Annie W. C. Kung

Meta‐Analysis of Genome‐Wide Scans Provides Evidence for Sex‐ and Site‐Specific Regulation of Bone Mass

Several genome‐wide scans have been performed to detect loci that regulate BMD, but these have yielded inconsistent results, with limited replication of linkage peaks in different studies. In an effort to improve statistical power for detection of these loci, we performed a meta‐analysis of genome‐wide scans in which spine or hip BMD were studied. Evidence was gained to suggest that several chromosomal loci regulate BMD in a site‐specific and sex‐specific manner.

Incidence, clinical characteristics and outcome of congestive heart failure as the initial presentation in patients with primary hyperthyroidism

Background: There are limited systematic data on the incidence, clinical characteristics and outcomes of congestive heart failure (CHF) in patients with hyperthyroidism. The aim of this study was to investigate the incidence, clinical characteristics and outcome of CHF as the initial presentation in patients with primary hyperthyroidism. Methods: The prevalence, clinical characteristics and outcome of CHF was studied in 591 consecutive patients (mean (SD) age 45 (1) years, 140 men) who presented with primary hyperthyroidism. Results: CHF was the presenting condition in 34 patients (5.8%) with hyperthyroidism. The presence of atrial fibrillation at presentation (OR 37.4, 95% CI 9.72 to 144.0, p<0.001) was an independent predictor for the occurrence of CHF. Of the 34 patients with CHF, 16 (47%) had systolic left ventricular dysfunction with left ventricular ejection fraction (LVEF)<50%. They were predominantly male (OR 26.6, 95% CI 2.6 to 272.5, p = 0.006) and had a lower serum thyroxine level (OR 0.93, 95% CI 0.87 to 0.99, p = 0.044) than patients with preserved left ventricular systolic function. In these patients, LVEF (55 (4)% vs 30 (2)%, p<0.001) and New York Heart Association functional class (1.2 (0.1) vs 2.5 (0.2), p<0.001) improved significantly 3 months after achieving euthyroid status. Systolic left ventricular dysfunction (mean (SD) LVEF 38 (4)%) persisted on long-term follow-up in five patients: no clinical parameter could be identified to predict the occurrence of this persistent cardiomyopathy (p>0.05). Conclusion: CHF was the initial clinical presentation in approximately 6% of patients with hyperthyroidism, and half of them had left ventricular systolic dysfunction. Symptoms of CHF subsided and LVEF improved after treatment for hyperthyroidism. Nonetheless, one-third of these patients developed persistent dilated cardiomyopathy.

Official Positions for FRAX ® Clinical Regarding International Differences. From Joint Official Positions Development Conference of the International Society for Clinical Densitometry and International Osteoporosis Foundation on FRAX ®

Osteoporosis is a serious worldwide epidemic. Increased risk of fractures is the hallmark of the disease and is associated with increased morbidity, mortality and economic burden. FRAX® is a web-based tool developed by the Sheffield WHO Collaborating Center team, that integrates clinical risk factors, femoral neck BMD, country specific mortality and fracture data and calculates the 10 year fracture probability in order to help health care professionals identify patients who need treatment. However, only 31 countries have a FRAX® calculator at the time paper was accepted for publication. In the absence of a FRAX® model for a particular country, it has been suggested to use a surrogate country for which the epidemiology of osteoporosis most closely approximates the index country. More specific recommendations for clinicians in these countries are not available. In North America, concerns have also been raised regarding the assumptions used to construct the US ethnic specific FRAX® calculators with respect to the correction factors applied to derive fracture probabilities in Blacks, Asians and Hispanics in comparison to Whites. In addition, questions were raised about calculating fracture risk in other ethnic groups e.g., Native Americans and First Canadians. In order to provide additional guidance to clinicians, a FRAX® International Task Force was formed to address specific questions raised by physicians in countries without FRAX® calculators and seeking to integrate FRAX® into their clinical practice. The main questions that the task force tried to answer were the following: The Task Force members conducted appropriate literature reviews and developed preliminary statements that were discussed and graded by a panel of experts at the ISCD-IOF joint conference. The statements approved by the panel of experts are discussed in the current paper.

Ten-year risk of osteoporotic fractures in postmenopausal Chinese women according to clinical risk factors and BMD T-scores: a prospective study.

Independent risk factors for osteoporotic fracture were identified for a Southern Chinese postmenopausal population. Clinical risk factor assessment with or without BMD measurement was shown to be an effective predictor of 10‐yr risk of osteoporotic fracture and provides a more accessible tool for patient evaluation.

