Racial difference in bioavailability of oral ibandronate between Caucasian and Taiwanese postmenopausal women.

Following 150 mg of oral ibandronate, Taiwanese females have greater serum and urine levels of this drug and bone resorption marker suppression than Caucasian women. These inter-ethnic differences seems to be partly explained by a 2.48-fold higher bioavailability of ibandronate in Taiwanese postmenopausal women. INTRODUCTION: Interethnic differences in the pharmacokinetics of oral ibandronate for osteoporosis are unknown. We compared the disposition of oral ibandronate between Caucasian and Taiwanese postmenopausal women. METHODS: Ibandronate 150 mg was administered to 35 Caucasian and 16 Taiwanese postmenopausal women in two separate phase 1 studies. Interethnic comparisons were performed to assess pharmacokinetic properties, including the area under the concentration-time curve (AUC), peak concentration (Cmax), elimination half-life, urinary drug recovery (Ae%), renal clearance (CLr), apparent total clearance (CL/F), and apparent volume of distribution (Vd/F). RESULTS: The mean AUC, Cmax, and Ae% were 2.41-, 1.69-, and 2.95-fold greater in the Taiwanese than in the Caucasian subjects, and the average CL/F and Vd/F were 2.48- and 2.46-fold smaller. There were no significant differences in mean CLr and half-life between both groups. As bisphosphonates are not biotransformed but are mainly excreted in the urine, the total body clearance is close to the CLr. These results suggested a larger bioavailability in the Taiwanese group which resulted in the differences in the CL/F and Vd/F. Multiple linear regression analysis demonstrated ethnicity influences of the pharmacokinetic properties after adjusting for the other variables. CONCLUSIONS: Bioavailability was largely responsible for the interethnic pharmacokinetic differences following oral administration of 150 mg ibandronate and seemed greater in the Taiwanese compared with the Caucasian subjects. Further dose-ranging studies are warranted to determine the optimal dosages of oral ibandronate in patients of Asian or Taiwanese ethnicity.

Serum fibroblast growth factor 23 and mineral metabolism in patients with euthyroid Graves' diseases: a case-control study.

This study investigated the alterations of mineral metabolism in patients with Graves' disease (GD) who achieved euthyroidism. They had higher fibroblast growth factor 23 (FGF23) and phosphorus as compared with healthy subjects. Serum FGF23 was negatively correlated with serum phosphorus. These indicated abnormal mineral metabolism even after 1.6 years of euthyroid status. INTRODUCTION: FGF23 is involved in the mineral homeostasis, especially the regulation of serum phosphorus. Graves' disease (GD) is associated with accelerated bone turnover, hyperphosphatemia, and elevated serum FGF23. Evidence suggested that serum FGF23 decreased after a 3-month treatment of GD. However, it remains unclear whether serum FGF23, serum phosphorus, and other markers of mineral metabolism will be normalized after euthyroid status achieved. METHODS: A total of 62 patients with euthyroid GD and 62 healthy control subjects were enrolled, and the median duration of euthyroid status was 1.6 years. Endocrine profiles including thyroid function test, autoantibodies, serum FGF23, and bone turnover markers were obtained and compared between the two groups. RESULTS: Euthyroid GD patients had significantly higher serum FGF23 and phosphorus, and lower 25-hydroxyvitamin D (25(OH)D) and intact parathyroid hormone (iPTH) levels as compared with the control group. Serum FGF23 was significantly and negatively correlated with phosphorus level after adjusted for age, gender, calcium, iPTH, and 25(OH)D in the euthyroid GD group. CONCLUSION: Serum phosphorus and FGF23 levels remain higher in GD patients even after euthyroid status has been achieved for a median of 1.6 years. Serum FGF23 was negatively correlated with serum phosphorus in euthyroid GD patients. Underlying mechanisms warrant further investigations. TRIAL REGISTRATION: Registration number: NCT01660308 and NCT02620085.

Identification of a novel HLA-B allele, B*07:162, in a Taiwanese individual.

The new allele, HLA-B*07:162, is identical to HLA-B*07:12 in exon 2 but has a non-synonymous substitution at position 419 (A to C) in exon 3.

SLURP1 mutation-impaired T-cell activation in a family with mal de Meleda.

