Gene polymorphisms and osteoporotic fractures: A study in postmenopausal French women (original) (raw)
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Calcified Tissue International, 2010
Osteoporosis is a complex disease involving many putative genetic factors. Association analysis of functional SNPs in candidate genes is an important tool for their identification. However, this approach is affected by limited power, population stratification, and other drawbacks that lead to discordant results. Replication in independent cohorts is essential. We performed association analyses of three functional polymorphisms previously associated with bone phenotypes-namely, Ala222Val in MTHFR, Ile1062Val in LRP6, and -13910C[T in LCT-in a cohort of 944 postmenopausal Spanish women, all of them with lumbar spine (LS) bone mineral density (BMD) data and most with femoral neck (FN) BMD and fracture data. We found significant differences between genotypes only for the MTHFR polymorphism and vertebral factures, with an OR of 2.27 (95% CI 1.17-4.38) for the TT vs. CC/ CT genotypes, P = 0.018. We present genotype and allele frequency data for LCT -13910C[T for a Spanish population, where the T allele (conferring lactase persistence) has a frequency of 38.6%. Genotype frequencies were consistent with observed clines in Europe and with the prevalence of lactase nonpersistence. The LCT -13910C[T polymorphism was significantly associated with height and weight, such that T allele carriers were 0.88 cm taller (95% CI 0.08-1.59 cm, P = 0.032, adjusted by age) than CC individuals and TT homozygotes were 1.91 kg heavier than CC/CT individuals (95% CI 0.11-3.71 kg, P = 0.038, adjusted by age). In conclusion, no significant association was observed between the studied polymorphisms and LS BMD or FN BMD in postmenopausal Spanish women, and only MTHFR Ala222Val was associated with vertebral fractures.
Osteoporosis and polymorphisms of osteoprotegerin gene in postmenopausal women – a pilot study
Reumatologia/Rheumatology, 2016
Objectives: Osteoprotegerin (OPG) has an important role in bone remodeling, and it has been proposed that the OPG gene might be a candidate gene for osteoporosis predisposition. Several studies have already assessed the connection between OPG gene polymorphism and bone mineral density (BMD). In this study we wanted to analyze the association of two polymorphisms in the OPG gene with BMD and bone turnover markers in women with and without osteoporosis. Material and methods: In 22 postmenopausal women with osteoporosis (aged 65.6 ±12.6) and 59 women without osteoporosis (aged 60.8 ±8.7) we analyzed the association of two polymorphisms in the OPG gene with BMD, measured by dual energy absorptiometry and with bone turnover markers (crosslaps and osteoprotegerin). A163G, G209A, T245G and G1181C polymorphisms were determined. Results: No significant differences in age, anthropometry, number of fractures, osteocalcin and cross-laps were found between women with and without osteoporosis. Women with osteoporosis were significantly longer in postmenopause. Significantly more women with osteoporosis had AG polymorphism (p = 0.038) compared to women without osteoporosis, while no significant difference was found in prevalence of TT and GG polymorphism between patients with and without osteoporosis. No relationship was found between investigated polymorphism and bone turnover markers. A significant negative correlation between total hip BMD and crosslaps (p = 0.046) as well as between total hip T score and crosslaps (p = 0.044) was found in women without osteoporosis Conclusions: Postmenopausal women with osteoporosis had AG polymorphism more frequently than women without osteoporosis. Our results indicate that A163G polymorphism could have an impact on higher bone loss in postmenopausal women.
Genetic factors , osteoporosis and bone fractures
2017
Bone fracture risk is influenced by a number of factors, including bone mineral density (BMD), bone quality parameters and non-skeletal factors affecting the risk of falls. Each of these factors is itself under at least partial genetic control. Several studies suggested that between 50 and 85% of the variance in peak bone mass was genetically determined. It was also presumed that genes contributed significantly to variability in age-related bone loss and other determinants of fracture risk. Candidate genes for osteoporosis were classified according to metabolic or hormonal pathways. It was found that polymorphisms of genes encoding and/or regulating the Wnt/β-catenin signaling pathway, the RANK-RANKL-OPG pathway, vitamin D receptor (VDR) and vitamin D binding protein (DBP), procollagen 1 molecule, and the estrogen receptor α influenced BMD and bone fracture risk.
Skeletal and genetic determinants of osteoporosis
2001
textabstractOsteoporosis, one of the critical diseases facing the ageing population and along with cardiovascular disease, diabetes and cancer, is a major concern for public health in western countries. Fractures, the clinical endpoint of osteoporosis, contribute considerably to overall morbidity, mortality and healthcare costs. It has been estimated that the lifetime risk to suffer a fracture is 40% for a 50-year-old white woman and 15% for men. Of those who have suffered a fracture of the hip, 50% are subsequently unable to walk unassisted and 20 % die within the first year after the hip fracture occurred. The total health care expenditures attributable to osteoporotic fractures in the United States was estimated at US$ 13.8 billion in 1995. In the Netherlands direct medical cost of osteoporosis-related fractures was estimated to be over 400 million guilders each year. Due to ageing, fractures from osteoporosis occurring each year are projected to increase world-wide from 1.7 mill...
