Common variants in FLNB/CRTAP, not ARHGEF3 at 3p, are associated with osteoporosis in southern Chinese women

Osteoporos Int. 2010 Jun;21(6):1009-20. doi: 10.1007/s00198-009-1043-6. Epub 2009 Sep 1.

Abstract

Summary: We performed an association study of five candidate genes within chromosome 3p14-25 in 1,080 Chinese female subjects. Polymorphisms in FLNB/CRTAP are associated with bone mineral density (BMD) in Chinese.

Introduction: Chromosomal region 3p14-25 has shown strong evidence of linkage to BMD in genome-wide linkage scans. The variants responsible for this linkage signal, nonetheless, remain obscure.

Methods: Thirty SNPs in five positional and functional candidate genes within 3p14-25 (PPARG, CRTAP, TDGF1, PTHR1, and FLNB) and rs7646054 in the ARHGEF3 gene were genotyped in a case-control cohort of 1,080 Chinese females. Allelic and haplotypic association were tested using logistic regression analysis implemented in PLINK software. Potential transcription factor binding sites were predicted with MatInspector.

Results: Multiple SNPs and haplotypes in FLNB were significantly associated with BMDs, with the strongest association between lumbar spine BMD and rs9828717 (p = 0.005). SNP rs7623768 and the haplotype G-C of rs4076086-rs7623768 in CRTAP were associated with femoral neck BMD (p = 0.009 and p = 0.003, respectively). PTHR1 showed haplotypic associations with lumbar spine and femoral neck BMD (p = 0.02 and p = 0.044, respectively). Nevertheless, the association between rs7646054 in ARHGEF3 and BMD observed in Caucasians was not replicated in our samples. Comparative genomics analysis indicated that rs9828717 is located within a highly conserved region. The minor T allele at rs9828717 may lead to loss of binding site for nuclear factor of activated T cells which binds and triggers the transcriptional program of osteoblasts.

Conclusions: Our data suggest that variants in FLNB and CRTAP at 3p are involved in BMD regulation in southern Chinese.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Asian People / genetics*
  • Bone Density / genetics
  • Chromosomes, Human, Pair 3 / genetics*
  • Computational Biology / methods
  • Contractile Proteins / genetics*
  • Epidemiologic Methods
  • Extracellular Matrix Proteins / genetics*
  • Female
  • Femur Neck / physiopathology
  • Filamins
  • Genetic Linkage / genetics
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Guanine Nucleotide Exchange Factors / genetics
  • Haplotypes
  • Hip Joint / physiopathology
  • Humans
  • Lumbar Vertebrae / physiopathology
  • Microfilament Proteins / genetics*
  • Middle Aged
  • Molecular Chaperones
  • Osteoporosis / genetics*
  • Osteoporosis / physiopathology
  • Polymorphism, Single Nucleotide
  • Rho Guanine Nucleotide Exchange Factors

Substances

  • ARHGEF3 protein, human
  • CRTAP protein, human
  • Contractile Proteins
  • Extracellular Matrix Proteins
  • FLNB protein, human
  • Filamins
  • Guanine Nucleotide Exchange Factors
  • Microfilament Proteins
  • Molecular Chaperones
  • Rho Guanine Nucleotide Exchange Factors