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Coeliac disease (CD) is a malabsorptive disorder of the small intestine resulting from ingestion of gluten. The HLA risk factors involved in CD are well known but do not explain the whole genetic susceptibility. Several regions of potential linkage on chromosomes 3q, 5q, 10q, 11q, 15q and 19q have already been reported in the literature. These six regions were analyzed with the Maximum Lod Score method on a dense set of markers. A new sample of 89 Italian sibpairs was available for study. There was no evidence for linkage for any of the regions tested, except for chromosome 5q. For this region, our data, as well as a sample of 93 sibpairs from our first genome screen (Greco et al. 1998), are compatible with the presence of a risk factor for CD with a moderate effect.

Coeliac disease (CD) is a multigenic and multifactorial enteropathy triggered by gluten-composing proteins. A possible involvement of the intestinal Aminopeptidase N (APN) was investigated by an association analysis. SSCP analysis detected four variants at position 281, 378, 956 and 2957 (referred to no. g178535, GenBank) that were studied in 193 Italian CD families. The haplotypic combinations were determined from family segregation and pairwise linkage disequilibria (D' = D/Dmax) between the polymorphic sites were calculated. Significant D' values ranged between 0.78 and 0.31. Association with CD was tested by TDT (Transmission Disequilibrium Test) utilizing as markers the nucleotide substitutions and their haplotypic combinations. No statistically significant transmission distortion to the probands or to their clinically silent sibs was observed. Our data exclude an involvement in CD of the tested markers and of further undetected variation in strong linkage disequilibrium (D' approximately equal to 1) with them. The power of the test was not adequate to detect an association with an unknown polymorphism which is not in complete linkage disequilibrium with those analysed.

Background and aims: We adopted the twin method to disentangle the genetic and environmental components of susceptibility to coeliac disease (CD). We estimated disease concordance rate by zygosity and HLA genotypes, discordance times, progression rates to disease, and heritability. Methods: We crosslinked the Italian Twin Registry with the membership lists of the Italian Coeliac Disease Association and recruited 23 monozygotic (MZ) and 50 dizygotic (DZ) twin pairs with at least one affected member. Zygosity was assigned by DNA fingerprinting, and HLA-DQ and DR alleles were genotyped. Disease status was ascertained by antiendomysial, anti-human tissue transglutaminase antibodies, and bowel biopsy. Results: Concordance was significantly higher in MZ (83.3% probandwise, 71.4% pairwise) than in DZ (16.7% probandwise, 9.1% pairwise) pairs. Concordance was not affected by sex or HLA genotype of the co-twin and being MZ was significantly associated with the occurrence of CD (Cox adjusted hazard ratio 14.3 (95% confidence interval 4.0–50.3)). In 90% of concordant pairs the discordance time was ⩽2 years. MZ and DZ co-twins had 70% and 9% cumulative probability of having symptomatic or silent forms of CD, respectively, within five years. Under ACE (additive genetic, common, and unshared environmental factors) models, with CD population prevalences of 1/91 and 1/1000, heritability estimates were 87% and 57%, respectively. Conclusion: MZ pairs have a high probability of being concordant, regardless of sex or HLA genotype. Most of the affected co-twins receive a diagnosis within two years. A remarkable proportion of phenotypic variance is due to genetic factors.

Celiac disease is a multifactorial disorder caused, in genetically susceptible patients, by the ingestion of dietary gluten. Very little is known about the genetic factors, but there is a strong association of two HLA haplotypes (DQ2 or alpha1*05, beta1*02 and DQ8 or alpha1*0301, beta1*0302) with the disease. We investigated the relationship between polymorphisms in the first exon of the MBL2 gene, which encodes for mannose binding lectin (MBL) and celiac disease. Moreover we studied the MBL role by immunohistochemistry and TUNEL. Results were confirmed by clinical findings. We enrolled 149 Italian celiac patients; 116 were characterized by the presence of DQ2 or DQ8. The HLA haplotype was established by allelic specific PCR while the MBL2 genotype was resolved by melting temperature assay. Immunohistochemistry and TUNEL assays were performed on serial sections of biopsy specimens from celiac patients and healthy controls. MBL2 allele and genotype frequencies varied significantly between celiac patients and healthy controls. The frequencies of the 0 allele were 28% in DQ2 or DQ8 celiac patients, 36% in HLA atypical celiac patients, and 22% in healthy controls. Interestingly, the MBL2 0/0 genotype was present in 7 of 33 HLA atypical celiac patients (21%) and in 13 of 116 HLA typical celiac patients (13%) but in only 7 of 147 healthy controls (5%). Furthermore, we found that MBL2 genotype is strongly associated with the occurrence of secondary autoimmune diseases. Immunohistochemistry and TUNEL findings support a role of MBL2 in the clearance of apoptotic cells. In conclusion, MBL2 variants, responsible for lower MBL levels, are associated with celiac disease and higher risk of developing autoimmune diseases. Here we propose a role for MBL in the disease which could be easily applied to other autoimmune disorders.

