Linkage and association analyses of the osteoprotegerin gene locus with human osteoporosis (original) (raw)
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Investigating the role of osteoprotegerin gene polymorphic variants in osteoporosis
Russian Open Medical Journal, 2021
In recent genome-wide association studies (GWAS), several polymorphic loci of the osteoprotegerin (OPG) gene were significantly associated with bone mineral density (BMD) and fractures in men over 50 years of age and postmenopausal women. The objective of our study was to search for associations of rs3102735, rs3134069, rs2073617, rs2073618, rs3102734 and rs7844539 of the OPG gene with the risk of osteoporotic fractures and the level of BMD in individual and comorbid conditions in men and women from the Volga-Ural region of Russia. Material and Methods — 828 women and 496 men of various ethnic groups (Russians, Turks) were examined using two-energy x-ray absorptiometry (DEXA) in the femoral neck and lumbar spine. 1324 deoxyribonucleic acid (DNA) samples were genotyped using a fluorescent endpoint genotyping system, after that we searched for associations of these polymorphic loci with fractures and low BMD levels of various localizations. As a result, there was a significant associa...
Bone, 2007
Bone mass is the single most important risk factor for osteoporotic fractures in the elderly and is mainly influenced by genetic factors accounting for 40-75% of the inter-individual variation. Critical for the bone remodeling process is the balance between the newly discovered members of the tumor necrosis factor ligand and receptor superfamilies, osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand, which mediate the effects of many upstream regulators of bone metabolism. In the present study, we evaluated the impact of sequence variations in the OPG gene on bone mass, bone-related biochemistry including serum OPG and fracture frequency in elderly Australian women. A total of 1101 women were genotyped for 3 different single nucleotide polymorphisms (SNP) within the OPG gene (G1181C, T950C and A163G). The effects of these SNPs and serum OPG on calcaneal quantitative ultrasound measurements, osteodensitometry of the hip and bone-related biochemistry were examined. We found no significant relationship between sequence variations in the OPG gene or serum OPG and bone mass, bone-related biochemistry or fracture frequency. Our findings confirm some recent publications investigating the same SNPs but diverge from others, indicating that generalization of the relationships found in this type of study must be done with caution and signify the importance of determining associations between polymorphisms and osteoporosis in different ethnic groups.
Osteoporosis International, 2010
Osteoprotegerin plays a key role in bone remodelling. We studied the association between 24 polymorphisms and haplotypes on the OPG gene and bone mineral density and fractures. After multiple-testing correction, one SNP and two block-haplotypes were significantly associated with FN BMD. Two other block-haplotypes were associated with fracture. a frequent long-range haplotype. Conclusions In conclusion, these results provide a detailed picture of the involvement of common variants and haplotypes of the OPG gene in bone phenotypes.
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.
Journal of Molecular Endocrinology, 2011
Polymorphisms within the TNFRSF11B gene have been studied and associated with osteoporosis and fracture risk. Osteoprotegerin (OPG), the product of this gene, is a key negative regulator of osteoclastogenesis and is secreted by osteoblasts/stromal cells. A previous study in Maltese postmenopausal women showed positive association of low bone mineral density (BMD) with a polymorphism found within the promoter region of this gene (C950T). In this study, direct DNA sequencing revealed 12 variants with polymorphisms C950T, G1181C and rs4876869 observed to be in strong linkage disequilibrium. The constructed haplotype T-G-T was found to increase the risk for a low BMD, while C-G-T and C-C-C have a protective role; thus, we investigated the functional role of both C950T and rs4876869 in vitro. The promoter region, including the C950T alleles, was amplified by PCR, cloned into pGL3 enhancer vector and transfected into HeLa, COS-7 and RAW264.7 cell lines. After incubation, luciferase activi...
Human molecular genetics, 2014
Osteoprotegerin (OPG) is involved in bone homeostasis and tumor cell survival. Circulating OPG levels are also important biomarkers of various clinical traits, such as cancers and atherosclerosis. OPG levels were measured in serum or in plasma. In a meta-analysis of genome-wide association studies in up to 10 336 individuals from European and Asian origin, we discovered that variants >100 kb upstream of the TNFRSF11B gene encoding OPG and another new locus on chromosome 17q11.2 were significantly associated with OPG variation. We also identified a suggestive locus on chromosome 14q21.2 associated with the trait. Moreover, we estimated that over half of the heritability of OPG levels could be explained by all variants examined in our study. Our findings provide further insight into the genetic regulation of circulating OPG levels.
