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Identification of LTBP2 on Chromosome 14q as a Novel Candidate Gene for Bone Mineral Density Variation and Fracture Risk Association

Department of Medicine (C.-L.C., V.C., A.W.C.K.), Genome Research Centre (P.C.S.), Orthopaedics and Traumatology (K.D.K.L.), The University of Hong Kong, Pokfulam, Hong Kong, China; and Program in Genetics and Genomic Biology (A.D.P.), The Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ontario M5G 1L7, Canada

Address all correspondence and requests for reprints to: Annie W. C. Kung, M.D., Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China. E-mail: awckung@hkucc.hku.hk; or Pak C. Sham, Ph.D., Genome Research Centre, The University of Hong Kong, Pokfulam, Hong Kong, China. E-mail: pcsham{at}hkucc.hku.hk.

Context: Low bone mineral density (BMD) is a major risk factor for osteoporotic fracture. Chromosome 14q has previously been linked to BMD variation in several genome-wide linkage scans in Caucasian populations.

Objective: Our objective was to replicate and identify the novel candidate genes in the quantitative trait loci (QTL) at chromosome 14q QTL.

Subjects and Methods: Eighteen microsatellite markers were genotyped for a 117-cM interval in 306 Southern Chinese pedigrees with 1459 subjects. Successful replication of the QTL was confirmed within this region for trochanter and total hip BMD. Using a gene prioritization approach as implemented in the Endeavour program, we genotyped 65 single-nucleotide polymorphisms in the top five ranking candidate genes within the linkage peak in 706 and 760 case-control subject pairs with extremely high and low trochanter and total hip BMD, respectively.

Results: Single-marker and haplotype analyses revealed that ESR2 and latent TGF-β binding protein 2 (LTBP2) had significant associations with trochanter and total hip BMD. Multiple logistic regression revealed a strong genetic association between LTBP2 gene locus and total hip BMD variation (P = 0.0004) and prevalent fracture (P = 0.01). Preliminary in vitro study showed differential expression of LTBP2 gene in MC3T3-E1 mouse preosteoblastic cells in culture.

Conclusions: Apart from ESR2, LTBP2 is a novel positional candidate gene in chromosome 14q QTL for BMD variation and fracture.