Genetic variants in the SOX6 gene are associated with bone mineral density in both Caucasian and Chinese populations
Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, People's Republic of China. Osteoporosis International
(Impact Factor: 4.17).
04/2011; 23(2):781-7. DOI: 10.1007/s00198-011-1626-x
Given the biological function of SOX6 and recent genome-wide association finding, we performed a fine-mapping association analyses to investigate the relationship between SOX6 and BMD both in Caucasian and Chinese populations. We identified many single-nucleotide polymorphisms (SNPs) within or near the SOX6 gene to be significantly associated with hip bone mineral density (BMD).
SOX6 gene is an essential transcription factor in chondrogenesis and cartilage formation. Recent genome-wide association studies (GWAS) detected a SNP (rs7117858) located at the downstream of SOX6 significantly associated with hip BMD.
Given the biological function of SOX6 and the GWAS finding, we considered SOX6 as a new candidate for BMD and osteoporosis. Therefore, in this study, we performed a fine-mapping association analyses to investigate the relationship between SNPs within and near the SOX6 gene and BMD at both hip and spine. A total of 301 SNPs were tested in two independent US Caucasian populations (2,286 and 1,000 unrelated subjects, respectively) and a Chinese population (1,627 unrelated Han subjects).
We confirmed that the previously reported rs7117858-A was associated with reduced hip BMD, with combined P value of 2.45 × 10(-4). Besides this SNP, we identified another 19 SNPs within or near the SOX6 gene to be significantly associated with hip BMD after false discovery rate adjustment. The most significant SNP was rs1347677 located at the intron 3 (P = 3.15 × 10(-7)). Seven additional SNPs in high linkage disequilibrium with rs1347677 were also significantly associated with hip BMD. SNPs in SOX6 showed significant skeletal site specificity since no SNP was detected to be associated with spine BMD.
Our study identified many SNPs in the SOX6 gene associated with hip BMD even across different ethnicities, which further highlighted the importance of the SOX6 gene influencing BMD variation and provided more information to the understanding of the genetic architecture of osteoporosis.
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- "The measurement of BMD has been considered for years to be the " gold standard " in osteoporosis diagnosis (Kiel et al., 2007). BMD is known to be highly heritable, and an increasing number of genes have been identified to have independent effects on BMD in osteoporosis, including pre-B-cell leukemia homeobox 1 (PBX1) (Cheung et al., 2009), apolipoprotein E (APOE) (Singh et al., 2010), Jagged1 (JAG1) (Kung et al., 2010), TWIST1 gene (Hwang et al., 2010), TN- FRSF11B (osteoprotegerin) (Vidal et al., 2011), and SOX6 (Yang et al., 2012). In addition, in osteoporotic women, femoral neck BMD shows associations with vitamin D receptor gene (VDR), and lumbar spine BMD with osteoprotegerin (OPG) and tumor necrosis factor superfamily member 11 (TNFSF11) (Mencej-Bedrač et al., 2009). "
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ABSTRACT: We searched for key genes that could accurately predict bone mineral density. The gene expression profile GSE7429 was downloaded from the Gene Expression Omnibus database, which includes 20 samples, 10 with high and 10 with low bone mineral density. The differentially expressed genes (DEGs) were identified with packages in R language. Further, BLASTX was used to obtain COG function classifications of all the DEGs. The GOTM software was used to find DEGs enriched modules. The functions of genes in the modules was also predicted with the software GENECODIS. Three hundred and three genes were identified as DEGs by comparing high and low bone mineral density samples; the selected genes were mapped to 14 modules collected in PPID. Genes VDR, ESR1, and NRIP1, located in the same module, were significantly enriched in intracellular receptor-mediated signaling biological processes. We conclude that the genes VDR, ESR1, NRIP1 in B cells have a close relationship with bone mineral density. The expression patterns of these genes could be used to determine osteoprotegerin function and for early diagnosis and prevention of low bone mineral density.
