The R30Q DLG5 variant is not associated with celiac disease or inflammatory bowel disease in the Spanish population.

Alterations in intestinal epithelial permeability could underlie inflammatory bowel disease (IBD) and celiac disease (CeD) etiology, as supported by previous association studies. One related gene, DLG5 [discs, large homologue 5 (Drosophila)], has been associated with IBD in several populations and with CeD in the Dutch population. We tried to confirm the involvement of DLG5 in CeD performing a case-control study (725 CeD patients and 803 controls) by analysing the R30Q variant (rs1248696). Genetic frequencies did not significantly differ between groups (P > 0.80) and the meta-analysis with the Dutch data did not show any association. Additionally, we evaluated the effect of R30Q in IBD risk (858 patients), as discordant results were previously obtained. No association was detected. Our study does not support the effect of the R30Q DLG5 variant in CeD or IBD predisposition in the Spanish population.

Celecoxib in a 12-year-old boy with familial adenomatous polyposis.

Familial Adenomatous Polyposis (FAP) is an autosomal dominant disorder characterized by colonic polyps in early adult life. Children with this disease are at risk for colonic cancer, so prophylactic colectomy is the standard treatment to prevent this complication. Chemoprevention experience with NSAIDs in children is exceptional. This case report describes our experience with Celecoxib, a COX-2 inhibitor, in a 12-year-old boy.

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

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 chi(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.

Association of IL18RAP and CCR3 with coeliac disease in the Spanish population.

BACKGROUND AND AIMS: Genome-wide association studies in coeliac disease (CD) have resulted in the finding of eight new genetic regions associated with disease susceptibility. However, a replication study performed in the Italian population could not confirm two of those new regions: 2q12 (IL18RAP) and 3p21 (CCR3). The aim of this study was to investigate the role of those regions in CD risk in a different Mediterranean population, the Spanish population. METHODS: A case-control study with 722 patients with CD and 794 ethnically matched healthy controls was performed. Two single-nucleotide polymorphisms, rs917997 (2q12) and rs6441961 (3p21), were genotyped and their genetic frequencies were compared between both groups using the chi(2) test. RESULTS: An association was found with rs6441961 (p = 0.0004, OR = 1.32, 95% CI 1.13 to 1.54). A non-significant result (but concordant with the initial study) was obtained for rs917997. CONCLUSION: The association of the 3p21 genetic region with CD susceptibility in the Spanish population was confirmed. In 2q12, the initially described OR is most probably overestimated and therefore the real situation may be the existence of a genuine but weak risk factor, which generates statistical power limitations.

Autoimmune disease association signals in CIITA and KIAA0350 are not involved in celiac disease susceptibility.

Celiac disease (CD) is a multifactorial disease characterized by intestinal inflammation after gluten exposure in genetically susceptible individuals. A strong influence of certain human leukocyte antigen (HLA) alleles (those coding the HLA-DQ2 and DQ8 heterodimers) is well established, but they cannot explain the overall genetic risk. CIITA could be a good candidate gene for CD because it is mainly transcriptionally regulated, and it encodes the master regulator of major histocompatibilty complex class II gene transcription. CIITA is located in 16p13, a region also containing KIAA0350 (CLEC16A), associated with two autoimmune diseases in genome-wide association studies. We aimed at studying the involvement of polymorphisms in CIITA and KIAA0350 in CD susceptibility, with special attention to evaluate the possible presence of more than one risk factor in the region. We performed a case-control study with 607 CD patients and up to 794 healthy controls, all Spaniards. All samples were genotyped for five single nucleotide polymorphisms: rs3087456 (-168A/G) and rs4774 in CIITA and rs7203459, rs6498169 and rs2903692 in KIAA0350. No significant results were obtained when comparing genotypic, allelic or haplotypic frequencies between patients and controls. Our results seem to discard the influence in CD susceptibility of CIITA and KIAA0350 markers previously associated with other autoimmune diseases.

IL23R: a susceptibility locus for celiac disease and multiple sclerosis?

Recent studies have shown association of the IL23R gene with inflammatory bowel disease, psoriasis and ankylosing spondylitis. We aimed at studying the involvement of IL23R in celiac disease (CD) and multiple sclerosis (MS). We performed a case-control study including 598 patients with CD, 414 with MS and 546 healthy controls, all of them white Spaniards. All samples were genotyped for two single nucleotide polymorphisms: rs7517847 and rs11209026 (Arg381Gln). Statistical analyses were performed using chi(2-)tests or the Fisher's exact test. The minor allele (Gln) of the coding variant Arg381Gln was significantly increased in CD and MS patients when compared to controls (8% in CD vs 6% in controls, P=0.02; 9% in MS, P=0.006). In MS, a stronger effect was observed in patients showing primary-progressive disease (16%, P=0.004). Moreover, heterozygotes for rs7517847 were significantly increased in this group of MS patients (81% in MS vs 48% in controls, P=0.0002). In conclusion, contrary to what has been described previously, the less frequent allele of the functional polymorphism Arg381Gln (rs11209026) seems to be increasing susceptibility to CD and MS, although in this last group of patients a stronger effect is observed in patients affected of a primary-progressive form.

