1. ¹Institute of Immunology, Faculty Division Rikshospitalet, University of Oslo, Oslo, Norway
2. ²Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway
3. ³Institute of Medical Genetics, Faculty Division Ullevål University Hospital, University of Oslo, Oslo, Norway
4. ⁴Department of Mathematical Statistics, Chalmers University of Technology, Göteborg, Sweden
5. ⁵Department of Mathematical Statistics, Göteborg University, Göteborg, Sweden
6. ⁶Department of Medical Genetics, Ullevål University Hospital, Oslo, Norway
7. ⁷Steno Diabetes Centre, Gentofte, Denmark
8. ⁸Department of Clinical Neurosciences, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden
9. ⁹Inserm U 558, University Paul Sabatier, Toulouse, France

Correspondence: Dr BA Lie, Institute of Immunology, Rikshospitalet University Hospital, Sognsvannsveien 20, Oslo 0027, Norway. E-mail: Benedicte.Lie@rr-research.no

¹⁰These authors contributed equally to work.

Received 23 December 2008; Accepted 13 February 2009; Published online 19 March 2009.

Abstract

The high-risk human leukocyte antigen (HLA)-DRB1, DQA1 and DQB1 alleles cannot explain the entire type 1 diabetes (T1D) association observed within the extended major histocompatibility complex. We have earlier identified an association with D6S2223, located 2.3 Mb telomeric of HLA-A, on the DRB1^*03-DQA1^*0501-DQB1^*0201 haplotype, and this study aimed to fine-map the associated region also on the DRB1^*0401-DQA1^*03-DQB1^*0302 haplotype, characterized by less extensive linkage disequilibrium. To exclude associations secondary to DRB1-DQA1-DQB1 haplotypes, 205 families with at least one parent homozygous for these loci, were genotyped for 137 polymorphisms. We found novel associations on the DRB1^*0401-DQA1^*03-DQB1^*0302 haplotypic background with eight single nucleotide polymorphisms (SNPs) located within or near the PRSS16 gene. In addition, association at the butyrophilin (BTN)-gene cluster, particularly the BTN3A2 gene, was observed by multilocus analyses. We replicated the associations with SNPs in the PRSS16 region and, albeit weaker, to the BTN3A2 region, in an independent material of 725 families obtained from the Type 1 Diabetes Genetics Consortium. It is important to note that these associations were independent of the HLA-DRB1-DQA1-DQB1 genes, as well as of associations observed at HLA-A, -B and -C. Taken together, our results identify PRSS16 and BTN3A2, two genes thought to play important roles in regulating the immune response, as potentially novel susceptibility genes for T1D.