BTN2A1 and BTN3A1 as Novel Coeliac Disease Risk Loci: An In Silico Analysis

Coeliac disease (CeD) is a gastrointestinal enteropathy triggered by the consumption of gluten in predisposed individuals. A recent study showed that individuals were at more than 10% risk of having CeD if a first-degree relative also had the disease. However, only around 50% of CeD genetic heritability is attributable to specific loci, with the majority of this heritable risk attributed to the <i>HLA</i> loci, while the remaining 50% of disease risk is currently unidentified. 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 a significantly increased <i>BTN2A1</i> 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 <i>BTN2A1</i>, ten <i>BTN3A1,</i> and thirteen <i>BTN3A2</i> SNPs were significantly associated with CeD status. These results are interesting, as <i>BTN2A1</i> and <i>BTN3A2</i> have not been associated with CeD risk previously but are known to modulate the activation of Vγ9+ γδ T cells and NK cells. Twenty of the 37 SNPs above were associated with CeD status independent of the risk-associated <i>HLA</i> genotypes. All twenty of these SNPs, alongside a novel SNP not included in the above SNPs, were associated with CeD in <i>HLA-DQ2.5</i>-matched case-control groups. We reaffirm the association of the <i>BTN3A2</i> locus with CeD risk and identify <i>BTN2A1</i> and <i>BTN3A1</i> as putative novel CeD risk loci.