Association of genetic variation of the RIL gene, encoding a PDZ-LIM domain protein and localized in 5q31.1, with low bone mineral density in adult Japanese women

Abstract

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:

Direct or indirect association in a complex disease: the role ofSLC22A4 andSLC22A5 functional variants in Crohn disease

“…The studies of Peltekova et al [2004] indicate that the 503F and -207G variants alter the function or expression of the OCTN1 and OCTN2 cation transporters encoded by these two genes, but the link between aberrant OCTN function and CD remains to be established. Neither the PDLIM4 nor the P4HA2 genes are obvious candidate susceptibility genes for CD [Omasu et al, 2003;Hofbauer et al, 2003]. It is also possible that other classes of polymorphism may contribute to susceptibility at this locus, such as variants in conserved noncoding sequences that regulate the function of one or more of its genes [Sallusto and Reiner, 2005], or gene copy number variation, which has recently been associated with autoimmune disease in rats and humans [Aitman et al, 2006].…”

Microarray Analysis of Human Adipose-Derived Stem Cells in Three-Dimensional Collagen Culture: Osteogenesis Inhibits Bone Morphogenic Protein and Wnt Signaling Pathways, and Cyclic Tensile Strain Causes Upregulation of Proinflammatory Cytokine Regulators and Angiogenic Factors

“…6a). Two genes upregulated in response to 10% cyclic tensile strain during osteogenesis of hASC were also validated with RT-PCR: (1) PDLIM4, one of the top five upregulated genes that have been shown to have polymorphisms found to associate with bone mineral density regulation 23,24 ; (2) VEGF A, a known angiogenic factor. Real-time RT-PCR results confirmed that expression of both genes was significantly increased by hASC in response to 10% uniaxial cyclic tensile strain (Fig.…”

“…Of particular interest was the upregulation of PDLIM4, one of the top five upregulated genes that have been shown to have polymorphisms found to associate with bone mineral density regulation. 23,24 The addition of 10% uniaxial cyclic tensile strain also resulted in hASC upregulation of two crucial factors in bone regeneration: (1) proinflammatory cytokine regulators IL1RN and SOCS3; (2) angiogenic inductors FGF2, MMP2, and VEGF A.…”

Finding cis-regulatory elements using comparative genomics: Some lessons from ENCODE data

“…The encoded protein has PDZ and LIM domains, and it regulates the association of actin stress fibers with actinin. Variants in the noncoding portion of this gene are associated with osteoporosis (Omasu et al 2003). The noncoding sequences in a 10-kb window encompassing the 5Ј flank and first two introns deviate significantly from neutrality, based on divergence from chimpanzee, and the low neutrality index suggests positive selection.…”