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

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Identification of LTBP2 on Chromosome 14Q As a Novel Candidate Gene for Bone Mineral Density Variation and Fracture Risk Association ORIGINAL ARTICLE Endocrine Research Identification of LTBP2 on Chromosome 14q as a Novel Candidate Gene for Bone Mineral Density Variation and Fracture Risk Association Ching-Lung Cheung, Pak C. Sham, Vivian Chan, Andrew D. Paterson, Keith D. K. Luk, and Annie W. C. Kung 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 Context: Low bone mineral density (BMD) is a major risk factor for osteoporotic fracture. Chro- mosome 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 con- firmed 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-␤ binding protein 2(LTBP2) had significant associations with trochanter and total hip BMD. Multiple logistic regres- sion revealed a strong genetic association between LTBP2 gene locus and total hip BMD variation (P ϭ 0.0004) and prevalent fracture (P ϭ 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. (J Clin Endocrinol Metab 93: 4448–4455, 2008) steoporosis is an important health problem worldwide as nificant bone loss. In addition, localization of candidate genes for O the prevalence of associated bone fractures is increasing BMD variation aids understanding of the pathogenesis of the due to prolonged life expectancy and aging of the population. disease and development of new therapies. Osteoporosis is a disorder in which there is a reduction in bone More than 20 genome-wide linkage scans (GWLS) have been strength that results in enhanced bone fragility and a consequent published on BMD and osteoporotic fractures. Nonetheless, in- increased fracture risk. Low bone mineral density (BMD) is one consistent results remain the major challenge in the quest for of the major determinants of bone strength and an important risk identification of genes that affect BMD. Suggestive or significant factor for osteoporotic fractures. BMD is under strong genetic linkages for BMD variation at several skeletal sites have been inference with a heritability estimate of 0.63–0.71 in women and detected on chromosome 14q (2–4). In our recent meta-analysis 0.74–0.79 in men (1). Early identification of at-risk subjects study of nine GWLS with 11,842 subjects, several significant allows preventive measures to be implemented before any sig- quantitative trait loci (QTL) were identified, and two neighbor- 0021-972X/08/$15.00/0 Abbreviations: BMD, Bone mineral density; CI, confidence interval; FN, femoral neck; Printed in U.S.A. GWLS, genome-wide linkage scans; LD, linkage disequilibrium; LRT, likelihood ratio test; MAF, minor allele frequency; QTL, quantitative trait loci; SNP, single-nucleotide Copyright © 2008 by The Endocrine Society polymorphism. doi: 10.1210/jc.2007-2836 Received December 26, 2007. Accepted August 5, 2008. First Published Online August 12, 2008 4448 jcem.endojournals.org J Clin Endocrinol Metab. November 2008, 93(11):4448–4455 The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 11 September 2015. at 16:25 For personal use only. No other uses without permission. All rights reserved. J Clin Endocrinol Metab, November 2008, 93(11):4448–4455 jcem.endojournals.org 4449 ing bins on chromosome 14, 14q13.1-q24.1 (P ϭ 0.003) and ment. All participants gave informed consent, and the study was ap- 14q23.3-q32.12 (P ϭ 0.022), were shown to be significantly proved by the Ethics Committee of the University of Hong Kong and linked to hip BMD variation (5). These combined findings sug- conducted according to the Declaration of Helsinki. For the family study, probands were identified from subjects with gest that chromosome 14 may harbor multiple candidate genes BMD Z score of less than or equal to Ϫ1.28 (the lowest 10th percentile that contribute to BMD variation at different skeletal sites. Es- of the population) at either the lumbar spine (L1–4) or hip; extended trogen receptor ␤ (ESR2) is one of the positional candidate genes family members were also invited to participate. We estimated family in this region that has been shown to contribute to BMD vari- informativeness for 1021 pedigrees. Based on previous heritability esti- ation (6). Given the QTL size and overall strength of linkage mates of BMD of 70% from a similar population, the expected LOD score for each pedigree was estimated, via regression, on the basis of signals observed on