Yingying Hu

The levels of bone turnover markers in Chinese postmenopausal women: Peking Vertebral Fracture study.

Objective:The aim of this study was to evaluate serum N-aminoterminal propeptide of type I collagen (P1NP), C-terminal telopeptide of type I collagen (&bgr;-CTX), and vitamin D status in healthy Chinese postmenopausal women. The study was also designed to investigate their possible relationships with osteoporosis phenotypes. Methods:A community-based population of 1,724 postmenopausal women in Beijing was randomly selected. Serum bone turnover markers and 25-hydroxyvitamin D [25(OH)D] were tested by an automated Roche electrochemiluminescence system. Dual-energy x-ray absorptiometry was used to measure bone mineral density (BMD). Results:The mean (SD) values of serum &bgr;-CTX and P1NP were 0.439 (0.210) and 56.7 (27.9) ng/mL, respectively. The 25(OH)D level of postmenopausal women in Beijing was remarkably low (13.2 ± 5.4 ng/mL). Serum &bgr;-CTX and P1NP levels were negatively correlated with BMDs of lumbar spine, femoral neck, and total hip (all P < 0.01). The cubic regression model better fitted the relationships of BMD and bone turnover markers. Serum &bgr;-CTX levels were significantly higher in women with sustained osteoporotic fracture or vertebral fracture (P = 0.006 and 0.012, respectively). No association between P1NP and fracture or vertebral fracture was detected. The same situation applied to 25(OH)D. 25(OH)D was negatively correlated with &bgr;-CTX and P1NP (r = −0.073 and −0.088, P = 0.002 and <0.001, respectively). Conclusions:Serum &bgr;-CTX and P1NP levels were negatively correlated with BMD. &bgr;-CTX was significantly higher in postmenopausal women with sustained fracture or vertebral fracture. Vitamin D deficiency was highly prevalent in postmenopausal women in Beijing.

Three Novel Mutations of the PHEX Gene in Three Chinese Families with X-linked Dominant Hypophosphatemic Rickets

X-linked dominant hypophosphatemia (XLH, OMIM307800), the most prevalent form of inherited rickets in humans, is a dominant disorder of phosphate homeostasis characterized by growth retardation, rachitic and osteomalacic bone disease, hypophosphatemia, and renal phosphate wasting. The gene responsible for XLH was identified by positional cloning and designated PHEX (formerly PEX) to depict a phosphate-regulating gene homologous with endopeptidases on the X chromosome. Recently, extensive mutation analysis of the PHEX gene has revealed a wide variety of gene defects in XLH. The ethnic distribution of the mutations is very widespread but only a few mutations in Chinese have been reported. To analyze the molecular basis in three unrelated Chinese families with XLH, we determined the nucleotide sequence of the PHEX gene and fibroblast growth factor 23 (FGF23) gene of affected members. The serum FGF23 concentrations of these patients with XLH were also measured. Three different novel mutations were observed in these three families: one deletion mutation c.264delG causing p.W88 X; one missense mutation c.1673C>G causing p.P558A; one nonsense mutation c.1809G>A causing p.W603 X. Serum concentration of FGF23 in XLH patients of these three families was significantly higher than normal. The results suggest that PHEX gene mutations were responsible for XLH in these patients and these mutations may contribute to a higher serum FGF23 level.

The efficacy and safety of calcitriol and/or Caltrate D in elderly Chinese women with low bone mass.

AbstractAim:To observe the efficacy and safety of Rocaltrol (calcitriol) and/or Caltrate D (calicum carbonate plus vitamin D) in elderly Chinese women with osteopenia or osteoporosis.Methods:One hundred fifty Chinese women aged over 65 years with osteopenia or osteoporosis from three centers were randomly divided into two groups. Seventy-six participants received Caltrate D as one pill daily; the other 74 participants received 0.25 μg Caltrate D plus Rocaltrol daily. The changes in bone mineral density (BMD) served as primary end-points. Height changes, the presence of new vertebral fractures, muscle strength and balance were evaluated.Results:The following are the mean percentage changes (and SD) in BMD over 12 months: at L2-L4, 0.83±3.88 in the Caltrate D group and 2.84±4.04 in the Rocaltrol+Caltrate D group (P=0.003, by ANCOVA); at the femoral neck, 0.04±3.94 in the Caltrate D group and 2.01±5.45 in the Rocaltrol+Caltrate D group (P=0.085, by ANCOVA); and in the trochanter, 1.59±4.57 in the Caltrate D group and 3.76±6.25 in the Rocaltrol+Caltrate D group (P=0.053, by ANCOVA). The stand and maximal forward reach test (SMFRT) was significantly enhanced in both groups during the 12 months of treatment, but no significant differences were found between these two groups. No severe adverse event related to these medications occurred throughout the study.Conclusion:Treatment with Rocaltrol plus Caltrate D or Caltrate D for 12 months in elderly Chinese postmenopausal women effectively increased BMD at the lumbar spine. Rocaltrol plus Caltrate D was more effective at the lumbar spine than Caltrate D alone.

