<em>BTN2A1</em> and <em>BTN3A1</em> as Novel Coeliac Disease Risk Loci: An <em>in silico</em> Analysis

Coeliac disease (CeD) is a gastrointestinal enteropathy triggered by the consumption of gluten in predisposed individuals. Only around 50% of CeD genetic risk is understood, with the majority of risk attributed to the HLA loci. We investigated the butyrophilin family of immunomodulators as novel CeD risk loci. We sequenced the butyrophilin loci of 48 CeD and 46 control patients and carried out gene-based burden testing on the captured single nucleotide polymorphisms (SNPs). We found significantly increased BTN2A1 gene burden in CeD patients. To validate these results, the SNP data of 3094 CeD patients and 29 762 control participants from the UK Biobank database were subjected to single variant analyses. Fourteen BTN2A1, 10 BTN3A1, and 13 BTN3A2 SNPs were significantly associated with CeD status. Twenty of the 37 SNPs above were associated with CeD status independent of the risk associated HLA genotypes. All twenty of these SNPs, alongside a novel SNP not included in the above SNPs were associated with CeD in HLA-DQ2.5-matched case-control groups. This study reaffirmed the association of the BTN3A2 locus with CeD risk, and identified BTN2A1 and BTN3A1 as putative novel CeD risk loci.