Benno Strauss with unidentified family members; Edel-Str. 6, Würzburg.

Verso: handwritten correspondence

Portrait of brothers Moshe Chayim Eliasberg (on left) and Samuel Eliasberg playing chess watched by Moshe's son Mulek Eliasberg Portraits Family

Moshe Chayim Eliasberg died 1920; Samuel Eliasberg died 1929; Mulek Eliasberg, 1886-1942

Portrait of a family and their dog sitting in a park Portraits Family

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Portrait of brother, mother and sister of Max Rieser seated outdoors; Franzensbad Portraits Family

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Schloss and Schoeneberg family portrait on the occasion of the 80th birthday of Jeanette Bildesheim nee Schoeneberg.

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Benno Strauss (far right) with unidentified family members.

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Pedigree of the Jacob family of Stavenhagen, Mecklenburg, Germany.

Family tree and genealogy of Jacob family in Stavenhagen, Mecklenburg, 1690-1975.

Family portrait at double wedding ceremony of the Heimann and Rosenfelder families Portraits; Family

Double Wedding Ceremony Heimann-Rosenfelder August 17, 1909

Painting of Freiherr Martin von Magnus Family Portraits Family

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Achtentuch family portrait; Odessa Portraits Family

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Jacob Picard with daughter Renate Portraits Family

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Studio portrait of Cora Berliner with her mother and sister; Hannover Portraits Family

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Bernstein-Kohlberg Portraits Family

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Valentin family portrait on the occasion of the 50th Wedding Anniversary of Heinrich and Helene Valentin; Berlin Portraits Groups

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Insights into the molecular genetics of celiac disease : Applying family- and population-based strategies

Celiac disease, or gluten intolerance, is triggered by dietary glutens in genetically susceptible individuals and it affects approximately 1% of the Caucasian population. The best known genetic risk factors for celiac disease are HLA DQ2 and DQ8 heterodimers, which are necessary for the development of the disease. However, they alone are not sufficient for disease induction, other risk factors are required. This thesis investigated genetic factors for celiac disease, concentrating on susceptibility loci on chromosomes 5q31-q33, 19p13 and 2q12 previously reported in genome-wide linkage and association studies. In addition, a novel genotyping method for the detection of HLA DQ2 and DQ8 coding haplotypes was validated. This study was conducted using Finnish and Hungarian family materials, and Finnish, Hungarian and Italian case-control materials. Genetic linkage and association were analysed in these materials using candidate gene and fine-mapping approaches. The results confirmed linkage to celiac disease on the chromosomal regions 5q31-q33 and 19p13. Fine-mapping on chromosome 5q31-q33 revealed several modest associations in the region, and highlighted the need for further investigations to locate the causal risk variants. The MYO9B gene on chromosome 19p13 showed evidence for linkage and association particularly with dermatitis herpetiformis, the skin manifestation of celiac disease. This implies a potential difference in the genetic background of the intestinal and skin forms of the disease, although studies on larger samplesets are required. The IL18RAP locus on chromosome 2q12, shown to be associated with celiac disease in a previous genome-wide association study and a subsequent follow-up, showed association in the Hungarian population in this study. The expression of IL18RAP was further investigated in small intestinal tissue and in peripheral blood mononuclear cells. The results showed that IL18RAP is expressed in the relevant tissues. Two putative isoforms of IL18RAP were detected by Western blot analysis, and the results suggested that the ratios and total levels of these isoforms may contribute to the aetiology of celiac disease. A novel genotyping method for celiac disease-associated HLA haplotypes was also validated in this thesis. The method utilises single-nucleotide polymorphisms tagging these HLA haplotypes with high sensitivity and specificity. Our results suggest that this method is transferable between populations, and it is suitable for large-scale analysis. In conclusion, this doctorate study provides an insight into the roles of the 5q31-q33, MYO9B, IL18RAP and HLA loci in the susceptibility to celiac disease in the Finnish, Hungarian and Italian populations, highlighting the need for further studies at these genetic loci and examination of the function of the candidate genes.