Allelic variation at the interleukin-1 receptor antagonist gene is associated with early postmenopausal bone loss at the spine

Keen, R W; Woodford-Richens, K. L.; Lanchbury, J. S.; Spector, Tim D.

doi:10.1016/s8756-3282(98)00109-4

Cited by 87 publications

(43 citation statements)

References 28 publications

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“…BMD is the major factor determining bone strength and, consequently, osteoporotic fracture risk, and can be considered a quantitative polygenic trait. It has been shown that several genes are associated with BMD, although conflicting results also exist (Kanis et al, 1994;Morrison et al, 1994;Kobayashi et al, 1996;Murray et al, 1997;Keen et al, 1998;Eisman, 1999;Yamada et al, 2001;Arko et al, 2002;Garcia-Giralt et al, 2002). IL10 is a powerful T H 2-cell cytokine, and the MCP gene family is a beta-chemokine that binds primarily to C-C chemokine receptors, such as CCR2 or CCR3.…”

Section: Discussionmentioning

confidence: 99%

“…This was supported by twin studies showing a much higher concordance of bone mineral density (BMD) in monozygotic than dizygotic twins (Slemenda et al, 1991;Kanis et al, 1994;Young et al, 1995;Arden and Spector 1997;Eisman 1999;Stewart and Ralston 2000). Numerous candidate genes and their genetic variants, including estrogen receptor (ER), transforming growth factor beta1 (TGFB1), Interleukin-1 receptor antagonist (IL1RA), Interleukin6 (IL6), collagen 1A1 (COL1A1) and osteoprotegerin (OPG), (Kobayashi et al, 1996;Murray et al, 1997;Keen et al, 1998;Yamada et al, 2001;Arko et al, 2002; Garcia-*To whom correspondence should be addressed. Tel: 82-2-3675-2186; Fax: 82-2-3675-2189 E-mail: hdshin@snp-genetics.com Giralt et al, 2002), have been proposed and implicated as genetic markers for BMD, since Morrison and his colleagues reported that vitamin D receptor (VDR) gene polymorphism was involved in bone metabolism (Morrison et al, 1992;Morrison et al, 1994) .…”

Section: Introductionmentioning

confidence: 96%

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Association of Interleukin 10 Haplotype with Low Bone Mineral Density in Korean Postmenopausal Women

Park¹,

Han²,

Lee³

et al. 2004

BMB Reports

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Osteoporosis is a disease characterized by exaggerated loss of bone mass, with as much as 50 to 85% of the variation in bone mineral density (BMD) commonly accepted as being genetically determined. Although intensive studies have attempted to elucidate the genetic effects of polymorphisms on BMD and/or osteoporosis in several genes, the genes involved are still largely unknown. The possible associations of genetic variants in five-candidate genes (IL10, CCR3, MCP1, MCP2 and GC) with spinal BMD were investigated in Korean postmenopausal women (n = 370). Fourteen SNPs in five candidate genes were genotyped, and the haplotypes of each gene constructed. The associations of adjusted spinal BMD by age, year since menopause (YSM) and body mass index (BMI), with genetic polymorphisms, were analyzed using multiple regression models. Genetic association analysis of Korean postmenopausal women revealed that IL10 -592A > C and/or IL10 ht2 were associated with decreased bone mass, whereas no significant associations were observed with all polymorphisms in other genes. The levels of spinal BMD in individuals bearing the IL10 -592CC genotype were lower (0.78 ± 0.16) than those in others (0.85 ± 0.17) (P = 0.02), and the BMD of IL10 ht2 bearing individuals were also lower (0.82 ± 0.15) than those in others (0.85 ± 0.17) (P = 0.04). Our results suggest that variants of IL10 might play a role in the decreased BMD, although additional study might need to be followed-up in a more powerful cohort.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Association of Interleukin 10 Haplotype with Low Bone Mineral Density in Korean Postmenopausal Women

Park¹,

Han²,

Lee³

et al. 2004

BMB Reports

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“…A VNTR of 86 bp repeats within intron 2 of the gene was tested for association with bone variables in several studies. Significant association of the VNTR polymorphism with rates of change in spinal bone mass, spine bone loss (Keen et al 1998), and lumbar and hip BMD (Langdahl et al 2000c, Fontova et al 2002 was identified.…”

