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


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-beta 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.
Cheung
Ching-Lung
CL
Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
Sham
Pak C
PC
Chan
Vivian
V
Paterson
Andrew D
AD
Luk
Keith D K
KD
Kung
Annie W C
AW
D016475:3T3 Cells; D000818:Animals; D044466:Asian People / Q000235:genetics; D015519:Bone Density / Q000235:genetics*; D002478:Cells, Cultured; D002681:China; D002874:Chromosome Mapping; D002883:Chromosomes, Human, Pair 14; D050723:Fractures, Bone / Q000453:epidemiology* / Q000235:genetics*; D008040:Genetic Linkage; D014644:Genetic Variation; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics*; D051379:Mice; D018895:Microsatellite Repeats; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D040641:Quantitative Trait Loci; D012307:Risk Factors
C509035:LTBP2 protein, human; D053779:Latent TGF-beta Binding Proteins