Min-jia Zhang

Analysis of Recently Identified Osteoporosis Susceptibility Genes in Han Chinese Women

BACKGROUND In Europeans and populations of European origin, several osteoporosis susceptibility genes, including ZBTB40, RANK, RANKL, OPG, MHC, and ESR1, were recently identified. However, none of these has been fully investigated in Han Chinese populations. OBJECTIVE AND DESIGN In this relatively large cross-sectional sample of 1012 Han Chinese women, 21 single-nucleotide polymorphisms (SNPs) within 11 candidate genes that were newly identified in Europeans were tested, and their associations with bone mineral densities (BMDs) and osteoporotic fracture were investigated. RESULTS A total of 21 SNPs were genotyped. Five SNPs in four genes [ZBTB40 (rs7524102, rs6696981), ESR1 (rs9479055), OPG (rs6469804), and RANK (rs3018362)] were found to be associated with lumbar spine BMD. Seven SNPs in five genes [ZBTB40 (rs7524102, rs6696981), OPG (rs6993813, rs6469804), RANK (rs3018362), LRP5 (rs3736228), and SOST (rs1513670)] were found to be associated with total hip BMD. SPTBN1 (rs11898505) and SOST (rs1107748) were associated with osteoporotic fracture. A significant gene-gene interaction for osteoporotic fracture involving rs1107748 in SOST and rs6469804 in OPG gene was identified from generalized multifactor dimensionality reduction analysis. CONCLUSIONS Our study provides an independent replication of the associations between several SNPs in ZBTB40, ESR1, OPG, RANK, LRP5, and SOST with lumbar spine and/or total hip BMDs in a large sample of Han Chinese women. The results of this study further support the significant associations found between osteoporotic fracture and SNPs in SPTBN1 and SOST. Our results suggest that these variants represent osteoporosis susceptibility genes in both Han Chinese and European populations.

The Changing Clinical Patterns of Primary Hyperparathyroidism in Chinese Patients: Data from 2000 to 2010 in a Single Clinical Center

CONTEXT In Western countries, most patients with primary hyperparathyroidism (PHPT) are asymptomatic. The incidence of parathyroid cancer is as low as 1% but is trending upward. The clinical outlook for Chinese patients with PHPT is unclear. OBJECTIVE Our objective was to describe the changing clinical patterns of benign and malignant PHPT in Chinese patients from 2000 to 2010. DESIGN AND SETTING This was a cross-sectional study. SUBJECTS A total of 249 patients with PHPT were studied. MAIN OUTCOME MEASURES The clinical manifestations and biochemical abnormalities of PHPT were analyzed. RESULTS Of our patients with PHPT, 61.4% were symptomatic, but asymptomatic PHPT has increased from <21% in 2000-2006 to 42.4% to 52.5% in 2007-2010. Of asymptomatic patients, 48.9% came to our center because of elevation of serum calcium levels, and another 46.9% came because of parathyroid nodule(s) incidentally discovered by thyroid ultrasonography, with a steady increase from 18.3% before 2007 to 35.7% in 2007-2008 and 61.5% in 2009-2010. Serum calcium and PTH concentrations greater than 2.77 mmol/L (area under the curve, 0.995; P < .001) and 316.3 pg/dL (area under the curve, 0.842; P < .001), respectively, are responsible for symptom development. The occurrence of parathyroid carcinoma was as high as 5.96%, but a trend downward from 10.53% to 4.44% was observed. CONCLUSIONS The overall clinical and biochemical features of PHPT in Chinese patients are still classic, but the disease is now evolving into a more asymptomatic type. The incidental parathyroid lesion captured by routine neck ultrasonography was the leading cause for such a dramatic change. The high incidence of parathyroid carcinoma is now decreasing.

Interactions of osteoporosis candidate genes for age at menarche, age at natural menopause, and maximal height in Han Chinese women.

Objective:Age at menarche (AAM), age at natural menopause (ANM), and maximal height are closely related to bone mineral densities and osteoporosis. It is still unclear whether osteoporosis susceptibility genes are also associated with AAM, ANM, and maximal height in Chinese women. Methods:In this relatively large cross-sectional sample of 722 Han Chinese postmenopausal women, 22 single nucleotide polymorphisms (SNPs) within 12 osteoporosis candidate genes that were identified from genome-wide association studies and replicated in our previous study were studied. The effects of a single gene on the AAM, ANM, and maximal height were investigated by linear regression analysis, whereas the gene-gene interactions were determined by a generalized multifactor dimensionality reduction method. Results:It was revealed that the major histocompatibility complex (MHC) gene (rs3130340) was associated with ANM even after Bonferroni correction (P = 0.001). A significant gene-gene interaction for ANM involving rs3130340 in MHC, rs1038304 and rs4870044 in estrogen receptor-&agr; gene (ESR1), and a significant three-SNP interaction model (SNP rs2273061 in jagged1, SNP rs6929137 in ESR1, and SNP rs2306033 in low-density lipoprotein receptor-related protein 4) for maximal height were identified. No single or combined effect of tested SNPs on AAM was discovered. Conclusions:Our study indicates that osteoporosis susceptibility SNPs, such as ESR1 (rs1038304, rs4870044, rs6929137), MHC (rs3130340), low-density lipoprotein receptor-related protein 4 (rs2306033), and jagged1 (rs2273061), might independently and/or in an interactive manner influence ANM and maximal height. All the SNPs tested had no association with AAM.

