Hip geometry variation is associated with bone mineralization pathway gene variants: The framingham study

Abstract

Mineralization of bone matrix is an important process in bone formation; thus defects in mineralization have been implicated in bone mineral density (BMD) and bone structure alterations. Three central regulators of phosphate balance, ALPL, ANKH, and ENPP1, are central in the matrix mineralization process; therefore, the genes encoding them are considered important candidates genes for BMD and bone geometry. To test for an association between these three candidate genes and BMD and bone geometry traits, 124 informative singlenucleotide polymorphisms (SNPs) were selected and genotyped in 1513 unrelated subjects from the Framingham offspring cohort. Initial results showed that SNP rs1974201 in the gene ENPP1 was a susceptibility variant associated with several hip geometric indices, with the strongest p value of 3.8 Â 10 À7 being observed for femoral neck width. A few modest associations were observed between SNPs in or near ALPL and several bone traits, but no association was observed with ANKH. The association signals observed for SNPs around rs1974201 were attenuated after conditional analysis on rs1974201. Transcription factor binding-site prediction revealed that the HOXA7 binding site was present in the reference sequence with the major allele, whereas this potential binding site is lost in the sequence with the minor allele of rs1974201. In conclusion, we found evidence for association of bone geometry variation with an SNP in ENPP1, a gene in the mineralization pathway. The alteration of a binding site of the deregulator of extracellular matrix HOXA7 warrants further investigation. ß

ENPP1 and ESR1 genotypes influence temporomandibular disorders development and surgical treatment response in dentofacial deformities

“…ENPP1 was also studied in the Framingham cohort, which identify polymorphisms associated with bone mineral density or bone morpho-biometrics. The SNP rs1974201 of ENPP1 gene is associated with bone morphology in the Framingham cohort (Cheung et al, 2009) while the SNP rs6569759 is associated with class III malocclusion (Deeley et al, 2015) suggesting that ENPP1 has a key role in bone morpho-biometrics. How these SNPs alter bone metabolism to affect bone formation remains unknown.…”

“…SNPs in genes of interest were selected based upon our previous findings of their potential role in development of malocclusion and or TMD, as described previously (Cheung et al, 2009; Deeley et al, 2015; Godel et al, 2014; Goding et al, 2003; Hottenstein et al, 2015; Kang et al, 2007; Kim et al, 2010; Liu et al, 2014; Nicot et al, 2014; Ribeiro-Dasilva et al, 2009; Sciote et al, 2015; Terkeltaub, 2001; Zebrick et al, 2014). These genes and their SNP characteristics are summarized in Table 1.…”

How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging

“…Therefore, klotho belongs to the group of key factors regulating mineral and vitamin D metabolism. (c) ENPP1, known to be the gene for insulin resistance/type 2 diabetes, hyperglycemia, and obesity (Meyre et al 2005), was recently shown by us and others to be associated with osteoporosisrelated traits (Cheung et al 2010). (d) Activation of the nuclear protein deacetylase Sirt1 (an antioxidant protein involved in aging) has recently been shown to decrease adipocyte development from preadipocytes, therefore promoting differentiation of mesenchymal stem cells into osteoblasts via inhibition of PPARγ (Backesjo et al 2009).…”

ENPP1 and ESR1 genotypes associated with subclassifications of craniofacial asymmetry and severity of temporomandibular disorders

“…10 Thirteen SNPs were selected for genotyping: in ACTN3 rs1815739, and rs678397 10 ; in ENPP1 rs937300, rs6569759, rs858339 and rs1409181 18,20–22 ; in ESR1 rs1643821, rs302318, rs3020377 and rs2077647 18,23–26 ; in PITX1 rs1131611 and in PITX2 rs2595110 4 to determine if specific allelic variants are over-represented in subjects with malocclusion sub-classifications. Thirty-three additional anonym SNPs were genotyped.…”