Dietary gluten has been associated with an increased risk of type 1 diabetes. We have evaluated inflammation and the mucosal immune response to gliadin in the jejunum of patients with type 1 diabetes. Small intestinal biopsies from 17 children with type 1 diabetes without serological markers of celiac disease and from 50 age-matched control subjects were examined by immunohistochemistry. In addition, biopsies from 12 type 1 diabetic patients and 8 control subjects were cultured with gliadin or ovalbumin peptic-tryptic digest and examined for epithelial infiltration and lamina propria T-cell activation. The density of intraepithelial CD3(+) and gammadelta(+) cells and of lamina propria CD25(+) mononuclear cells was higher in jejunal biopsies from type 1 diabetic patients versus control subjects. In the patients' biopsies cultured with peptic-tryptic gliadin, there was epithelial infiltration by CD3(+) cells, a significant increase in lamina propria CD25(+) and CD80(+) cells and enhanced expression of lamina propria CD54 and crypt HLA-DR. No such phenomena were observed in control subjects, even those with celiac disease-associated HLA haplotypes. In conclusion, signs of mucosal inflammation were present in jejunal biopsies from type 1 diabetic patients, and organ culture studies indicate a deranged mucosal immune response to gliadin.

The first genome wide screening performed on Italian affected sib-pair families (Greco et al. 1998) gave evidence for linkage with coeliac disease in the 5q region. This finding was replicated in a second independent dataset (Greco et al. 2001). Overall, pooling both samples, the highest MLS value (2.92) was found for the most centromeric marker tested, D5S640. In the present study, the 5q31-q33 region was saturated with 12 new markers around D5S640, in order to verify whether there would be a shift of the MLS position. This study allowed us to support our previous finding of linkage for the region 5q31-q33, with the most significant MLS value at D5S2014, very close to the marker D5S640. No evidence for interaction between this risk factor and the one in the HLA region was found. Furthermore, many different groups have independently obtained analogous results for this region, confirming the presence of a susceptibility locus in the region 5q31-q33. This region contains several interesting candidate genes for coeliac disease.

Coeliac disease (CD) is a malabsorptive disorder of the small intestine resulting from ingestion of gluten. The HLA risk factors involved in CD are well known but do not explain the whole genetic susceptibility. Several regions of potential linkage on chromosomes 3q, 5q, 10q, 11q, 15q and 19q have already been reported in the literature. These six regions were analyzed with the Maximum Lod Score method on a dense set of markers. A new sample of 89 Italian sibpairs was available for study. There was no evidence for linkage for any of the regions tested, except for chromosome 5q. For this region, our data, as well as a sample of 93 sibpairs from our first genome screen (Greco et al. 1998), are compatible with the presence of a risk factor for CD with a moderate effect.

Celiac disease (CD) patients usually express a DQ2 heterodimer, whose chains DQalpha1*0501/DQbeta1*0201, are encoded by the genes HLA-DQA1*0501 and DQB1*0201, respectively. Among the DQ2 carriers, the risk of developing disease was shown to correlate with the number of DQbeta1*0201 chains encoded. Studying two separate cohorts of Italian and Tunisian patients, we now show a significant association of celiac disease with expression of either the DQ2 or DR53 heterodimers. The risk is maximal for individuals that carry both DQ2 and DR53 heterodimers. When twenty synthetic peptides overlapping most of A-gliadin sequence were tested for the binding to various purified DR molecules, it was found that DR53 molecules bind selectively and with high affinity (IC50

SummaryCeliac disease (CD), a malabsorption disorder of the small intestine, results from ingestion of gluten. The HLA risk factors involved in CD are well known but do not explain the entire genetic susceptibility. To determine the localization of other genetic risk factors, a systematic screening of the genome has been undertaken. The typing information of 281 markers on 110 affected sib pairs and their parents was used to test linkage. Systematic linkage analysis was first performed on 39 pairs in which both sibs had a symptomatic form of CD. Replication of the regions of interest was then carried out on 71 pairs in which one sib had a symptomatic form and the other a silent form of CD. In addition to the HLA loci, our study suggests that a risk factor in 5qter is involved in both forms of CD (symptomatic and silent). Furthermore, a factor on 11qter possibly differentiates the two forms. In contrast, none of the regions recently published was confirmed by the present screening.

Coeliac disease (CD) is an autoimmune enteropathy triggered by ingestion of wheat gluten or related protein from rye and barley, and is one of the most frequently occurring, treatable, lifelong disorders.1,2 Undetected or untreated CD may cause other, more severe, complications later, such as autoimmune diseases, osteoporosis, neurological disorders, and infertility.3,4 Several studies have shown CD clusters in families with a sibling relative risk of 20–60 and high concordance between monozygotic twins (75%),5–8 which indicates a strong genetic component to coeliac disease. As expected in complex autoimmune diseases, human leukocyte antigen (HLA) linked genes are the main genetic factor involved in CD. More than 90% of patients suffering from CD share the major histocompatibility complex II class HLA-DQ2 haplotype. Most of the remainder present HLA-DQ8. However, there are patients who present neither HLA-DQ8 nor HLA-DQ2 on their antigen-presenting cells. These genetic findings strongly indicate the involvement of other genes in the pathogenesis of coeliac disease. So far, various genome-wide linkage analyses have been performed in order to identify non-HLA linked genes responsible for CD. A recent study by Greco et al. 9 on Italian coeliac families demonstrated the existence of a genetic risk factor on chromosome 5 (5q31–33), which has been reported in other linkage studies in different populations.10,11 This genomic region contains several candidate genes for CD, including the interleukin ( IL12B ) gene, the polymorphisms of which do not seem to be associated with CD,12 and the gene encoding for CD14.13 CD14 is a multifunctional receptor involved in the innate immune response. In fact, it is thought to be one of the most important receptors for lipopolysaccharide and other bacterial wall-derived components.14–16 However it is well known that CD14 has several other functions,17,18 including the clearance …