Ks Lau

Vitamin D receptor gene polymorphisms and peak bone mass in southern Chinese women.

Controversial results were reported on the association of vitamin D receptor (VDR) polymorphisms and bone mineral density (BMD). We studied allelic frequencies of the BsmI, ApaI, and TaqI restriction fragment length polymorphisms (RFLPs) in 144 normal healthy southern Chinese premenopausal women aged between 30 and 40 years, and correlated their peak bone mass with the VDR genotypes. In comparison to Western populations, the B allele of the BsmI site is only found in 5% of the Chinese population. The BBAAtt genotype is virtually nonexistent in Chinese people. Except for the slightly higher BMD values at the midlateral L-3 vertebra (13.8%, p = 0.045) and at the Wards triangle (13.3%, p = 0.08) in the bb subjects, no difference could be detected at other sites between the Bb and bb subjects. The same findings were observed when comparing the Tt to tt subjects. Analysis of the VDR genotype revealed that subjects with BbAaTt and BbAATt haplotypes had the lowest peak bone mass. Their L2-4 lumbar spine, midlateral L-3 vertebra, and Wards triangle BMD was 1.04, 0.90, and 0.75 standard deviation (SD), respectively, lower than the bbAATT counterparts, but none of the comparisons were statistically significant. However, with the low frequency of the B allele, our study had limited power to detect a small difference in the BMD of the various genotypes. In conclusion, although VDR polymorphism is believed to affect calcium absorption, this study failed to confirm a strong relationship between the VDR genotype and peak bone mass in our population with low dietary calcium intake.

Thyrotoxic periodic paralysis and polymorphisms of sodium–potassium ATPase genes

Objective  Thyrotoxic periodic paralysis (TPP) is a complication of hyperthyroidism association with recurrent, reversible episodes of muscle weakness. Increased sodium–potassium ATPase (Na/K‐ATPase) pump activity is postulated to contribute to the hypokalaemic paralytic attacks in TPP. The aim of this study was to determine the genetic predisposition to TPP in relation to Na/K‐ATPase genes.

Genetic variant in vitamin D binding protein is associated with serum 25-hydroxyvitamin D and vitamin D insufficiency in southern Chinese.

Previous large-scale genome-wide meta-analysis identified four loci affecting 25-hydroxyvitamin D (25(OH)D) concentrations. However, whether these loci are associated with 25(OH)D concentration in southern Chinese remain unknown. Our primary aim was to examine whether the four top hits (rs2282679, rs10741657, rs12785878 and rs6013897) could be replicated in 712 southern Chinese women. The associations between these single-nucleotide polymorphisms (SNPs), serum 25(OH)D concentration (continuous variable) and vitamin D insufficiency (dichotomized variable) were examined using multivariable linear regression and logistic regression, respectively. Age, body mass index and season were adjusted in the model. Among these four SNPs, rs2282679 was associated with serum 25(OH)D levels (β=−0.066; P=9 × 10−5) and vitamin D insufficiency (odds ratio (OR)=1.51, 95% confidence interval (CI) 1.19–1.93; P=8.6 × 10−4), whereas rs12785878 was nominally associated with vitamin D insufficiency only (OR=0.79, 95% CI 0.63–0.99; P=0.042). Genotype risk score (GRS), by summing risk variants of these two SNPs, had more significant association with vitamin D insufficiency (OR=1.38; 95% CI 1.17–1.64; Ptrend=1.76 × 10−4) than the model that included only either SNP. The areas under receiver operating characteristic curves of rs2282679 and GRS were 0.561 (P=0.005) and 0.576 (P=5 × 10−4), respectively. Our study provides an independent evidence of the associations of rs2282679 and probably rs12785878 with 25(OH)D and vitamin D insufficiency in southern Chinese.

Ethanolic extract of Actaea racemosa (black cohosh) potentiates bone nodule formation in MC3T3-E1 preosteoblast cells

Aceaea racemosa (formerly Cimicifuga racemosa, black cohosh, AR) extracts have been widely used as an alternative to hormonal replacement therapy for menopausal symptoms. Recent evidences suggest AR extracts are also effective in protecting against postmenopausal bone loss. To determine whether AR has any direct anabolic effect on osteoblasts, we investigated the ethanolic extract of AR on bone nodule formation in mouse MC3T3-E1 preosteoblast cells. AR did not stimulate osteoblast proliferation. Rather, at high doses of 1000 ng/mL for 48 h, AR suppressed (7.2+/-0.9% vs. control) osteoblast proliferation. At 500 ng/mL, a significant increase in bone nodule formation was seen with Von Kossa staining. Using quantitative PCR analysis, AR was shown to enhance the gene expression of runx2 and osteocalcin. Co-treatment with ICI 182,780, the selective estrogen receptor antagonist, abolished the stimulatory effect of AR on runx2 and osteocalcin gene induction, as well as on bone nodule formation in MC3T3-E1 cells. This is a first report of the direct effect of AR on enhancement of bone nodule formation in osteoblasts, and this action was mediated via an estrogen receptor-dependent mechanism. The results provide a scientific rationale at the molecular level for the claim that AR can offer effective prevention of postmenopausal bone loss.

