The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency

Haimila, Katri; Einarsdottir, Elisabet; Kauwe, Andrea de; Koskinen, Lotta; Pan‐Hammarström, Qiang; Kaartinen, Tanja; Kurppa, Kalle; Ziberna, Fabiana; Not, Tarcisio; Vatta, Serena; Ventura, Alessandro; Korponay-Szabó, Ilma Rita; Ádány, Róza; Pocsai, Zsuzsa; Széles, György; Dukes, Emma; Kaukinen, Katri; Mäki, Markku; Koskinen, Sinikka; Partanen, Jukka; Hammarström, Lennart; Saavalainen, Päivi

doi:10.1038/gene.2008.89

Cited by 44 publications

(21 citation statements)

References 53 publications

(57 reference statements)

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“…A variety of studies found elevated levels of the soluble CTLA-4 protein in the plasma of patients with a variety of immunologically mediated diseases (Magistrelli et al, 1999). Polymorphisms in CTLA-4 have been associated with several autoimmune diseases including type 1 diabetes, inflammatory bowel disease, RA, celiac disease, multiple sclerosis, and systemic lupus erythematous (Haimila et al, 2009;Plant et al, 2010;Rai and Wakeland al., 2011). Two SNPs may influence the cell surface expression of the CTLA-4 molecule: -318C/T in the promoter region (rs5742909) and +49A/G in the first exon (rs231775).…”

Section: Discussionmentioning

confidence: 99%

CTLA-4 and CD86 genetic variants and haplotypes in patients with rheumatoid arthritis in southeastern China

Liu

Jiang²,

Wang³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. The cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and costimulatory molecule (CD80/CD86) genes are important susceptibility genes associated with autoimmune diseases. CTLA-4 polymorphisms have been found to be associated with various autoimmune diseases. However, the association data are inconsistent for rheumatoid arthritis (RA). We investigated the genetic association of CTLA-4 and CD86 polymorphisms with RA in a Chinese population. Four single nucleotide polymorphisms (SNPs) (rs5742909 and rs231775 in CTLA-4, and rs17281995 and rs1129055 in CD86) were genotyped in 213 patients with RA and 303 healthy controls using polymerase chain reaction-restriction fragment length polymorphism. The genotype and allele distributions of rs5742909 differ significantly between RA patients and controls (P < 0.05) and the dominant model was found to be the best inheritance model. Stratification studies showed that CTLA-4 gene polymorphisms were more significantly associated with rheumatoid factor-negative and anti-cyclic citrullinated peptide-negative subgroups in the southeastern Han Chinese population. We also found that the haplotype of 2 CTLA-4 SNPs showed significant association with the disease (P = 0.0025) with the T-A (OR = 1.88, 95%CI = 1.12-3.15) and T-G (OR = 3.45, 95%CI = 1.10-10.87) haplotypes being observed more frequently in cases than in controls. We failed to find any significant association of the 2 CD86 SNPs with RA. These results indicate that the polymorphisms of CTLA-4 (rs5742909) may be important genetic factors for RA risk in the southeastern Han Chinese population.

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Section: Discussionmentioning

confidence: 99%

CTLA-4 and CD86 genetic variants and haplotypes in patients with rheumatoid arthritis in southeastern China

Liu

Jiang²,

Wang³

et al. 2013

Genet. Mol. Res.

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“…This region also contains the candidate CTLA4/ICOS genes, approximately 20 Mb apart, extensively studied in relation to CD due to their role in T-lymphocyte activity regulation, and recently associated with CD susceptibility in a population with proven linkage. 8 The PPP6C and PBX3 loci are located in 9q. This region showed linkage to CD in the North American population 9 but, in contrast to 2q33, no replication has been reported.…”

Section: Resultsmentioning

confidence: 99%

Lack of replication of celiac disease risk variants reported in a Spanish population using an independent Spanish sample

et al. 2009

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Celiac disease (CD) is an inflammatory condition affecting small bowel and triggered by gluten (or related proteins) ingestion in genetic susceptible individuals. Polymorphisms in three genes, SERPINE2, PPP6C and PBX3, have recently been associated with CD in the Spanish population. However, this association could not be replicated in the UK population using imputed data. As this second study analyzed a different population, we aimed at reevaluating the role of those polymorphisms using an independent Spanish sample. We genotyped three single nucleotide polymorphisms: rs6747096 in SERPINE2, rs458046 in PPP6C and rs7040561 in PBX3, in 417 CD patients, 527 ethnically matched healthy controls and parents of 304 CD patients. A case-control study using the w 2 -test and a familial study using the transmission disequilibrium test were performed. No association was detected in those analyses. Therefore, our results seem to discard the role of the previously described polymorphisms in SERPINE2, PPP6C and PBX3 in CD susceptibility. IntroductionCeliac disease (CD) is a complex disease mediated by immune processes triggered after ingestion of gluten or related proteins in genetically susceptible individuals. 1 The genetic basis of this disease is being slowly unraveled by advances in experimental techniques. Combining two different gene-search approaches, Castellanos-Rubio et al. 2 reported new CD risk variants in the Spanish Basque population. They combined information provided by whole-genome expression profiling experiments and linkage studies (that is, functional and positional information) and found significant association with four single nucleotide polymorphisms (SNPs) located in the SERPINE2 (serine protease inhibitor, clade E, member 2), PPP6C (protein phosphatase 6, catalytic subunit) and PBX3 (pre-B-cell leukemia homeobox 3) genes.The SERPINE2 gene maps in the CD linkage region 2q33-q35 and PPP6C and PBX3 in 9q33-q34. SERPINE2 is involved in extracellular matrix production and it has been widely studied in relation to COPD (chronic obstructive pulmonary disease). 3 PPP6C encodes a protein phosphatase which seems to be involved in cell-cycle regulation. 4 Finally, PBX3 is a transcription factor implicated in basic developmental functions, including some related to immune cells. 5 The association between those genes and CD susceptibility described by Castellanos-Rubio et al. was questioned by Hunt et al., 6 who used data from a genome-wide association study performed in the British population to impute data corresponding to the previously associated SNPs. No replication was obtained and the authors suggested different possible explanations. Therefore, the debate is open because for every SNP the imputation is not 100% accurate, an issue recently discussed. 7 As an explanation of the observed discrepancies between the two studies could be owed to population or clinical heterogeneity, we aimed at evaluating the role of those SNPs in an independent Spanish sample of pediatric typical CD patients. Results and discuss...

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“…The etiology of this disease is still unknown; several studies have shown the important association of certain HLA alleles with IgAD, although the specific location of the gene/s involved is controversial [3][4][5]. However, the HLA genetic component cannot explain the totality of the genetic influence on the disease, and very few additional genes have been associated with this immunodeficiency [6,7].…”

Section: Introductionmentioning

confidence: 99%

Lack of evidence of a role of XBP1 and PRDM1 polymorphisms in Spanish patients with immunoglobulin A deficiency

et al. 2009

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The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency

Cited by 44 publications

References 53 publications

CTLA-4 and CD86 genetic variants and haplotypes in patients with rheumatoid arthritis in southeastern China

CTLA-4 and CD86 genetic variants and haplotypes in patients with rheumatoid arthritis in southeastern China

Lack of replication of celiac disease risk variants reported in a Spanish population using an independent Spanish sample

Lack of evidence of a role of XBP1 and PRDM1 polymorphisms in Spanish patients with immunoglobulin A deficiency

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