Non-transmitted maternal HLA DQ2 or DQ8 alleles and risk of Type I diabetes in offspring:: the importance of fetal or post partum exposure to diabetogenic molecules

Aims/hypothesis. Type I (insulin-dependent) diabetes mellitus results from an immune-mediated destruction of pancreatic beta cells for which HLA haplotypes DR3-DQ2 and DR4-DQ8 represent the strongest genetic risk markers. Mothers of patients with rheumatoid arthritis carry more frequently the HLA DR4-DQ8 haplotype as non-transmitted haplotype than mothers of healthy control subjects. As maternal cells have been shown to persist in their offspring up to 30 years after birth, we investigated whether the association of HLA DR3-DQ2 and DR4-DQ8 with Type I diabetes is purely a genetic effect acting through inheritance or whether it can also act as an environmental factor, for example through foetal exposure in utero to maternal circulating cells. Methods. We analysed the non-transmitted parental HLA DQ alleles of 464 families (1367 subjects) with a Type I diabetic offspring. HLA DQ alleles were assessed using sequence-specific primers and allele-specific oligonucleotides hybridisation. A chi-square test was done to compare allele and transmission frequencies in the respective subsets of families. Results. The non-transmitted HLA DR3-DQ2 and DR4-DQ8 were more frequent in mothers than in fathers of all non-DQ2/DQ8 heterozygous diabetic offspring (p=0.0001) as well as in offspring not carrying any HLA high-risk allele (p=0.0243). In patients with either risk allele alone, more maternal than paternal non-transmitted risk alleles complemented the constellation to DQ2/DQ8 (p<0.0099). Conclusion/interpretation. HLA high risk alleles were more frequent among maternal non-inherited (but possibly exposed) alleles than among paternal non-inherited alleles. These results indicate that HLA DR-DQ is an environmental risk factor for Type I diabetes.