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.

Rudolfine Menzel with brothers ? Portraits Family

Digital Image

Rudolfine Menzel with her parents-in-law Portraits Family

Digital Image

Studio portrait of seven of David Gruenspecht and Rebecca Gruenspecht nee Hoffman's ten children Portraits Family

Includes Louis Gruenspecht, Max Gruenspecht, Abraham (Adolf) Gruenspecht, Babette Gruenspecht, Isaac Gruenspecht, Moses (Moritz) Gruenspecht and Michael Gruenspecht; Missing are Rosalie Gruenspecht, Sarah Gruenspecht and Hirsch Gruenspecht

Studio portrait of David Gruenspecht and Rebecca Gruenspecht nee Hoffman with one of their young sons Portraits Family

Digital Image

Edna and Moses Stern with daughters Erna and Annie Portraits Family

Grandparents of Margot Gerson

Portrait of the Herzer family of Lwow (Lemberg) Portraits; Family

Verso: Standing l-r: Sigmund (Malka's husband), Sima, Friedka, Zosia, Bernard, Siko (Yehoshua); Sitting l-r: Malka, Esther (Tinka), Pinchas, Sara (Bernard's wife); Inset: Hedva and Tziza, Bernard and Sara's children circa 1931 ages 4 and 5

Portrait of Molling and Sanger (Loewy) families on vacation; Marienbad Portraits Family

Therese Molling (1890-1981) is in back row in white dress, to her left is her mother Henny Molling nee Meyerhof (1864-1934), her husband (and Therese's father) Adolf Molling (1865-1921) is posing on the grass in front.

Elizabeth Engel nee Benjamin-Rasmussen with her daughter Dorel Hall nee Engel in Elizabeth's home; Silver Springs, Maryland Portraits Family

Digital Image

John and Ursula Schlosstein nee Gottschalk with their infant son Ralph. portraits family

Digital Image

Therese Godshaw's nee Molling 70th birthday party at the Krakauer home; Boston Portraits Family

Left to right behind table: John Krakauer, Donald, Michael and Robert Godshaw (Children of Hal and Anne), Grandma Therese Godshaw nee Molling, Julius Pick (Grandfather of Robert, Michael and Donald). In front of table: Wendy and Gerry Godshaw (children of Kurt and Edith.

Outdoor family portrait after the memorial services for Therese Godshaw nee Molling at Hal Godshaws house; Argonne Drive, Kenmore, New York.

Front row from left to right: Robert Godshaw, Wendy Godshaw, Rosel Pick (Anne Godshaw's mother), Debbie Godshaw born Mariner, Hal Godshaaw, Francis Schlosstein; 2nd row from left to right: David Dysert, Mickey Sloan born McMath, Edith Godshaw nee Osterer, baby (probably Gary Godshaw), Anne Godshaw born Pick, Julius Pick (Anne's father), Ursula Schlosstein born Gottschalk, Elizabeth Krakauer nee Gottschalk, Michael Godshaw; back row from left to right: Charlie Sloan, Gerald Godshaw (partially hidden), unknown, Kurt Godshaw, John Krakauer, Donald Godshaw, Tom Krakauer, Ralph Schlosstein, John Schlosstein.

Portrait of Elly Goldschmidt and her children Ilse and Robert. Portraits Family

Digital Image

Portrait of Joseph and his sister Elly Schoenbeck; Cologne, Germany. Portraits family

Digital Image