Relation of Alleles of the Collagen Type Iα1 Gene to Bone Density and the Risk of Osteoporotic Fractures in Postmenopausal Women

Uitterlinden, André G.; Burger, Huibert; Huang, Qiuju; Fang, Yue; McGuigan, Fiona; Grant, Struan F A; Hofman, Albert; Leeuwen, Johannes P.T.M. van; Pols, Huibert A. P.; Ralston, Stuart H.

doi:10.1056/nejm199804093381502

Cited by 400 publications

(294 citation statements)

References 33 publications

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“…However, the r 2 for the linkage disequilibrium was relatively small, and the two SNPs were not within the same LD block (Supplementary Figure). Thus, the possibility cannot be excluded that the intronic SNP may affect the expression level of the gene via an unknown mechanism, similar, for example, to the actions of intronic SNPs in Calpain10 [28] and COLIA1 [29].…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in the peroxisome proliferator activated receptor α gene are associated with levels of apolipoprotein CIII and triglyceride in African-Americans but not Caucasians

Shin¹,

Kanaya

Krauss³

2008

Atherosclerosis

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Section: Discussionmentioning

confidence: 99%

Polymorphisms in the peroxisome proliferator activated receptor α gene are associated with levels of apolipoprotein CIII and triglyceride in African-Americans but not Caucasians

Shin¹,

Kanaya

Krauss³

2008

Atherosclerosis

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“…Most research has focused on a polymorphism within intron 1, which is situated at a binding site for the transcription factor Sp1. The COLIA1 Sp1-binding site polymorphism has been associated with various osteoporosis-related phenotypes, including bone density (Grant et al 1996;Uitterlinden et al 1998), fragility fractures (Grant et al 1996;Uitterlinden et al 1998), postmenopausal bone loss (Harris et al 2000;MacDonald et al 2001), bone geometry (Qureshi et al 2001), bone quality (Mann et al 2001), and bone mineralization . Functional analysis has shown that the osteoporosis-associated T allele ("s") of the Sp1 polymorphism is associated with increased DNA-protein binding, increased transcription, and abnormally increased production of the COLIA1 mRNA and protein (Mann et al 2001).…”

Section: Collagen Type I␣ Imentioning

confidence: 99%

Genetic regulation of bone mass and susceptibility to osteoporosis

Ralston¹,

Crombrugghe²

2006

Genes Dev.

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293

229

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Osteoporosis is a common disease with a strong genetic component characterized by reduced bone mass and increased risk of fragility fractures. Twin and family studies have shown that the heritability of bone mineral density (BMD) and other determinants of fracture risksuch as ultrasound properties of bone, skeletal geometry, and bone turnover-is high, although heritability of fracture is modest. Many different genetic variants of modest effect size are likely to contribute to the regulation of these phenotypes by interacting with environmental factors such as diet and exercise. Linkage studies in rare Mendelian bone diseases have identified several previously unknown genes that play key roles in regulating bone mass and bone turnover. In many instances, subtle polymorphisms in these genes have also been found to regulate BMD in the general population. Although there has been extensive progress in identifying the genetic variants that regulate susceptibility to osteoporosis, most of the genes and genetic variants that regulate bone mass and susceptibility to osteoporosis remain to be discovered.Osteoporosis is characterized by reduced bone mass, alterations in the microarchitecture of bone tissue, reduced bone strength, and an increased risk of fracture (Kanis et al. 1994). Osteoporosis is a common condition that affects up to 30% of women and 12% of men at some point in life. The prevalence of osteoporosis increases with age due to an imbalance in the rate at which bone is removed and replaced during the bone remodeling cycle, which is an important physiological process that is essential for maintenance of a healthy skeleton. Many factors influence the risk of osteoporosis-including diet, physical activity, medication use, and coexisting diseases-but one of the most important clinical risk factors is a positive family history, emphasizing the importance of genetics in the pathogenesis of osteoporosis. In this article, we first review the evidence for a genetic contribution to osteoporosis and related phenotypes, and discuss the mechanisms by which mutations and polymorphisms in genes that regulate susceptibility to osteoporosis affect major signaling pathways in bone. Genetic influences on osteoporosisGenetic factors have long been recognized as playing an important role in the pathogenesis of osteoporosis. Evidence from twin and family studies suggests that between 50% and 85% of the variance in peak bone mass is genetically determined, depending on skeletal site and the age of the subjects studied (Smith et al. 1973;Pocock et al. 1987;Krall and Dawson-Hughes 1993;Gueguen et al. 1995). Heritability studies have also shown evidence of significant genetic effects on other key determinants of osteoporotic fracture risk, including quantitative ultrasound properties of bone (Arden et al. 1996), femoral neck geometry (Arden et al. 1996), muscle strength (Arden and Spector 1997), bone turnover markers (Hunter et al. 2001), and body mass index (Kaprio et al. 1995). The role of genetic factors in the pathogenesis of bon...

