CTLA4 polymorphisms in Spanish patients with rheumatoid arthritis

González‐Escribano, María Francisca; Rodríguez, R. M. Jiménez; Valenzuela, A.; García, Alicia; García-Lozano, José R.; Núñez‐Roldán, Antonio

doi:10.1034/j.1399-0039.1999.530311.x

Cited by 94 publications

(57 citation statements)

References 19 publications

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“…Initial comparison showed an increased frequency of the +49 A/G*A allele in the RA group (data not shown). As the majority of studies reporting disease association with this SNP hint towards increased frequency of the G allele (Cai et al, 2005;Lee et al, 2003;Vaidya et al, 2002;Yanagawa et al, 2000;Matsushita et al, 1999;Gonzalez-Escribano et al, 1999;Seidl et al, 1998), we wondered whether the association seen in our study could be due to any idiosyncratic characteristics specific to this control population (168 healthy blood donors). Therefore, + 49 A/G distribution in a second, distinctive Northern Irish control population consisting of 307 Northern Irish 12 to 15-year-old school children was compared to that in Group 1.…”

Section: Resultsmentioning

confidence: 87%

“…The authors of the latter study also found the G allele of this SNP to be associated with lower mRNA levels of soluble CTLA-4 isoform, thus providing a rationale for a functional role in susceptibility to autoimmune diseases. Table 1 summarizes all the studies that have been done to date investigating the effects of CTLA-4 gene in RA (Cai et al, 2005;Lee et al, 2003;Rodríguez et al, 2002;Vaidya et al, 2002;Hadj Kacem et al, 2001;Yanagawa et al, 2000;Matsushita et al, 1999;Gonzalez-Escribano et al, 1999;Seidl et al, 1998;Orozco et al, 2004;Lee et al, 2002;Barton et al, 2000;Milicic et al, 2001). Results have been conflicting with some studies hinting towards association with RA, while others claiming to find no association at all.…”

Section: Introductionmentioning

confidence: 99%

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The CTLA4 + 49A/G and CT60 polymorphisms and chronic inflammatory arthropathies in Northern Ireland

Suppiah

O’Doherty

Heggarty

et al. 2006

Experimental and Molecular Pathology

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Rheumatoid and juvenile idiopathic arthritis (RA, JIA) are chronic inflammatory arthropathies with an autoimmune background. The cytotoxic T-lymphocyte antigen-4 (CTLA-4) protein plays a key role in the down-regulation of T cell activation.We analyzed the CTLA4 +49A/G and CT60 polymorphisms in cohorts of Northern Irish RA and JIA patients and healthy control subjects using restriction fragment length polymorphism methods.The +49 A allele was increased in RA (61.2%; P = 0.02; OR = 1.28; 95% C.I. = 1.04 -1.58) and JIA (61.8%; P = 0.14) patients compared to the control population (55.3%). No significant association was observed for the CT60 polymorphism. Haplotype analysis revealed a significantly different distribution of +49 A/G-CT60 haplotypes in RA and JIA patients compared to controls ( P value < 0.00001 and 0.030 for comparison of RA and JIA patients with controls, respectively).Our results suggest that the CTLA-4 gene is involved in predisposition to inflammatory arthropathies in the Northern Irish population. D

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Section: Resultsmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

The CTLA4 + 49A/G and CT60 polymorphisms and chronic inflammatory arthropathies in Northern Ireland

Suppiah

O’Doherty

Heggarty

et al. 2006

Experimental and Molecular Pathology

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“…4 Homozygosity for −318/T in the promoter of Ctla-4 is rarely present in a Caucasian population. [4][5][6][7] In our previous study, the frequencies of individuals with genotypes −318C/C, C/T, and T/T were 86%, 17% and 0%, respectively, in healthy individuals (n = 122) and 69%, 31%, 0%, respectively, in patients with Wegener's granulomatosis (n = 32). When we considered the prevalence of longer (AT)n in the 3Ј-untranslated region together with the promoter single nucleotide polymorphism (SNP), we found that all patients carrying the −318T allele were homozygous for (AT)n Ͼ86 bp alleles.…”

