Article

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: 4.04). 04/2011; 23(2):781-7. DOI: 10.1007/s00198-011-1626-x
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
67 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Bone mass and inflammation are implicated in the pathogenesis of osteoporosis. We hypothesized that leptin and leptin receptor gene might be associated with osteoporosis by activating the inflammatory pathway. Therefore, we analyzed polymorphisms of the leptin (gene symbol, LEP) and leptin receptor (gene symbol, LEPR) genes and determined their associations with proinflammatory cytokine levels in patients with osteoporosis. We assessed polymorphisms in LEP (-2548G > A) and LEPR (Lys109Arg, Gln223Arg, and Lys656Asn) and calculated odds ratios for the genotype and allele distributions between patients and controls. Serum leptin, soluble leptin receptor, interleukin (IL)-1, IL-6, IL-7, and tumor necrosis factor (TNF) levels were measured by enzyme-linked immunosorbent assays (ELISA) and were verified by in vitro lymphocyte proliferation assays and ELISAs. We found a higher frequency of the A allele for LEP at -2548 in patients with osteoporosis compared with the control group. The A allele was associated with differences in serum leptin, soluble leptin receptor, IL-1, IL-6, and TNF levels compared with the wild-type G allele (p < 0.05). The G allele in Lys109Arg and Gln223Arg was associated with increased risk of osteoporosis and with differences in serum leptin, soluble leptin receptor, IL-1, IL-6, and TNF levels compared with the wild-type A allele (p < 0.05). The Lys656Asn genotype was not associated with the risk of osteoporosis. In vitro lymphocyte proliferation assays and ELISAs confirmed these results. Polymorphisms in LEP and LEPR are associated with increased risk of osteoporosis, possibly by increasing the expression of proinflammatory cytokines.
    Endocrine 03/2013; 44(2). DOI:10.1007/s12020-013-9899-9 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Osteoporosis, the most common type of bone disease worldwide, is clinically characterized by low bone mineral density (BMD) and increased susceptibility to fracture. Multiple genetic and environmental factors and gene-environment interactions have been implicated in its pathogenesis. Osteoporosis has strong genetic determination, with the heritability of BMD estimated to be as high as 60%. More than 80 genes or genetic variants have been implicated in risk of osteoporosis by hypothesis-free genome-wide studies. However, these genes or genetic variants can only explain a small portion of BMD variation, suggesting that many other genes or genetic variants underlying osteoporosis risk await discovery. Here, we review recent progress in genome-wide studies of osteoporosis and discuss their implications for medicine and the major challenges in the field.
    Genome Medicine 05/2013; 5(5):44. DOI:10.1186/gm448 · 4.94 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: SOX6, a member of the SOX gene family, plays a key role in the development of several mammalian tissues and organs, including the central nervous system. Specifically, this gene modulates the differentiation and proliferation of interneurons in the medial ganglionic eminence, as well as oligodendrocytes in the spinal cord. We describe the case of a 4-year-old girl with global developmental delay and a spinal cord syrinx who presented with recurrent episodes of parkinsonian symptoms subsequent to febrile illnesses. The symptoms included gait instability, tremor, and dysarthria, with a progressive relapsing-remitting course over the span of 2 years. The patient was later found to have a large deletion-type mutation in the SOX6 gene. This case is the first report in humans implying a role for SOX6 in basal ganglia function, as well as spinal cord development.
    Journal of child neurology 01/2014; 29(11). DOI:10.1177/0883073813514134 · 1.59 Impact Factor