Section: Other Genetic Polymorphismsmentioning

confidence: 97%

Molecular studies of identification of genes for osteoporosis: the 2002 update

Liu¹,

Liu²,

Recker³

et al. 2003

Journal of Endocrinology

213

168

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We aim to give a comprehensive review, updated to 2002, of the most important and representative molecular genetic studies, performed mainly within the past decade, that aimed to identify the gene(s) involved in osteoporosis. Early reviews were largely confined to association studies in humans, but we review here, separately, the results of both association and linkage studies in humans, and quantitative trait locus (QTL) mapping in animal models. The main results of all the studies are tabulated for comparison and ease of reference, and to provide a comprehensive retrospective view of molecular genetics studies of osteoporosis. The most striking findings and the most representative studies are singled out for comment regarding the immediacy of their influence on present understanding of the genetics of osteoporosis and on the current status of genetic research in osteoporosis. This is particularly relevant for studies on the association of the vitamin D receptor (VDR) gene, for which there has been a large body of studies and reviews published. The format adopted by this review should be ideal for accommodating future new advances and studies in a fairly young field that is still developing rapidly.

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“…Population-based association studies have suggested that genetic effects can be ascribed to polymorphisms of a number of genes involved in bone metabolism, although the genetic basis of osteoporosis is not well understood. Polymorphisms of genes encoding vitamin D receptor (VDR), estrogen receptor (ER), collagen type I alpha (COL1A1), calcitonin receptor (CTR), osteocalcin, transforming growth factor-beta (TGF-beta), interleukin-1 receptor antagonist (IL-1RN), insulin-like growth factor-I (IGF-I), calcitonin receptor (CTR), parathyroid hormone (PTH), peroxisome proliferator-activated receptor gamma (PPAR gamma), calcitonin (CT), and interleukin-6 (IL6) have all been implicated as genetic markers for BMD (Morrison et al 1994;Sano et al 1995;Grant et al 1996;Dohi et al 1998;Keen et al 1998;Masi et al 1998;Miyao et al 1998;Taboulet et al 1998;Yamada et al 1998;Hosoi et al 1999;Ogawa et al 1999;Tsukamoto et al 1999;Miyao et al 2000).…”

Section: Introductionmentioning

confidence: 99%

A nucleotide variant in the promoter region of the interleukin-6 gene associated with decreased bone mineral density

et al. 2001

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Interleukin-6 (IL6) has come to be regarded as a potential osteoporotic factor because it has stimulatory effects on cells of the osteoclast lineage, and, thus, may play a role in the pathogenesis of bone loss associated with estrogen deficiency. We previously described association of the IL6 microsatellite with bone mineral density (BMD), as well as genetic linkage of the IL6 locus to human osteoporosis, by means of sib-pair analysis. However, the molecular mechanism by which this locus regulates BMD remains unknown. Accordingly, we searched for polymorphisms in the 5Ј and 3Ј flanking regions and in all five exons of the IL6 gene in a Japanese population sample. We identified three single-nucleotide sequence variations: a C/G substitution at nucleotide (nt) Ϫ634 in the promoter region, a G/A substitution at nt 4391 in the 3Ј noncoding region, and a variation in the AnTn tract around nt Ϫ447. The last of these had already been observed in Caucasians, as well as in Japanese. The single-nucleotide polymorphism at Ϫ634 created a restriction site for the BsrBI endonuclease, and the frequency of the minor (G) allele was 0.184. Five haplotypes were constructed among three variations examined in the population. Linkage disequilibrium was observed between the variation at Ϫ634 and the variation at 4391, as well as between the variation at Ϫ634 and the AnTn tract variation. We found a significant correlation, in 470 subjects, between the presence of the G allele and decreased BMD, by analysis of variance. When BMD values were compared among the three genotypic groups (G/G, G/C, C/C) at nt Ϫ634, BMD was lowest among the G/G homozygotes (mean Ϯ SD; 0.284 Ϯ 0.062 g/cm 2 ), highest among the C/C homozygotes (0.314 Ϯ 0.059 g/cm 2 ), and intermediate among the heterozygotes (0.303 Ϯ 0.066 g/cm 2 ; P Ͻ 0.05).Given the several lines of evidence from different genetic studies, we suggest that IL6 is, indeed, one of the genes affecting bone metabolism, in which variations can lead to osteoporosis.

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Allelic variation at the interleukin-1 receptor antagonist gene is associated with early postmenopausal bone loss at the spine

Cited by 87 publications

References 28 publications

Association of Interleukin 10 Haplotype with Low Bone Mineral Density in Korean Postmenopausal Women

Association of Interleukin 10 Haplotype with Low Bone Mineral Density in Korean Postmenopausal Women

Molecular studies of identification of genes for osteoporosis: the 2002 update

A nucleotide variant in the promoter region of the interleukin-6 gene associated with decreased bone mineral density

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