Avances en la base genética de la enfermedad celíaca en población española

La enfermedad celíaca (EC) es una enfermedad inflamatoria crónica intestinal que se desencadena en individuos genéticamente predispuestos al ingerir alimentos ricos en prolaminas que provienen del trigo, cebada o centeno. Se caracteriza por ser genéticamente compleja, con múltiples genes implicados, así como interacciones entre ellos y con el ambiente. El objetivo de este trabajo es la búsqueda de nuevos factores genéticos que contribuyan a la susceptibilidad a padecer esta enfermedad. Para ello se llevan a cabo estudios de asociación caso-control y familiares, por ser las estrategias más utilizadas y con mayor éxito en la detección de factores genéticos implicados en enfermedades complejas.[ABSTRACT]Celiac disease (CD) is a chronic inflammatory intestinal disease triggered by the ingestion of prolamins from wheat, rye and barley in genetically susceptible individuals. CD is a genetically complex disease with several genes involved but also interactions among them and with environmental factors. The aim of this work is the search of new genetic factors that could contribute to CD susceptibility. We performed case-control and familial association studies, which are the most followed and successful strategies to detect genetic susceptibility factors in complex diseases

Th17-Related Genes and Celiac Disease Susceptibility

Th17 cells are known to be involved in several autoimmune or inflammatory diseases. In celiac disease (CD), recent studies suggest an implication of those cells in disease pathogenesis. We aimed at studying the role of genes relevant for the Th17 immune response in CD susceptibility. A total of 101 single nucleotide polymorphisms (SNPs), mainly selected to cover most of the variability present in 16 Th17-related genes (IL23R, RORC, IL6R, IL17A, IL17F, CCR6, IL6, JAK2, TNFSF15, IL23A, IL22, STAT3, TBX21, SOCS3, IL12RB1 and IL17RA), were genotyped in 735 CD patients and 549 ethnically matched healthy controls. Case-control comparisons for each SNP and for the haplotypes resulting from the SNPs studied in each gene were performed using chi-square tests. Gene-gene interactions were also evaluated following different methodological approaches. No significant results emerged after performing the appropriate statistical corrections. Our results seem to discard a relevant role of Th17 cells on CD risk

HLA and celiac disease susceptibility: new genetic factors bring open questions about the HLA influence and gene-dosage effects.

Celiac disease (CD) is a chronic inflammatory disorder triggered after gluten ingestion in genetically susceptible individuals. The major genetic determinants are HLA-DQA1*05 and HLA-DQB1*02, which encode the DQ2 heterodimer. These alleles are commonly inherited in cis with DRB1*03∶01, which is associated with numerous immune-related disorders, in some cases contributing with a different amount of risk depending on the haplotype context. We aimed at investigating those possible differences involving DRB1*03∶01-carrying haplotypes in CD susceptibility. A family (274 trios) and a case-control sample (369 CD cases/461 controls) were analyzed. DRB1*03∶01-carrying individuals were classified according to the haplotype present (ancestral haplotype (AH) 8.1, AH 18.2 or non-conserved haplotype) after genotyping of HLA-DRB1, -DQA1, -DQB1, -B8, TNF -308, TNF -376 and the TNFa and TNFb microsatellites. We observe that the AH 8.1 confers higher risk than the remaining DRB1*03∶01-carrying haplotypes, and this effect only involves individuals possessing a single copy of DQB1*02. CD risk for these individuals is similar to the one conferred by inherit DQA1*05 and DQB1*02 in trans. It seems that an additional CD susceptibility factor is present in the AH 8.1 but not in other DRB1*03∶01-carrying haplotypes. This factor could be shared with individuals possessing DQ2.5 trans, according to the similar risk observed in those two groups of individuals

Genetic polymorphisms which showed a nominal significant value after case-control comparisons (in decreasing significance).

<p>ORs are referred to the mutant genotype or carrier of the mutant allele (specified below “genotype”).</p

Frequency and comparison of the diverse <i>DRB1*03∶01</i> haplotypes in celiac disease (CD) patients (2N = 738) and controls (2N = 922), overall and classified according to the different HLA CD risk categories.

<p>% are referred to the total number of haplotypes.</p><p>Non-AH 8.1 includes AH 18.2 and non-conserved haplotypes.</p><p>DQ2.5 cis = <i>DQB1*02∶01-DQA1*05∶01</i>; DQ2.2 = <i>DQB1*02∶02-DQA1*02∶01</i>.</p

Genotypic data (N (%)) for rs4969170 in the original and the replication sets.

<p>AA genotype:</p><p>*: p = 0.0018 OR = 0.59 95% CI 0.42–0.84;</p>#<p>, p = 0.20 95% CI OR = 0.75 (0.46–1.20).</p

Transmission data of the diverse <i>DRB1*03∶01</i>-containing haplotypes from <i>DRB1*03∶01</i> homozygous parents (N = 27).

<p>T = transmitted; TDT = transmission disequilibrium test.</p

Multiple common variants for celiac disease influencing immune gene expression.

We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) &lt; 10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance (P(combined) &lt; 5 x 10(-8)); most contain genes with immune functions (BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1), with ETS1, RUNX3, THEMIS and TNFRSF14 having key roles in thymic T-cell selection. There was evidence to suggest associations for a further 13 regions. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P &lt; 0.0028, FDR 5%) with cis gene expression