Sunee Saetung

Changes in circulating 25-hydroxyvitamin D according to vitamin D binding protein genotypes after vitamin D3 or D2supplementation

BackgroundIt is not known whether genetic variation in the vitamin D binding protein (DBP) influences 25-hydroxyvitamin D levels [25(OH)D] after vitamin D supplementation. We aimed to investigate the changes of total 25(OH)D, 25(OH)D3 and 25(OH)D2 in a Thai cohort, according to type of vitamin D supplement (vitamin D3 or D2) and DBP genotype, after receiving vitamin D3 or D2 for 3u2009months.MethodsThirty-nine healthy subjects completed the study. All subjects received 400u2009IU of either vitamin D3 or D2, plus a calcium supplement, every day for 3u2009months. Total serum 25(OH)D, 25(OH)D3 and 25(OH)D2 were measured by LC-MS/MS. Individual genotyping of rs4588 in the DBP gene was performed using real-time PCR.ResultsVitamin D3 supplementation of 400u2009IU/d increased 25(OH)D3 significantly (+16.2u2009±u20094.2u2009nmol/L, p <0.001). Vitamin D2 (400u2009IU/d) caused increased 25(OH)D2 levels (+22.0u2009±u20092.11u2009nmol/L, p <0.001), together with a decrease of 25(OH)D3 (−14.2u2009±u20092.0u2009nmol/L, p <0.001). At 3u2009month, subjects in vitamin D3 group tended to have higher total 25(OH)D levels than those in vitamin D2 (67.8u2009±u20093.9 vs. 61.0u2009±u20093.0u2009nmol/L; pu2009=u20090.08). Subjects were then classified into two subgroups: homozygous for the DBP rs4588 C allele (CC), and the rest (CA or AA). With D3 supplementation, subjects with CA or AA alleles had significantly less increase in 25(OH)D3 and total 25(OH)D when compared with those with the CC allele. However, no difference was found when the supplement was vitamin D2.ConclusionGenetic variation in DBP (rs4588 SNP) influences responsiveness to vitamin D3 but not vitamin D2.

Association of a G2014A Transition in Exon 8 of the Estrogen Receptor-α Gene with Postmenopausal Osteoporosis

Abstract: We report the association of a newly identified synonymous G2014A single nucleotide polymorphism (SNP) which does not alter the amino acid sequence in exon 8 of the estrogen receptor-α (ERα) gene with osteoporosis in Thai postmenopausal women. Subjects consisted of 228 postmenopausal women aged more than 55 years divided into two groups – with vertebral or femoral osteoporosis (n= 106) or without osteoporosis (n= 122) – according to bone mineral density (BMD) criteria. The exon 8 G2014A SNP, which is 6 nucleotides upstream from the end of the stop codon, was identified by PCR-RFLP. Data are expressed as the mean and 95% CI. The allele frequency of the G2014A polymorphism was 26.4% in osteoporotic subjects and was significantly higher than that in non-osteoporotic women (15.2%) (p<0.05). By stepwise logistic regression analysis, it was found that the G2014A polymorphism was related to the presence of osteoporosis (odds ratio 2.7 per A allele, 95% CI 1.49–4.76) independently of body weight (odds ratio 0.93 per kg, 95% CI 0.89–0.96) and years since menopause (odds ratio 1.12 per year, 95% CI 1.08–1.19). In a multiple linear regression model, L2–L4 BMD of osteoporotic subjects was associated with body weight (p<0.05), endogenous estradiol levels (p<0.05) and the G2014A genotype (p<0.001), while it was related only to body weight (p<0.05) and estradiol levels in non-osteoporotic women (p<0.05). We conclude that a G2014A SNP in exon 8 of ERα is associated with the presence and severity of postmenopausal osteoporosis. Linkage disequilibrium between this polymorphism and the 3′-untranslated region of the ERα gene which may participate in the regulation of ERα gene expression remains to be determined.