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“…Because sequence variations in COL1A1 , COL1A2 , LRP5 , OPG , and ESR1 increase the risk of low bone mass or osteoporotic fractures, we first examined their possible role in the pathogenesis of stress fractures by scanning all their exons and exon boundaries in the 72 subjects and the 120 controls for mutations using CSGE [14,15,17,20]. The analysis revealed no putative disease-causing mutations.…”

Section: Resultsmentioning

confidence: 99%

“…Mutations or allelic variants in the genes leading to a variety of bone pathologies that increase bone fragility, such as collagen I, ( COL1A1 and COL1A2 ) [14,15], vitamin D receptor ( VDR ) [16], osteoprotegerin ( OPG ) [17], calcitonin receptor ( CTR ) [18], estrogen receptor ( ESR ) [19], low density lipoprotein receptor-related protein 5 ( LRP5 ) [20], and interleukin 6 ( IL-6 ) [21] may also increase the risk of stress fractures. Sequence variations in these genes are associated with a low peak bone mass, osteoporosis, osteogenesis imperfecta, osteoporosis-pseudoglioma syndrome, and high bone mass, but their role in predisposing to stress fracture is not clear [14-21].…”

Section: Introductionmentioning

confidence: 99%

Genetic predisposition for femoral neck stress fractures in military conscripts

et al. 2010

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BackgroundStress fractures are a significant problem among athletes and soldiers and may result in devastating complications or even permanent handicap. Genetic factors may increase the risk, but no major susceptibility genes have been identified. The purpose of this study was to search for possible genetic factors predisposing military conscripts to femoral neck stress fractures.ResultsEight genes involved in bone metabolism or pathology (COL1A1, COL1A2, OPG, ESR1, VDR, CTR, LRP5, IL-6) were examined in 72 military conscripts with a femoral neck stress fracture and 120 controls. The risk of femoral neck stress fracture was significantly higher in subjects with low weight and body mass index (BMI). An interaction between the CTR (rs1801197) minor allele C and the VDR C-A haplotype was observed, and subjects lacking the C allele in CTR and/or the C-A haplotype in VDR had a 3-fold higher risk of stress fracture than subjects carrying both (OR = 3.22, 95% CI 1.38-7.49, p = 0.007). In addition, the LRP5 haplotype A-G-G-C alone and in combination with the VDR haplotype C-A was associated with stress fractures through reduced body weight and BMI.ConclusionsOur findings suggest that genetic factors play a role in the development of stress fractures in individuals subjected to heavy exercise and mechanical loading. The present results can be applied to the design of future studies that will further elucidate the genetics of stress fractures.

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Relation of Alleles of the Collagen Type Iα1 Gene to Bone Density and the Risk of Osteoporotic Fractures in Postmenopausal Women

Abstract: The COLIA1 polymorphism is associated with reduced bone density and predisposes women to osteoporotic fractures.

Cited by 400 publications

References 33 publications

Polymorphisms in the peroxisome proliferator activated receptor α gene are associated with levels of apolipoprotein CIII and triglyceride in African-Americans but not Caucasians

Polymorphisms in the peroxisome proliferator activated receptor α gene are associated with levels of apolipoprotein CIII and triglyceride in African-Americans but not Caucasians

Genetic regulation of bone mass and susceptibility to osteoporosis

Genetic predisposition for femoral neck stress fractures in military conscripts

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