1, SOST Gene And DKK1 Gene Polymorphism And Alendronate Sodium In The Treatment Of Postmenopausal Osteoporosis 2, Bruck Syndrome, Adrenal White Matter Malnutrition Gene Mutation Study

Objective:Wnt pathway is a critical regulator for activities of osteoblasts, which exerts an important role in net gain of bone mass during anti-osteoporotic treatment. Sclerostin （SOST） and Dickkopf1（DKK1） are inhibitors for Wnt pathway. The aim of this study was to investigate the relationship of SOST and DKK1gene polymorphisms with response to alendronate （ALN） in Chinese postmenopausal women with osteoporosis, and to evaluate the effect of different doses of ALN on life quality of patients.Methods:632postmenopausal osteoporotic or osteopenia women （average aged62.40±6.83years） were recruited from seven clinical centers of Beijing, Shanghai, Changsha, Chengdu, Xi’an, Guangzhou, Harbin. They randomly received low dose （70mg/2w） or standard dose （70mg/w） of alendronate （ALN） for one year. Serum β-isomerized carboxy-telopeptide of type I collagen （p-CTX） and total alkaline phosphatase （ALP） levels at baseline,3months and12months of ALN treatment were assessed by chemiluminescence immunoassay and automatic analyser, respectively. Bone mineral density （BMD） at lumbar spine2-4（L2-4）, femoral neck （FN） and total hip （TH） at baseline,6months and12months of treatment was measured by dual-energy x-ray absorptiometry. Six tag single nucleotide polymorphisms （SNP） of SOST, one reported loci of SOST associated with BMD and five tag SNP of DKK1were determined by TaqMan allelic discrimination assay. General linear model-analysis of covariance, linear regression and partial correlation were used for association analysis of SOSTand DKK1polymorphisms with bone turnover marker levels and BMD at baseline, and changes in them after ALN treatment. For participants included in our center, the quality of life was evaluated by SF-36, including eight sections of physical functioning （PF）, role-physical （RP）, bodily pain （BP）, general health （GH）, vitality （VT）, social functioning （SF）, role-emotional （RE）, mental health （MH）.Results:Serum bone turnover marker levels were significantly decreased （P<0.01） and BMD at all sites was obviously increased （P<0.05） after12months of ALN treatment. A total of545DNA samples were suitable for genetic analysis. SOST rs1234612polymorphism was associated with baseline L2-4BMD and percentage change of L2-4BMD after12months of treatment （P=0.044and0.015, respectively）. SOSTrs851054polymorphism was associated with baseline serum ALP levels and L2-4BMD （P=0.003and0.020, respectively）. SOST rs865429polymorphism was associated with percentage change of FN BMD after12months of treatment （P=0.030）. SOST rs1513670polymorphism was associated with percentage change of serum ALP levels after3months of treatment （P=0.005）. DKK1rs1896367polymorphism was associated with baseline BMD at L2-4, FN and TH （P=0.029,0.017and0.002, respectively）. DKK1rs1528877polymorphism was associated with baseline serum β-CTX levels and TH BMD （P=0.046and0.006, respectively）. DKK1rs2241529polymorphism was associated with baseline serum β-CTX levels, L2-4BMD and percentage change of TH BMD after12months of treatment （P=0.032,0.025and0.040, respectively）.92women in our center completed the observation of life quality during the treatment. The scores of PF （P=0.006）, RP （P=0.002）, BP （P=0.033）, VT （P=0.006） and RE （P=0.011） were significantly increased after the treatment of standard-dose ALN. The scores of PF （P=0.015）, GH （P=0.000） and SF （P=0.041） were significantly increased after the treatment of low-dose ALN.Conclusions:Treatment with ALN of70mg/w or70mg/2w could not only effectively reduce serum bone turnover marker levels, increase BMD at lumbar spine and proximal femur in postmenopausal women with osteopenia or osteoporosis, but also improve the quality of life of the patients. SOST and DKK1may be important candidate genes for predicting the impact of ALN on bone turnover biochemical markers and BMD, which may provide preliminary evidence for individualized treatment according to genotypes of the patients in future. Further studies in larger sample population is needed to explore the detail molecular mechanism, of which SOST and DKK1polymorphisms affect the efficacy of bisphosphonates. Objective:Bruck syndrome （BS） is an extremely rare disease characterized by recurrent fractures, congenital joints contractures and short stature. We screened mutations in FKBP10and PLOD2and described the phenotypes in two Chinese patients with BS.Methods:Two patients from two different healthy non-consanguineous families were studied. BS was diagnosed according to the specific clinical manifestations, bone mineral density, X-ray films of skull and long bone. Mutation analysis was performed by PCR amplification and direct sequencing of all the exons and exon-intron junctions of FKBP10and PLOD2. Both of the two patients were treated with bisphosphonates.Results:Novel compound heterozygous mutations of c.764₇72dup （p.257₂58insHVL） in exon5and c.1405G>T （p.G469X） in exon9of FKBP10were identified in one proband. Novel compound heterozygous mutations of c.1624delT （p.Y542Tfs*18） in exon14and c.1880T>C （p.V627A） in exon17of PLOD2were detected in another probrand. Their parents were asymptomatic heterozygous carriers of these mutations. Bone mineral density of the two patients was significantly increased and their activity abilities were also significantly improved after bisphosphonates treatment.Conclusions:This is the first report of BS in Asians. The novel mutations in FKBP10and PLOD2not only expanded the genotypic spectrum of BS, but also indicated that FKBP10and PLOD2exerted an important role in pathophysiological process of BS through affecting molecular stability and post-translational modification of type I procollagen. Objective:Adrenoleukodystrophy （ALD） is a very rare X-linked recessive inherited disease which is related to mutation of ABCD1gene. We analysed the clinical features of two kindred with ALD and detected the mutations of ABCD1gene.Methods:A Chinese ALD kindred with four affected males in four-generation and another Chinese ALD kindred with only one affected boy in two-generation were studied. ALD was diagnosed according to clinical manifestation, abnormal cranial MRI image and increased serum very long chain fatty acid （VLCFA） level. Mutations of ABCD1were detected by direct DNA sequencing of polymerase chain reaction amplification product.Results:Primary adrenocortical insufficiency and neurological dysfunction were the main manifestations of the patients. MRI image indicated extensive cerebral white matter demyelination. Serum VLCFA levels were significantly high. A novel missense substitution （c.1850G>T） in exon8of ABCD1was identified in the first family and another missense mutation （c.1849C>G） at the close position in exon8of ABCD1was identified in the second family. All affected males were hemizygotes and female carriers were heterzygotes.Conclusions:The typical manifestations of ALD were primary adrenocortical insufficiency and neurological dysfunction. A missense substitution （c.1850G>T） in exon8of ABCD1was novel mutation firstly detected in this Chinese pedigree with ALD.