Lynch syndrome in a 15-year-old boy.

Hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome, dominantly inherited, is characterized by the development of a variety of cancers due to germline mutations in DNA mismatch repair genes (MMR). This syndrome was diagnosed in a 15-year-old boy because his father and grandmother were also found to have the same kind of cancer. Microsatellite instability prompted a search for germline mutations in the MLH1, MSH2, MSH6, and PMS2 genes. Use of immunohistochemical staining for MMR proteins, genomic sequencing, and deletion studies, evidenced MSH2 axonal deletion. Neoplastic lesions of colon are most often encountered in the adult population but can, on rare occasions, be found in younger patients. We would like to emphasize the importance of suspecting Lynch syndrome and performing genetic studies, even in young patients, when there is a family history of colorectal cancer.

No evidence of association of the MYO9B polymorphisms with celiac disease in the Spanish population.

Inconsistent results concerning the association of polymorphisms in the MYO9B gene with celiac disease (CD) have been recently published. This gene encodes a myosin with a guanosine-triphosphatase (GTPase)-activating protein domain for the Rho-family of small G proteins, which are involved in cytoskeleton remodeling and therefore potentially involved in intestinal permeability. Functional and positional reasons led us to investigate the role of MYO9B polymorphisms in the Spanish CD population. A case-control study, including 415 CD patients and 433 ethnically matched healthy controls, and a familial study, including parents of 145 of those CD patients, was performed. Six MYO9B variants previously associated with CD were analyzed: rs2305767, rs2279003, rs962917, rs1457092, rs2305765 and rs2305764. No MYO9B variants or MYO9B haplotypes were found associated with CD, either before or after stratification of the patients for the human leucocyte antigen (HLA)-DQ2-positive risk factor. The family study revealed no distorted transmission of the aforementioned MYO9B polymorphisms or haplotypes. Our results support a negligible influence of this gene on CD predisposition.

A functional variant in the CD209 promoter is associated with DQ2-negative celiac disease in the Spanish population.

AIM: To address the role of CD209 in celiac disease (CD) patients. Non-human leukocyte antigen (HLA) genetic factors in CD predisposition are poorly understood, and environmental factors like infectious pathogens may play a role. CD209 is a dendritic and macrophage surface molecule involved in pathogen recognition and immune activation. Recently, a functional variant in the promoter of the CD209 gene (-336A/G) has been shown to affect the transcriptional CD209 activity in vitro and it has been associated with a higher susceptibility to/or severity of infection. METHODS: The study population was composed of two case-control cohorts of 103 and 386 CD patients and 312 y 419 healthy controls as well as a panel of 257 celiac families. Genotyping for the -336A/G CD209 promoter polymorphism was performed using a TaqMan 5' allelic discrimination assay. HLA-DQ was determined by hybridization with allele specific probes. RESULTS: Initially, the case-control and familial studies did not find any association of the -336 A/G CD209 genetic variant with CD susceptibility. However, the stratification by HLA-DQ2 did reveal a significant association of CD209 promoter polymorphism in the HLA-DQ2 (-) group (carrier A vs GG in DQ2 (-) vs DQ2 (+) patients (P = 0.026, OR = 3.71). CONCLUSION: The -336G CD209 allele seems to be involved in CD susceptibility in HLA-DQ2 (-) patients. Our results might suggest a possible role of pathogens in the onset of a minor group of CD patients.

Triplet repeat polymorphism in the transmembrane region of the MICA gene in celiac disease.

Celiac disease (CD) is characterized by a striking expansion of gamma delta T cells in the intestine. These cells interact with MICA, a cell surface protein encoded by a major histocompatibility complex gene. We investigated whether MICA gene polymorphism could contribute to susceptibility to CD. DNA typing for HLA-DR, DQA1, DQB1, TNF-308, TNFa, TNFb and a triplet repeat polymorphism in the transmembrane region of the MICA gene were carried out. We performed case-control stratified association studies and transmission disequilibrium tests. Our results indicate that although there is no primary association between MICA polymorphism and CD, there is, in addition to HLA-DQ, a second susceptibility locus on the 8.1 ancestral haplotype in strong linkage disequilibrium with MICA A5.1 allele.

Celiac disease and TNF promoter polymorphisms.