Section: Resultsmentioning

confidence: 99%

A CTLA-4 gene polymorphism at position −318 in the promoter region affects the expression of protein

et al. 2002

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Sweden CTLA-4 is an important negative regulator of the immune system. The regulation of the CTLA-4 gene (Ctla-4) transcription is poorly understood. A single nucleotide polymorphism (SNP) at −318 in the Ctla-4 promoter region is associated with certain autoimmune diseases. Since the −318 SNP occurs in a potential regulatory region, it is conceivable that the CЈ T transition may affect the expression of In the present study, we show that the −318T allele is associated with a higher promoter activity than the −318C allele (8.13 ± 0.46 vs 6.87 ± 0.49 CTLA-4 plays an important role in the immune system as a T cell inhibitory factor. This inhibitory signal not only determines whether T cells become activated, but also affects the clonal representation in an immune response. CTLA-4 regulates cell cycle progression rather than directly the induction of apoptosis. 1 CTLA-4 Ig and anti-CTLA-4 have been applied for the treatment of both autoimmune diseases and cancers.Little is known about the regulatory mechanism for CTLA-4 expression. Polymorphisms in the Ctla-4 are associated with several autoimmune diseases, and polymorphisms at certain locations of the Ctla-4 might conceivably affect its expression. We have described a higher prevalence of thymine at position −318 of the Ctla-4 promoter (−318T) in patients with Wegener's granulomatosis. 2 Recently, Ligers and colleagues reported that individuals carrying −318T exhibited significantly increased expression both of cell-surface CTLA-4 in activated cells and of Ctla-4 mRNA in non-stimulated cells, 3 suggesting a potential role for the CЈ T transition in the regulation of expression. In the present study, we examined the effect of CЈ T switch at −318 on the Ctla-4 promoter activity. Our results demonstrated that the −318T allele was associated with a significantly higher promoter activity than the −318C allele. Results and discussionTo determine whether the CЈ T transition at position −318 transcriptionally regulates the Ctla-4 gene expression, we made two Ctla-4 promoter reporter constructs which contained C and T alleles, respectively. As shown in Figure 1, the −318T allele was associated with a higher promoter activity than the −318C allele (8.13 ± 0.46 vs 6.87 ± 0.49). This result was also confirmed in the THP-1 cell line transfected with these two reporter constructs, and stimulated with IFN-␥ (5 mg/ml) and PMA (10 ng/ml).Our allele-specific transcription data indicate that the −318T allele is associated with higher transcriptional activity than the −318C allele. The -318T allele could be considered as protective against autoimmune reactions. Our results could explain the increased expression of CTLA-4 3 and the observed associations of the −318T allele to some diseases. 4 Homozygosity for −318/T in the promoter of Ctla-4 is rarely present in a Caucasian population. [4][5][6][7] In our previous study, the frequencies of individuals with genotypes −318C/C, C/T, and T/T were 86%, 17% and 0%, respectively, in healthy individuals (n = 122) and 69%, 31%, 0%, respective...

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“…Recent research indicates that several of the non-HLA regions linked to Type I diabetes also show linkage to other autoimmune diseases, suggesting common pathogenic pathways shared by Type I diabetes and these other disorders [127,128]. For example, the IDDM3 region on chromosome 15q26 has been reported to be linked to coeliac disease [129,130], the IDDM6 region on chromosome 18q21 has been reported to be linked to Graves disease [131] as well as multiple sclerosis and rheumatoid arthritis [69], the IDDM8 region on chromosome 6q27 has been reported to be linked to rheumatoid arthritis [132], the IDDM12 (CTLA4) region on chromosome 2q33 has been reported to be linked to coeliac disease [133,134], Graves disease [78,135], multiple sclerosis [136] and rheumatoid arthritis [137,138], the IDDM16 region on chromosome 14q32 has been reported to be linked to multiple sclerosis [139], and the chromosome 1q42 region containing an unnamed diabetes locus has been reported to be linked to systemic lupus erythematosus [140,141] (for additional examples, see [128]). Although some of these co-localizations could be coincidental, the possibility remains that at least a few IDDM loci would be more accurately called autoimmunity susceptibility loci.…”

Section: Is Positional Candidate Mapping Feasible?mentioning

confidence: 99%

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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CTLA4 polymorphisms in Spanish patients with rheumatoid arthritis

Cited by 94 publications

References 19 publications

The CTLA4 + 49A/G and CT60 polymorphisms and chronic inflammatory arthropathies in Northern Ireland

The CTLA4 + 49A/G and CT60 polymorphisms and chronic inflammatory arthropathies in Northern Ireland

A CTLA-4 gene polymorphism at position −318 in the promoter region affects the expression of protein

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

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