Tatsuo Yanagawa

CTLA-4 gene polymorphism may modulate disease in Japanese multiple sclerosis patients

Multiple sclerosis (MS) is widely believed to have a T-cell-mediated autoimmune etiology. The CTLA-4 gene is a strong candidate for involvement in autoimmune diseases because it plays an important role in the termination of T-cell activation. To examine the genetic association of the CTLA-4 gene locus with MS, we analyzed the CTLA-4 gene exon 1 A/G polymorphism in 74 Japanese MS patients and 93 controls. We also investigated the possible interactions of the CTLA-4 gene polymorphism with clinical course and severity, with MRI findings, with another genetic marker-HLA antigens, and with oligoclonal bands (OCB) in the cerebrospinal fluid (CSF). The CTLA-4 exon 1 polymorphism was similar between MS patients and controls. Conversely, clinical disability was significantly more severe in AA homozygous patients than in the other patients, and the allele frequency and the phenotype frequency of the A allele were significantly higher in patients with severe-grade MRI findings of cerebral white matter than in patients with mild-grade MRI findings. The allele frequency and the phenotype frequency of the A allele were significantly higher in patients with OCB than in patients without. This CTLA-4 polymorphism may modulate the prognosis of patients with MS and may be relevant to generation of OCB in the CSF.

Vitamin D receptor initiation codon polymorphism influences genetic susceptibility to type 1 diabetes mellitus in the Japanese population

BackgroundVitamin D has been shown to exert manifold immunomodulatory effects. Type 1 diabetes mellitus (T1DM) is regarded to be immune-mediated and vitamin D prevents the development of diabetes in the NOD mouse. We studied the association between T1DM and the initiation codon polymorphism in exon 2 of the vitamin D receptor gene in a Japanese population. We also investigated associations between the vitamin D receptor polymorphism and GAD65-antibody (Ab) positivity. We carried out polymerase chain reaction-restriction fragment length polymorphism analysis in 110 Japanese T1DM patients and 250 control subjects. GAD65 antibodies were assessed in 78 patients with T1DM.ResultsWe found a significantly higher prevalence of the F allele / the FF genotype in the patients compared to the controls (P = 0.0069 and P = 0.014, respectively). Genotype and allele frequencies differed significantly between GAD65-Ab-positive patients and controls (P = 0.017 and P = 0.012, respectively), but neither between GAD65-Ab-negative patients and controls (P = 0.68 and P = 0.66, respectively) nor between GAD65-Ab-positive and -negative patients (P = 0.19 and P = 0.16, respectively).ConclusionsOur findings suggest that the vitamin D receptor initiation codon polymorphism influences genetic susceptibility to T1DM among the Japanese. This polymorphism is also associated with GAD65-Ab-positive T1DM, although the absence of a significant difference between GAD65-Ab-negative patients and controls might be simply due to the small sample size of patients tested for GAD65 antibodies.

Lack of association between CTLA-4 gene polymorphism and IDDM in Japanese subjects

Susceptibility to insulin-dependent diabetes mellitus (IDDM) is determined by both environmental and genetic factors. The main gene associated with predisposition to IDDM is HLA. Recent studies have described linkage and association of IDDM to the CTLA-4 gene (IDDM12) in Caucasians. CTLA-4 is a candidate gene for T-cell-mediated autoimmune diseases because it is a negative regulator of T-cell proliferation. We investigated the distribution of a CTLA-4 gene polymorphism in 110 Japanese patients with IDDM and 200 control subjects. In 84 patients, we also investigated associations between this CTLA-4 gene polymorphism and GAD65 antibody positivity. An A/G transition at position 49 of exon 1 was analyzed by the polymerase chain reaction-restriction fragment length polymorphism method. GAD65 antibody was detected using a radioligand binding assay. There was no significant difference in the distribution of CTLA-4 alleles in patients and controls and no difference was observed in prevalence of CTLA-4 alleles when GAD65 antibody-positive and -negative individuals in the IDDM groups were compared. The present study did not support an association between the CTLA-4 gene and IDDM in the Japanese population.

No association of type 1 diabetes with a microsatellite marker for CTLA-4 in a Japanese population.

Susceptibility to insulin-dependent (type 1) diabetes mellitus is determined by both environmental and genetic factors. The primary gene associated with predisposition to type 1 diabetes is the human leukocyte antigen (HLA) class II gene (IDDM1). Recent studies have described linkage and association of type 1 diabetes to the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene (IDDM12)m Caucasians. CTLA-4 is a candidate gene for T-cell-mediated autoimmune diseases because it is a negative regulator of T-cell proliferation. We investigated distribution of a CTLA-4 (AT)n microsatellite marker in 118 Japanese patients with type 1 diabetes and 195 control subjects. We also investigated association between this CTLA-4 gene polymorphism and GAD65 antibody positivity in 103 of the patients. CTLA-4 microsatellite marker loci were determined by polymerase chain reaction amplification of genomic DNA and resolution of the products on sequencing gels. GAD65 antibody was detected by radioligand binding assay. There was no significant difference in the distribution of CTLA-4 alleles between patients and controls, and no difference was observed in the prevalence of CTLA-4 alleles when GAD65 antibody-positive and -negative individuals with the type 1 diabetes were compared. The present study did not support an association between the CTLA-4 microsatellite marker and type 1 diabetes in our Japanese study population

CTLA-4 Gene in the Pathogenesis of Graves’ Disease

There is growing evidence that CTLA-4 is an important susceptibility gene in Graves’ disease (GD), as well as in many other autoimmne diseases. We have the honor of being pioneers in this field, and our data and others are presented in this paper.