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

PURPOSE: We 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. METHODS: This 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. RESULTS: Circulating 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 ß = 0.061, P = 0.005). CONCLUSIONS: In 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.

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.

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.

The influence of the genetic and non-genetic factors on bone mineral density and osteoporotic fractures in Chinese women.

To investigate the effects of genetic and non-genetic factors on bone mineral densities (BMDs) and osteoporotic fractures. This was a cross-sectional study to investigate the relationships between 18 SNPs and non-genetic factors with BMDs and osteoporotic fractures in 1012 Chinese Han women. Five SNPs in genes GPR177, CTNNB1, MEF2C, SOX6, and TNFRSF11B were associated with L1-4 or total hip BMDs. rs11898505 in SPTBN1 gene was associated with osteoporotic fractures. Subjects carrying the largest number of risk alleles (highest 10 %) not only had lower BMD values as compared to those carrying the least number of risk alleles (lowest 10 %), they also had a higher risk of fracture [P = 0.002, OR = 2.252, 95 %CI (1.136, 4.463)]. Results from multivariate stepwise regression analysis revealed that age [P < 0.001, OR = 1.038, 95 % CI (1.018, 1.058)], number of falls in a year [P < 0.001, OR = 2.347, 95 % CI (1.459, 3.774)], the G risk allele in rs11898505 [P = 0.023, OR = 1.559, 95 % CI (1.062, 2.290)], and the L1-4 BMD [P = 0.017, OR = 0.286, 95 % CI (0.102, 0.798)] were associated with the occurrence of osteoporotic fractures. Genetic (rs11898505) and non-genetic factors (age, number of falls in a year and L1-4 BMD) could work in concert to contribute to the risk of osteoporotic fractures.

Post-genome wide association studies and functional analyses identify association of MPP7 gene variants with site-specific bone mineral density.

Our previous genome-wide association study (GWAS) in a Hong Kong Southern Chinese population with extreme bone mineral density (BMD) scores revealed suggestive association with MPP7, which ranked second after JAG1 as a candidate gene for BMD. To follow-up this suggestive signal, we replicated the top single-nucleotide polymorphism rs4317882 of MPP7 in three additional independent Asian-descent samples (n= 2684). The association of rs4317882 reached the genome-wide significance in the meta-analysis of all available subjects (P(meta)= 4.58 × 10(-8), n= 4204). Site heterogeneity was observed, with a larger effect on spine than hip BMD. Further functional studies in a zebrafish model revealed that vertebral bone mass was lower in an mpp7 knock-down model compared with the wide-type (P= 9.64 × 10(-4), n= 21). In addition, MPP7 was found to have constitutive expression in human bone-derived cells during osteogenesis. Immunostaining of murine MC3T3-E1 cells revealed that the Mpp7 protein is localized in the plasma membrane and intracytoplasmic compartment of osteoblasts. In an assessment of the function of identified variants, an electrophoretic mobility shift assay demonstrated the binding of transcriptional factor GATA2 to the risk allele 'A' but not the 'G' allele of rs4317882. An mRNA expression study in human peripheral blood mononuclear cells confirmed that the low BMD-related allele 'A' of rs4317882 was associated with lower MPP7 expression (P= 9.07 × 10(-3), n= 135). Our data suggest a genetic and functional association of MPP7 with BMD variation.

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-α 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.

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.

Relationships between serum levels of thyroid hormones and serum concentrations of asymmetric dimethylarginine (ADMA) and N-terminal-pro-B-type natriuretic peptide (NT-proBNP) in patients with Graves' disease.

Endothelial dysfunction as well as abnormal thyroid hormone levels may be responsible for increased cardiovascular risk in Graves' disease (GD). Asymmetric dimethylarginine (ADMA) and N-terminal-pro-B-type natriuretic peptide (NT-proBNP) are new markers of endothelial and myocardial dysfunction, respectively. The purpose of this study was to investigate the relationship among the serum levels of ADMA, NT-proBNP, and thyroid hormones in GD patients. This was a cross-sectional investigation conducted in a university teaching hospital. Two hundred and thirty-nine GD (Female: 182, Male: 57) patients and 81 normal controls were enrolled in this study. Serum levels of ADMA were positively related with FT3 (r = 0.584, P < 0.001), FT4 (r = 0.551, P < 0.001), and TRAb levels (r = 0.502, P < 0.001). Serum NT-proBNP levels were positively associated with FT3 (r = 0.243, P < 0.001) and FT4 levels (r = 0.274, P < 0.001), as well as heart rate (r = 0.271, P < 0.03). The elevation of serum ADMA and NT-proBNP levels were also observed in patients with controlled hyperthyroidism. It is thus concluded that serum ADMA and NT-proBNP levels were increased in GD patients. Future studies may determine the usefulness of these two biomarkers to detect early signs of endothelial dysfunction, vascular stiffness, and fluid volume in GD patients.

Lymph node uptake of 18F-fluorodeoxyglucose detected with positron emission tomography/computed tomography mimicking malignant lymphoma in a patient with Kikuchi disease.

[18]F-Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is sensitive in detecting a variety of malignancies; however, the specificity is low in differential infections or inflammatory diseases from tumors. We present the case of a female with right cervical lymphadenopathy and fever for 3 weeks who underwent an 18F-FDG PET/CT scan. The imaging showed multiple lymph node enlargement and agglomeration with increased metabolic activity even with the involvement in the abdomen, giving the impression of malignant lymphoma. However, biopsy of the affected nodes proved it to be Kikuchi-Fujimoto disease and the patient was cured after steroid therapy.

F-18 FDG PET/CT in primary tonsillar lymphoma.

