and African populations were greater. The genotype frequencies of CC, CT, TT of rs2789366were61.2%,33.6%,5.2%, and the frequencies of alleles C, T were78%,22%. The genotype frequencies of rs2789366have not been reported in other populations.2. At baseline, there were312(49.4%) osteopenia and162(25.6%) osteoporotic women in lumber spine, and42(6.6%) osteopenia and504(79.7%) osteoporotic women in femoral neck. After3months treatment, serum bone turnover biochemical markers decreased significantly. Serum ALP and CTX decreased by (-18.3±19.5)%,(-38.7±70.9)%respectively in low dose group, and (-24.9±18.8)%,(-57.8±73.3)%in conventional dose group.After12months treatment,serum ALP and CTX decreased by (-20.0±29.1)％,(-42.7±73.5)％respectively in low dose group,and(-25.1±28.8)％,(-53.0±72.4)％in conventional dose group.After6months treatment,BMD at lumbar spine and proximal femur increased significantly.BMD at Iumbar spine,femoral neck, trochanter,total hip increased by(3.7±4.8)％,(2.6±37.3)％,(3.6±5.2)％,(7.8±47.8)％respectively in low dose group,and(4.1±5.1)％,(-2.3±10.1)％,(3.3±6.0)％,(2.9±4.8)％in conventional dose group.After12months treatment,BMD at1umbar spine,femoral neck,trochanter,total hip increased by(6.4±8.8)％,(4.0±33.9)％,(5.0±13.1)％,(7.2±42.9)％respectively in low dose group,and(2.2±8.1)％,(-1.8±13.9)％,(2.7±12.5)％,(1.4±8.9)％in conventional dose group.3.Baseline serum CTX levels were0.45±0.02,0.41±0.02,0.36±0.02ng/ml respectively in women carrying TT,TC,CC genotypes in rs10925503,and the differences were statistically significant (P=0.012).Baseline serum CTX leve1was higher in women carrying TT genotype.4.After3months treatment in low dose group,the change percentages of ALP were (-14.9±2.3)％,(-22.5±3)％,(-28.5士5.7)％respectiVely in women carrying CC,C G,GG genotypes in rs2789367,and ALP deereased more in women carrying GG genotype(P=0.031.5.After6months treatment in conventional dose group,the change percentages of BMD at trochanter were(5.9±1.0)％,(2.3±0.8)％,(3.0±1.3)％respectively in women carrying TT,TC,CC genotypes in rs10925503,BMD increased more in women carrying TT genotype (P=0.019).The change percentages of BMD at trochanter were(4.5±0.6)％,(1.7±0.9)％,(1.5±3.3)％respectively in women carrying CC,C T,TT genotypes in rs2789366,BMD increased more in women carrying CC genotype (P=0.048).After6months treatment in converttional dose group,the response rates of total hip BMD were86.3％,89.1％,66.7％respectively in women carrying TT,TC,CC genotypes in rsl0925503,and the response rate was significantly lower in women carrying CC genotype((P=0.015).6.After12months treatment in conventional dose group,the response rates of total hip BMD were74.1％,72.7％,28.6％respectively in women carrying A/A,A/-,-/-genotypes in rs3840452,and the response rate was significantly lower in women carrying-/-genotype(P=0.034).The response rates of total hip BMD were75.7％,70.3％,33.3％ respectively in women carrying CC, CG, GG genotypes in rs2789367, and the response rate was significantly lower in women carrying GG genotype (P=0.025). The response rates of total hip BMD were73.8%,73.3%,28.6%respectively in women carrying AA, AG, GG genotypes in rs10802624, and the response rate was significantly lower in women carrying GG genotype (P=0.034). The response rates of trochanter BMD were66.7%,85.1%,62.8%respectively in women carrying TT, TC, CC genotypes in rsl0925503, and the response rates of total hip BMD were70.7%,79.7%,58.1%. The differences were statistically significant, and the response rates were lower in women carrying CC genotype at these two sites (P=0.011, P=0.044).7. After6months and12months treatment in low dose group, the change percentages and the response rates of BMD at lumbar spine and proximal femur were not significantly different between different genotypes in the six SNPs of GGPS1(P>0.05).Conclusion:1. The genotype frequencies of rs3840452in Chinese postmenopausal women with osteoporosis were similar to those of Korean. The genotype frequencies of rs2803851, rs2789367, rs10802624, rs10925503in this population were different from those in populations of Japan, Europe and Africa. The genotype frequencies of rs2789366have not been reported in other populations, and this study firstly reported the genotype frequencies of rs2789366in Chinese women with postmenopausal osteoporosis.2. Baseline bone resorption level was higher in patients carrying TT genotype in rs1092550.3. After3months treatment in low dose group, ALP decreased more in women carrying GG genotype in rs2789367.4. After6months treatment in conventional dose group, BMD at trochanter increased more in women carrying TT genotype in rs10925503, and the response rate of total hip BMD was significantly lower in women carrying CC genotype. BMD at trochanter increased more in women carrying CC genotype in rs2789366. These results indicated that the allele T and C were more sensitive to treatment respectively in rsl0925503and rs2789366.5. After12months treatment in conventional dose group, the response rate of total hip BMD was significantly lower in women carrying-/-genotype in rs3840452. The response rate of total hip BMD was significantly lower in women carrying GG genotype in rs2789367. The response rate of total hip BMD was significantly lower in women carrying GG genotype in rs10802624. The response rates of trochanter and total hip BMD were lower in women carrying CC genotype in rs10925503. These results indicated that the allele A, C, A, T were more sensitive to treatment respectively in rs3840452, rs2789367, rs10802624, rs10925503.6. After6months and12months treatment in low dose group, the change percentages and the response rates of BMD at lumbar spine and proximal femur were not significantly different between different genotypes in the six SNPs of GGPS1.7. The study firstly reported that the gene polymorphisms of GGPS1encoding geranylgeranyl diphosphate synthase1, a key enzyme of the mevalonate pathway, may have effect on the response of alendronate treatment in Chinese women with postmenopausal osteoporosis. GGPS1may be an important candidate gene for predicting the impact of bisphosphonates on bone turnover biochemical markers and BMD. Further study in larger sample population is needed to explore the specific molecular mechanism by which GGPS1polymorphisms affect the efficacy of bisphosphonates. |
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