Shared and Distinct Genetic Variants in Type 1 Diabetes and Celiac Disease

Smyth, Deborah J.; Plagnol, Vincent; Walker, Neil M.; Cooper, Jason D.; Downes, Kate; Yang, Jennie H.M.; Howson, Joanna M.M.; Stevens, Helen; McManus, Ross; Wijmenga, Cisca; Heap, Graham A.; Dubois, P; Clayton, David; Hunt, Karen A.; Heel, David A. van; Todd, John A.

doi:10.1056/nejmoa0807917

Cited by 649 publications

(554 citation statements)

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“…Indeed, there are at least seven common genetic loci determining the susceptibility of both diseases. 3 However, this finding cannot explain several characteristics of the association between CD and T1D, for example, why T1D patients are more prone to develop CD than CD patients to develop T1D. 2 It is also unclear why patients with recently developed T1D have a higher likelihood of developing CD than patients with long-lasting T1D.…”

Section: Discussionmentioning

confidence: 99%

“…2 Both diseases are autoimmune in origin and develop as a result of complex pathological mechanisms, involving several common genetic, environmental and immunological factors. Among these, the common susceptibility loci of HLA and other immune system-related genes, 3 permeability changes in the small-bowel mucosa, 4 and association with wheat consumption 4,5 are prominent. Both diseases are increasing in most regions of the world, 6,7 as are several other autoimmune diseases, but the actual cause of the disease remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Celiac disease in patients with type 1 diabetes: a condition with distinct changes in intestinal immunity?

et al. 2011

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Two common chronic childhood diseases-celiac disease (CD) and type 1 diabetes (T1D)-result from complex pathological mechanisms where genetic susceptibility, environmental exposure, alterations in intestinal permeability and immune responses play central roles. In this study, we investigated whether these characteristics were universal for CD independently of T1D association. For this purpose, we studied 36 children with normal small-bowel mucosa and 26 children with active CD, including 12 patients with T1D. In samples from the small-bowel mucosa, we detected the lowest expression of tight junction protein 1 (TJP1) mRNA in CD patients with T1D, indicating an increase in intestinal permeability. Furthermore, these samples displayed the highest expression of forkhead box P3 (FoxP3) mRNA, a marker for regulatory T cells, as compared with other patient groups. At the same time, serum levels of IgA antibodies specific for the CD-related antigens deamidated gliadin and tissue transglutaminase (tTG) were the highest in CD patients with T1D. In contrast, no significant differences were found in IgA or IgG antibodies specific for bovine beta-lactoglobulin or Bifidobacterium adolescentis DSM 20083-derived proteins. There were also no differences in the transamidating activity of serum autoantibodies between patients and control individuals. Our results show that patients with T1D and newly detected CD exhibit severely altered intestinal permeability, strong local immune activation and increased immunoregulatory mechanisms in the small bowel. Further study is required to determine whether these extreme changes in this CD subgroup are due to some specific environmental factors (virus infections), unknown genetic effects or autoimmune reactions to antigenic targets in intracellular tight junctions. INTRODUCTIONWith an approximate prevalence of 1.0% in Western countries, celiac disease (CD) is one of the most common lifelong chronic disorders. 1 CD and type 1 diabetes (T1D) form a significant sector of childhood diseases with high rate of co-occurrence. 2 Both diseases are autoimmune in origin and develop as a result of complex pathological mechanisms, involving several common genetic, environmental and immunological factors. Among these, the common susceptibility loci of HLA and other immune system-related genes, 3 permeability changes in the small-bowel mucosa, 4 and association with wheat consumption 4,5 are prominent. Both diseases are increasing in most regions of the world, 6,7 as are several other autoimmune diseases, but the actual cause of the disease remains unknown. However, several recent studies have highlighted the role of environmental and social changes that have taken place over the last several decades. 8,9 The central event in the pathogenesis of CD is damage to the small intestinal mucosa that occurs after ingestion of gluten or related prolamins in genetically susceptible individuals. During this process, several morphological and immunological alterations have been demonstrated in the small-bowel mucos...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Celiac disease in patients with type 1 diabetes: a condition with distinct changes in intestinal immunity?