Non-Hodgkin lymphomas quite often present in the head and neck but primary tonsillar lymphomas of extranodal non-Hodgkin lymphomas are far less than 1% of head and neck malignancies. Reports of F-18 fluorodeoxyglucose positron emission tomography (F-18 FDG PET/CT) related to primary tonsillar lymphoma are seldom. A 59-year-old man suffered from painful swelling of the bilateral tonsil. Biopsy diagnosed diffuse large B-cell lymphoma. F-18 FDG PET/CT was performed for disease staging. Whole-body F-18 FDG PET/CT revealed the intense FDG uptake of bilateral tonsil with an additional small lymph node in the right side of the neck. This case also highlights the usefulness of staging and assessing therapy response in rare types of lymphoma.

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.

Association of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies.

Bone mineral density (BMD), a diagnostic parameter for osteoporosis and a clinical predictor of fracture, is a polygenic trait with high heritability. To identify genetic variants that influence BMD in different ethnic groups, we performed a genome-wide association study (GWAS) on 800 unrelated Southern Chinese women with extreme BMD and carried out follow-up replication studies in six independent study populations of European descent and Asian populations including 18,098 subjects. In the meta-analysis, rs2273061 of the Jagged1 (JAG1) gene was associated with high BMD (p = 5.27 x 10(-8) for lumbar spine [LS] and p = 4.15 x 10(-5) for femoral neck [FN], n = 18,898). This SNP was further found to be associated with the low risk of osteoporotic fracture (p = 0.009, OR = 0.7, 95% CI 0.57-0.93, n = 1881). Region-wide and haplotype analysis showed that the strongest association evidence was from the linkage disequilibrium block 5, which included rs2273061 of the JAG1 gene (p = 8.52 x 10(-9) for LS and 3.47 x 10(-5) at FN). To assess the function of identified variants, an electrophoretic mobility shift assay demonstrated the binding of c-Myc to the "G" but not "A" allele of rs2273061. A mRNA expression study in both human bone-derived cells and peripheral blood mononuclear cells confirmed association of the high BMD-related allele G of rs2273061 with higher JAG1 expression. Our results identify the JAG1 gene as a candidate for BMD regulation in different ethnic groups, and it is a potential key factor for fracture pathogenesis.

Tumor necrosis factor alpha (TNF-alpha) polymorphisms in Chinese patients with Graves' disease.

OBJECTIVES: Tumor necrosis factor alpha (TNF-alpha) may play a central role in the development of Graves' disease (GD). The aim of this study was to investigate the association of TNF-alpha polymorphisms with GD in Chinese population. DESIGN AND METHODS: Genomic DNA was extracted from peripheral blood lymphocyte of 436 GD patients and 316 control subjects. TNF-alpha polymorphisms at positions -308 (G-308A, rs1800629), -238 (G-238A, rs361525), and +419 (G+419A, rs3093661) were genotyped. RESULTS: The distribution of TNF-alpha -238 and +419 allelic frequencies between GD and control individuals was significantly different. Both the G alleles of TNF-alpha -238 (OR 2.385, 95%CI 1.359-4.184) and +419 (OR 2.293, 95%CI 1.303-4.035) SNPs conferred higher risk of GD as compared with A alleles. No significant difference of -308 allelic frequency was observed. Further haplotype analysis revealed that the haplotype GGG was associated with an increased risk of GD (OR 1.554, 95%CI 1.125-2.146), whereas the haplotype GAA was found to be protective (OR 0.419, 95%CI 0.239-0.736). CONCLUSIONS: This study demonstrated the association of TNF-alpha gene with GD in Chinese patients.

Clinical associations of the genetic variants of CTLA-4, Tg, TSHR, PTPN22, PTPN12 and FCRL3 in patients with Graves' disease.

OBJECTIVE: Graves' disease (GD) is an organ-specific autoimmune disorder. Both immune-modulating genes and thyroid-specific genes are involved in its genetic pathogenesis. It remains unclear, however, how the interactions of various susceptibility genes contribute to the pathogenesis and clinical severity of the disease. The purpose of this study was to investigate the relationships between GD and single nucleotide polymorphisms (SNPs) from CTLA-4, PTPN22, PTPN12, FCRL3 (general autoimmunity genes regulating T and B cells) and the TSHR and Tg genes (disease-specific genes). Furthermore, we evaluated the influences these SNPs have on the risk and severity of GD. DESIGN AND METHODS: This cross-sectional clinical study was performed in 436 GD patients and 316 healthy, gender-matched individuals. Twenty-eight SNPs from CTLA-4, PTPN22, PTPN12, FCRL3, TSHR and Tg genes were genotyped and their associations with the risk and severity of GD were analysed. RESULTS: The CTLA-4 rs231779, Tg rs2069550 and PTPN22 rs3789604 SNPs were associated with GD, with additive risk effects present in rs231779 and rs2069550. The ACACC and ACGCT haplotypes, composed of five SNPs in the CTLA-4 gene (rs4553808, rs5472909, rs231775, rs231777 and rs231779), were protective and risk haplotypes respectively. The AA genotype of PTPN22 rs3789604 and AA genotype of FCRL3 rs7528684 were correlated with a reduced risk of GD, while the CC genotype of TSHR rs2239610 was associated with higher serum concentrations of FT4 and TRAb. Logistic analysis confirmed the contribution of CTLA-4 rs231779 to the development of GD. CONCLUSIONS: These preliminary results demonstrate that the immune-regulatory gene CTLA-4 and the thyroid-specific gene Tg contribute to the risk of Graves' disease with additive effects, while PTPN22 rs3789604 and FCRL3 rs7528684 polymorphisms are protective against the disease. In addition, the TSHR rs2239610 SNP is related to the severity of Graves' disease.