Single nucleotide polymorphisms in new candidate genes are associated with bone mineral density and fracture risk

Abstract

Objective: Osteoporosis (OP) is a multifactorial disease with high heritability but its exact genetic background is still poorly understood. We examined the effect of 24 single nucleotide polymorphisms (SNPs) located in five genes -alkaline phosphatase, matrix metalloproteinase-2, tissue inhibitor of metalloproteases-2 (TIMP2), fibroblast growth factor receptor-1 (FGFR1), and fatty acid-binding protein-3 (FABP3) -previously not associated with OP. Design: We performed a genotype-phenotype association study at a university hospital. Methods: A total of 360 Hungarian postmenopausal women were involved in the study. Bone mineral density (BMD) was determined at spine, hip, and distal radius. Genomic DNA was extracted from venous blood samples and a high-throughput genotyping method based on single-based primer extension was applied for allelic discrimination. Robust statistical tools were utilized for multiplex data analysis. Results: SNP rs6996321 in FGFR1 was significantly related to spine BMD (PZ0.002) and rs10914367 in FABP3 was associated with hip BMD (PZ0.028). Non-vertebral fracture risk was significantly increased in carriers of ' A' allele of rs9900972 in TIMP2 (odds ratioZ2.06, PZ0.0187). We could also identify validated gene-gene interactions significantly affecting BMD and fracture risk. Conclusions: We identified two previously unreported SNPs in FGFR1 and FABP3 associated with BMD and a third SNP in TIMP2 related to risk for non-vertebral osteoporotic fractures. This is the first report about the association between these allelic variants and the phenotypes of postmenopausal OP. Further studies need to clarify the role of these genes and their polymorphisms in the process of bone loss.

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

“…The other candidate gene in the current study, ALPL , is a well‐known early osteogenic marker in osteoblast differentiation and as such is an excellent candidate for BMD and bone geometry variation. However, we observed only a few modest associations of ALPL with BMD and hip geometry variation, and all became insignificant after correction for multiple testing; this is in agreement with a previous study that did not reveal any significant associations between SNPs in ALPL and BMD variation 52…”

Functional Genomics Complements Quantitative Genetics in Identifying Disease-Gene Associations

“…However, there is limited evidence in the literature that these genes may play a role in bone biology. Polymorphisms in the human Timp2 gene were found to be weakly associated with increased risk of non-vertebral osteoporotic fracture in a small study of post-menopausal women [42]. Abcg8 is involved in cholesterol absorption and serum cholesterol levels [43], which are processes that have been related to bone homeostasis through other genes [44], [45].…”

The human fatty acid-binding protein family: Evolutionary divergences and functions

“…Other association studies performed in Beijing-You chickens and pigs have related SNPs to intramuscular fat deposition and other fatness traits (back fat thickness and body weight) [94-96]. A newly published report analysing postmenopausal osteoporosis in Hungarian women found a significant correlation between the homozygous recessive genotype of rs10914367 in the promoter region of FABP3 and increased hip bone mineral density [97]. This polymorphism tags the first exon and intron of FABP3 , which contain the transcription factor binding sites forkhead box protein P3 (GCCAAC), C/EBP-β (CCAA) and progesterone receptor isoforms A and B (AACACCA).…”