Shu-Feng Lei

Differentiation of Caucasians and Chinese at bone mass candidate genes: implication for ethnic difference of bone mass.

Bone mineral density (BMD) is an important risk factor for osteoporosis and has strong genetic determination. While average BMD differs among major ethnic groups, several important candidate genes have been shown to underlie BMD variation within populations of the same ethnicity. To investigate whether important candidate genes may contribute to ethnic differences in BMD, we studied the degree of genetic differentiation among several important candidate genes between two major ethnic groups: Caucasians and Chinese. The genetic variability of these two populations (1131 randomly selected individuals) was studied at six restriction sites exhibiting polymorphisms of five important candidate genes for BMD: the BsaHI polymorphism of the calcium‐sensing receptor (CASR) gene, the SacI polymorphism of the α2HS‐glycoprotein (AHSG) gene, the PvuII and XbaI polymorphisms of the estrogen receptor α (ESR1) gene, the ApaI polymorphism of the vitamin D receptor (VDR) gene, and the BstBI polymorphism of the parathyroid hormone (PTH) gene. The two ethnic groups showed significant allelic and genotypic differentiation of all the polymorphisms studied. The mean FST was 0.103, which significantly differed from zero (P < 0.01). The Chinese population had lower mean heterozygosity (0.331) than the Caucasian one (0.444); the CASR‐BsaHI and PTH‐BstBI polymorphisms contributed most significantly to this difference. Analysis of the intra‐ and inter‐population variability suggests that various types of natural selection may affect the observed patterns of variation at some loci. If some of the candidate genes we studied indeed underlie variation in BMD, their population differentiation revealed here between ethnic groups may contribute to understanding ethnic difference in BMD.

Molecular genetic studies of gene identification for osteoporosis: the 2009 update.

Osteoporosis is a complex human disease that results in increased susceptibility to fragility fractures. It can be phenotypically characterized using several traits, including bone mineral density, bone size, bone strength, and bone turnover markers. The identification of gene variants that contribute to osteoporosis phenotypes, or responses to therapy, can eventually help individualize the prognosis, treatment, and prevention of fractures and their adverse outcomes. Our previously published reviews have comprehensively summarized the progress of molecular genetic studies of gene identification for osteoporosis and have covered the data available to the end of September 2007. This review represents our continuing efforts to summarize the important and representative findings published between October 2007 and November 2009. The topics covered include genetic association and linkage studies in humans, transgenic and knockout mouse models, as well as gene-expression microarray and proteomics studies. Major results are tabulated for comparison and ease of reference. Comments are made on the notable findings and representative studies for their potential influence and implications on our present understanding of the genetics of osteoporosis.

Genetic determination and correlation of body mass index and bone mineral density at the spine and hip in Chinese Han ethnicity

The purpose of the present study was to evaluate the magnitude of genetic determination of spine and hip bone mineral density (BMD) and body mass index (BMI), and to explore the genetic, environmental, and phenotypic correlations among the above phenotypes in Chinese Han ethnicity. The sample was composed of at least 217 complete nuclear families in Chinese Han ethnicity. BMD at the spine and hip was measured using a dual-energy X-ray absorptiometry scanner. The heritability ( h 2) of BMI and BMD at the spine and hip, the genetic correlation ( ρ G) and environmental correlation ( ρ E) among the three phenotypes were evaluated via variance analysis, with age, sex, and age-by-sex interaction as covariates. The phenotypic correlation ( ρ P) and the bivariate heritability ρG2 were also calculated. The heritability for BMD and BMI was ~0.70 and ~0.50, respectively ( p <0.0001). The common environment shared by household members (household effect) is significant for BMI variation ( p =0.0004). Significant genetic, environmental, and phenotypic correlation was observed. The ρG2 values were 0.13 for BMI/spine BMD, 0.18 for BMI/hip BMD, and 0.58 for the spine BMD/hip BMD. While BMD at the spine and hip have significant genetic determination, BMI is more likely to be affected by environmental factors than BMD. In addition, BMD at the spine and hip shares more genetic effect (pleiotropy) than BMI and BMD do in Chinese Han ethnicity, though the effects are significant for both.

