ECTS2016 Poster Presentations Genetics and Epigenetics (25 abstracts)
Search for BMD-related variants of DKK1 and SOST by resequencing in the BARCOS cohort
Núria Martínez-Gil 1 , Neus Roca-Ayats 1 , Roser Urreizti 1 , Héctor Franco-Valls 1 , Natalia Garcia-Giralt 2 , Leonardo Mellibovsky 2 , Xavier Nogués 2 , Adolfo Díez-Pérez 2 , Daniel Grinberg 1 & Susana Balcells 1
1Department of Genetics, Faculty of Biology, Universitat de Barcelona, CIBERER, IBUB, Barcelona, Spain; 2URFOA, IMIM, RETICEF, Parc de Salut Mar, Barcelona, Spain.
In a meta-analysis by Estrada et al. (2012), 56 loci were found associated with BMD, 14 of which were also associated with osteoporotic fracture. Several of these genes belong to the Wnt signaling pathway, including two inhibitors: DKK1 and SOST.
To better understand the role of these genes in BMD determination and fracture susceptibility, we aimed to explore their allelic architecture by resequencing all coding exons and flanking regions in two extreme BMD groups from the BARCOS cohort: 55 women with the highest BMD (HBM) and 53 with the lowest BMD (LBM). Once these variants were determined, the most promising ones were genotyped in the complete BARCOS cohort and, where appropriate, tested for association.
Resequencing of DKK1 and SOST identified 11 and 3 SNVs, respectively. Half of them had frequencies above 1%, and the rest were observed in only one or two samples, each. Only the rare variant c.*752C>T, in DKK1, was novel. One low-frequency variant in DKK1 showed significant differences between the genotype frequencies of the two extreme groups (rs74711339, P=0.0224).
This SNP and two SNPs (DKK1: rs1569198, SOST: rs17882143) and one rare variant (SOST: rs570754792) with a potential biological function were genotyped in n=1625 women from the BARCOS cohort. We tested the association of the three SNPs with LS-BMD and nominal significant results were only obtained for rs17882143. This SNP is a missense variant (p.V10I) and in our cohort it is in strong linkage disequilibrium with rs4792909 (the ‘GWAS hit’). Regarding the rare variant rs570754792, it was found in heterozygosity in only three women, whose values were below the mean BMD of the BARCOS cohort. It lies in a putative transcriptional regulation site.
In conclusion, our results suggest that the SOST p.V10I missense variant may play role in BMD determination. Functional studies to test this hypothesis are underway.
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