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.

Sosiaalityön ammattilaiset refleksiivisinä toimijoina : tutkimus erikoistumiskoulutuksesta Margaret Archerin teorian valossa

In Finland, specialized studies in social work (professional licentiate education) were begun in the year 2000. The education is targeted at experienced social workers and leads to a licentiate degree (a degree between master s and doctorate). In this study, the experiences of members of the first study cohort, specializing in social work with children and young people, are examined. The study s theoretical frame of reference is based on the morphogenetic approach, developed by British sociologist Margaret Archer. In it, the potential powers of both an agent as well as social and cultural structures are considered important and worth taking into account. Archer sees reflexivity, a person s ability to analyze herself/himself, as an essential starting point for agency. Thanks to reflexivity, people are able to engage in internal conversations , discuss the concerns that are important to them and form agential projects . In Archer s theory, the social structures and traits of the cultural system are seen as having potential power in relation to people s agential projects; these powers can enable but also restrain the realization of the projects. On the other hand, individuals can try to review the factors affecting their agential projects and find ways of action that facilitate them. The research task is to study the self-understanding of social work professionals in the 21st century, the issues and goals professionally important for them, as well as the contexts framing the realization of these goals. The research questions are as follows: 1) What kind of internal conversations, concerns and agential projects related to their work did the professionals taking part in licentiate education bring to light? 2) What kind of enabling and restraining factors can be identified in their situations? And 3) What kind of social structures and traits related to the cultural system are connected to these factors? The research material was collected by interviewing the students in different phases of their education. In 2001 and 2004 all members of the study group (n = 25) were interviewed. In 2007, 13 students took part. The themes of the internal conversations brought to light in the interviews were divided into four broad thematic categories: professional development, the position of children in social work, multiprofessional work and structural social work. In relation to these themes the students formed different kinds of agential projects. In addition, the study reveals several cultural and social structures that have enabled but also restrained the realization of the agential projects. These structures are linked, for example, to the relations between employees and employers, students and teachers, children and adults as well as between the representatives of different professions. Working conditions which social workers often consider weak are discussed as a focal issue related to many themes. These working conditions become evident, for example, in the great imbalance which exists between the professional tasks and the amount of time that social workers have for them. Difficult situations arise when social workers feel they cannot reach the goals that are professionally important to them because of the strict external conditions of the work.