Alterations in Gastric Microbiota After H. Pylori Eradication and in Different Histological Stages of Gastric Carcinogenesis

The role of bacteria other than Helicobacter pylori (HP) in the stomach remains elusive. We characterized the gastric microbiota in individuals with different histological stages of gastric carcinogenesis and after receiving HP eradication therapy. Endoscopic gastric biopsies were obtained from subjects with HP gastritis, gastric intestinal metaplasia (IM), gastric cancer (GC) and HP negative controls. Gastric microbiota was characterized by Illumina MiSeq platform targeting the 16 S rDNA. Apart from dominant H. pylori, we observed other Proteobacteria including Haemophilus, Serratia, Neisseria and Stenotrophomonas as the major components of the human gastric microbiota. Although samples were largely converged according to the relative abundance of HP, a clear separation of GC and other samples was recovered. Whilst there was a strong inverse association between HP relative abundance and bacterial diversity, this association was weak in GC samples which tended to have lower bacterial diversity compared with other samples with similar HP levels. Eradication of HP resulted in an increase in bacterial diversity and restoration of the relative abundance of other bacteria to levels similar to individuals without HP. In conclusion, HP colonization results in alterations of gastric microbiota and reduction in bacterial diversity, which could be restored by antibiotic treatment.

Genetic variants in GREM2 are associated with bone mineral density in a southern Chinese population.

CONTEXT Gremlin 2 (GREM2) is a regulator of osteoblast differentiation and osteogenesis. A recent genome-wide association study identified GREM2 as a novel susceptibility gene for trabecular volumetric bone mineral density (BMD). OBJECTIVE We investigated whether GREM2 gene variants were associated with areal BMD in southern Chinese people. RESEARCH DESIGN AND METHODS We genotyped 108 single-nucleotide polymorphisms (SNPs) in 417 cases (defined as BMD Z-score ≤-1.28) and 359 controls (defined as BMD Z-score ≥+1). Multivariable logistic regression using an additive model was used to evaluate the association. The most associated SNPs of BMD at the spine, femoral neck, and total hip was then replicated in an additional 454 cases and 401 controls. RESULTS Twelve, 13, and 14 SNPs showed nominal association with BMD at the spine, femoral neck, and total hip, respectively. The minor alleles of rs9728351 (odds ratio [OR] = 2.56; 95% confidence interval [CI] = 1.33-4.92), rs11588607 (OR = 1.65; 95% CI = 1.14-2.4), and rs4454537 (OR = 1.87; 95% CI = 1.22-2.86) were associated with the low BMD at the spine, femoral neck, and total hip, respectively. Among these SNPs most associated with BMD, rs4454537 was successfully replicated in an independent cohort (OR = 1.59; 95% CI = 1.05-2.4). Meta-analysis showed that the minor allele of rs4454537 was associated with low total hip BMD with an OR of 1.72 (95% CI = 1.28-2.31) (P = 3.2 × 10(-4); P(corrected) = .043). CONCLUSIONS The minor allele of rs4454537 is significantly associated with low BMD at the total hip of southern Chinese people. Our study further suggests GREM2 as a novel susceptibility gene for osteoporosis.

Meta-analysis of genome-wide association studies identifies two loci associated with circulating osteoprotegerin levels

Osteoprotegerin (OPG) is involved in bone homeostasis and tumor cell survival. Circulating OPG levels are also important biomarkers of various clinical traits, such as cancers and atherosclerosis. OPG levels were measured in serum or in plasma. In a meta-analysis of genome-wide association studies in up to 10 336 individuals from European and Asian origin, we discovered that variants >100 kb upstream of the TNFRSF11B gene encoding OPG and another new locus on chromosome 17q11.2 were significantly associated with OPG variation. We also identified a suggestive locus on chromosome 14q21.2 associated with the trait. Moreover, we estimated that over half of the heritability of OPG levels could be explained by all variants examined in our study. Our findings provide further insight into the genetic regulation of circulating OPG levels.

A man with hypophosphataemia

A 76 year old man was referred with hypophosphataemia. He had a history of hypertension and gout. He presented with a six month history of generalised bone pain and lower limb weakness. Examination showed weak hip flexion and extension (power 4/5). Complete blood count, serum glucose, and kidney function tests were normal. Serum calcium was 2.33 mmol/L (normal 2.10-2.60), serum phosphate was 0.49 mmol/L (0.8-1.4), and alkaline phosphatase was 204 U/L (47-124). He had no family history of hypophosphataemia or bone disorders. Parathyroid hormone (PTH) was within the normal range (53 ng/L; normal 11-54). Serum calcidiol was low at 38 nmol/L (50-250), and serum calcitriol was also low at 26.8 pmol/L (65.3-171.9). Maximal tubular reabsorption of phosphate was 0.44-0.49 mmol/L (0.9-1.35). A skeletal survey (radiographs including posteroanterior view of the chest; anteroposterior and lateral views of the whole spine, humeruses, and femora; anteroposterior and lateral views of the skull; and anteroposterior view of the pelvis) showed no evidence of fracture or lytic lesion. Technetium-99m-methylene diphosphonate bone scintigraphy showed multiple hot spots over rib cage, involving the costochondral and costovertebral junctions. He was treated with phosphate 500 mg twice daily and calcitriol 0.25 µg daily. ### 1 What is the most likely diagnosis? #### Short answer The patient has tumour induced osteomalacia, with coexisting vitamin D insufficiency. #### Long answer ### 1 Tumour induced osteomalacia Tumour induced osteomalacia, or oncogenic osteomalacia, is a rare acquired metabolic disorder of renal phosphate wasting and hypophosphataemia. Mesenchymal tumours in osteomalacia were first recognised to cause osteomalacia in 1959,1 and more than 120 cases of tumour induced osteomalacia have been reported since then. It is the only paraneoplastic syndrome that affects mineral metabolism and the skeleton. Patients with tumour induced osteomalacia …