Prevalence and Impact of Vitamin D Insufficiency in Southern Chinese Adults

Introduction: Vitamin D is a vital element for bone health but the problem of vitamin D deficiency is underestimated in Hong Kong. Methods: Serum 25(OH)D and parathyroid hormone (PTH) levels were evaluated in 382 community dwelling Chinese adults >50 years for their relation with bone mineral density (BMD) and risks of osteoporotic fractures and falls. Results: The mean age of the subjects was 69 ± 9 years. The mean 25(OH)D level was 28.3 ± 10.8 ng/ml with 62.8% of the subjects having levels <30 ng/ml. 6.3% of the subjects had elevated PTH levels. A curvilinear relation between serum PTH and 25(OH)D was found, with PTH starting to increase when 25(OH)D level fell below 30 ng/ml (r = –0.233, p < 0.05). Although subjects with vitamin D <30 ng/ml had significantly lower BMD, only sex, age and PTH but not 25(OH)D were predictors of BMD at the spine and hip. Subjects with elevated PTH levels had a 2.92-fold increased risk of falls and 2.94-fold increased risk of fractures at the hip and spine. Conclusions: Vitamin D insufficiency and its complication of secondary hyperparathyroidism is common even in subtropical region and is an important risk factor for low bone mass, falls and fractures.

European bone mineral density loci are also associated with BMD in East-Asian populations

Most genome-wide association (GWA) studies have focused on populations of European ancestry with limited assessment of the influence of the sequence variants on populations of other ethnicities. To determine whether markers that we have recently shown to associate with Bone Mineral Density (BMD) in Europeans also associate with BMD in East-Asians we analysed 50 markers from 23 genomic loci in samples from Korea (n = 1,397) and two Chinese Hong Kong sample sets (n = 3,869 and n = 785). Through this effort we identified fourteen loci that associated with BMD in East-Asian samples using a false discovery rate (FDR) of 0.05; 1p36 (ZBTB40, P = 4.3×10−9), 1p31 (GPR177, P = 0.00012), 3p22 (CTNNB1, P = 0.00013), 4q22 (MEPE, P = 0.0026), 5q14 (MEF2C, P = 1.3×10−5), 6q25 (ESR1, P = 0.0011), 7p14 (STARD3NL, P = 0.00025), 7q21 (FLJ42280, P = 0.00017), 8q24 (TNFRSF11B, P = 3.4×10−5), 11p15 (SOX6, P = 0.00033), 11q13 (LRP5, P = 0.0033), 13q14 (TNFSF11, P = 7.5×10−5), 16q24 (FOXL1, P = 0.0010) and 17q21 (SOST, P = 0.015). Our study marks an early effort towards the challenge of cataloguing bone density variants shared by many ethnicities by testing BMD variants that have been established in Europeans, in East-Asians.

Determinants of peak bone mineral density and bone area in young women

Osteoporosis is a disease caused by compromised bone strength, and individuals with a high peak bone mass at a young age are likely to have a high bone mass in old age. To identify the clinical determinants of peak bone mass in young adult women, 418 southern Chinese women, aged 20–39 years, were studied. Low bone mass was defined as areal bone mineral density (aBMD) Z-score < −1 at either the spine or total hip. Within the cohort, 62 (19.0%) and 86 (26.4%) women had low aBMD at the spine and hip, respectively. Regression model analysis revealed that low body weight (<44 kg) was associated with an 8.3-fold (95% CI, 3.7–18.9) and a 6.8-fold (95% CI, 3.0–15.6) risk of having low aBMD at the spine and hip, respectively. Low body weight was also predictive of low volumetric BMD (vBMD) at the spine (odds ratio (OR) 7.8, 95% CI, 3.1–20.1) and femoral neck (OR 3.0, 95% CI, 1.3–7.1). A body height below 153 cm was associated with a 4.8-fold risk in the small L2–4 bone area (95% CI, 2.3–9.8) and a 3.9-fold risk in the small femoral neck area (95% CI, 1.9–8.1). Delayed puberty (onset of menstruation beyond 14 years) was associated with a 2.2-fold (95% CI, 1.0–4.9) increased risk of having low aBMD at the hip. Physical inactivity was associated with a 2.8-fold risk of low spine vBMD (OR 2.8, 95% CI, 1.1–6.7) and a 3.3-fold risk of low hip aBMD (95% CI, 1.0–10.0). Pregnancy protected against low spine aBMD (OR 0.4, 95% CI, 0.1–1.2) and spine vBMD (OR 0.1, 95% CI, 0.0–1.0), low femoral neck vBMD (OR 0.3, 95% CI, 0.1–1.1) and small L2–4 bone area vBMD (OR 0.3, 95% CI, 0.1–1.1). In conclusion, this study identified a number of modifiable determinants of low peak bone mass in young adult women. Maintaining an ideal body weight, engaging in an active lifestyle, and diagnosing late menarche may enable young women to maximize their peak bone mass and so reduce their risk of osteoporosis in later life.