Molecular genetic studies of gene identification for sarcopenia

Sarcopenia, which is characterized by a progressive decrease of skeletal muscle mass and function with aging, is closely related to several common diseases (such as cardiovascular and airway diseases) and functional impairment/disability. Strong genetic determination has been reported for muscle mass and muscle strength, two most commonly recognized and studied risk phenotypes for sarcopenia, with heritability ranging from 30 to 85% for muscle strength and 45–90% for muscle mass. Sarcopenia has been the subject of increasing genetic research over the past decade. This review is designed to comprehensively summarize the most important and representative molecular genetic studies designed to identify genetic factors associated with sarcopenia. We have methodically reviewed whole-genome linkage studies in humans, quantitative trait loci mapping in animal models, candidate gene association studies, newly reported genome-wide association studies, DNA microarrays and microRNA studies of sarcopenia or related skeletal muscle phenotypes. The major results of each study are tabulated for easy comparison and reference. The findings of representative studies are discussed with respect to their influence on our present understanding of the genetics of sarcopenia. This is a comprehensive review of molecular genetic studies of gene identification for sarcopenia, and an overarching theme for this review is that the currently accumulating results are tentative and occasionally inconsistent and should be interpreted with caution pending further investigation. Consequently, this overview should enhance recognition of the need to validate/replicate the genetic variants underlying sarcopenia in large human cohorts and animal. We believe that further progress in understanding the genetic etiology of sarcopenia will provide valuable insights into important fundamental biological mechanisms underlying muscle physiology that will ultimately lead to improved ability to recognize individuals at risk for developing sarcopenia and our ability to treat this debilitating condition.

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.

Pharmacogenetics and pharmacogenomics for rheumatoid arthritis responsiveness to methotrexate treatment: the 2013 update

Rheumatoid arthritis (RA) is a complex, systemic autoimmune disease characterized by chronic inflammation of multiple peripheral joints, which leads to serious destruction of cartilage and bone, progressive deformity and severe disability. Methotrexate (MTX) is one of the first-line drugs commonly used in RA therapy owing to its excellent long-term efficacy and cheapness. However, the efficacy and toxicity of MTX treatment have significant interpatient variability. Genetic factors contribute to this variability. In this review, we have summarized and updated the progress of RA response to MTX treatment since 2009 by focusing on the fields of pharmacogenetics and pharmacogenomics. Identification of genetic factors involved in MTX treatment response will increase the understanding of RA pathology and the development of new personalized treatments.

Evaluation of compressive strength index of the femoral neck in Caucasians and chinese.

Compressive strength index (CSI) of the femoral neck is a parameter that integrates the information of bone mineral density (BMD), femoral neck width (FNW), and body weight. CSI is considered to have the potential to improve the performance of assessment for hip fracture risk. However, studies on CSI have been rare. In particular, few studies have evaluated the performance of CSI, in comparison with BMD, FNW, and bending geometry, for assessment of hip fracture risk. We studied two large populations, including 1683 unrelated U.S. Caucasians and 2758 unrelated Chinese adults. For all the study subjects, CSI, femoral neck BMD (FN_BMD), FNW, and bending geometry (section modulus [Z]) of the samples were obtained from dual-energy X-ray absorptiometry scans. We investigated the age-related trends of these bone phenotypes and potential sex and ethnic differences. We further evaluated the performance of these four phenotypes for assessment of hip fracture risk by logistic regression models. Chinese had significantly lower FN_BMD, FNW, and Z, but higher CSI than sex-matched Caucasians. Logistic regression analysis showed that higher CSI was significantly associated with lower risk of hip fracture, and the significance remained after adjusting for covariates of age, sex, and height. Each standard deviation (SD) increment in CSI was associated with odds ratios of 0.765 (95% confidence interval, 0.634, 0.992) and 0.724 (95% confidence interval, 0.569, 0.921) for hip fracture risk in Caucasians and Chinese, respectively. The higher CSI in Chinese may partially help explain the lower incidence of hip fractures in this population compared to Caucasians. Further studies in larger cohorts and/or longitudinal observations are necessary to confirm our findings.