et al. 2011

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“…1,5,6 Therefore, we sought to test newly identified rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis, ankylosing spondylitis (AS) and Crohn's disease (CD) loci for association in T1D [7][8][9][10][11][12][13][14][15][16][17] with the assumption of an increased prior probability of association based on the previous evidence of overlapping risk alleles across autoimmune diseases. 18 We selected single nucleotide polymorphisms (SNPs) for genotyping that had shown a convincing evidence of association with at least one other autoimmune disease from genome-wide association scans published over the past 2 years. We genotyped SNPs from the genes: CD58 (rs12044852) which has been associated with multiple sclerosis; 8 STAT3 (rs3816769) which has been associated with CD; 7 IL1A (rs17561) and ERAP1, previously called ARTS1 (rs30187) which have been associated with AS; 15,17 MMEL1-TNFRSF14 (rs3890745), CDK6 (rs42041), the 7q23 gene desert (rs11761231), CCL21 (rs2812378), TRAF1/C5 (rs3761847), KIF5A(rs1678542) and CD40 (rs4810485), which have been associated with RA; 7,12,19 BANK1 (rs10516487), FAM167A previously called C8orf13 (rs13277113) and ITGAM (rs9888739) which have been associated with SLE [9][10][11]20 and STAT4 (rs7574865) and TNFAIP3 (rs6920220 and rs10499194) which have been associated with both RA and SLE 13,14,16,21,22 (See Table 1 for full gene names).…”

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confidence: 99%

Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus

et al. 2008

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“…4 -7 Studies on T1D suggested that the IL2RA association with this disease could be narrowed down to three independent haplotypic blocks spanning a genomic region around the 5 0 end of gene. 4,15,17,22 In this regard, the IL2RA genetic variants that we have analysed (rs11594656, rs12722495 and rs2104286) represent the highest association signals for T1D susceptibility that best define the common disease-associated IL2RA haplotypes, and it has been hypothesised that the causative variants of these associations may alter the protein levels. 22 However, heterogeneity in the genetic associations has been observed between T1D and multiple sclerosis at the IL2RA region, and there are evidences pointing to a correlation between multiple IL2RA variants and sIL-2RA levels independently.…”

Section: Discussionmentioning

confidence: 99%

The autoimmune disease-associated IL2RA locus is involved in the clinical manifestations of systemic sclerosis

et al. 2011

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Regulatory T cells (T regs ) are crucial in the maintenance of the immune tolerance and seem to have an important role in systemic sclerosis (SSc). The interleukin 2 receptor a (IL2RA) is an important T reg marker, and polymorphisms of IL2RA gene are associated with a number of autoimmune diseases. Therefore, we aimed to investigate for the first time the association of the IL2RA locus in SSc. For this purpose, a total of 3023 SSc patients and 2735 matched healthy controls, from six European Caucasian cohorts, were genotyped for the IL2RA gene variants rs11594656, rs2104286 and rs12722495 using the TaqMan allelic discrimination technology. The overall meta-analysis reached statistical significance when the three polymorphisms were tested for association with SSc, the limited subtype (lcSSc) and anti-centromere auto-antibodies (ACAs). However, no significant P-values were obtained when the ACA-positive patients were removed from the SSc and lcSSc groups, suggesting that these associations rely on ACA positivity. The strongest association signal with ACA production was detected for rs2104286 (P FDR ¼ 2.07 Â 10 À4 , odds ratio ¼ 1.30 (1.14 -1.47)). The associations of rs11594656 and rs12722495 were lost

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Shared and Distinct Genetic Variants in Type 1 Diabetes and Celiac Disease

Abstract: BACKGROUND-The inflammatory disorders type 1 diabetes (T1D) and celiac disease cosegregate in populations, suggesting a common genetic origin. Both are associated with the HLA class II genes on chromosome 6p21, and the present paper tested whether non-HLA loci are shared.

Cited by 649 publications

References 35 publications

Celiac disease in patients with type 1 diabetes: a condition with distinct changes in intestinal immunity?

Celiac disease in patients with type 1 diabetes: a condition with distinct changes in intestinal immunity?

Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus

The autoimmune disease-associated IL2RA locus is involved in the clinical manifestations of systemic sclerosis

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