Available from: PubMed Central
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ABSTRACT: Although the World Health Organization had recommended that every child be vaccinated for Hepatitis B by the early 1980s, large multinational pharmaceutical companies held monopolies on the recombinant Hepatitis B vaccine. At a price as high as USD$23 a dose, most Indians families could not afford vaccination. Shantha Biotechnics, a pioneering Indian biotechnology company founded in 1993, saw an unmet need domestically, and developed novel processes for manufacturing Hepatitis B vaccine to reduce prices to less than $1/dose. Further expansion enabled low-cost mass vaccination globally through organizations such as UNICEF. In 2009, Shantha sold over 120 million doses of vaccines. The company was recently acquired by Sanofi-Aventis at a valuation of USD$784 million.
The case study and grounded research method was used to illustrate how the globalization of healthcare R&D is enabling private sector companies such as Shantha to address access to essential medicines. Sources including interviews, literature analysis, and on-site observations were combined to conduct a robust examination of Shantha's evolution as a major provider of vaccines for global health indications.
Shantha's ability to become a significant global vaccine manufacturer and achieve international valuation and market success appears to have been made possible by focusing first on the local health needs of India. How Shantha achieved this balance can be understood in terms of a framework of four guiding principles. First, Shantha identified a therapeutic area (Hepatitis B) in which cost efficiencies could be achieved for reaching the poor. Second, Shantha persistently sought investments and partnerships from non-traditional and international sources including the Foreign Ministry of Oman and Pfizer. Third, Shantha focused on innovation and quality - investing in innovation from the outset yielded the crucial process innovation that allowed Shantha to make an affordable vaccine. Fourth, Shantha constructed its own cGMP facility, which established credibility for vaccine prequalification by the World Health Organization and generated interest from large pharmaceutical companies in its contract research services. These two sources of revenue allowed Shantha to continue to invest in health innovation relevant to the developing world.
The Shantha case study underscores the important role the private sector can play in global health and access to medicines. Home-grown companies in the developing world are becoming a source of low-cost, locally relevant healthcare R&D for therapeutics such as vaccines. Such companies may be compelled by market forces to focus on products relevant to diseases endemic in their country. Sanofi-Aventis' acquisition of Shantha reveals that even large pharmaceutical companies based in the developed world have recognized the importance of meeting the health needs of the developing world. Collectively, these processes suggest an ability to tap into private sector investments for global health innovation, and illustrate the globalization of healthcare R&D to the developing world.
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ABSTRACT: OBJECTIVE:Genomic copy number variations (CNVs) have been strongly implicated as important genetic factors for obesity. A recent genome-wide association study identified a novel variant, rs12444979, which is in high linkage disequilibrium with CNV 16p12.3, for association with obesity in Europeans. The aim of this study was to directly examine the relationship between the CNV 16p12.3 and obesity phenotypes, including body mass index (BMI) and body fat mass.SUBJECTS:Subjects were a multi-ethnic sample, including 2286 unrelated subjects from a European population and 1627 unrelated Han subjects from a Chinese population. Body fat mass was measured using dual energy X-ray absorptiometry.RESULTS:Using Affymetrix Genome-Wide Human SNP Array 6.0, we directly detected CNV 16p12.3, with the deletion frequency of 27.26 and 0.8% in the European and Chinese populations, respectively. We confirmed the significant association between this CNV and obesity (BMI: P=1.38 × 10(-2); body fat mass: P=2.13 × 10(-3)) in the European population. Less copy numbers were associated with lower BMI and body fat mass, and the effect size was estimated to be 0.62 (BMI) and 1.41 (body fat mass), respectively. However, for the Chinese population, we did not observe significant association signal, and the frequencies of this deletion CNV are quite different between the European and Chinese populations (P<0.001).CONCLUSION:Our findings first suggest that CNV 16p12.3 might be ethnic specific and cause ethnic phenotypic diversity, which may provide some new clues into the understanding of the genetic architecture of obesity.International Journal of Obesity advance online publication, 6 March 2012; doi:10.1038/ijo.2012.31.
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