Introduction: Osteoporosis results from the interplay of multiple environmental and genetic determinants. The gene encoding vitamin D-binding protein (DBP), a key factor for regulating calcium homeostasis through the vitamin D endocrine system, is a probable candidate for conferring susceptibility to osteoporosis. Methods: To test a possible contribution of the DBP gene for determination of bone mineral density (BMD) of adult women, we have characterized 13 single nucleotide polymorphisms (SNPs) within the DBP gene in DNA from 384 adult Japanese women and attempted to correlate specific SNPs with BMD.
Correlation between 13 genetic variations of the glutaminyl-peptide cyclotransferase gene and adjusted aBMD was tested among 384 adult women. Among 13 variations with strong linkage disequilibrium, R54W showed a prominent association (p ؍ 0.0003), which was more striking when examined among 309 elder subjects (>50 years; p ؍ 0.0001). Contribution for postmenopausal bone loss was suggested.Introduction: Alterations in homeostatic regulation of estrogen through the hypothalamus-pituitary-gonadal axis (HPG axis) importantly affect the pathogenesis of osteoporosis. Osteoporosis-susceptibility genes have been proposed in this hormonal axis, such as estrogen receptor genes and the gonadotropin-releasing hormone gene (GnRH). Here we report another example of genes: glutaminyl-peptide cyclotransferase gene (QPCT), an essential modifier of pituitary peptide hormones, including GnRH. Materials and Methods: Analyses of association of 13 single nucleotide polymorphisms (SNPs) at the QPCT locus with adjusted areal BMD (adj-aBMD) were carried out among 384 adult women. Linkage disequilibrium (LD) was analyzed by haplotype estimation and calculation of DЈ and r 2 . Multiple regression analysis was applied for evaluating the combined effects of the variations. Results and Conclusions: LD analysis indicated strong linkage disequilibrium within the entire 30-kb region of the QPCT gene. Significant correlations were observed between the genotypes of the six SNPs and the radial adj-aBMD, among which R54W (nt ϩ 160CϾT) presented the most prominent association (p ϭ 0.0003). Striking association was observed for these SNPs among the 309 subjects Ͼ50 years of age (R54W, p ϭ 0.0001; Ϫ1095TϾC, p ϭ 0.0002; Ϫ1844CϾT, p ϭ 0.0002). Multiple regression analyses indicated that multiple SNPs in the gene might act in combination to determine the radial adj-aBMD. These results indicate that genetic variations in QPCT are the important factors affecting the BMD of adult women that contribute to susceptibility for osteoporosis. The data should provide new insight into the etiology of the disease and may suggest a new target to be considered during treatment.
Twin and family studies had shown that genetic factors are important determinants of bone mass. Multiple genes might be involved. One candidate gene, the reversion-induced LIM gene (RIL), is a PDZ and LIMdomain-containing protein and has been localized within the cytokine cluster of chromosome 5 (5q31.1). In a genetic study of 370 adult Japanese women, we investigated the correlation between radial bone mineral density (BMD) and a genetic variation ()3333T fi C) of the 5'-flanking region of RIL gene. A significant association was identified between the RIL variation )3333T fi C and radial BMD (r=0.15, P=0.003). The variation of the RIL locus may be an important determinant of osteoporosis.Keywords Single-nucleotide polymorphism AE RIL AE Bone mineral density AE Association study
IntroductionOsteoporosis is a multi-factorial common disease that is characterized by reduced bone mass and increasing risk of fracture. Genetic and environmental factors play important roles in the determination of bone mineral density (BMD) (Hirota et al. 1992;Suleiman et al. 1997;Pocock et al. 1987;Krall and Dawson-Hughes 1993).Previous studies have examined associations of candidate gene polymorphisms with BMD. Examples are the genes encoding the vitamin D receptor, the estrogen receptor, the apolipoprotein E and type I collagen, combinations of which may determine individual BMD levels (Morrison et al. 1994;Melhus et al. 1994;Greenfield and Goldberg 1997;Kobayashi et al. 1996;Shiraki et al. 1997;Uitterlinden et al. 1998). In addition to these makers, numbers of unidentified polymorphic genes may participate in determining the bone mass of an individual. Candidates might be genes involved in cytokine-signaling pathways, the hormonal regulation of calcium balance and bone mineral, or the cellular function of bone cells.One possible candidate gene localized within the cytokine cluster of chromosome 5 (5q31.1) is the reversion-induced LIM gene (RIL), whose mRNA expression in human bone marrow stromal cells has been strongly detected in a previous study (Bashirova et al. 1998). Although its exact function is not defined as yet, an involvement of osteoblast development/function is implicated.In this study, we have carried out a correlation study of genetic variations in RIL gene for radial BMD levels. Involvement of an RIL gene polymorphism was tested with respect to the regulation of BMD.
Subjects and methodsSubjects DNA samples were obtained from peripheral blood of 370 adult Japanese women (Shinohara et al. 2001). BMD was measured in all of these subjects. Mean ages and body mass indices (BMI) with standard deviations (SD) were 58.4±8.6 years (range:
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