Circulating Sclerostin and Irisin Are Related and Interact with Gender to Influence Adiposity in Adults with Prediabetes

Objectives. Sclerostin, an osteocyte-specific protein, has been found to be related to adiposity and glucose metabolism. Irisin, a myokine, can affect browning of white fat and influence glucose and energy homeostasis. Taken together, this suggests a probable network among fat, bone, and muscle that may influence health outcomes. The aims of this study were to investigate the relationship of circulating sclerostin and irisin and their association with adiposity (assessed by body mass index (BMI)). Materials/Methods. A cross-sectional study included 98 adults with impaired fasting glucose and/or impaired glucose tolerance. 75u2009gm OGTT was performed in all subjects. Fasting plasma samples were obtained for glycated hemoglobin, calcium, creatinine, serum sclerostin and irisin. Results. Circulating irisin and sclerostin were highly correlated (r = −0.4; P < 0.001). After controlling for age, gender, and BMI, irisin was significantly related to sclerostin (P < 0.001). Multivariate linear regression analysis demonstrated that circulating sclerostin (β = −0.45; P < 0.05) and irisin (β = −0.46; P < 0.05) were negatively associated with BMI, independent of age in males. In females, no relationship of sclerostin or irisin to BMI was found. Conclusions. Circulating irisin and sclerostin are highly related. Interventions targeting irisin could affect sclerostin and vice versa.

Association of a T262C transition in exon 1 of estrogen-receptor-α gene with skeletal responsiveness to estrogen in post-menopausal women

Polymorphic genetic markers of estrogen-receptor-α (ERα) gene studied so far in osteoporosis reside in non-coding region with uncertain functional significance. The purpose of the present study was to search for nucleotides changes in the exon 1 and 5′ regulatory region of ERα gene, to study the nature of their linkages to the previously reported Pvull polymorphism in intron 1 and their functional significance in post-menopausal osteoporosis. Direct sequencing of exon 1 and promotor region of ERα gene revealed a synonymous nucleotide substitution from T to C at position 262, 29 nucleotides downstream from the putative start codon. No nucleotide change was found in the promotor region. Linkage disequilibrium between the T262C polymorphism and the Pvull polymorphism in intron 1 of ERα gene was demonstrated in 129 post-menopausal women (p<0.001). After treating 96 post-menopausal with 0.3 mg or 0.625 mg conjugated equine estrogen (CEE) for 2 yr, vertebral bone mineral density (BMD) increased regardless of the T262C genotype. However, with regard to femoral neck BMD, only those subjects that were homozygous for the T262C polymorphism had an increase in femoral BMD (+5.9±1.4%, mean±SE; p<0.0001). Using analysis of covariance to assess the effects of the T262C polymorphism, the intronic Pvull polymorphism, doses of CEE and the corresponding baseline BMD on the changes in vertebral or femoral BMD after treatments, it was found that the change in vertebral BMD was related only to the baseline BMD (p<0.05). The change in femoral BMD was independently related to the T262C polymorphism (p<0.01) and the baseline femoral BMD (p<0.01). No effect of the Pvull polymorphism or the doses of CEE on femoral BMD was demonstrated. We concluded that the previously described intronic Pvull polymorphism of ERα gene is in linkage disequilibrium with a T262C polymorphism in exon 1. This T262C polymorphism appears to be more directly related to the skeletal response after long-term treatment with estrogen.

The implication of assessing a polymorphism in estrogen receptor alpha gene in the risk assessment of osteoporosis using a screening tool for osteoporosis in Asians