Endocrine Reviews, 2002
Osteoporosis is a common multifactorial disorder of reduced bone mass. The disorder in its most common form is generalized, affecting the elderly, both sexes, and all racial groups. Multiple environmental factors are involved in the pathogenesis. Genes also play a major role as reflected by heritability of many components of bone strength. Quantitative phenotypes in bone strength in the normal population do not conform to a monogenetic mode of inheritance. The common form of osteoporosis is generally considered to be a polygenic disorder arising from the interaction of common polymorphic alleles at quantitative trait loci, with multiple environmental factors. Finding the susceptibility genes underlying osteoporosis requires identifying specific alleles that coinherit with key heritable phenotypes in bone strength. Because of the close correspondence among mammalian genomes, identification of the genes underlying bone strength in mammals such as the mouse is likely to be of major assistance in human studies. Identification of susceptibility genes for osteoporosis is one of several important approaches toward the long-term goal of understanding the molecular biology of the normal variation in bone strength and how it may be modified to prevent osteoporosis. As with all genetic studies in humans, these scientific advances will need to be made in an environment of legal and ethical safeguards that are acceptable to the general public. (Endocrine Reviews 23: 303-326, 2002)
European Journal of Endocrinology, 2008
Objective: Osteoporosis (OP) is a multifactorial disease with high heritability but its exact genetic background is still poorly understood. We examined the effect of twenty four single nucleotide polymorphisms (SNPs) located in five genesalkaline phosphatase (ALPL), matrix metalloproteinase 2 (MMP2), tissue inhibitor of metalloproteases 2 (TIMP2), fibroblast growth factor receptor 1 (FGFR1) and fatty acid binding protein 3 (FABP3)previously not associated with OP.
High-density polymorphisms analysis of 23 candidate genes for association with bone mineral density
2010
Osteoporosis is a bone disease characterized by low bone mineral density (BMD), a highly heritable and polygenic trait. Women are more prone than men to develop osteoporosis due to a lower peak bone mass and accelerated bone loss at menopause. Peak bone mass has been convincingly shown to be due to genetic factors with heritability up to 80%. Menopausal bone loss has been shown to have around 38% to 49% heritability depending on the site studied. To have more statistical power to detect small genetic effects we focused on premenopausal women. We studied 23 candidate genes, some involved in calcium and vitamin-D regulation and others because estrogens strongly induced their gene expression in mice where it was correlated with humerus trabecular bone density. High-density polymorphisms were selected to cover the entire gene variability and 231 polymorphisms were genotyped in a first sample of 709 premenopausal women. Positive associations were retested in a second, independent, sample of 673 premenopausal women. Ten polymorphisms remained associated with BMD in the combined samples and one was further associated in a large sample of postmenopausal women (1401 women). This associated polymorphism was located in the gene CSF3R (granulocyte colony stimulating factor receptor) that had never been associated with BMD before. The results reported in this study suggest a role for CSF3R in the determination of bone density in women.
Osteoporosis International, 2000
In view of the reported associations between osteoporosis and polymorphisms of the vitamin D receptor (VDR), collagen Ia1 (COLIA1) and estrogen receptor (ER) genes, an association study was performed between VDR, COLIA1, and ER genotypes and bone mineral density, biochemical markers of bone turnover and hip fracture occurrence in Belgian older postmenopausal women. The gene polymorphisms were evaluated by restriction fragment length polymorphism analyses, using the restriction enzymes BsmI (VDR), AccB7I (COLIA1), and PvuII and XbaI (ER), respectively. As expected, bone mineral density and biochemical analyses demonstrated signi®cant differences between hip fracture patients and elderly controls. However, no signi®cant differences in genotype distributions or allele frequencies were observed between the cases (n = 135, age 78 + 9 years) and controls (n = 239, age 76 + 4 years) for any of the gene polymorphisms. Strati®cation of both study populations according to VDR, COLIA1 or ER genotype did not reveal any statistically signi®cant difference in bone density or bone turnover between subgroups with different genotypes. In conclusion, despite its limited statistical power the outcome of this study does not support the hypothesis of a major contribution of the VDR, COLIA1 or ER polymorphisms to explain variations in bone mineral density or bone turnover, or to identify elderly women at risk of osteoporotic hip fracture.
A familial risk profile for osteoporosis
Genetics in Medicine, 2000
Purpose: To describe genetic epidemiologic aspects of osteoporosis. Methods: 6 9 patients with O S~~O P O~O S~S were interviewed regarding personal and family histories of osteoporosis and related fractures. Family history information was obtained on 4 2 1 first degree and 748 second degree relatives. Results: 45% of cases reported a family history of osteoporosis. Familial cases were characterized neither by an earlier age of diagnosis nor by a greater degree of phenotypic severity. Empiric risks for osteoporosis were highest for mothers, 33%, and were 19% for sisters. Conclusion: These results provide an initial genetic epidemiologic profile for osteoporosis and information useful for genetic counseling. Genetics in Medicine, 2000:2(4):222-225.