Fracture, bone mineral density, and the effects of calcitonin receptor gene in postmenopausal Koreans
ABSTRACT In a candidate gene association study, we found that the variations of calcitonin receptor (CALCR) gene were related to the risk of vertebral fracture and increased bone mineral density (BMD).
Calcitonins through calcitonin receptors inhibit osteoclast-mediated bone resorption and modulate calcium ion excretion by the kidney and also prevent vertebral bone loss in early menopause.
To identify genetically susceptible factors of osteoporosis, we discovered the variations in CALCR gene, genotyped in Korean postmenopausal women (n = 729), and examined the potential involvement of seven single-nucleotide polymorphism (SNPs) and their haplotypes in linkage disequilibrium block (BL_hts).
The SNPs, +43147G > C (intron 7), +60644C > T (exon13, 3' untranslated region), and their haplotypes, BL2_ht1 and BL2_ht2, showed a significant association with risk of vertebral fracture (p = 0.048-0.004) and BL2_ht1 showed a highly significant protective effect. Moreover, the polymorphism +60644C > T showed a highly significant association with BMD at both lumbar spine and femoral neck. The subjects carrying CC and CT genotypes with the SNP, +60644C > T, had higher BMD values at the lumbar spine (p = 0.01-0.001) and femoral neck (p = 0.025-0.009).
These results indicate that the CALCR gene may regulate bone metabolism, and +60644C > T in the CALCR gene may genetically modulate bone phenotype.
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ABSTRACT: In this study, we have investigated the association between osteoporosis and osteocalcin (BGLAP) − 298 C>T, estrogen receptor 1 (ER1) 397 T>C, collagen type1 alpha 1 (Col1A1) 2046 G>T and calcitonin receptor (CALCR) 1340 T>C polymorphisms. Genomic DNA was obtained from 266 persons (158 osteoporotic and 108 healthy controls). Genomic DNA was extracted from EDTA-preserved peripheral venous blood of patients and controls by a salting-out method and analyzed by PCR-RFLP. As a result, there was no statistically significant difference in the genotype and allele frequencies of patients and controls for BGLAP − 298 C>T, Col1A1 2046 G>T, ER1 397 T>C and CALCR 1340 T>C polymorphisms. However, ER1 CC genotype compared with TT + TC genotypes was found to increase the two fold the risk of osteoporosis [p = 0.039, OR = 2.156, 95% CI (1.083–4.293)] and CALCR CC genotype compared with TT + TC genotypes was found to have protective effect against osteoporosis [p = 0.045, OR = 0.471, 95% CI (0.237–0.9372)]. In the combined genotype analysis, ER1/CALCR TCCC combined genotype was estimated to have protective effect against osteoporosis [p = 0.0125, OR = 0.323, 95% CI (0.1383–0.755)] whereas BGLAP/Col1A1 CCTT and ER1/CALCR CCTT combined genotypes were estimated as risk factors for osteoporosis in Turkish population (p = 0.027, p = 0.009 respectively).Gene 02/2013; 515(1):167–172. DOI:10.1016/j.gene.2012.10.041 · 2.08 Impact Factor
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ABSTRACT: Clinical risk factors (CRFs), with or without bone mineral density (BMD), are used to determine the risk of osteoporotic fracture (OF), which has a heritable component. This study investigated whether genetic profiling can additionally improve the ability to predict OF. Using 1,229 unrelated Korean postmenopausal women, 39 single-nucleotide polymorphisms (SNPs) in 30 human genomic loci were tested for association with osteoporosis-related traits, such as BMD, osteoporosis, vertebral fracture (VF), non-vertebral fracture (NVF), and any fracture. To estimate the effects of genetic profiling, the genetic risk score (GRS) was calculated using five prediction models: (model I) GRSs only; (model II) BMD only; (model III) CRFs only; (model IV) CRFs and BMD; and (model V) CRFs, BMD and GRS. A total of 21 SNPs within 19 genes associated with one or more osteoporosis-related traits and were included for GRS calculation. GRS associated with BMD before and after adjustment for CRFs (P = < 0.001 to 0.018). GRS associated with NVF before and after adjustment for CRFs and BMD (P = 0.017 to 0.045), and with any fracture after adjustment for CRFs and femur neck BMD (P = 0.049). In terms of predicting NVF, the area under the receptor-operator characteristics curve (AUC) for model I was 0.55, which was lower than the AUCs of models II (0.60), III (0.64), and IV (0.65). Adding GRS to model IV (in model V) increased the AUC to 0.67, and improved the accuracy of NVF classification by 11.5% (P = 0.014). In terms of predicting any fracture, the AUC of model V (0.68) was similar to that of model IV (0.68), and model V did not significantly improve the accuracy of any fracture classification (P = 0.39). Thus, genetic profiling may enhance the accuracy of NVF predictions and help to delineate the intervention threshold.Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 10/2013; 28(10). DOI:10.1002/jbmr.1955 · 6.59 Impact Factor
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ABSTRACT: Introduction: In this study the full sequence of the calcitonin receptor gene (CALCR) in a group of Iranian males suffering from recurrent calcium urinary stones was compared with that of a control group. Methods: Serum and urinary biochemistry related to urolithiasis were evaluated in 105 males diagnosed with recurrent kidney calcium stones and 101 age-matched healthy control males. The polymerase chain reaction single-strand conformation polymorphism method was used to detect new polymorphisms in the CALCR. Results: Nine polymorphisms were detected; seven were in the non-coding and two in the coding region. The T allele associated with the 3'UTR+18C>T polymorphism was observed exclusively in the stone formers. The exact odds ratio for the T allele in this locus for those at risk of stone formation was 36.72 (95% CI 4.95-272.0) (p < 0.001). The mean (standard deviation) urine calcium concentration was 117 (60) mg/l in patients with the C allele and 152 (72) mg/l in those with the T allele (p = 0.03). In addition, IVS1-6T>C and IVS1insA polymorphisms in intron 1 were associated with kidney stone disease (p < 0.001). Regarding single nucleotide polymorphism 447, mean (standard deviation) of serum calcitonin levels were 16.7 (18.7) pg/ml, 10.5 (11.0) pg/ml and 9.94 (9.7) pg/ml in subjects with TT, TC and CC genotypes, respectively (p = 0.01). Conclusion: Our data indicate a potential association between 3'UTR+18C>T and intron 1 polymorphisms in the CALCR and the risk of kidney stone disease. © 2013 S. Karger AG, Basel.Urologia Internationalis 11/2013; 92(3). DOI:10.1159/000353348 · 1.15 Impact Factor