The -9247 T/C polymorphism in the SOST upstream regulatory region that potentially affects C/EBPα and FOXA1 binding is associated with osteoporosis.

Accumulating evidence shows that genes that cause monogenic diseases also contribute to similar complex disease in the general population. We sought to determine whether the allelic variation in seven monogenic bone disease genes (CLCN7, TCIRGI, SOST, CA2, CSTK, TGFB1 and SLC26A2) contributes to osteoporosis/bone mineral density (BMD) variation in the normal Chinese population. We conducted a gene-wide tag SNP-based association study in 1243 Chinese subjects with low BMD (Z-scores < or = -1.28, equivalent to the lowest 10% of the population) and high BMD (Z-score > or = +1.0). Twenty-two tag SNPs were selected and genotyped by using the high-throughput Sequenom genotyping platform. Allelic and haplotype association tests were conducted by Haploview and binary logistic regression analyses. The -9247 polymorphism rs1230399 in the upstream regulatory region of the sclerostin gene showed significant genotypic/allelic associations with spine, femoral neck, trochanter and total hip BMD (P=0.03-0.004). The T-allele of rs1230399 increased the risk of osteoporosis (OR=1.52, P=0.005). Computational analysis showed that rs1230399 is located at the core consensus recognition site of two cooperating transcription factors C/EBPalpha and FOXA1 that modulate estrogen receptor function. T-->C polymorphism abolishes the binding of both C/EBPalpha and FOXA1 to the sclerostin gene. Our data suggest a mechanistic link between rs1230399 and BMD through estrogen ERalpha/FOXA1 signaling pathways driven by long-distance enhancers.

PvuII polymorphisms of the estrogen receptor α and bone mineral density in healthy southern Chinese women

Abstract. The association between PvuII polymorphisms of the estrogen receptor α (ERα) gene and total as well as regional bone mineral density (BMD) in healthy Chinese women (n = 182) was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), where P indicated the absence and p the presence of PvuII restriction sites. Subjects with PP genotype had significantly higher BMD at the thoracic spine and ribs (both P < 0.05) when compared with those with Pp and pp genotypes. Although PP genotype had slightly higher BMD values at the lumbar spine L2-L4 region and hip by 8% and 7%, respectively, the results failed to reach statistical significance. After adjusting for age, height, weight, and years since menopause, PP genotype had higher BMD at the left (P < 0.02) and right (P < 0.05) rib region but not at the thoracic spine (P= 0.056). Analyzing the premenopausal subjects alone (n = 64) revealed that subjects with PP genotype had higher adjusted BMD at the right rib region (P < 0.05). When only the postmenopausal women (n = 118) were analyzed, the adjusted BMD of the PP genotype at the thoracic spine was significantly higher (P < 0.05) than the other two groups. In conclusion, estrogen receptor gene has a role in determining bone mass but the clinical impact on its own is probably small.

Risk of ischemic stroke after new-onset atrial fibrillation in patients with hyperthyroidism

BACKGROUND Hyperthyroidism is one of the most common reversible causes of atrial fibrillation (AF); nevertheless, the risk of ischemic stroke in patients with hyperthyroidism who present with new-onset AF is unclear. OBJECTIVE This study sought to investigate the clinical outcome of hyperthyroidism-induced AF with regard to risk of ischemic stroke risk. METHODS We prospectively studied the incidence, time course, and clinical predictors for ischemic stroke in patients with hyperthyroidism-induced AF (n = 160). They were compared with age- and sex-matched cohorts of hyperthyroid patients without AF (n = 160) and AF patients without hyperthyroidism (n = 160). RESULTS Baseline characteristics were comparable among the 3 groups. At 1 year, 86 hyperthyroid patients with AF (54%) and 92 patients with nonthyroid AF (58%) had spontaneous or pharmacological sinus conversion (P = .20). Ischemic stroke was observed in 15 hyperthyroid patients with AF (9.4%) versus 5 patients with nonthyroid AF (3.1%, P = .02), and 1 hyperthyroid patient without AF (0.6%, P < .001). Furthermore, the majority of ischemic stroke (>70%) in patients with AF occurred within the first 30 days of presentation, whereas AF was still present. Cox regression analysis showed that hyperthyroidism (hazard ratio [HR]: 3.5, 95% confidence interval [CI]: 1.15 to 10.42, P = .03) and persistent AF (HR: 13.0, 95% CI: 2.88 to 58.80, P < .01) predicted the occurrence of ischemic stroke; warfarin therapy reduced the risk of ischemic stroke (HR: 0.17, 95% CI: 0.04 to 0.79, P = .02). CONCLUSION In hyperthyroid patients who presented with new-onset AF, there was an increased risk of ischemic stroke clustering during the initial phase of presentation. This should prompt early use of anticoagulation therapy in hyperthyroid patients with AF.