Identification of LTBP2 on chromosome 14q as a novel candidate gene for bone mineral density variation and fracture risk association

Abstract

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. Copyright © 2008 by The Endocrine Society.