Chinese Bone Turnover Marker Study: Reference Ranges for C-Terminal Telopeptide of Type I Collagen and Procollagen I N-Terminal Peptide by Age and Gender

Background Bone formation marker procollagen I N-terminal peptide (PINP) and resorption marker C-terminal telopeptide of type I collagen (β-CTX) are useful biomarkers for differential diagnosis and therapeutic evaluation of osteoporosis, but reference values are required. Methods The multi-center, cross-sectional Chinese Bone Turnover Marker Study included 3800 healthy volunteers in 5 Chinese cities. Serum PINP, β-CTX, parathyroid hormone (PTH) and 25OHD levels were measured by chemiluminescence assay. Lumbar spine and proximal femur BMD were measured by dual-energy X-ray absorptiometry. Serum PINP and β-CTX levels were assessed by age, gender, weight, recruitment latitude, levels of PTH and 25OHD. Results Subjects (n = 1436, M∶F, 500∶936; mean age 50.6±19.6 years) exhibited non-normally distributed PINP and β-CTX peaking between 15–19 years, gradually declining throughout adulthood, elevating within 10 years of postmenopause, and then declining by age 70. In women between the age of 30 and menopause, median PINP and β-CTX levels were 40.42 (95% CI: 17.10–102.15) and 0.26 (95% CI: 0.08–0.72) ng/mL, respectively. β-CTX and PINP were positively linearly correlated (r = 0.599, P<0.001). β-CTX correlated positively (r = 0.054 and 0.093) and PINP correlated negatively (r = −0.012 and −0.053) with 25OHD and PTH (P<0.05). Conclusions We established Chinese reference ranges for PINP and CTX. Chinese individuals exhibited high serum PINP and β-CTX levels between 15 and 19 years of age and at menopause, which gradually declined after 70 years of age.

Novel mutations of CYP27B1 gene lead to reduced activity of 1α-hydroxylase in Chinese patients.

Pseudovitamin D-deficiency rickets (PDDR) is an autosomal recessive disorder resulting from a defect in renal 25-hydroxyvitamin D 1α-hydroxylase, the key enzyme in the pathway of vitamin D metabolism. We identified ten different mutations in the 1α-hydroxylase gene (CYP27B1) in eight Chinese families with PDDR by DNA-sequence analysis. Six of them are novel missense mutations: G57V, G73W, L333F, R432C, R459C, and R492W; three are novel deletion mutations: c48-60del, c1310delG, and c1446delA; and an insertion mutation c1325-1332insCCCACCC reported previously. Functional assay revealed that the missense mutants identified in this study retain 5.5-12.1% 1α-hydroxylase activity of the wild type. The study describes nine novel mutations in addition to 37 known mutations of CYP27B1 gene and shows the correlation between these mutations and the clinical findings of 1α-hydroxylase deficiency.

Germinal mosaicism of GATA3 in a family with HDR syndrome

Germinal Mosaicism of GATA3 in a Family With HDR Syndrome Yue Sun, Weibo Xia,* Xiaoping Xing, Mei Li, Ou Wang, Yan Jiang, Yu Pei, Ping Ye, Huaicheng Liu, Yingying Hu, Xunwu Meng, and Xueying Zhou Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China Department of Endocrinology, Second Artillery Forces General Hospital, People’s Liberation Army, Beijing, China Dalian Red Cross Blood Center, Dalian, Liaoning Province, China

Clinical phenotypes of Chinese primary hyperparathyroidism patients are associated with the calcium-sensing receptor gene R990G polymorphism

OBJECTIVE The purpose of this study was to investigate the distribution of the A986S and R990G polymorphisms of the calcium-sensing receptor (CASR) gene in the Chinese population and whether there is an association between genetic variants and the risk of developing primary hyperparathyroidism (PHPT) and its associated clinical phenotypes. METHODS A total of 164 Chinese Han PHPT patients (M/F: 51/113) and 230 healthy controls (M/F: 50/180) were enrolled. The common clinical parameters of PHPT patients including biochemical markers, bone mineral density (BMD), kidney stone occurrence, and pathology results were analyzed. Genotyping was conducted for both the patients and controls, and it was carried out using standard procedures. RESULTS The R990G variant was more frequently present than the A986S variant in this group of Chinese PHPT patients. The R allele increased the risk of PHPT (odds ratio=1.134, 95% CI: 1.008, 1.277, and P=0.036). Patients with either the RR or RG genotype had lower blood calcium levels and higher alkaline phosphate levels than patients with the GG genotype. The lumbar BMD T-score was -2.20 (-2.63, -0.32) in patients with the GG genotype, and it was significantly lower in patients with the RR+RG genotype (-2.53 (-3.70, -1.72) P=0.036). Patients with the R allele had a significantly higher incidence of hyperplasia (25.0%) and carcinomas (7.1%) than those with the GG genotype (5.3 and 0% respectively; P=0.025). The prevalence of osteoporosis and parathyroid carcinomas was higher in Chinese PHPT patients with the R allele. CONCLUSION The R990G polymorphism is most frequently present in the Chinese population and among patients with PHPT. Additional studies in the Chinese population are needed to elaborate the relationship between genetics and PHPT.