Both genetic and environmental factors interact to determine bone mass and the risk for developing postmenopausal osteoporosis. Recently, an Asian-specific tool, the Osteoporosis Self-Assessment Tool for Asians (OSTA), has been developed to assess the risk of osteoporosis in women. An index is calculated by multiplying the difference in body weight in kilograms and age in years by 0.2 and disregarding the decimal digits. The risk of osteoporosis is classified as high, intermediate or low according to the OSTA index less than −4, −4 to −1 and greater than −1. In the present study we examined how a single nucleotide polymorphism (SNP) in exon 8 of the estrogen receptor α (ERα) gene affected the predictive value of the OSTA index. Subjects consisted of 358 postmenopausal women who were at least 55xa0years old. BMDs were measured by DXA, and the SNP in the ERα gene was assessed by PCR-RFLP. When considering both the OSTA index and ERα genotype in a logistic regression model, it was found that both the OSTA index and the ERα genotype independently contributed to the risk of osteoporosis. The odds ratios were 1.58 (95% CI 1.26–1.91) and 2.51 (95% CI 1.42–4.44) for one unit decrement in the OSTA index and each copy of the A allele of the ERα genotype, respectively. The joint effect conformed more to a multiplicative model of interaction than an additive model. This suggests that persons with the high-risk genotype are at far greater risk of developing osteoporosis with advancing age or decreasing body weight, the two variables from which the OSTA index is derived. Targeting preventive measures for osteoporosis subjects with risk factors and also disease-susceptibility alleles is likely to be more cost effective.

Higher sleep variability is associated with poorer glycaemic control in patients with type 1 diabetes.

Sleep disturbances have been linked to insulin resistance and poor glycaemic control in patients with type 2 diabetes. However, the data are limited in type 1 diabetes. Recently, varying day‐to‐day sleep schedules, i.e. sleep variability, have been associated with adverse metabolic profile in healthy individuals. This study explored whether sleep variability affects glycaemic control and insulin requirement in type 1 diabetes. Forty‐one adult patients with type 1 diabetes wore an actigraphy for 5u2005nights. Standard deviation of sleep duration, efficiency and mid‐sleep time were sleep variability parameters. Sleep apnoea risk and self‐reported sleep quality were assessed by the Berlin questionnaire and Pittsburgh Sleep Quality Index. Haemoglobin A1c, diabetes complications and insulin regimen were obtained from medical records. After adjusting for neuropathic symptoms, sleep apnoea risk and poor self‐reported sleep quality, higher sleep variability was significantly associated with poorer glycaemic control (standard deviation of sleep duration, B = 0.100, P = 0.004; and standard deviation of mid‐sleep time, B = 0.068, P = 0.04). In addition, standard deviations of sleep duration and mid‐sleep time were highly correlated, suggesting that participants changed their sleep duration along with sleep timing. After adjusting for covariates, the standard deviation of sleep duration (P = 0.009) and standard deviation of mid‐sleep time (P = 0.012) were associated with higher insulin requirement. In summary, higher sleep variability, which likely reflects sleep deprivation alternating with sleep compensation along with shifts in their circadian timing, was associated with poorer glycaemic control and higher insulin requirement in patients with type 1 diabetes. Increased sleep regularity may improve metabolic control in type 1 diabetes.

Shorter sleep duration is associated with poorer glycemic control in type 2 diabetes patients with untreated sleep-disordered breathing

PurposeThe purpose of this study is to explore the impact of sleep duration on glycemic control in type 2 diabetes patients with untreated sleep-disordered breathing (SDB).MethodsNinety type 2 diabetes patients participated in the study. SDB was diagnosed using an overnight in-home monitoring device (WatchPAT200). Sleep duration was recorded by wrist actigraphy for 7xa0days. Medical records were reviewed for hemoglobin A1c (HbA1c) values.ResultsSeventy-one patients (78.8xa0%) were diagnosed with SDB [apnea-hypopnea index (AHI)xa0≥xa05]. In patients with SDB, there was no significant relationship between AHI and glycemic control. In addition, oxygen desaturation index, minimum oxygen saturation, and time spent below oxygen saturation of 90xa0% were not significantly correlated with glycemic control. Sleep duration, however, was inversely correlated with HbA1c (rxa0=xa0−0.264, p 0.026). Multiple regression analysis adjusting for age, sex, body mass index, insulin use, diabetes duration, and AHI revealed that sleep duration was significantly associated with HbA1c (pxa0=xa00.005). Each hour reduction in sleep duration was associated with a 4.8xa0% increase in HbA1c of its original value (95xa0% CI 1.5–8.0).ConclusionIn type 2 diabetes patients with untreated SDB, shorter sleep duration was independently associated with poorer glycemic control. Sleep duration optimization may lead to improved glycemic control in this population.

