Association Analyses of RANKL/RANK/OPG Gene Polymorphisms with Femoral Neck Compression Strength Index Variation in Caucasians

Key Laboratory of Biomedical Information Engineering, Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, People's Republic of China.
Calcified Tissue International (Impact Factor: 3.27). 06/2009; 85(2):104-12. DOI: 10.1007/s00223-009-9255-5
Source: PubMed


Femoral neck compression strength index (fCSI), a novel phenotypic parameter that integrates bone density, bone size, and body size, has significant potential to improve hip fracture risk assessment. The genetic factors underlying variations in fCSI, however, remain largely unknown. Given the important roles of the receptor activator of the nuclear factor-kappaB ligand/receptor activator of the nuclear factor-kappaB/osteoprotegerin (RANKL/RANK/OPG) pathway in the regulation of bone remodeling, we tested the associations between RANKL/RANK/OPG polymorphisms and variations in fCSI as well as its components (femoral neck bone mineral density [fBMD], femoral neck width [FNW], and weight). This was accomplished with a sample comprising 1873 subjects from 405 Caucasian nuclear families. Of the 37 total SNPs studied in these three genes, 3 SNPs, namely, rs12585014, rs7988338, and rs2148073, of RANKL were significantly associated with fCSI (P = 0.0007, 0.0007, and 0.0005, respectively) after conservative Bonferroni correction. Moreover, the three SNPs were approximately in complete linkage disequilibrium. Haplotype-based association tests corroborated the single-SNP results since haplotype 1 of block 1 of the RANKL gene achieved an even more significant association with fCSI (P = 0.0003) than any of the individual SNPs. However, we did not detect any significant associations of these genes with fBMD, FNW, or weight. In summary, our findings suggest that the RANKL gene may play an important role in variation in fCSI, independent of fBMD and non-fBMD components.

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Available from: Yan Guo, Nov 26, 2014
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    • "Another study implied some role in longevity [45]. Other studies examining femoral neck compression strength [46], susceptibility to rheumatoid arthritis [47], or breast cancer [48] did not see any association. "
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    ABSTRACT: The receptor activator of NF-κB (RANK) pathway is involved in bone health as well as breast cancer (BC) pathogenesis and progression. Whereas the therapeutic implication of this pathway is established for the treatment of osteoporosis and bone metastases, the application in adjuvant BC is currently investigated. As genetic variants in this pathway have been described to influence bone health, aim of this study was the prognostic relevance of genetic variants in RANK and RANKL. Single nucleotide polymorphisms in RANK(L) (rs1054016/rs1805034/rs35211496) were genotyped and analyzed with regard to bone metastasis-free survival (BMFS), disease-free survival, and overall survival for a retrospective cohort of 1251 patients. Cox proportional hazard models were built to examine the prognostic influence in addition to commonly established prognostic factors. The SNP rs1054016 seems to influence BMFS. Patients with two minor alleles had a more favorable prognosis than patients with at least one common allele (HR 0.37 (95% CI: 0.17, 0.84)), whereas other outcome parameters remained unaffected. rs1805034 and rs35211496 had no prognostic relevance. The effect of rs1054016(RANKL) adds to the evidence that the RANK pathway plays a role in BC pathogenesis and progression with respect to BMFS, emphasizing the connection between BC and bone health.
    09/2014; 2014(S 01):842452. DOI:10.1155/2014/842452
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    • "Other studies could not demonstrate these associations [25-28]. Among the SNPs of the RANKL studied, the minor allele (G) of the rs2277438 has been related to a higher femoral neck compression strength index [29] but not to BMD [19,29,30]. The aim of this study is to analyze the relationship between BMD and fractures and the three aforementioned SNPs of the OPG and the rs2277438 SNP of the RANKL, in patients with sporadic primary hyperparathyroidism, a model of chronic PTH hyperstimulation of the skeleton. "
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    ABSTRACT: Primary hyperparathyroidism (PHPT) affects mainly cortical bone. It is thought that parathyroid hormone (PTH) indirectly regulates the activity of osteoclasts by means of the osteoprotegerin/ligand of the receptor activator of nuclear factor-κβ (OPG/RANKL) system. Several studies have confirmed that OPG (osteoprotegerin) and RANKL (ligand of the receptor activator of nuclear factor-κβ) loci are determinants of bone mineral density (BMD) in the general population. The aim of this study is to analyze the relationship between fractures and BMD and the rs3102735 (163 A/G), rs3134070 (245 T/G) and rs2073618 (1181 G/C) SNPs of the OPG and the rs2277438 SNP of the RANKL, in patients with sporadic PHPT. We enrolled 298 Caucasian patients with PHPT and 328 healthy volunteers in a cross-sectional study. We analyzed anthropometric data, history of fractures or renal lithiasis, biochemical determinants including markers for bone remodelling, BMD measurements in the lumbar spine, total hip, femoral neck and distal radius, and genotyping for the SNPs to be studied. Regarding the age of diagnosis, BMI, menopause status, frequency of fractures or renal lithiasis, we found no differences between genotypes in any of the SNPs studied in the PHPT group. Significant lower BMD in the distal radius with similar PTH levels was found in the minor allele homozygotes (GG) compared to heterozygotes and major allele homozygotes in both OPG rs3102735 (163 A/G) and OPG rs3134070 (245 T/G) SNPs in those with PHPT compared to control subjects. We found no differences between genotypes of the OPG rs2073618 (1181 G/C) SNP with regard to BMD in the PHPT subjects. In the evaluation of rs2277438 SNP of the RANKL in PHPT patients, we found a non significant trend towards lower BMD in the 1/3 distal radius and at total hip in the minor allele homocygotes (GG) genotype group versus heterocygotes and major allele homocygotes (AA). Our study provides the first evaluation of the relationship between SNPs of the OPG/RANK system and sporadic PHPT. Subjects with PHPT and minor homocygote genotype (GG) for the OPG rs3102735 (163 A/G) and OPG rs3134070 (245 T/G) SNPs have lower BMD in the distal radius, and this association does not appear to be mediated by differences in PTH serum levels.
    BMC Medical Genetics 12/2011; 12(1):168. DOI:10.1186/1471-2350-12-168 · 2.08 Impact Factor
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    ABSTRACT: Osteoporosis is characterized by low bone mineral density and structural deterioration of bone tissue, leading to an increased risk of fractures. It is the most common metabolic bone disorder worldwide, affecting one in three women and one in eight men over the age of 50. In the past 15 years, a large number of genes have been reported as being associated with osteoporosis. However, only in the past 4 years we have witnessed an accelerated pace in identifying and validating osteoporosis susceptibility loci. This increase in pace is mostly due to large-scale association studies, meta-analyses, and genome-wide association studies of both single nucleotide polymorphisms and copy number variations. A comprehensive review of these developments revealed that, to date, at least 15 genes (VDR, ESR1, ESR2, LRP5, LRP4, SOST, GRP177, OPG, RANK, RANKL, COLIA1, SPP1, ITGA1, SP7, and SOX6) can be reasonably assigned as confirmed osteoporosis susceptibility genes, whereas, another >30 genes are promising candidate genes. Notably, confirmed and promising genes are clustered in three biological pathways, the estrogen endocrine pathway, the Wnt/beta-catenin signaling pathway, and the RANKL/RANK/OPG pathway. New biological pathways will certainly emerge when more osteoporosis genes are identified and validated. These genetic findings may provide new routes toward improved therapeutic and preventive interventions of this complex disease.
    Human Genetics 03/2010; 127(3):249-85. DOI:10.1007/s00439-009-0773-z · 4.82 Impact Factor
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