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      Association of interleukin-1 beta (-511C/T) polymorphisms with osteoporosis in postmenopausal women

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          Abstract

          BACKGROUND AND OBJECTIVES:

          Osteoporosis is a common disease of the elderly, in which genetic and clinical factors contribute to the disease phenotype. Since the production of interleukin-1 (IL-1) has been implicated in the bone mass and skeletal disorders, we investigated whether IL-1 system gene polymorphisms are associated with the pathogenesis of osteoporosis in postmenopausal Taiwanese women.

          METHODS:

          Osteoporosis is diagnosed by dual-energy x-ray absorptiometry, which measures bone mineral density (BMD) at multiple skeletal sites. We studied the IL-1α (-889C/T), IL-1β (-511C/T) and the 86 base pair variable number tandem repeat (VNTR) in intron 2 of the IL-1 receptor antagonist (IL-1ra) gene in 117 postmenopausal women with osteoporosis and 135 control subjects without a history of symptomatic osteoporosis. These gene polymorphisms were analyzed by polymerase chain reaction and restriction fragment length polymerase. Blood sugar and other risk factors were also determined.

          RESULTS:

          The frequencies of IL-1β (-511C/T) genotypes ( P=.022, odds ratio=1.972) and alleles ( P=.02, odds ratio=2.909) showed a statistically significant difference between the two groups. However, we did not find any statistically significant difference in IL-1α and IL-1ra polymorphisms ( P>.05). We also observed a positive relationship between osteoporosis and cholesterol and a weak inverse relationship between blood sugar and osteoporosis in postmenopausal women.

          CONCLUSIONS:

          These experimental results suggest that the pathogenesis of osteoporosis is associated with IL-1β (-511C/T) polymorphism in postmenopausal women. This polymorphism is an independent risk factor for osteoporosis.

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          Most cited references29

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          Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat.

          We have investigated the polymorphism in intron 2 of the interleukin-1 receptor antagonist gene and identified two new alleles of the system. We have shown that the polymorphism is caused by the variable copy number of an 86-bp sequence, by using the polymerase chain reaction and primers immediately flanking the repeat region, and by direct sequencing. The repeat region contains three potential protein-binding sites and therefore the variable copy number may have functional significance.
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            Genetic regulation of bone mass and susceptibility to osteoporosis.

            Osteoporosis is a common disease with a strong genetic component characterized by reduced bone mass and increased risk of fragility fractures. Twin and family studies have shown that the heritability of bone mineral density (BMD) and other determinants of fracture risk-such as ultrasound properties of bone, skeletal geometry, and bone turnover-is high, although heritability of fracture is modest. Many different genetic variants of modest effect size are likely to contribute to the regulation of these phenotypes by interacting with environmental factors such as diet and exercise. Linkage studies in rare Mendelian bone diseases have identified several previously unknown genes that play key roles in regulating bone mass and bone turnover. In many instances, subtle polymorphisms in these genes have also been found to regulate BMD in the general population. Although there has been extensive progress in identifying the genetic variants that regulate susceptibility to osteoporosis, most of the genes and genetic variants that regulate bone mass and susceptibility to osteoporosis remain to be discovered.
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              The polymorphism in the caudal-related homeodomain protein Cdx-2 binding element in the human vitamin D receptor gene.

              The major physiological activity of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] is the regulation of calcium absorption in the small intestine, and the level of vitamin D receptor (VDR) is an important factor in this regulation. In a previous study, we indicated-that the caudal-related homeodomain Cdx-2 played an important role in the intestine-specific transcription of the human VDR gene. In this study, the polymorphism was identified in the core sequence 5'-ATAAAAACTTAT-3' in the Cdx-2 binding site in the VDR gene promoter. In 261 Japanese women with genotyped VDR polymorphisms, 48 were genotype Cdx-A (adenine at -3731 nucleotides [nt] relative to the transcription start site of human VDR gene 5-ATAAAAACTTAT), 82 were genotype Cdx-G (guanine at -3731 nt, 5'-GTAAAAACTTAT-3'), and 131 were genotype Cdx-A/G (heterozygote). In postmenopausal Japanese women, the bone mineral density (BMD) in the lumbar spine (L2-L4) with the Cdx-G homozygote was 12% lower than that with the Cdx-A homozygote (p < 0.05). In electrophoretic gel mobility shift assay (EMSA), the oligonucleotide with Cdx-G allele markedly decreased the binding to Cdx-2 compared with that in the Cdx-A allele. The transcriptional activity of the VDR promoter with Cdx-G allele was decreased to 70% of the Cdx-A allele. In addition, in the herpes simplex virus thymidine kinase promoter, the Cdx-2 binding element with the G allele showed significantly lower transcriptional activity than that of the A allele. Thus, the polymorphism in the Cdx-2 binding site of the VDR gene (Cdx-polymorphism) would affect the expression of VDR in the small intestine. In addition, this polymorphism may modulate BMD in postmenopausal Japanese women.
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                Author and article information

                Journal
                Ann Saudi Med
                ASM
                Annals of Saudi Medicine
                Medknow Publications (India )
                0256-4947
                0975-4466
                Nov-Dec 2010
                : 30
                : 6
                : 437-441
                Affiliations
                [a ]From the Department of Orthopedics, Zuoying Armed Forces General Hospital, Kaohsiung, Taiwan
                [b ]From the Asia-Pacific Biotech Developing, Inc., Kaohsiung, Taiwan
                [c ]From the Department of Biotechnology, Yung-Ta Institute of Technology & Commerce, Pingtung, Taiwan
                Author notes
                Correspondence: Dr. Wen-Tung Wu · Yung-Ta Institute of Technology & Commerce, 316, Chung Shan Road, Lin Ti Tsun Lin Lo, 909, ROC, PingTung, Taiwan · gerrywu8769@ 123456yahoo.com.tw
                Article
                ASM-30-437
                10.4103/0256-4947.71062
                2994158
                20940514
                5a498776-37dd-4482-9ec3-c9f66203d335
                © Annals of Saudi Medicine

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : April 2010
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                Original Article

                Medicine
                Medicine

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