Su-Mei Xiao

An in vivo genome wide gene expression study of circulating monocytes suggested GBP1, STAT1 and CXCL10 as novel risk genes for the differentiation of peak bone mass.

Peak bone mass (PBM) is an important determinant of osteoporosis. Circulating monocytes serve as early progenitors of osteoclasts and produce important molecules for bone metabolism. To search for genes functionally important for PBM variation, we performed a whole genome gene differential expression study of circulating monocytes in human premenopausal subjects with extremely low (N=12) vs. high (N=14) PBM. We used Affymetrix HG-U133 plus2.0 GeneChip arrays. We identified 70 differential expression probe sets (p<0.01) corresponding to 49 unique genes. After false discovery rate adjustment, three genes [STAT1, signal transducer and activator of transcription 1; GBP1, guanylate binding protein 1; CXCL10, Chemokine (C-X-C motif) ligand 10] expressed significantly differentially (p<0.05). The RT-PCR results independently confirmed the significantly differential expression of GBP1 gene, and the differential expression trend of STAT1. Functional analyses suggested that the three genes are associated with the osteoclastogenic processes of proliferation, migration, differentiation, migration, chemotaxis, adhesion. Therefore, we may tentatively hypothesize that the three genes may potentially contribute to differential osteoclastogenesis, which may in the end lead to differential PBM. Our results indicate that the GBP1, STAT1 and CXCL10 may be novel risk genes for the differentiation of PBM at the monocyte stage.

Establishment of peak bone mineral density in Southern Chinese males and its comparisons with other males from different regions of China

Peak bone mineral density (PBMD) is an important determinant of osteoporotic fracture and a precondition for correct diagnosis of osteoporosis. The objective of this study was to establish the reference data of PBMD at the lumber spine and hip in Southern Chinese males. Bone mineral density (BMD) was measured at the lumbar spine and hip (femoral neck, trochanter, intertrochanter, and total) in 1155 Chinese men aged 15–39 years, using dual-energy X-ray absorptiometry (DXA). We utilized a fit curve method to determine the best age range over which to calculate PBMD. Our results indicated that the PBMD was observed at the age range of 18–25 years at the various sites. The mean value and standard deviation of PBMD was 0.753 ± 0.117, 1.156 ± 0.148, 0.896 ± 0.120, 0.989 ± 0.122, and 0.980 ± 0.116 g/cm2 at the trochanter, intertrochanter, femoral neck, total hip, and spine, respectively. When the present PBMD reference was compared with the documented PBMD reference of males from other regions of China, we found great difference in standardized PBMD between Changsha males and those from other regions of China. The PBMD for Chinese males in Changsha at the various sites were 3.19%–11.33% lower than that for American Caucasian males. In conclusion, the PBMD at the spine and hip may be used as normal reference data for Southern Chinese males in Changsha instead of documented PBMD from other regions of China and the manufacturers reference data.

Genetic and environmental correlations between bone phenotypes and anthropometric indices in Chinese

Height, weight, bone mineral density (BMD), and bone size are all influenced by genetic and environmental factors as well as interactions between them. Height and weight are often used in population studies to adjust the bone phenotypes. However, it is still unknown what proportion of genetic and environmental variability is shared between these anthropometric characteristics and the bone phenotypes. The genetic and environmental correlations between the bone phenotypes and anthropometric indices in Chinese subjects were studied by bivariate quantitative genetic analysis on a sample of 931 healthy subjects from 292 Chinese nuclear families aged from 19 to 79 years. BMD and bone size at the lumbar spine (L1–L4) and the hip of all subjects were measured by dual-energy X-ray absorptiometry. We found significant genetic correlations between weight and spine BMD, hip BMD, spine bone size and hip bone size, which were 0.50 (P<0.01), 0.45 (P<0.01), 0.36 (P=0.02), and 0.38 (P<0.01), respectively. Likewise, significant genetic correlations between height and spine BMD, spine bone size, and hip bone size were 0.30 (P=0.02), 0.54 (P<0.01), and 0.58 (P<0.01), respectively. The environmental correlations were found to be significant only between height and spine bone size (P<0.001) and weight and hip BMD (P=0.02). These results suggest the probability that the same genetic and environmental factors contribute to these different phenotypes. Moreover, when a candidate gene or genomic region is responsible for the variation of both bone phenotypes and anthropometric indices, its true genetic effect on the bone phenotypes may be lost after one has adjusted the phenotypic values with weight and height as random environmental factors. It may have implications for population studies of candidate genes that underlie the complex bone phenotypes and for the development of strategies for therapeutic application.