The possibility that genetic susceptibility to celiac disease (CD) might be influenced by tumor necrosis factor (TNF) genes polymorphism has repeatedly been put forward. To date, this has only been investigated in case-control studies and results have been contradictory. In order to avoid any possible ethnic mismatching between patients and controls, we have approached this problem studying 71 celiac families, establishing the parental haplotypes and comparing CD versus control haplotypes (the so-called AFBAC or affected family-based controls). We used DNA-based methods to screen for HLA-DRB1, -DQA1, and -DQB1 alleles, TNFalpha promoter polymorphims and TNFa and b microsatellites. The guanine-to-adenine polymorphism at position -308 of the TNFalpha gene promoter region was found associated with CD as the TNF-308A allele appeared significantly increased in frequency in CD haplotypes, and this was shown to be independent of the association between CD and the DRB1*0301,DQA1*0501,DQB1*0201 alleles. Our results indicate that at least another gene, in addition to the known association of CD with HLA class II, has a susceptibility role in this disease. This should be either TNFalpha or another polymorphic gene in the telomeric end of the HLA class III region.

Importancia del factor de necrosis tumoral en la enfermedad celíaca / Importance of tumor necrosis factor in coeliac disease

Las asociaciones de los microsatélites de TNF a y b con la susceptibilidad a la enfermedad celíaca (EC), han sido estudiadas en 137 pacientes y 324 controles. Nuestros datos indican una asociacíón entre EC y el haplotipo a2b3 del factor de necrosis tumoral (AU)

Polymorphism within the HLA-DQB1*02 promoter associated with susceptibility to coeliac disease.

Susceptibility to coeliac disease is associated with a particular HLA-DQ alpha beta heterodimer encoded by the DQA1*0501 and DQB1*02 genes. A single base polymorphism in the DQB1*02 promoter region in DR7, DQA1*0201, DQB1*02 haplotypes was observed, associated with an increased susceptibility to the disease. This finding suggests a novel mechanism of susceptibility to immune-mediated diseases.

HLA-DQ2-negative celiac disease in Finland and Spain.

Genetic susceptibility to celiac disease (CD) is strongly associated with DQA1*0501 and DQB1*02 (= DQ2). To study whether CD patients without DQ2 share other MHC class II or TNF alleles, we screened DQ2-negative patients in Finland and Spain. Twelve of 84 (14%) Finnish patients and 13 of 189 (6%) Spanish patients were negative for DQ2. We observed that all but two of altogether 25 DQ2-negative patients had the DR4 DQ8 haplotype, or either DQA1*0501 or DQB1*02 alone. Also, all but three were positive for DRB4*01. The only patients without any of these alleles were both positive for DR 13. There was a clear difference between Finland and Spain: Ten (83%) of the 12 Finnish DQ2-negative patients but only five (38%) of the 13 Spanish patients had DRB1*03, DQA1*03, DQB1*0302 (= DQ8) alleles. Of the Spanish patients, eight (62%) had DQB1*02 without DQA1*0501 and three (23%) had DQA1*0501 without DQB1*02. None of the TNF, TAP, or DPB1 alleles was found to be significantly associated with CD. Our results indicate that in addition to the DQ2 heterodimer, the other major risk alleles for CD are DR4 DQ8, and either DQA1*0501 or DQB1*02 alone. Patients without these alleles appear to be very rare, only two (0.7%) were identified in altogether 253 patients tested.

HLA-linked genes acting as additive susceptibility factors in celiac disease.

Susceptibility to developing CD is widely accepted to be primarily associated with a particular HLA-DQ alpha beta heterodimer encoded by the DQA1*0501 and DQB1*0201 alleles in cis position on the DR3,DQ2 haplotype or in trans position by DR5,DQ7/DR7,DQ2 heterozygotes. We performed genomic HLA-DR and -DQ typing of 100 unrelated Spanish celiac children and 180 ethnically matched controls. As expected, most (92 out of 100) celiac patients carried the HLA-DQ alpha beta heterodimer, and we selected these individuals for further studies. The results corroborate that although the DQA1*0501 and DQB1*0201 genes in single dosage appear sufficient for conferring disease susceptibility, individuals homozygotes for DQB1*0201 show an increased risk. Furthermore, our data also show that those carrying the genotype DR5,DQ7/DR7,DQ2 have a significantly increased risk of developing CD as compared to those that are non-DR7 positive, also carrying the CD-associated HLA-DQ alpha beta heterodimer. This strongly suggests that there is an MHC linked non-HLA-DQ gene primarily associated with CD present on DR7,DQ2 haplotype, which should either be DR7 or in strong linkage disequilibrium with it. Our data also indicate that, as has already been suggested, another HLA-associated CD susceptibility gene may be present on some DR4-carrying haplotypes.