| 1. |
- Brändström, Helena, et al.
(författare)
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A single nucleotide polymorphism in the promoter region of the osteoprotegerin gene is related to intima-media thickness of the carotid artery in hypertensive patients : The Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA)
- 2004
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Ingår i: Blood Pressure. - : Informa UK Limited. - 0803-7051 .- 1651-1999. ; 13:3, s. 152-157
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Tidskriftsartikel (refereegranskat)abstract
- Osteoprotegerin (OPG) is a secreted member of the tumor necrosis factor receptor family, and in previous studies has been shown to regulate osteoclast activity and differentiation. Ablation of the OPG gene in mice results in calcification of the aorta and renal arteries. We have previously reported an association between a single nucleotide polymorphism in the promoter region of OPG and vascular morphology and function in healthy humans. The objective with this study was to confirm our previous results in a larger population, and in addition, to study subjects with hypertension. The OPG genotype was determined by restriction fragment length and the intima-media thickness (IMT) of the common carotid artery was measured by ultrasound in 100 patients with hypertension and left ventricular hypertrophy, and 75 healthy normotensive control subjects. In the hypertensive group subjects with the CC genotype (n=24) showed a significantly increased IMT compared to those with the TC (n=52, p=0.007) and TT (n=24, p=0.009) genotype, in the hypertensive group only (mean +/- SD for TT=0.88 +/- 0.21 mm, TC=0.90 +/- 0.16 mm, CC=1.05 +/- 0.31 mm). The allele distribution did not differ between hypertensive and control individuals. The present study confirms our previous finding and shows that polymorphism in the promoter region of OPG is associated with vascular morphology in hypertensive subjects.
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| 2. |
- Brändström, Helena, et al.
(författare)
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A single nucleotide polymorphism in the promoter region of the human gene for osteoprotegerin is related to vascular morphology and function
- 2002
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - 0006-291X .- 1090-2104. ; 293:1, s. 13-17
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Tidskriftsartikel (refereegranskat)abstract
- Osteoprotegerin (OPG) is a secreted member of the tumor necrosis factor receptor family, and has previously been shown to regulate bone mass by inhibiting osteoclast differentiation and activation. Recent evidence indicates that OPG also plays a role in the vascular system, since ablation of the OPG gene in mice results in calcification of the aorta and renal arteries, and association has been found between serum levels of OPG and cardiovascular mortality. This study presents a novel single nucleotide polymorphism, a T/C transition located 129 bp upstream the TATA-box of the human OPG gene, detected by sequence analysis. The OPG genotype was determined by restriction fragment length polymorphism in a cohort consisting of 59 healthy subjects. The intima-media thickness (IMT) in the common carotid artery and maximal post-ischemic forearm blood flow (FBF) were investigated. Subjects with the CC genotype showed a significantly increased IMT (p<0.05) and a concommitantly reduced maximal FBF (p<0.01) as compared to those with the T allele. Thus, our results show that the polymorphism in the promoter region of OPG is associated with both vascular morphology and function in apparently healthy subjects.
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| 3. |
- Brändström, Helena, et al.
(författare)
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Single nucleotide polymorphisms in the human gene for osteoprotegerin are not related to bone mineral density or fracture in elderly women
- 2004
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Ingår i: Calcified Tissue International. - : Springer Science and Business Media LLC. - 0171-967X .- 1432-0827. ; 74:1, s. 18-24
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Tidskriftsartikel (refereegranskat)abstract
- Osteoprotegerin (OPG), a secreted member of the tumor necrosis factor receptor family, is a potent inhibitor of osteoclast activation and differentiation. In animal models OPG prevents bone loss, and in humans bone resorption can be reduced by injections of OPG. OPG may also play a role in cardiovascular disease since mice lacking the OPG gene display arterial calcification. In a screening effort of the OPG gene, we recently discovered a single nucleotide polymorphism in the promoter region of OPG (T950C), and reported an association with vascular morphology and function in 59 healthy individuals. Due to the pronounced effect of OPG on bone turnover, the present study was conducted to investigate whether OPG polymorphisms are also associated with bone mineral density or with fracture. The relationship between single nucleotide polymorphisms in the promoter region of OPG (T950C) and the first intron (C1217T), and bone mineral density, measured by DXA in the hip or spine or ultrasound of the heel, was investigated in the Malmö OPRA-study of 1044 women, all 75 years old. The possible relation to fracture incidence was also analyzed. Among the 858 and 864 individuals respectively, genotyped, no significant associations between the investigated single nucleotide polymorphisms and bone mineral density measurements (T950C P = 0.50-0.64, C1217T P = 0.51-1.00), quantitative ultrasound measurements of the calcaneus, or fractures (T950C P = 0.61-0.66, C1217T P = 0.14-0.33) were found. Thus, our results show that polymorphisms in the OPG gene, one of which has previously been found to be associated with cardiovascular morphology and function, are not associated with bone mineral density in elderly Swedish women.
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| 4. |
- Gerdhem, Paul, et al.