BACKGROUND: Mal de Meleda (MDM) is palmoplantar erythrokeratoderma with an autosomal recessive inheritance and is caused by a mutation in the gene encoding SLURP-1 (lymphocyte antigen 6/urokinase-type plasminogen activator receptor related protein-1). SLURP-1 is an allosteric agonist to the nicotinic acetylcholine receptor (nAchR) and it regulates epidermal homeostasis. In addition, murine studies have shown that nAchR signalling is important for the regulation of T-cell function. Among the family members, patients with the homozygous SLURP1 (previously known as ARS component B) mutation are prone to melanoma and viral infection, which might link to defective T-cell function as well as a derangement of epidermal homeostasis. OBJECTIVES: To investigate the association of the SLURP1 gene mutation with T-cell activation in a Taiwanese family with MDM. To test that SLURP-1 is essential for T-cell activation. METHODS: Human peripheral blood mononuclear cells (PBMCs) were isolated from a Taiwanese MDM family bearing the G to A substitution in nucleotide 256 in the SLURP1 gene, corresponding to a glycine to arginine substitution at amino acid 86 (G86R) in the SLURP-1 protein. PBMCs from homozygotes and wild-type controls were stimulated with anti-CD3/anti-CD28 antibodies and the level of T-cell activation was determined by the stimulation index. RESULTS: PBMCs with the heterozygous and homozygous SLURP-1 G86R mutation had defective T-cell activation. This was restored by the addition of 0·5 µg mL(-1) recombinant human SLURP-1 protein. CONCLUSIONS: Patients with MDM with the homozygous SLURP-1 G86R mutation may have an impaired T-cell activation. The presence of wild-type SLURP-1 is essential for normal T-cell activation.

Family-based association study of cytotoxic T-lymphocyte antigen-4 with susceptibility to Graves' disease in Han population of Taiwan.

Graves' disease (GD) is a common organ-specific autoimmune disorder inherited as a complex trait. Although there has not been consensus regarding the genuine susceptibility alleles, many population-based genetic studies showed association of the cytotoxic T-lymphocyte antigen-4 (CTLA4) gene with GD. In contrast, evidence utilizing family-based studies came only from the Caucasian population. Here we performed a family-based association study in the Han population in Taiwan. We enrolled 374 affected individuals and 347 unaffected family members in 151 GD pedigrees. Four single-nucleotide polymorphisms (SNP) and a short tandem repeat polymorphism (STRP) at CTLA4 were genotyped. Association of GD with a novel risk SNP at the 5' upstream region, CTLA4_-1722_T/C (rs733618), was demonstrated (P=0.0096). We also replicated the association signal of a coding SNP, CTLA4_+49_G/A (rs231775, P=0.0219). A common haplotype composed of CTLA4_-1722_T/C and CTLA4_(AT)n (an STRP marker: UniSTS:48500) showed protective effect (P=0.0004). Our results of family-based association study, taken together with those from the Caucasian population, provide evidence that CTLA4 confers susceptibility to GD across different ethnic backgrounds.

Lower plasma adiponectin is correlated to higher alanine aminotransferase independent of metabolic factors and hepatitis B virus carrier status.

BACKGROUND: Adiponectin has been linked to the metabolic syndrome and coronary artery disease in recent years. The animal and human data also suggest that adiponectin may be beneficial for liver functions. The aim of this study was to investigate the correlation between plasma adiponectin level and liver function tests in adults with or without chronic hepatitis B virus (HBV) infection. METHODS: We analysed the blood levels of liver enzymes and adiponectin in 140 apparently healthy adults, including 21 HBV carriers. RESULTS: We found that the plasma adiponectin levels were inversely correlated to aspartate aminotransferase (r = -0.314, P = 0.000) and alanine aminotransferase (ALT) (r = -0.430, P = 0.000). Among the HBV carriers, the ALT correlated with the plasma adiponectin levels (r = -0.521, P = 0.015). In linear regression models adjusting for age, sex and the other metabolic variables, the ALT was independently related to the plasma adiponectin levels (beta = -0.371 +/- 0.134, P = 0.007), even in HBV carriers (beta = -1.143 +/- 0.482, P = 0.034). The ALT was also independently correlated to the plasma adiponectin levels (beta = 0.552 +/- 0.132, P < 0.001) with adjustment for age, sex and insulin-resistance index by homeostasis model assessment, even in HBV carriers (beta = -1.202 +/- 0.562, P = 0.048). The subjects with normal ALT had a significantly higher least square mean of plasma adiponectin than those with abnormal ALT (4.01 +/- 0.19 vs 3.30 +/- 0.30, P = 0.014) with adjustment for age, sex, homeostasis model assessment insulin resistance and HBV status. CONCLUSION: ALT was inversely related to adiponectin levels, independent of the metabolic factors and HBV status. Whether there is any potential prognostic and therapeutic value of adiponectin in human liver diseases remains to be investigated.

Insulin resistance, obesity, and metabolic syndrome among non-diabetic pre- and post-menopausal women in North Taiwan.

