Long-distance movement of phosphate starvation-responsive microRNAs in Arabidopsis.

Plant microRNAs are small RNAs that are important for genetic regulation of processes such as plant development or environmental responses. Specific microRNAs accumulate in the phloem during phosphate starvation, and may act as long-distance signalling molecules. We performed quantitative PCR on Arabidopsis hypocotyl micrograft tissues of wild-type and hen1-6 mutants to assess the mobility of several phosphate starvation-responsive microRNA species. In addition to the previously confirmed mobile species miR399d, the corresponding microRNA* (miR399d*) was identified for the first time as mobile between shoots and roots. Translocation by phosphate-responsive microRNAs miR827 and miR2111a between shoots and roots during phosphate starvation was evident, while their respective microRNA*s were not mobile. The results suggest that long-distance mobility of microRNA species is selective and can occur without the corresponding duplex strand. Movement of miR399d* and root-localised accumulation of miR2111a* opens the potential for persisting microRNA*s to be mobile and functional in novel pathways during phosphate starvation responses.

HLA-B*38:02:01 predicts carbimazole/methimazole-induced agranulocytosis.

Thioamides antithyroid-drugs (ATDs) are important in hyperthyroid disease management. Identification of the susceptibility locus of ATD-induced agranulocytosis is important for clinical management. We performed a genome-wide association study (GWAS) involving 20 patients with ATD-induced agranulocytosis and 775 healthy controls. The top finding was further replicated. A single-nucleotide polymorphism (SNP), rs185386680, showed the strongest association with ATD-induced agranulocytosis in GWAS (odds ratio (OR) = 36.4; 95% confidence interval (CI) = 12.8-103.7; P = 1.3 × 10(-24)) and replication (OR = 37; 95% CI = 3.7-367.4; P = 9.6 × 10(-7)). HLA-B*38:02:01 was in complete linkage disequilibrium with rs185386680. High-resolution HLA typing confirmed that HLA-B*38:02:01 was associated with carbimazole (CMZ)/methimazole (MMI)-induced agranulocytosis (OR = 265.5; 95% CI = 27.9-2528.0; P = 2.5 × 10(-14)), but not associated with propylthiouracil (PTU). The positive and negative predictive values of HLA-B*38:02:01 in predicting CMZ/MMI-induced agranulocytosis were 0.07 and 0.999. Approximately 211 cases need to be screened to prevent one case. Screening for the risk allele will be useful in preventing agranulocytosis in populations in which the frequency of the risk allele is high.

A secular increase in BMD in Chinese women.

Population-based studies have revealed a decline in the incidence of age-adjusted hip fractures in southern Chinese women during the past decade. To determine whether there was a secular change in population characteristics that accounted for this decline, we compared the bone mineral density (BMD) and lifestyle habits of two cohorts of women who were more than 50 years of age and who were recruited from 1995 to 2000 and 2005 to 2010. The BMD levels in the 2005-2010 cohort were significantly higher at the spine and hip and ranged from 3.6 to 17.8% among the different age groups. Additionally, a significantly lower prevalence of subjects with osteoporosis and osteopenia was observed. Longer reproductive years, higher levels of physical activity, higher estradiol and 25(OH) vitamin D levels, and lower alkaline phosphatase levels were found in the 2005-2010 cohort. After adjusting for bone-determining factors, significant differences were detected in the BMD levels at the lumbar spine, femoral neck, and total hip (4.17, 9.02, and 9.34%, respectively) in women >50 years of age but not in women ≤50 years of age. The secular increase in BMD and healthier lifestyles most likely led to the decline in the incidence of age-adjusted fractures.

Determinants of bone mineral density in Chinese men.

Osteoporotic fractures are increasing among Asian populations in both genders, but the risk factors for low bone mineral density (BMD) in Asian men is unclear. To determine the hormonal and lifestyle risk factors for low BMD in Asian men, we studied 407 community-dwelling southern Chinese men aged 50 years and above. Medical history and lifestyle habits were obtained with a structured questionnaire. Dietary calcium and phytoestrogen intake were assessed by a semi-quantitative questionnaire. BMD at the spine and hip were measured by dual-energy X-ray absorptiometry (DXA). Fasting blood was analyzed for 25(OH)D, parathyroid hormone (PTH), total and bioavailable estradiol (bio-E) and testosterone (bio-T). The mean age of the cohort was 68.42+/-10.4 (50-96) years. In the linear regression model, weight, age, body mass index (BMI), bio-E, PTH, cigarette smoking and weight-bearing exercise were significant determinants of total hip BMD. Together they explained 55% of the total variance of hip BMD, with body weight being the most important determining factor. With age and weight adjustment, height, bio-T and flavonoid intake were identified as additional determinants of total hip BMD. Strategies to prevent bone loss and osteoporosis in Asian men should include lifestyle modification and maintenance of hormonal sufficiency.

Genetic and environmental determinants of bone mineral density in Chinese women.

