Clinical and genetical aspects of celiac disease

Celiac disease (CD), or gluten-sensitive enteropathy, is one of the most common chronic diseases in childhood but is diagnosed in all ages. CD is a genetically driven immunological intolerance to dietary gluten. Th e treatment is a gluten-free diet. Th e diagnostic criteria are the ESPGHAN criteria, which include the histological characteristics of villous atrophy, crypt hyperplasia and increased number of intraepithelial lymphocytes (IEL). Th e clinical manifestations in CD range from severely aff ected young children to children and adults with milder symptoms as well as patients with silent CD. Th ere is a strong heredity in CD with the well-known HLA components DQ2 and DQ8. Th e genetics in CD are believed to confer up to 40% HLA genetics and otherwise non-HLA genetics. 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 being aff ected in CD sib-pair families, identify the chromosomal region containing susceptibility 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 total of 224 CD siblings, as well as their healthy siblings and parents. Screening for CD was performed in these apparently healthy members and the estimated risk for CD in the third sibling and parent was then calculated. Th irteen new CD cases were diagnosed, six siblings and 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 higher compared to siblings of one aff ected sibling. Considering the high level of knowledge of CD in these families, the number of undiagnosed cases was surprisingly high. We suggested that 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 cant evidence of linkage to CD with an interesting region on chromosome 5q31-33 and on chromosome 11q. 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 of a possible interaction between the phenotypes and HLA class II risk alleles, the CTLA4 +49 A/G polymorphism, the haplotype MH30*G:-1147*T:+49*A:CT60*G:CT61*A and the 5q31-33 locus, in CD. Th e patients were grouped according to symptoms at presentation, the age at diagnosis and gender. Th e heritability of the phenotype was estimated to be 0.45. Th e AA genotype at the CTLA4 +49A/G polymorphism was associated with clinically silent disease. No other correlations 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 in the largest DQ2-negative CD group that has been published compared to DQ2-positive CD controls in a European population. Th e fi nding was that the clinical presentation diff ered signifi cantly between DQ2-negative and DQ2-positive CD patients in Italy and Sweden. In both 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-negative cases. 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 in sibpair families, as the expected risk of being aff ected in polygenic diseases is higher in families with multiple cases compared to single-case families. Th e genome scan indicated signifi cant linkage to 11q and 5q, which makes these regions interesting for further fi ne mapping of these regions using association analysis. Genotype-phenotype analysis of both HLA and non-HLA locus showed some signifi cant correlation between silent 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.