OBJECTIVE: To investigate the relationship between the metabolic syndrome and its related factors among non-diabetic pre- and post-menopausal women in North Taiwan. DESIGN: A cross-sectional study in a medical center in North Taiwan. SUBJECTS: Five hundred and ninety-four, non-diabetic middle-aged women (age range=40-64 years, mean=48.9+/-5.4 years) were recruited. MEASUREMENTS: The fasting plasma glucose, insulin, lipids levels and anthropometric indices were measured. The homeostasis model assessment was applied to estimate the degree of insulin resistance (HOMA-IR). Metabolic syndrome was defined by using the National Cholesterol Education Panel (NCEP) criteria and modified NCEP criteria (waist circumference >80 cm). RESULTS: The prevalence of metabolic syndrome was 6.2% using NCEP criteria, and 8.9% using modified NCEP criteria. Post-menopausal women had a higher prevalence of metabolic syndrome and its individual components compared to pre-menopausal women except hyperglycemia and low HDL-C. In multiple logistic regression analysis with adjustment for age and menopausal status, both BMI and HOMA-IR were independently associated with the metabolic syndrome. CONCLUSION: The prevalence of metabolic syndrome was higher in post-menopausal than pre-menopausal women. Both obesity and insulin resistance may play an important role in the development of metabolic syndrome among the middle-aged women in North Taiwan.

Adiponectin mRNA levels in the abdominal adipose depots of nondiabetic women.

BACKGROUND: The human adiponectin gene has been implicated in the pathophysiology of obesity, type II diabetes mellitus, dyslipidemia and atherosclerosis. Investigation of the physiological functions of the adiponectin gene in humans was mainly conducted at the levels of plasma proteins or DNA polymorphisms. The depot-specific adiponectin mRNA levels also could be relevant to these physiological functions. OBJECTIVES: The relation between the adipose depot-specific adiponectin mRNA expression levels and various metabolic factors, including BMI, fasting plasma glucose, insulin, triglycerides (TGs) and HDL-cholesterol and insulin resistance index by HOMA, was investigated among 66 nondiabetic women using quantitative real-time PCR. RESULTS: The subcutaneous relative adiponectin mRNA levels (SRAmR) correlated significantly with the omental relative adiponectin mRNA levels (ORAmR) (gamma=0.468, P=0.0001). The SRAmR correlated inversely with the fasting plasma glucose with a borderline significance (gamma=-0.35, P=0.058). On the other hand, the ORAmR correlated negatively with serum TG levels with the adjustment for age (gamma=-0.33, P=0.007) or age plus BMI (gamma=-0.27, P=0.027). CONCLUSION: These results indicate that the adiponectin mRNA levels in different adipose depots were at least related to certain phenotypes of metabolic syndrome. The expression levels of adiponectin in the omental adipose depots are related to TG metabolism.

Genetic epistasis of adiponectin and PPARgamma2 genotypes in modulation of insulin sensitivity: a family-based association study.

AIMS/HYPOTHESIS: Genetic interactions in modulating the phenotypes of a complex trait, such as insulin sensitivity, were usually taken for granted. However, this has not been commonly shown. Previous studies have suggested that both PPARgamma2 and adiponectin genes could influence insulin sensitivity. Therefore it is likely that they could modulate insulin sensitivity through gene to gene interactions. METHODS: We genotyped 1793 subjects of Chinese and Japanese descendents from 601 hypertensive families recruited in Sapphire study for a T94G in the adiponectin gene exon 2 and the PPARgamma2 Pro12Ala polymorphisms. Serum insulin concentrations and insulin resistance index (HOMA(IR)) were used as the markers of insulin sensitivity. RESULTS: We found that the T allele of adiponectin gene was associated with a higher Ins60 and higher area under curve of insulin (AUCi) in OGTT utilizing all subjects in a mixed model that corrected for family effects. Important interactions between adiponectin and PPARgamma2 genotypes were found in fasting insulin concentrations (Ins0), insulin concentrations at 2-h (Ins120) in OGTT and insulin resistance index (HOMA(IR)). The main effects of the PPARgamma2 genotypes were in the plasma glucose concentrations in OGTT. In contrast, the main effects of adiponectin genotypes were in every insulin variable, including Ins0, Ins60, Ins120, AUCi and HOMA(IR). The subjects carrying the adiponectin G allele and the PPARgamma2 Ala12 allele seemed to be more insulin sensitive. CONCLUSION/INTERPRETATION: These results showed that adiponectin is a genetic factor associated with insulin sensitivity. Interactions with PPARgamma2 genotypes modified this association.