Genetic polymorphisms of osteopontin in association with multiple sclerosis in Japanese patients

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Abstract

Osteopontin (OPN) exhibits pleiotropic functions and abundant transcripts for OPN are present in brains of patients with multiple sclerosis (MS). The aim of this study was to investigate the role of OPN genes in the pathogenesis of MS. Polymorphisms at the 8090th, 9250th and 9583rd positions in OPN were detected by PCR-RFLP from DNAs of 116 MS Japanese patients and 124 healthy controls. The C/C genotype at the 8090th position in exon 6 was more prevalent in MS than in control (p<0.0001), and C allele was more prevalent in MS than in control (p<0.0001, OR=2.57, 95% CI=1.65–4.00). For the 9583rd position polymorphism in exon 7, patients with G/G genotype (age; 32.1±12.5 years, mean±S.D.) showed a later disease onset than G/A (age; 25.9±7.8 years, p=0.01) and A/A (age; 25.2±8.9 years, p=0.01) genotypes. There were no significant correlations between OPN gene polymorphisms and disease progression. Our results suggest that the 8090th polymorphism might be associated with susceptibility to MS, while the 9583rd polymorphism might be associated with age of onset of MS.

Introduction

Osteopontin (OPN) is one of the major non-collagenous bone matrix proteins produced by osteoblasts and osteoclasts Reinholt et al., 1990, Young et al., 1990. Previous studies indicated that OPN also acts as a key cytokine involved in the regulation of tissue repair and inflammation, and labeled OPN as early T cell activation-1 Oldberg et al., 1986, Fisher et al., 2001. OPN is a secreted adhesive, glycosylated phosphoprotein that contains the arginine–glycine–aspartic acid (RGD) cell-binding sequence, which is found in various forms of the extracellular matrix (Oldberg et al., 1986). The OPN gene is expressed in T cells early in the course of bacterial infections (within 48 h), and interaction of its protein product with macrophages can induce inflammatory responses Singh et al., 1990, Yu et al., 1998. Furthermore, OPN costimulates T cell proliferation (O'Regan et al., 2000) and is classified as a Th-1 cytokine, because of its ability to enhance IFN-γ and IL-12 production and to diminish IL-10 production (Ashkar et al., 2000). In addition to the role of OPN as a pro-inflammatory cytokine, an anti-inflammatory function is suggested by OPN-dependent inhibition of nitric oxide production by macrophages in vitro Rollo et al., 1996, Rittling and Denhardt, 1999. Large-scale sequencing of cDNA libraries, derived from plaques dissected from brains of patients with multiple sclerosis (MS), indicated abundance of transcripts for OPN (Chabas et al., 2001). Taken together, the OPN gene is considered as one of the susceptible genes for MS.

The recent full genome screening studies for MS suggested that multifactorial etiology, including both environmental and multiple genetic factors of moderate effect, was more likely than an etiology based on simple Mendelian disease gene Ebers et al., 1996, Haines et al., 1996, Sawcer et al., 1996. In addition, the complex multifactorial inheritance pattern, the highly variable clinical course and differences of age of disease onset are features of the disease that have confounded both epidemiological and genetic analyses. The human gene of OPN is located on chromosome 4q21–25 (Young et al., 1990). In the OPN gene, three single-nucleotide polymorphisms (SNPs) in the exon have been described in Japanese individuals (Iwasaki et al., 2001). Two of those SNPs were in the coding region of exon 6 (8090th) and exon 7 (9250th) and the other was in the 3′ untranslated region of exon 7 (9583rd) (Iwasaki et al., 2001). In the present study, we investigate the polymorphisms at the 8090th, 9250th and 9583rd positions of the OPN gene in 116 Japanese patients with MS and 124 Japanese controls, taking age of disease onset and disease progression into consideration.

Section snippets

Patients and healthy individuals

Selected for this study were 116 unrelated Japanese patients with relapsing and remitting type or secondary progressive type MS who, after having been observed for at least 1 year, diagnosed as MS according to the criteria of McDonald et al. (2001) (Table 1). They were “conventional” MS patients as described previously (Fukazawa et al., 1992), quite similar to MS patients in Western countries. MS patients of the “optic-spinal form” were excluded from this study. The female/male ratio was 2.7:

OPN genotype and allele frequencies

We were successful in determining the polymorphisms at 8090th, 9250th and 9583rd positions in all patients and control subjects. Table 2 shows the proportions of OPN genotypes and allele frequencies in both groups. In control subjects, each genotype frequency of OPN polymorphisms conformed to Hardy–Weinberg expectations. The rate of the C/C genotype at the 8090th position in MS patients (77.6%) was significantly higher than in the controls (48.4%, p<0.0001). The C allele at the 8090th position

Discussion

The major findings of the present study were the following: (1) The frequency of the C/C genotype at the 8090th position in MS patients was significantly higher than in control subjects. (2) Disease onset in patients with the G/G genotype at the 9583rd position was delayed compared with that of patients with other genotypes. (3) There were no significant correlations between progression index and OPN gene polymorphisms in Japanese patients with MS.

OPN exhibits pleiotropic functions Denhardt and

Acknowledgements

This work was supported in part by a research grant from the Research on Brain Science, the Ministry of Health and Welfare of Japan.

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