The (GT) n polymorphism and haplotype of the COL1A2 gene, but not the (AAAG) n polymorphism of the PTHR1 gene, are associated with bone mineral density in Chinese

Collagen type I α2 (COL1A2) and parathyroid hormone (PTH)/PTH-related peptide receptor (PTHR1) are two prominent candidate genes for bone mineral density (BMD). To test their importance for BMD variation in Chinese, we recruited 388 nuclear families composed of both parents and at least one healthy daughter with a total of 1,220 individuals, and simultaneously analyzed population stratification, total-family association, and within-family association between BMD at the spine and hip and the (GT)n marker in the intron 1 of the COL1A2 gene and the (AAAG)n marker in the P3 promoter of PTHR1 gene. We also performed these association analyses with haplotypes of the MspI and (GT)n polymorphisms in the COL1A2 gene. Significant within-family association was found between the M(GT)12 haplotype and trochanter BMD (P<0.001). Individuals with this haplotype have, on average, 9.53% lower trochanter BMD than the non-carriers. Suggestive evidence of the within-family association was detected between the (GT)17 allele and BMD at the spine (P=0.012), hip (P=0.011), femoral neck (P=0.032), trochanter (P=0.023), and intertrochanter (P=0.034). The association was confirmed by subsequent permutation tests. For the association, the proportion of phenotypic variance explained by the detected markers ranged from 1.2 to 3.9%, with the highest 3.9% at the trochanter for the M(GT)12 haplotype. This association indicates that there is strong linkage disequilibrium between the polymorphisms (MspI and GT repeat polymorphism) in the COL1A2 gene and a nearby quantitative trait locus (QTL) underlying BMD variation in Chinese, or the markers themselves may have an important effect on the variation of BMD. On the other hand, no significant within-family association, population stratification and total-family association between the PTHR1 polymorphism and BMD were found in our Chinese population.

Absence of linkage to 8q23.3-q24.1 and 2p11.1-q12.2 in a new BAFME pedigree in China: Indication of a third locus for BAFME

Benign adult familial myoclonic epilepsy (BAFME) were mapped on chromosome 8q24 and 8q23.3-q24.1 in Japanese pedigrees and mapped on 2p11.1-2q12.2 in European pedigrees, respectively. Recently, we recruited a large BAFME pedigree in China. After genotyping 11 microsatellite markers covering the two previously identified chromosome regions, we performed linkage analyses. However, evidence of negative linkage was found in the two previously reported candidate regions (LOD score <-3.0 at no recombination). Our data suggest that the causative gene responsible for BAFME in the Chinese pedigree may be located on a new region other than 8q23.3-q24.1 and 2p11.1-q12.2, indicating the presence of a third locus for BAFME.

Correlation and prediction of trunk fat mass with four anthropometric indices in Chinese males.

To increase our understanding of the relationships of trunk fat mass (FMtrunk) and four anthropometric indices in Chinese males, 1090 males aged 20-40 years were randomly recruited from the city of Changsha, China. Waist circumference (WC) and hip circumference (HC) were measured using standardized equipment, and three other anthropometric indices of BMI, waist:hip ratio (WHR) and conicity index (CoI) were calculated using weight, height, HC and WC. FMtrunk (in kg) was measured using a Hologic QDR 4500 W dual-energy X-ray absorptiometry scanner. There was an increasing trend of FMtrunk, %FMtrunk (percentage of FMtrunk) and BMI, WC, WHR, CoI in successively older age groups (e.g. the mean FMtrunk values were 4.63 (SD 2.58), 5.39 (SD 2.74), 5.93 (SD 2.82), 6.57 (SD 2.94) in four 5-year age groups, respectively). FMtrunk and %FMtrunk were significantly correlated with four anthropometric indices with the Pearsons correlation coefficients ranging from 0.25 to 0.86. Principal component analysis was performed to form three principal components that interpreted over 99.5% of the total variation of four related anthropometric indices in all age groups, with over 65% of the total variation accounted by principal component 1. Multiple regression analyses showed that three principal components explained a greater variance (R(2) 70.0-80.1%) in FMtrunk than did BMI or WC alone (R(2) 57.8-74.1%). The present results suggest that there is an increasing trend of FMtrunk and four anthropometric indices in successively older age groups; that age has important effects on the relationships of FMtrunk and studied anthropometric indices; and that the accuracy of predicting FMtrunk using four anthropometric indices is higher than using BMI or WC alone.