BMD is a complex trait determined by genetic and lifestyle factors. To assess the genetic and environmental determinants of BMD in southern Chinese women, we studied a community-based cohort of 531 pre- and postmenopausal southern Chinese women and assessed the influence of 12 candidate gene loci and lifestyle risk factors on spine and hip BMD. The candidate genes studied include estrogen receptor alpha (ESR1) and beta (ESR2), calcium sensing receptor (CASR), vitamin D receptor (VDR), collagen type Ialpha1 (COLIA1), and LDL receptor-related protein 5 (LRP5). Social, medical, reproductive history, dietary habits and lifestyle factors were determined using a structured questionnaire. Single nucleotide polymorphisms (SNPs) of the COLIA1 and LRP5 gene in Chinese were determined by direct sequencing. Nucleotide (nt) -1363C/G and -1997 G/T of COLIA1, nt 266A/G, 2220C/T and 3989C/T of LRP5 gene were analyzed. Using stepwise multiple linear regression analyses, body weight was the strongest predictor for BMD in premenopausal women (n = 262), which accounted for 15.9% of the variance at the spine, 20% at femoral neck, 17.1% at trochanter, 24.3% at total hip and 10.9% at the Ward's triangle. Other significant predictors were ESR1 Ivs1-397T/C genotype (2.2% at the spine); LRP5 2220C/T genotype (1.3% at the spine, 1.6% at the trochanter); LRP5 266A/G genotype (1.1% at Ward's triangle); age at menarche (1.3% at trochanter) and age (2.0% at Ward's triangle). As for postmenopausal women (n = 269), body weight ( approximately 25% at various sites) and age (approximately 16% at femoral neck, trochanter, total hip and Ward's triangle sites) were the strongest predictors of BMD. Other significant predictors were age at menarche (4.4% at spine, 0.7% at femoral neck, 1.4% at trochanter, and 1.4% at Ward's triangle); weight bearing physical activity (2.1% at trochanter and 1% at total hip); calcium intake (1.1% at femoral neck, 0.9% at trochanter, and 1.7% at total hip) ; height (0.7% at trochanter); and ESR2 1082A/G genotype (0.8% at trochanter). We conclude that BMD at various sites and at different time span of a woman is modified by different genetic and lifestyle factors, suggesting that BMD is highly dependent on gene-environmental interactions.

Transforming growth factor-beta1 gene polymorphisms and bone turnover, bone mineral density and fracture risk in southern Chinese women.

Genetic contributions play an important role in determining bone mineral density (BMD) and bone turnover. Transforming growth factor-beta (TGF-beta) is abundant in bone and has been implicated as an important regulator of both bone formation and resorption. Several polymorphisms of the TGF-beta1 gene have recently been suggested to be associated with BMD and susceptibility to osteoporotic spine fractures. To determine the relationship between TGF-beta1 polymorphisms and BMD in southern Chinese women, three SNPs at C(-1348) -T, T29 -C, and T(861-20) -C of TGF-beta1 gene were analyzed in 237 postmenopausal southern Chinese women by RFLP and direct sequencing. BMD at the lumbar spine and hip region, biochemical markers of bone turnover, as well as serum levels of TGF-beta1 were measured. Only the T29 -C polymorphism of TGF-beta1 gene was associated with BMD and fracture risk. The prevalence of fragility fractures was significantly higher in individuals with TC genotype (P < 0.05). Serum alkaline phosphatase and osteocalcin levels as well as urinary N-telopeptide excretion were significantly higher in women with TC than with TT or CC genotypes, and the difference remained significant after adjusting for age and BMI (all P < 0.05). Women with TC genotype had lower BMD at the trochanteric (P < 0.03) and total hip region (P = 0.05). No difference was observed in the serum TGF-beta1 levels among the three genotypes. In conclusion, an association between T29 -C polymorphisms of TGF-beta1 gene and BMD, bone turnover as well as fragility fractures were demonstrated in postmenopausal southern Chinese women.

Estrogen receptor beta gene polymorphisms are associated with higher bone mineral density in premenopausal, but not postmenopausal southern Chinese women.

Bone mineral density (BMD), the main determining risk factor for osteoporotic fractures, has a strong genetic component. Estrogen and its receptors play a critical role in both skeletal maturity and bone loss. We investigated the association between dinucleotide (cytosine-adenine; CA) repeat polymorphisms located in the flanking region of the estrogen receptor beta gene and bone mineral density (BMD) in 325 healthy southern Chinese women. BMD at the lumbar spine and hip region were measured using dual-energy X-ray absorptiometry (DEXA). The number of the repeats observed in our population ranged from 16 to 28. After adjusting for age, height, weight, and years of estrogen exposure, we observed that premenopausal subjects (n = 120) bearing at least one allele of 20 CA repeats had significantly higher BMD at the L2-4 lumbar spine (1.049 +/- 0.016 vs. 0.984 +/- 0.015; p = 0.01), total hip (0.836 +/- 0.014 vs. 0.813 +/- 0.013; p < 0.02), femoral neck (0.773 +/- 0.014 vs. 0.728 +/- 0.013; p = 0.02), trochanter (0.665 +/- 0.013 vs. 0.614 +/- 0.012; p = 0.01), and Ward's triangle (0.715 +/- 0.017 vs. 0.651 +/- 0.016; p = 0.02). There was no difference in the vertebral area of L-3 and femoral neck width in these premenopausal women with or without 20 CA repeats. However, in postmenopausal women (n = 205), Estrogen receptor beta (ER beta) gene polymorphisms were not related to BMD at any skeletal site. We conclude that ER beta gene polymorphisms are associated with higher BMD in premenopausal women, suggesting that the ER beta gene may have a modulatory role in bone metabolism in young adulthood.