Bone mineral density in elderly Chinese: effects of age, sex, weight, height, and body mass index

To enhance our understanding of the relationship between bone mineral density (BMD) and sex, age, body mass index (BMI), weight, and height in elderly Chinese, we studied 258 males aged 50–80 years (mean ± SD, 62.9 ± 6.2 years) and 193 females aged 46–75 years (59.0 ± 6.2 years). We measured BMD at the lumbar spine (L1–L4), hip (femoral neck, trochanter, and intertrochanter), and Ward’s triangle. A significant difference of age-adjusted BMD among male-female groups (P ≪ 0.0001) was observed. After adjustment for weight, the magnitude of the sex difference in BMD was reduced at all studied skeletal sites; for example, the difference declined from 18.3% to 5.5% at the spine. There were significant differences in BMD among age-stratified groups at all the sites in both sexes (P ≪ 0.01), except for spine BMD in males (P = 0.928). Regression analysis suggested that, with aging, greater differences of BMD distribution exist in elderly females than in males. Weight accounted for the greatest proportion of age-adjusted BMD variation (e.g., at femoral neck, R2 = 0.17 in males) among four variables: weight, height, BMI, and a principal component formed from weight and height. These results suggested that weight decreased the sex difference in BMD in elderly Chinese. Patterns of age-related BMD distribution and BMD change among different age groups differed between the sexes and between the studied sites. Weight accounted for most of the effect of two correlated variables (weight and height) on BMD in our sample.

Searching for genes underlying susceptibility to osteoporotic fracture: current progress and future prospect

IntroductionOsteoporotic fracture (OF) is a public health problem. It is a common practice in the genetics of osteoporosis that bone mineral density (BMD) was studied as a major surrogate phenotype in gene search for risk of OF (ROF) because of their high phenotypic correlation. However, some studies indicate that the genetic correlation between BMD and ROF is very low. This implies that most genes found important for BMD may not be relevant to ROF. Ideally, employing OF per se as a direct study phenotype can directly find the relevant genes underlying ROF.EvidenceHere, we summarized some evidence supporting ROF under moderate genetic control, and the current progress of molecular genetic studies employing OF as the direct study phenotype, then give our consideration on the future prospects in the genetics of ROF.

Tests of linkage and association of the COL1A2 gene with bone phenotypes’ variation in Chinese nuclear families

In the present study, we simultaneously test linkage and/or association of the collagen type I alpha 2 (COL1A2) gene with bone mineral density (BMD) and bone area. A total of 1280 subjects from 407 Chinese nuclear families (including both parents and their daughters) were genotyped for an intragenic marker MspI in the COL1A2 gene. BMD and bone area at the lumbar spine and hip were measured by dual-energy X-ray absorptiometry. Applying the QTDT (quantitative transmission disequilibrium test) program, we performed tests for population stratification, within-family association (via transmission disequilibrium test), total association, linkage, and linkage while modeling association. Significant or marginal within-family associations were found with BMD at the lumbar spine (P = 0.013), trochanter (P = 0.004), and total hip (P = 0.053) and with bone area at the intertrochanteric region (P = 0.024) and total hip (P = 0.048). The positive associations were confirmed in permutations except for bone area at total hip (P > 0.10). A small proportion (<1%) of the population variance of bone phenotypes can be explained by the MspI polymorphism; however, it may be underestimated given the significant population stratification detected in our sample. Due to the limited number of sib pairs in this sample, we did not find evidence of linkage. In summary, the MspI polymorphism is likely to be in linkage disequilibrium with a nearby functional mutation affecting BMD and bone area.