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Platelet-activating factor receptor gene polymorphism in Japanese patients with multiple sclerosis

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Abstract

We evaluated the association of the platelet-activating factor receptor (PAFR) gene polymorphism (A224D) with the susceptibility and severity of multiple sclerosis (MS) in a Japanese population. DNA was collected from 162 Japanese patients with clinically definite ‘conventional’ MS (MS) and 245 healthy controls. The missense mutation A224D that impairs PAF-PAFR signaling was determined by polymerase chain reaction restriction fragment length polymorphism. The frequency of the AD/DD genotypes was significantly higher in MS patients (21.0%) than in healthy controls (13.5%) (p=0.045; odds ratio (OR), 1.71; 95% confidence interval (CI), 1.01–2.89). Moreover, the frequency of D allele in MS patients (11.7%) was also significantly higher than those in healthy controls (6.9%) (p=0.019; OR, 1.78; 95% CI, 1.10–2.89). These findings suggest that the PAFR gene missense mutation has a relation to the susceptibility for MS.

Introduction

Increased levels of platelet-activating factor (PAF) receptor (PAFR) mRNA are reported in multiple sclerosis (MS) plaques together with several genes encoding molecules associated with allergic responses (Lock et al., 2002). In experimental allergic encephalomyelitis (EAE), an animal model of MS, transcripts for PAFR were reported as elevated in the CNS during the disease, and PAFR antagonist was shown to reduce the severity of EAE (Pedotti et al., 2003). Moreover, in cerebrospinal fluid and plasma of patients with the relapsing–remitting MS, elevation of PAF that correlated with the number of gadolinium-enhancing lesions was found on brain MRI (Callea et al., 1999). Taken together, the above findings are suggestive that PAF might have a proinflammatory role in MS.

PAF is a very potent chemotactic stimulant for inflammatory cells such as eosinophils (Wardlaw et al., 1986) and polymorphonuclear neutrophils (O'Flaherty et al., 1981). PAF not only promotes leukocyte adhesion and transmigration by the induction of intracellular adhesion molecule-1 (ICAM-1) on endothelial cells (Chihara et al., 1992), but also upregulates major histocompatibility complex (MHC) class I and II expressions in some brain cells that are critical in antigen presentation (Martin-Mondière et al., 1987). These proinflammatory and vasoactive actions of PAF are mediated through a specific G-protein-coupled receptor, PAFR (Honda et al., 1991, Nakamura et al., 1991). A single amino acid substitution (A224D) in the third cytoplasmic loop of human PAFR that modifies its function has been reported, with the variant being relatively common in Japanese, with 13.8% heterozygous and 0.9% homozygous (Fukunaga et al., 2001). Fukunaga et al. also found that Chinese hamster ovary cells expressing A224D mutant PAFR displayed a partial but significant reduction of PAF-induced intracellular signaling, and that the variant exhibited impaired coupling to G-proteins.

The present study aimed to elucidate the effect of the PAFR polymorphism on the development of MS in Japanese; thus, we investigated the PAFR gene polymorphism (A224D) in MS patients, and correlated the findings with clinical parameters.

Section snippets

Patients

A total of 162 patients (59 men and 103 women) with MS, according to the recommended diagnostic criteria (McDonald et al., 2001), were recruited from the Department of Neurology, Kyushu University Hospital, the Department of Neurology, Hokkaido University Hospital, and the Hokuyukai Neurological Hospital. Hematological and biochemical studies and serologic tests for syphilis were performed in all patients and the results were not contributory. None of the patients was seropositive for human

PAFR genotype and allele frequencies in MS

The proportions of PAFR genotypes (AA, AD, and DD) and alleles (A allele, D allele) in MS patients and healthy controls are shown in Table 1. The frequency of the AD/DD genotypes was significantly higher in MS patients (21.0%) than in healthy controls (13.5%) (p=0.045; odds ratio (OR), 1.71; 95% confidence interval (CI), 1.01–2.89). In control subjects, the genotype frequencies are similar to those found in other Japanese studies (Fukunaga et al., 2001). Moreover, the frequency of D allele in

Discussion

In the present study, we disclosed a significant association between susceptibility for MS and the PAFR polymorphism that has a partial but significant reduction of PAF-induced intracellular signaling.

PAF is a proinflammatory mediator produced early in response to several immunological stimuli, including immune complexes and proinflammatory cytokines (Camussi et al., 1981, Valone and Epstein, 1988). Moreover, PAF itself mediates some of the biological effects exerted by cytokines, such as tumor

Acknowledgements

We thank Ms. N. Kinukawa (Department of Medical Information Science, Kyushu University Hospital) for help with statistical analyses. This work was supported, in part, by grants from the Ministry of Education, Science, Sports, and Culture of Japan, the Neuroimmunological Disease Research Committee, and the Ministry of Health and Welfare of Japan for Research on Brain Science.

References (29)

  • C. Confavreux et al.

    Relapses and progression of disability in multiple sclerosis

    N. Engl. J. Med.

    (2000)
  • S. Denault et al.

    Transcriptional activation of the interleukin-8 gene by platelet-activating factor in human peripheral blood monocytes

    Immunology

    (1997)
  • C. Dubois et al.

    Platelet-activating factor (PAF) enhances tumor necrosis factor production by alveolar macrophages. Prevention by PAF receptor antagonists and lipoxygenase inhibitors

    J. Immunol.

    (1989)
  • V.A. Fadok et al.

    Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-β, PGE2, and PAF

    J. Clin. Invest.

    (1998)
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