Clinical and Genetic Analysis of Multiple Endocrine Neoplasia Type 1-Related Primary Hyperparathyroidism in Chinese.

Objective Multiple endocrine neoplasia type 1-related primary hyperparathyroidism (MHPT) differs in many aspects from sporadic PHPT (SHPT). The aims of this study were to summarize the clinical features and genetic background of Chinese MHPT patients and compare the severity of the disease with those of SHPT. Design and Methods A total of 40 MHPT (27 sporadic, 7 families) and 169 SHPT cases of Chinese descent were retrospectively analyzed. X-rays and ultrasound were used to assess the bone and urinary system. Dual energy x-ray absorptiometry (DXA) were performed to measure bone mineral density (BMD). Besides direct sequencing of the MEN1 and CDKN1B genes, multiplex ligation-dependent probe amplification (MLPA) was used to screen gross deletion for the MEN1 gene. Results Compared with SHPT patients, MHPT patients showed lower prevalence of typical X-ray changes related to PHPT (26.3% vs. 55.7%, P = 0.001) but higher prevalence of urolithiasis/renal calcification (40.2% vs. 60.0%, P = 0.024). MHPT patients showed higher phosphate level (0.84 vs. 0.73mmol/L, P<0.05) but lower ALP (103.0 vs. 174.0U/L, P<0.001) and PTH (4.0 vs. 9.8×upper limit, P<0.001) levels than SHPT patients. There were no significant differences in BMD Z-scores at the lumbar spine and femoral neck between the two groups. Mutations in the MEN1 gene were detected in 27 MHPT cases. Among the nine novel mutations were novel, one of them involved the deletion of exon 5 and 6. Conclusions MHPT patients experienced more common kidney complications but less skeletal issues, and a milder biochemical manifestation compared with SHPT patients. MEN1 mutation detection rate was 79.4% and 9 of the identified mutations were novel.

A haplotype of MATN3 is associated with vertebral fracture in Chinese postmenopausal women: Peking Vertebral Fracture (PK-VF) study.

The Matrilin3 gene (MATN3) encodes an extracellular matrix protein, which modulates chondrocyte differentiation. The aim of this study was to test for association of MATN3 polymorphisms with bone mineral density (BMD), fracture, vertebral fracture, bone turnover or 25-hydroxyvitamin D [25(OH)D] in postmenopausal women. A community-based population of 1488 postmenopausal women was randomly selected in Beijing. The history of fracture and vertebral fracture was obtained via questionnaire and vertebral X-ray respectively. BMD of lumbar spine (2-4), femoral neck and total hip were measured by dual energy X-ray absorptiometry. Serum N-terminal procollagen of type 1 collagen (P1NP), β-isomerized type I collagen C-telopeptide breakdown products (β-CTX) and 25(OH)D were quantified. Binary logistic regression revealed that Haplotype-4 was significantly associated with vertebral fracture risk in both additive model (p=0.023, OR=1.521) and dominant model (p=0.028, OR=1.623). The significance remained after 10,000 permutation tests to correct multiple testing (p=0.042). Re-selected age matched vertebral fracture case-control groups revealed similar associations in additive model (p=0.014, OR=1.927, 95%CI=1.142-3.253) and in dominant model (p=0.011, OR=2.231, 95%CI=1.200-4.148). However, no significant association was found between MATN3 polymorphisms and serum β-CTX, P1NP, 25(OH)D levels, or BMD. In linear regression, Haplotype-2 approached marginal significance in association with femoral neck BMD T-score (p=0.050), but this would account for only 0.2% of BMD variation in our sample. This study suggests that Haplotype-4 of MATN3 is associated with vertebral fracture risk independent of BMD in Chinese postmenopausal women. Efforts should be made to replicate our finding in other, similar and ethnically diverse, populations.

Mutation update and short-term outcome after treatment with active vitamin D 3 in Chinese patients with pseudo-vitamin D-deficiency rickets

Summary Pseudovitamin D-deficiency rickets is a rare disease which is caused by CYP27B1. In this study, we identified 9 mutations in 7 PDDR patients. In addition, we observed the response to long-term treatment of calcitriol in 15 Chinese patients with PDDR, which showed that the biochemical abnormalities had been corrected satisfactorily after 1-year treatment.