CTLA4 gene polymorphism correlates with the mode of onset and presence of ICA512 Ab in Japanese Type 1 diabetes

Abe, Takahiro; Takino, Hirofumi; Yamasaki, Hironori; Ozaki, Masako; Sera, Yoshihisa; Kondo, Hideaki; Sakamaki, Hiroyuki; Kawasaki, Eiji; Awata, Takuya; Yamaguchi, Yoshihiko; Eguchi, Katsumi

doi:10.1016/s0168-8227(99)00084-4

Cited by 41 publications

(35 citation statements)

References 29 publications

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“…The findings were similarly negative in the Belgian and Swedish surveys, where the CTLA4 3′ UTR (AT)n microsatellite was used as genetic marker [7,24]. However, IA-2A and CTLA4+49 A/G were reported to be associated with type 1 diabetes in Japanese patients, but this observation might be secondary to the increased prevalence of autoimmune thyroid disease among the patients included in that study [25]. Our findings indicate that the two polymorphisms in the CTLA4 region studied have no major role in type 1 diabetes-related humoral autoimmunity, the statistical power of the analysis being more than 90% to detect a hazard ratio of 1.6; α=0.05.…”

Section: Discussionmentioning

confidence: 61%

“…Data on the effect of the CTLA4 gene region on beta cell autoimmunity are similarly ambiguous. The CTLA4-3′(AT)n microsatellite and the +49A/G polymorphism showed no association with humoral autoimmunity in Swedish and Belgian cohorts, whereas IA-2A showed association with the G allele of the +49A/G polymorphism in a Japanese study [7,24,25].…”

Section: Introductionmentioning

confidence: 85%

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The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

et al. 2005

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Aims/hypothesis: The aim of this study was to explore the contribution of genetic factors to the emergence of beta-cell-specific humoral autoimmunity. Subjects and methods: We analysed the effect of HLA class II, insulin (INS; −23 HphI variant) and cytotoxic T-lymphocyteassociated protein 4 (CTLA4 [+49 and CT60]) genes on the appearance of beta-cell-specific autoantibodies in a large population-based birth cohort recruited in Finland. Infants carrying increased risk HLA DQB1 genotypes were monitored for the appearance of autoantibodies (islet cell autoantibodies [ICA], insulin autoantibodies [IAA], glutamic acid decarboxylase autoantibodies [GADA] and islet antigen 2 antibodies ). Those who developed betacell-specific autoantibodies were studied (n=574, mean follow-up time: 4.9 years; range 0.5-9.3). Results: IAA emerged at a higher rate in children with the −23 HphI AA INS genotype than in those carrying AT or TT variants (hazard ratio 2.1, 95% CI 1.4-2.9, p<0.001). This effect of the INS locus was present in both HLA DQB1 risk groups. The appearance of IAA showed a strong association also with the HLA DRB1*0401 allele (hazard ratio 13.1, 95% CI 1.8-93.4, p<0.001). The development of IA-2A was also somewhat accelerated by the DRB1*0401 variant (p=0.03). Isolated ICA positivity was independent of the HLA and INS genotypes. None of the humoral immune markers showed association with the CTLA4 gene. Conclusions/interpretation: The INS and the DRB1 loci appear to contribute to the pathogenesis of type 1 diabetes by initiating/modifying insulin-specific autoimmunity. The emergence of IAA represents a crucial step in the development of beta cell autoimmunity in young children, in whom the appearance of GADA and IA-2A is linked to IAA.

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Section: Discussionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 85%

The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

et al. 2005

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“…3 These results were confirmed in other populations such as Asians, populations of European ancestry, and Mexican-Americans. [11][12][13][14][15][16] Nevertheless, in other studies with populations of European ancestry, no evidence of association was found. [17][18][19][20] Recently, an association with a novel polymorphism at position 159 has been found in West African populations, but not in Chinese.…”

Section: Introductionmentioning

confidence: 78%

Association of the CTLA4 promoter region (−1661G allele) with type 1 diabetes in the South Moroccan population

et al. 2003

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The contribution of the candidate gene CTLA4 to type 1 diabetes is not well established. Although several polymorphisms have been repeatedly associated to the disease, several studies have not confirmed the association. The joint analysis of three SNPs in the CTLA4 promoter region (À1722, À1661, and À319), one SNP in the first exon (+49), and one dinucleotide repeat in the 3 0 untranslated region, in a case-control study in a North African population, shows a strong association of the CTLA4 region with the disease. The À1661G allele showed a significant association with an odds ratio of 2.13. Moreover, the internal structure of the dinucleotide repeat has been deeply analyzed. The present results reveal the importance of polymorphisms in the CTLA4 promoter region, their probable role in gene expression and, ultimately, their relation to the etiology of type 1 diabetes. Previous contradictory association studies might be due to the effect of linkage disequilibrium between the polymorphism analyzed and the alteration within the CTLA4 region. This alteration may be different depending on the genetic background of the population. The present work stresses the need to perform exhaustive analysis of the promoter region polymorphisms in order to detect association with the disease.

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“…170 There is a microsatellite marker in the 3ЈUTR of the CTLA4 sequence, and several polymorphisms have been detected at CTLA4. 39 These polymorphisms, in particular the exon 1 (49 GϾA) SNP, have been investigated by TDT analysis in several populations, 41,140,[171][172][173][174][175][176][177][178][179][180][181][182][183][184][185][186] and combined data sets from these large studies support linkage of the CTLA4 locus to T1D. 168,171,187 Interestingly, some evidence has also been produced to suggest that CTLA4 polymorphisms may influence gene expression.…”

Section: Iddm2-the Insulin Gene (Ins) Regionmentioning

confidence: 99%

Genetics of type 1 diabetes mellitus

2002

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CTLA4 gene polymorphism correlates with the mode of onset and presence of ICA512 Ab in Japanese Type 1 diabetes

Cited by 41 publications

References 29 publications

The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

Association of the CTLA4 promoter region (−1661G allele) with type 1 diabetes in the South Moroccan population

Genetics of type 1 diabetes mellitus

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