(författare)
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Association of the collagen type 1 (COL1A 1) Sp1 binding site polymorphism to femoral neck bone mineral density and wrist fracture in 1044 elderly Swedish women
- 2004
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Ingår i: Calcified Tissue International. - : Springer Science and Business Media LLC. - 0171-967X .- 1432-0827. ; 74:3, s. 264-269
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Tidskriftsartikel (refereegranskat)abstract
- Identification of risk factors for osteoporosis has been essential for understanding the development of osteoporosis and related fragility fractures. A polymorphism of the binding site for the transcription factor Sp1 of the collagen I alpha 1 gene (COLIA1) has shown an association to bone mass and fracture, but the findings have not been consistent, which may be related to population differences. The Sp1 polymorphism was determined in 1044 women, all 75 years old, participating in the population-based Osteoporosis Prospective Risk Assessment study in Malmö (OPRA). Bone mineral density, heel ultrasound and all previous fractures were registered. BMD was 2.7% lower in the femoral neck in women carrying at least one copy of the "s" allele ( P = 0.027). There was no difference in bone mass at any other site, weight, BMI or age at menopause. Women with a prevalent wrist fracture (n = 181) had an increased presence of the "s" allele. The odds ratio for prevalent wrist fracture was 2.73 (95% CI 1.1-6.8) for the ss homozygotes and 1.4 (95% CI 1.0-2.0) for the Ss heterozygotes when compared with the SS homozygotes. In conclusion, in this large and homogeneous cohort of 75-year-old Swedish women, there was an association among the Sp1 COLIA1 polymorphism, bone mass, and fracture. The presence of at least one copy of the "s" allele was associated with lower femoral neck BMD and previous wrist fracture and in addition, it was related to an increased risk for wrist fracture.
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| 5. |
- Nordström, Anna, 1973-, et al.
(författare)
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Interleukin-6 promoter polymorphism is associated with bone quality assessed by calcaneus ultrasound and previous fractures in a cohort of 75-year-old women.
- 2004
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Ingår i: Osteoporosis international. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 15:10, s. 820-6
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin 6 (IL-6) is a multifunctional cytokine and a potent stimulator of bone resorption and has been implicated in the pathogenesis of osteoporosis in postmenopausal women. The aim of this study was to investigate if a functional IL-6 promoter polymorphism (-174) was related to bone mass and fractures in a cohort consisting of 964 postmenopausal Caucasian women aged 75 years. Bone mineral density (BMD; g/cm2) of the femoral neck, lumbar spine and total body was measured using dual energy X-ray absorptiometry (DXA). Quantitative ultrasound (QUS) was also measured in the calcaneus and quantified as speed of sound (SOS; m/s), broadband ultrasound attenuation (BUA; dB/MHz), and stiffness index (SI). IL-6 genotypes was determined by restriction fragment length polymorphism (RFLP) using the restriction enzyme NlaIII. The frequencies of the different IL-6 genotypes were 27.5% (GG), 47.9% (GC), 24.6% (CC). The IL-6 polymorphism (presence of G) was independently related to a lower stiffness (beta=-0.07; P=0.03) and BUA (beta=-0.08; P=0.02), but not to BMD at any site measured by DXA. In the cohort, 420 subjects (44%) reported at least one fracture during their lifetime, and 349 (36%) reported at least one fracture after the age of 50. Using binary logistic regression, the IL-6 polymorphism (presence of G) was significantly related to an increased risk of a previous fracture during life (odds ratio 1.46, 95% CI 1.08-1.97) and to an increased risk of a fracture occurring after 50 years of age (odds ratio 1.37, 95% CI 1.004-1.88). The risk was further increased for fractures grouped as osteoporotic fractures (odds ratio 1.67, 95% CI 1.14-2.45), including forearm fractures (odds ratio 1.59, 95% CI 1.05-2.40). In conclusion, presence of G allele in the IL-6 promoter polymorphism at position -174 is independently related to previous fractures in postmenopausal women. This association may be related primarily to an altered bone quality identified by QUS and not a lower bone mass. This is also the first demonstration of association of IL-6 gene polymorphism to calcaneal QUS.
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| 6. |
- Wedrén, Sara, et al.
(författare)
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Oestrogen receptor alpha gene haplotype and postmenopausal breast cancer risk : a case control study
- 2004
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 6:4, s. R437-49
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- INTRODUCTION: Oestrogen receptor alpha, which mediates the effect of oestrogen in target tissues, is genetically polymorphic. Because breast cancer development is dependent on oestrogenic influence, we have investigated whether polymorphisms in the oestrogen receptor alpha gene (ESR1) are associated with breast cancer risk. METHODS: We genotyped breast cancer cases and age-matched population controls for one microsatellite marker and four single-nucleotide polymorphisms (SNPs) in ESR1. The numbers of genotyped cases and controls for each marker were as follows: TAn, 1514 cases and 1514 controls; c.454-397C --> T, 1557 cases and 1512 controls; c.454-351A --> G, 1556 cases and 1512 controls; c.729C --> T, 1562 cases and 1513 controls; c.975C --> G, 1562 cases and 1513 controls. Using logistic regression models, we calculated odds ratios (ORs) and 95% confidence intervals (CIs). Haplotype effects were estimated in an exploratory analysis, using expectation-maximisation algorithms for case-control study data. RESULTS: There were no compelling associations between single polymorphic loci and breast cancer risk. In haplotype analyses, a common haplotype of the c.454-351A --> G or c.454-397C --> T and c.975C --> G SNPs appeared to be associated with an increased risk for ductal breast cancer: one copy of the c.454-351A --> G and c.975C --> G haplotype entailed an OR of 1.19 (95% CI 1.06-1.33) and two copies with an OR of 1.42 (95% CI 1.15-1.77), compared with no copies, under a model of multiplicative penetrance. The association with the c.454-397C --> T and c.975C --> G haplotypes was similar. Our data indicated that these haplotypes were more influential in women with a high body mass index. Adjustment for multiple comparisons rendered the associations statistically non-significant. CONCLUSION: We found suggestions of an association between common haplotypes in ESR1 and the risk for ductal breast cancer that is stronger in heavy women.
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