Heterozygosity for a coding SNP in COL1A2 confers a lower BMD and an increased stroke risk

Department of Medical Sciences, Uppsala University Hospital ing. 70, 3 tr., 751 85 Uppsala, Sweden.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 05/2009; 384(4):501-5. DOI: 10.1016/j.bbrc.2009.05.006
Source: PubMed


Genetic variation plays an important role in osteoporosis and a prime candidate gene is Collagen alpha2(I) (COL1A2). A coding polymorphism (rs42524) in COL1A2 has previously been associated with intracranial aneurysms. Here the effects of this polymorphism have been studied in relation to bone mineral density (BMD) and prevalences of stroke and myocardial infarction (MI). rs42524 was genotyped in elderly men (n = 2004) from the Swedish MrOS cohort. Genotypes were analysed for association to BMD and certain health parameters. Significant associations (overall P < 0.05), were observed between rs42524 genotype and BMD at several skeletal sites. Surprisingly, the heterozygote genotype class exhibited lower BMD than either homozygote group. When subjects were classified as heterozygotes or homozygotes, the heterozygous genotype was found to confer a lower BMD at total hip, femoral neck and trochanter Furthermore, the heterozygote genotype had an increased risk of stroke and MI, with population Attributable Risks being 0.12 and 0.08, respectively.

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    • "This gene has also been shown to be involved in vascular development, stabilization, maturation, and remodeling [40,41]. Furthermore, many vascular abnormalities, including stroke, myocardial infarction, and IA, have been found to be due to defects in COL1A2 [28,39,42]. Given the results of these previous studies, we aimed to discover whether COL1A2 plays a role in the pathogenesis of PCV or neovascular AMD. "
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    ABSTRACT: We have previously documented that neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) have multiple different clinical and genetic characteristics. In this study, we investigated the association of rs42524 in the alpha-2 type I collagen (COL1A2) gene, which has been identified as a risk variant for intracranial aneurysm, with nAMD and PCV in a Han Chinese population. The study prospectively recruited 195 patients with PCV, 136 patients with nAMD, and 181 control individuals. We genotyped the rs42524 polymorphism of COL1A2 using the Multiplex SNaPshot System and direct DNA sequencing. Genotype and allele frequencies were evaluated with PLINK software. The rs42524 polymorphism was modestly significantly associated with nAMD [minor allele: G, p(allelic)=0.04253, odds ratio=0.5285 (95% confidence interval: 0.2832-0.9866)], but not with PCV [minor allele: G, p(allelic)=0.4164, odds ratio=1.2110 (95% confidence interval: 0.7631-1.9210)]. The pvalues for the additive model were significant for nAMD but not for the dominant or recessive models. None of the models for PCV were statistically significant. The size of our sample cohort resulted in a post hoc power of more than 80% to detect associations of rs42524 with nAMD and PCV. The rs42524 polymorphism is a risk allele for nAMD in a Han Chinese population. rs42524 in COL1A2 confers different levels of susceptibility to nAMD and PCV.
    Molecular vision 06/2012; 18:1787-93. · 1.99 Impact Factor
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    • "Mutations in this gene are associated with low BMD and fracture risk [163]. Interestingly, besides low BMD, individuals with a SNP in the COL1A gene (rs42524) had an increased prevalence of stroke and MI [164]. "
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    ABSTRACT: Both cardiovascular disease and osteoporosis are important causes of morbidity and mortality in the elderly. The co-occurrence of cardiovascular disease and osteoporosis prompted us to review the evidence of an association between cardiovascular (CV) disease and osteoporosis and potential shared common pathophysiological mechanisms. A systematic literature search (Medline, Pubmed and Embase) was conducted to identify all clinical studies that investigated the association between cardiovascular disease and osteoporosis. Relevant studies were screened for quality according to guidelines as proposed by the Dutch Cochrane Centre and evidence was summarized. Seventy studies were included in this review. Due to a large heterogeneity in study population, design and outcome measures a formal meta-analysis was not possible. Six of the highest ranked studies (mean n = 2,000) showed that individuals with prevalent subclinical CV disease had higher risk for increased bone loss and fractures during follow-up compared to persons without CV disease (range of reported risk: hazard ratio (HR) 1.5; odds ratio (OR) 2.3 to 3.0). The largest study (n = 31,936) reported a more than four times higher risk in women and more than six times higher risk in men. There is moderate evidence that individuals with low bone mass had higher CV mortality rates and incident CV events than subjects with normal bone mass (risk rates 1.2 to 1.4). Although the shared common pathophysiological mechanisms are not fully elucidated, the most important factors that might explain this association appear to be, besides age, estrogen deficiency and inflammation. The current evidence indicates that individuals with prevalent subclinical CV disease are at increased risk for bone loss and subsequent fractures. Presently no firm conclusions can be drawn as to what extent low bone mineral density might be associated with increased cardiovascular risk.
    Arthritis research & therapy 01/2011; 13(1):R5. DOI:10.1186/ar3224 · 3.75 Impact Factor
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    ABSTRACT: Osteoporosis is a complex human disease that results in increased susceptibility to fragility fractures. It can be phenotypically characterized using several traits, including bone mineral density, bone size, bone strength, and bone turnover markers. The identification of gene variants that contribute to osteoporosis phenotypes, or responses to therapy, can eventually help individualize the prognosis, treatment, and prevention of fractures and their adverse outcomes. Our previously published reviews have comprehensively summarized the progress of molecular genetic studies of gene identification for osteoporosis and have covered the data available to the end of September 2007. This review represents our continuing efforts to summarize the important and representative findings published between October 2007 and November 2009. The topics covered include genetic association and linkage studies in humans, transgenic and knockout mouse models, as well as gene-expression microarray and proteomics studies. Major results are tabulated for comparison and ease of reference. Comments are made on the notable findings and representative studies for their potential influence and implications on our present understanding of the genetics of osteoporosis.
    Endocrine reviews 03/2010; 31(4):447-505. DOI:10.1210/er.2009-0032 · 21.06 Impact Factor
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