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PLoS One. 2014 Apr 15;9(4):e94607. doi: 10.1371/journal.pone.0094607. eCollection 2014.

Genetic analysis of high bone mass cases from the BARCOS cohort of Spanish postmenopausal women.

Author information

1
Departament de Genètica, Universitat de Barcelona, IBUB, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain; Institut de Biomedicina Universitat de Barcelona (IBUB), Barcelona, Spain.
2
Unitat de Recerca en Fisiologia Òssia i Articular (URFOA), Institut Municipal d'Investigacions Mèdiques (IMIM), Hospital del Mar, Barcelona, Spain; Red Tematica de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), Instituto de Salud Carlos III, Barcelona, Spain.
3
Departament d'Estadística, Universitat de Barcelona, Barcelona, Spain.
4
Departament de Genètica, Universitat de Barcelona, IBUB, Barcelona, Spain.
5
Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
6
Red Tematica de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), Instituto de Salud Carlos III, Barcelona, Spain; CETIR Medical Imaging Centre, Barcelona, Spain.

Abstract

The aims of the study were to establish the prevalence of high bone mass (HBM) in a cohort of Spanish postmenopausal women (BARCOS) and to assess the contribution of LRP5 and DKK1 mutations and of common bone mineral density (BMD) variants to a HBM phenotype. Furthermore, we describe the expression of several osteoblast-specific and Wnt-pathway genes in primary osteoblasts from two HBM cases. A 0.6% of individuals (10/1600) displayed Z-scores in the HBM range (sum Z-score >4). While no mutation in the relevant exons of LRP5 was detected, a rare missense change in DKK1 was found (p.Y74F), which cosegregated with the phenotype in a small pedigree. Fifty-five BMD SNPs from Estrada et al. [NatGenet 44:491-501,2012] were genotyped in the HBM cases to obtain risk scores for each individual. In this small group of samples, Z-scores were found inversely related to risk scores, suggestive of a polygenic etiology. There was a single exception, which may be explained by a rare penetrant genetic variant, counterbalancing the additive effect of the risk alleles. The expression analysis in primary osteoblasts from two HBM cases and five controls suggested that IL6R, DLX3, TWIST1 and PPARG are negatively related to Z-score. One HBM case presented with high levels of RUNX2, while the other displayed very low SOX6. In conclusion, we provide evidence of lack of LRP5 mutations and of a putative HBM-causing mutation in DKK1. Additionally, we present SNP genotyping and expression results that suggest additive effects of several genes for HBM.

PMID:
24736728
PMCID:
PMC3988071
DOI:
10.1371/journal.pone.0094607
[Indexed for MEDLINE]
Free PMC Article

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