chromosome 14q, it is likely that more than phenotypic values, by using the option rankFamilies in Merlin-re- one susceptibility locus may reside within the QTL. Nonetheless, gress. Families with the highest informativeness were selected for it remains largely unknown which genes in the region also play evaluation (1). Three hundred six families with 1459 subjects (293 a role in BMD regulation. males and 1166 females) spanning two to four generations were an- alyzed. These pedigrees contained 1260 sib pairs, 143 cousin pairs, In this study, we carried out a linkage analysis of the chro- 2356 parent-child pairs, 522 grandparent-grandchild pairs, and 512 mosome 14 region in an independent set of southern Chinese avuncular pairs. Detailed descriptions of these families have been families in attempt to replicate the previously reported linkage reported previously (7, 8). findings. Using a newly developed bioinformatics tool for To increase the power of the association study, a threshold-defined gene prioritization, the five top-ranked genes under the QTL case-control design was adopted, and unrelated subjects from the op- posite extreme of the distribution of BMD were studied for the associ- were selected for association analysis using the tagging ap- ation analysis. Low BMD subjects were arbitrarily defined as those with proach. Our results revealed a novel candidate gene LTBP2 on a BMD Z score of less than or equal to Ϫ1.28 (equivalent to the lowest chromosome 14q that is associated with hip BMD variation 10th percentile of the population) at either the spine or hip. High BMD and fracture prevalence. subjects were sex-matched controls with a BMD Z score higher than ϩ1 (approximately equivalent to the 85th percentile of the population) at the corresponding bone site. We identified 833 unrelated case-control pairs of subjects, with 706 trochanter case-control pairs and 760 total Subjects and Methods hip case-control pairs. A total of 633 pairs constituted both trochanter and total hip cohorts. The case-control cohorts were sex and age Study population matched. Detailed inclusion and exclusion criteria have been de- scribed previously (8, 9). The study subjects were extracted from an expanding database being compiled at the Osteoporosis Centre at Queen Mary Hospital, the Uni- versity of Hong Kong, to determine the genetic and environmental risk BMD measurements and prevalent fracture assessment factors for osteoporosis. All study subjects were individuals of southern BMD (grams per square centimeter) at the spine L1–L4, femoral neck Chinese descent resident in the local community. They were recruited at (FN), trochanter, and total hip was measured by dual-energy x-ray ab- road shows and health talks on osteoporosis held between 1998 and sorptiometry (Hologic QDR 4500 plus; Hologic Waltham, MA). The in 2003 and were invited to the Osteoporosis Centre for BMD measure- vivo precision of the machine for spine, FN, and total hip region was 1.2, 1.5, and 1.5%, respectively (10). Weight and height were measured at the same visit. Thoraco- lumbar spine x-rays were assessed for radio- graphic evidence of spine fracture at baseline using the semiquantitative method (11). All low- trauma fractures at the spine, hip, and distal ra- dius and morphometric fracture at the spine were included in the final analysis. Microsatellite marker genotyping Genomic DNA was extracted from peripheral blood leukocytes using a phenol/chloroform extraction method. A total of 18 high-density mi- crosatellite markers were genotyped in the chro- mosome 14 region delineated by D14S972 (lo- cated at 14q12) and D14S1007 (located at 14q32.2) encompassing a 117-cM interval. This region showed significant linkage to hip BMD variation in a recent meta-analysis. All markers were commercially available through PE Applied Biosystems (ABI PRISM Linkage Mapping Sets, version 2; Norwalk, CT). Marker order and map positions were obtained from the Marshfield map (Fig. 1). The average intermarker distance was 6.5 cM, and average population heterozygosity was 70%. Genotyping was performed on an ABI PRISM 3700 genetic analyzer using the GENES- CAN and GENOTYPER software for allele iden- FIG. 1. Multipoint LOD scores for linkage of spine, FN, trochanter, and total hip BMD to chromosome 14q. tification and sizing. The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 11 September 2015. at 16:25 For personal use only.
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