The efficacy of calcium supplementation alone in elderly Thai women over a 2-year period: a randomized controlled trial

SummarySupplementation with elemental calcium 500xa0mg/day alone for 2xa0years is able to decrease bone turnover and is effective in retarding bone loss at lumbar spine and slowing bone loss at femoral neck in elderly Thai women who had low dietary calcium intake.IntroductionMost elderly Thais have a total dietary calcium intake of less than the recommended amount. The aim of the study was to investigate the effect of calcium supplementation on bone mineral density and biochemical indices of bone remodeling in Thai postmenopausal women.MethodsFour hundred and four healthy postmenopausal women 60xa0years old or older without osteoporosis were recruited and conducted in a randomized, double-blinded, placebo-controlled trial. They were randomly given elementary calcium 500xa0mg/day or placebo for 2xa0years. Dietary calcium intake was calculated from the nutrient compositional analysis of the 3-day food records. Serum 25 hydroxyvitamin D was measured by radioimmunoassay and bone turnover markers were determined by electrochemiluminescence immunoassay.ResultsThe age of the subjects was 65.8u2009±u20094.4xa0years. All baseline characteristics of the subjects in the calcium-supplemented group and the placebo group were not statistically different. At the end of the study, significant decreases in serum C-terminal telopeptide of type I collagen and serum total procollagen type I amino terminal propeptide in the calcium-supplemented group were observed, while there was no change in the placebo group. In addition, plasma parathyroid hormone decreased, although not significantly, only in the calcium-supplemented group. Percent changes from baseline of lumbar spine (L2–L4) bone mineral density increased 2.76xa0% in the calcium-supplemented group and 0.87xa0% in the placebo group, whereas the percent changes from baseline of femoral neck decreased 0.21xa0% in the calcium-supplemented group and 0.90xa0% in the placebo group.ConclusionsCalcium supplementation is necessary for the decrease of bone turnover and prevention of bone loss in Thai elderly women.

Genetic variant in the aquaporin 9 gene is associated with bone mineral density in postmenopausal women

This study investigated whether single nucleotide polymorphisms (SNP) in the aquaporin 9 (AQP9) gene is associated with bone mineral density (BMD) in Thai postmenopausal women, after an initial genome-wide screening using high-throughput SNP genotyping in pooled DNA samples. Subjects consisted of 516 postmenopausal women aged 50 or more. High-throughput SNP screening was performed by comparing the estimated allele frequency derived from hybridization signal intensities of pooled DNA samples on the Affymetrix 500xa0K SNP genotyping chip set. The SNP was then genotyped for each subject individually. Data were expressed as meanxa0±xa0SEM. Pooled DNA SNP screening revealed the allele frequency of an intronic A/T SNP rs2414539 in the AQP9 gene as being different between subjects with femoral neck BMD in tertiles 1 and 3. Individual genotyping in all subjects revealed that femoral neck BMD in subjects with TT, TA, and AA genotypes were 0.79xa0±xa00.06 (nxa0=xa03), 0.75xa0±xa00.01 (nxa0=xa098), and 0.71xa0±xa00.01xa0g/cm2 (nxa0=xa0415), respectively. The presence of the T allele in rs2414539 was associated with femoral neck BMD (rxa0=xa00.11, Pxa0<xa00.05) but not with lumbar spine BMD. The relationship was still significant after controlling for body weight and age (Pxa0<xa00.05). Genetic variation in the AQP9 gene is associated with femoral neck BMD in postmenopausal women, and may represent one of the susceptibility genes for phenotypes related to bone mass.

Discrepant influence of vitamin D status on parathyroid hormone and bone mass after two years of calcium supplementation

Objectiveu2002 To investigate the influence of vitamin D status on parathyroid hormone and bone mass after a 2‐year supplementation of calcium alone.