Osteoprotegerin Gene Polymorphisms in Men with Coronary Artery Disease
The Journal of Clinical Endocrinology & Metabolism, 2004
Osteoprotegerin (OPG) antagonizes receptor activator of nuclear factor-B ligand (RANKL), the principal regulator of osteoclasts. Of note, OPG-deficient mice display osteoporosis and arterial calcification. Recently, OPG gene polymorphisms have been associated with osteoporosis and early predictors of cardiovascular disease. In this study, we examined OPG gene polymorphisms in 468 men who had absence of coronary artery disease (CAD) or single-, double-, or triple-vessel disease on coronary angiography. Denaturing gradient gel electrophoresis followed by DNA sequencing revealed nucleotide substitutions 149 T3 C, 163 A3 G, 209 G3 A, 245 T3 G, 950 T3 C (all promoter), 1181 G3 C (exon 1), and 6890 A3 C (intron 4), respectively. Although single polymorphisms were not associated with CAD, linkage of polymorphisms 950 and 1181 revealed that haplotypes were overrepresented in men with CAD ( 2 ؍ 17.05; P ؍ 0.03) with an increased risk of CAD in carriers of genotypes 950 TC/1181 GC and 950 CC/1181 CC (odds ratio, 1.67; 95% confidence interval, 1.02-2.72; P ؍ 0.04). Furthermore, serum OPG levels were correlated with the presence of a C allele at position 950 (P ؍ 0.02). In summary, linkage of genetic variations of the OPG gene at positions 950 and 1181 may confer an increased risk of CAD in Caucasian men
Turkish Journal of Osteoporosis
Amaç: Reseptör aktivatör nükleer faktör-B ligandı (RANKL) ve osteoprotegerinin (OPG) kemik yeniden modelleme ve osteoporozda önemli bir rolü olduğu gösterilmiştir. Bu çalışmada, Endonezya menopoz sonrası kadınlarda düşük kemik mineral yoğunluğu (KMY) ile RANKL ve OPG genlerinin polimorfizmleri (sırasıyla TNFSF11 ve TNFRSF11B) arasındaki ilişkinin araştırılması amaçlanmıştır. Gereç ve Yöntem: Elli-altmış beş yaş arası 60 postmenopozal kadın uygun bulundu. KMY, çift-enerjili X-ışını absorpsiyometrisi kullanılarak ölçülmüştür. TNFSF11 ve TNFRSF11B'nin genotipleri polimeraz zincir reaksiyonu-kısıtlama fragman uzunluğu polimorfizmleri ve DNA dizileme yöntemleri ile elde edildi. TNFSF11'den (-290C> T,-643C> T,-693G> C) ve TNFRSF11B'den (163A>G, 950T>C, 1181G>C) üç tek nükleotid polimorfizmleri (SNP) seçildi. Allel dağılımı ile KMY arasındaki ilişki ki-kare veya Fischer kesin testi kullanılarak hesaplandı. Kemik bölgelerindeki tüm SNP'leri ve BMD'yi analiz etmek için çoklu lojistik regresyon kullanıldı. Anlamlılık p<0,05 olarak ayarlandı. Bulgular: Çoğu birey daha düşük KMY'ye (%83,3) sahipti. Sağlıklı ve düşük KMY arasındaki bireylerin özellikleri karşılaştırılabilir bulundu (hepsi p>0,05). TNSSF11 ve TNFRSF11B'de genotiplerin ve allellerin sağlıklı ve düşük KMY'ler arasındaki dağılımı anlamlı olarak farklı değildi (hepsi p>0,05). Tüm kemik bölgelerinde TNFSF11 ve TNFRSF11B'nin SNP'leri ile KMY arasında ilişki yoktu (hepsi p>0,05). Objective: Prior studies have shown that receptor activator of nuclear factor-B ligand (RANKL) and osteoprotegerin (OPG) have an essential role in bone remodeling and osteoporosis. This study aimed to investigate the association between RANKL (TNFSF11) and OPG (TNFRSF11B) genes' polymorphisms with low bone mineral density (BMD) in Indonesian postmenopausal women. Materials and Methods: Sixty postmenopausal women aged between 50-65 years were eligible. The BMD was measured by using dualenergy X-ray absorptiometry. The genotypes of TNFSF11 and TNFRSF11B were obtained by polymerase chain reaction-restriction fragment length polymorphisms and DNA sequencing methods. Three single nucleotide polymorphisms (SNPs) from TNFSF11 (-290C>T,-643C>T,-693G>C) and from TNFRSF11B (163A>G, 950T>C, 1181G>C) were selected. The association between alleles distribution and BMD was computed using chi-square or Fischer's exact test. Multiple logistic regression was used to analyze between all SNPs and BMD at bone sites. Significance was set at p<0.05. Results: Most subjects had lower BMD (83.3%). Characteristics of subjects between healthy and low BMD were comparable (all p>0.05). The distribution of genotypes and alleles in TNSSF11 and TNFRSF11B between healthy and low BMD were not significantly different (all p>0.05). There was no association between SNPs of TNFSF11 and TNFRSF11B with BMD at all bone sites (all p>0.05). Conclusion: The present study suggests that TNFSF11 and TNFRSF11B gene polymorphisms are not associated with BMD in Indonesian postmenopausal women aged between 50-65 years old.