Clinical and genetical aspects of celiac disease

Abstract: Celiac disease (CD), or gluten-sensitive enteropathy, is one of the most common chronicdiseases in childhood but is diagnosed in all ages. CD is a genetically driven immunologicalintolerance to dietary gluten. Th e treatment is a gluten-free diet. Th e diagnosticcriteria are the ESPGHAN criteria, which include the histological characteristics ofvillous atrophy, crypt hyperplasia and increased number of intraepithelial lymphocytes(IEL). Th e clinical manifestations in CD range from severely aff ected young children tochildren and adults with milder symptoms as well as patients with silent CD. Th ere is astrong heredity in CD with the well-known HLA components DQ2 and DQ8. Th e geneticsin CD are believed to confer up to 40% HLA genetics and otherwise non-HLAgenetics. Th e knowledge of the genotype-phenotype association in CD is limited.Th e aim of this study has been to estimate the risk of a third sibling beingaff ected in CD sib-pair families, identify the chromosomal region containingsusceptibility genes in CD and study the genotype-phenotype association in CD.Material was collected from 107 families with at least two aff ected siblings, making a totalof 224 CD siblings, as well as their healthy siblings and parents. Screening for CD wasperformed in these apparently healthy members and the estimated risk for CD in the thirdsibling and parent was then calculated. Th irteen new CD cases were diagnosed, six siblingsand seven parents. Th e estimated sibling risk was 26.3% and the parent risk was 12.9%.Th e risk of a sibling of two aff ected siblings having CD was approximately three times highercompared to siblings of one aff ected sibling. Considering the high level of knowledgeof CD in these families, the number of undiagnosed cases was surprisingly high. We suggestedthat serological screening should be off ered all fi rst-degree relatives of CD patients.Genome-wide linkage scan was performed in the same material. Th is work showed signifi cantevidence of linkage to CD with an interesting region on chromosome 5q31-33 and on chromosome11q. Simplex CD family material was collected for further genetic association studies.Th e phenotype-genotype association was examined in two studies. An investigation was made ofa possible interaction between the phenotypes and HLA class II risk alleles, the CTLA4 +49 A/Gpolymorphism, the haplotype MH30'G:-1147'T:+49'A:CT60'G:CT61'A and the 5q31-33locus, in CD. Th e patients were grouped according to symptoms at presentation, the age at diagnosisand gender. Th e heritability of the phenotype was estimated to be 0.45. Th e AA genotypeat the CTLA4 +49A/G polymorphism was associated with clinically silent disease. No othercorrelations were found between genotypes and clinical presentation, age at diagnosis or gender.A genotype-phenotype analysis was made of phenotypes in DQ2-negative CD patients inthe largest DQ2-negative CD group that has been published compared to DQ2-positive CDcontrols in a European population. Th e fi nding was that the clinical presentation diff eredsignifi cantly between DQ2-negative and DQ2-positive CD patients in Italy and Sweden. Inboth samples there was an association between DQ2-negative cases and classic symptoms.In the Italian sample there was also an association between silent grade and DQ2-negativecases. Autoimmune disease was signifi cantly overrepresented in DQ8-positive patients.Th is thesis shows that the risk for third sibling and parents is, as expected, increased insib-pair families, as the expected risk of being aff ected in polygenic diseases is higher infamilies with multiple cases compared to single-case families. Th e genome scan indicatedsignifi cant linkage to 11q and 5q, which makes these regions interesting for furtherfi ne mapping of these regions using association analysis. Genotype-phenotypeanalysis of both HLA and non-HLA locus showed some signifi cant correlation betweensilent CD and both CTLA4 +49 AA genotype and the DQ2-negatives. In addition,an association was shown between classic symptom grade and DQ2-negative cases.

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