Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups

Marron, Michele P.; Raffel, Leslie J.; Garchon, Henri Jean; Jacob, Chaim O.; Serrano-Rı́os, Manuel; Larrad, Maria Teresa Martínez; Teng, Wei Ping; Park, Yong Soo; Zhang, Zhi Xing; Goldstein, Darlene R.; Tao, Yi; Beaurain, Geneviève; Bach, Jean François; Huang, Huei-Jean; Luo, De Fang; Zeidler, Adina; Rotter, Jerome I.; Yang, Mark C. K.; Modilevsky, Tamara; Maclaren, Noel K.; She, Jin‐Xiong

doi:10.1093/hmg/6.8.1275

Cited by 356 publications

(259 citation statements)

References 37 publications

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“…This result is consistent with the absence of association of this marker with T1D in West Africans 21 and Asians. 11,13,19 The absence of association between different alleles of the dinucleotide (AT) repeat and the level of CTLA4 expression as well as the stability of CTLA4 mRNA has been reported. 25 Therefore, the differences of frequencies found for the smallest allele (allele 7) of the (AT) n repeat in our population and the previously observed association between T1D and longer alleles may be the result of LD between specific microsatellite alleles and the true etiological factor of susceptibility.…”

Section: Discussionmentioning

confidence: 99%

“…[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. And conversely, the CTLA4+49 (A-G) marker conferred a risk of T1D in Chinese but not in west Africans.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2003

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“…IDDM12 was mapped by linkage (MLS 3.2), and by association with CTLA4 in Italian and Spanish datasets (combined p value 0.0001) but not in American, British or Sardinian datasets [76]. It was confirmed by demonstration of highly significant association with an A/G (Thr/Ala) polymorphism in exon 1 of CTLA4 in 669 multiplex and 357 simplex families (p = 0.00 005) [77]. Again, there was marked population heterogeneity for this association: Italian, Spanish, French, Mexican, and Korean samples showed significantly increased transmission of the G allele to diabetics, while British, Sardinian, Chinese, and European-Americans showed little or no increased transmission of this allele.…”

Section: Is Positional Candidate Mapping Feasible?mentioning

confidence: 92%

Genetic linkage and association studies of Type I diabetes: challenges and rewards

Field

2002

Diabetologia

104

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Type I diabetes (formerly called insulin-dependent diabetes mellitus) results from the autoimmune destruction of the insulin-producing beta cells of the pancreas. It is now known that Type I diabetes is a genetically complex disease, i. e. a disease caused by multiple genes interacting with non-genetic (environmental and stochastic) factors. Family studies have clearly shown a genetic basis but inheritance of the disease does not follow a simple mendelian single-locus pattern. Population and family studies also suggest that most (perhaps all) affected individuals are genetically predisposed to Type I diabetes, particularly through HLA region genes. However, non-genetic factors appear to be required to precipitate the disease in these genetically susceptible persons because in monozygote (MZ) twin pairs in which one twin has Type I diabetes the MZ twin concordance rate is less than 100 %. It is not clear whether there are any purely genetic cases of Type I Diabetologia (2002) AbstractFamily and twin studies have shown clearly that Type I (insulin-dependent) diabetes mellitus has a genetic basis. However, only within the past decade has it been possible to systematically attempt to identify the genes that increase susceptibility to this disorder using linkage and association analysis of genetic markers distributed across the genome. More than 20 putative diabetes-predisposing genes have been localised in addition to HLA region susceptibility genes detected more than 25 years ago. Unfortunately, the effects of most diabetes-predisposing genes are weak, with the exception of HLA region susceptibility genes (which contribute about half of the genetic risk). The overall effects of diabetes-predisposing genes could be weak because the susceptibility gene occurs in only a small proportion of diabetic patients or the susceptibility gene (although it might be common) produces only a modest increase in risk, probably by acting in concert with other such genes to cause disease. The weak effects of these genes have made them difficult to locate, difficult to confirm in independent studies and difficult to isolate by genetic procedures. This paper summarizes the major challenges that have faced geneticists in mapping Type I diabetes genes, and reviews the progress achieved to date. The rewards of the genetic studies will be twofold: increased understanding of the causes of Type I diabetes, facilitating creation of preventative therapies, and enabling clinicians in the future to use genetic information to predict which children are predisposed to diabetes in order to target them for preventative therapies. [Diabetologia (2002) 45: 21±35]

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“…The insulin gene (INS; IDDM2) and the cytotoxic T-lymphocyteassociated protein 4 (CTLA4) gene regions (IDDM12) are considered as confirmed non-HLA disease susceptibility loci [12][13][14][15][16]. Short (class I) alleles of the insulin gene 5′ variable number of tandem repeats (VNTR) are associated with increased type 1 diabetes susceptibility fitting an allele dosage model, while long class III alleles confer protection [17].…”

Section: Introductionmentioning

confidence: 99%

“…Short (class I) alleles of the insulin gene 5′ variable number of tandem repeats (VNTR) are associated with increased type 1 diabetes susceptibility fitting an allele dosage model, while long class III alleles confer protection [17]. In the CTLA4 region, a number of variants, like the +49A/G, have shown disease association in various ethnic groups, while the CT60 polymorphism was identified as a candidate causative disease variant [14][15][16]18].…”

Section: Introductionmentioning

confidence: 99%

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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Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups

Cited by 356 publications

References 37 publications

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

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

Genetic linkage and association studies of Type I diabetes: challenges and rewards

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

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