Serum Sema3A Is in a Weak Positive Association With Bone Formation Marker Osteocalcin But Not Related to Bone Mineral Densities in Postmenopausal Women

CONTEXT The chemorepellent semaphorin-3A (Sema3A) was shown to favor bone metabolism in mice, but its bone effects in humans are not described. OBJECTIVE The aim of the study was to investigate the associations between serum Sema3A, bone biochemical markers, and bone mineral densities (BMDs) in women. DESIGN, SETTING, AND PARTICIPANTS This was a cross-sectional study involving 1012 pre- and postmenopausal women. MAIN OUTCOME MEASURES Fasting serum Sema3A, osteocalcin (Ocn), and cross-linked C-telopeptide of type 1 collagen were measured. Dual-energy X-ray absorptiometry was performed to determine the BMDs at the lumbar spine and femoral neck. History of osteoporotic fractures was reported by the participants. RESULTS In postmenopausal women (n = 860), a significant positive association between Sema3A and Ocn levels was demonstrated (r = 0.077, P = 0.025) when age was adjusted. The serum Ocn level was significantly higher in the fourth quartile of serum Sema3A as compared with the first quartile (21.09 ± 0.56 ng/mL vs 19.45 ± 0.44 ng/mL, P = .018). Serum Sema3A concentrations were similar in subjects with normal BMD, osteopenia or osteoporosis, and those with and without osteoporotic fractures. Multivariate stepwise regression analysis revealed that cross-linked C-telopeptide of type 1 collagen, body mass index, creatinine, Sema3A, L1-4 BMDs, and age were determinants of Ocn (adjusted R(2) for the model = 0.532, P < .001) . CONCLUSIONS The positive correlation between Sema3A and bone formation marker Ocn revealed in this human study partly supports the recently findings in mice studies. However, the general effects of Sema3A on bone metabolism are weak and not clear as evidenced by lack of association between this parameter and BMDs and osteoporotic fractures.

PTH inhibition rate is useful in the detection of early-stage primary hyperparathyroidism.

OBJECTIVE This study was to establish biochemical thresholds for the intravenous calcium suppression test in the early diagnosis of primary hyperparathyroidism (PHPT). DESIGN AND METHODS One hundred and thirty-three patients were divided into three groups: Group 1: surgically proven hypercalcemic PHPT, Group 2 surgically proven mild PHPT, and Group 3: normocalcemia with elevated serum PTH levels. Intravenous calcium suppression tests were performed in Groups 2 and 3 as well as in 20 controls with normal serum calcium and PTH concentrations. RESULTS The serum PTH inhibition rate (PTH-IR) was less pronounced in Group 2 compared with Group 3 (P<0.001) and the controls (P<0.001). Receiver operating characteristic curve analysis suggests that a serum calcium level higher than 2.43mmol/L and a PTH-IR less than 73% may differentiate Group 2 from normal controls. CONCLUSION It is quite useful to combine serum calcium levels with the PTH-IR to identify patients at early stage of PHPT, even in the presence of vitamin D deficiency.

Identification of two novel mutations in the GALNT3 gene in a Chinese family with hyperphosphatemic familial tumoral calcinosis

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare, autosomal recessive genetic disease. This disease is characterized by the progressive calcification of soft tissues leading to symptoms of pressure and hyperphosphatemia but normal concentrations of serum calcium with or without an elevation of 1,25-dihydroxyvitamin D3 levels.HFTC is caused by loss-of-function mutations in the GALNT3, FGF23 or KL genes. Here, we identified two novel mutations in the GALNT3 gene in a Chinese family with HFTC. Identification of a novel genotype in HFTC provides clues for understanding the phenotype–genotype relationships in HFTC and may assist not only in the clinical diagnosis of HFTC but also in the interpretation of the genetic information used for prenatal diagnosis and genetic counseling.

The relationship among serum lipocalin 2, bone turnover markers, and bone mineral density in outpatient women

PurposeWe aimed to investigate associations among serum levels of LCN2, bone resorption marker carboxy-terminal cross-linking telopeptide of type-1 collagen (CTx), bone formation marker osteocalcin (OCN), and bone mineral densities (BMDs) in ambulatory healthy women.MethodsThis cross-sectional study analyzed 1012 previously enrolled outpatient Han Chinese women. BMDs of the lumbar spine and femoral neck were measured using dual energy X-ray absorptiometry. Serum levels of LCN2, CTx, OCN, and creatinine (Scr) were measured.ResultsCirculating LCN2 was inversely correlated with BMDs at the lumbar spine and femoral neck (Spearman’s r = −0.08, P = 0.010 and r = −0.14, P < 0.001; respectively). A significant positive correlation between LCN2 and CTx (r = 0.11, P < 0.001), OCN (r = 0.06, P = 0.047), age (r = 0.21, P < 0.001), and Scr (r = 0.24, P < 0.001) was also observed. After adjusting for age and Scr, the correlation among LCN2, BMDs and OCN disappeared, but LCN2 was still positively associated with CTx (r = 0.08, P = 0.010). The circulating concentration of LCN2 showed no significant difference between subjects with and without osteoporotic fractures (43.63 (35.29, 53.66) vs. 42.25 (34.43, 51.46) ng/ml, respectively, P = 0.111). Serum CTx concentrations rose with serum LCN2 increasing from the lowest to the highest quartile (P for trend = 0.005), even after adjusting for age and Scr (P for trend = 0.040). In multivariate regression analysis, LCN2 was one of the main determinants for changes in serum CTx (standard β = 0.061, P = 0.005).ConclusionsIn ambulatory healthy women, the relationships among serum LCN2 level, BMDs, and OCN were confounded by age and Scr. Although LCN2 was positively related with CTx, the correlation was very weak and may not be physiologically relevant.