POSTER NO: 445

Not transmitted parental HLA DQ2 or DQ8 alleles and risk of type 1 diabetes in offspring: the importance of fetal exposure to diabetogenic molecules

¹Michael A. Pani, ²Bart J. van der Auwera, ²Frans K. Gorus, ¹Klaus-H. Usadel, ¹Klaus Badenhoop
¹Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany, ²Diabetes Research Center, Free University, Brussels, Belgium

Type 1 diabetes results from an immune mediated destruction of pancreatic beta cells. HLA alleles DR3-DQ2 and DR4-DQ8 represent the strongest genetic risk markers for type 1 diabetes. Mothers of patients with rheumatoid arthritis carry more frequently than mothers of healthy controls the HLA DR4 allele as not transmitted haplotype. As maternal cells have been shown to persist in their offspring up to 30 years after birth, we wondered whether the association of HLA DR3-DQ2 and DR4-DQ8 with type 1 diabetes is purely a genetic effect acting through inheritance or whether it may also act as an environmental factor for example through exposure of the fetus in utero to maternal circulating cells. We therefore analyzed 371 families (1113 individuals) with a type 1 diabetic offspring in terms of not transmitted parental HLA DR-DQ alleles. HLA genotyping was performed using allele-specific standard primers. The not transmitted DR4-DQ8 was significantly more frequent in mothers than in fathers of all diabetic offspring (p<0.02) as well as in the subset of children not carrying any HLA risk allele (p<0.03). In patients with either risk haplotype alone significantly more maternal than paternal not transmitted risk haplotypes complemented the constellation to DR3-DQ2/DR4-DQ8 (p<0.05). Thus, HLA high risk alleles were more frequent among maternal not inherited (but possibly exposed) haplotypes than among paternal not inherited haplotypes. These results extend the concept of HLA DR-DQ risk for type 1 diabetes from a genetic to an environmental dimension.