Genetic risk for co-occurrence of type 1 diabetes and celiac disease is modified by HLA-C and killer immunoglobulin-like receptors

The prevalence of celiac disease (CD) in patients with type 1 diabetes (T1D) has been reported to be 5–7 times higher than in the general population. Risk factors for co‐occurrence of both diseases have not been entirely established. The aim of our study was to analyze possible impact of human leukocyte antigen (HLA) class I and killer cell immunoglobulin‐like receptors (KIRs) on the co‐occurrence of T1D and CD. We analyzed 67 patients with T1D, 68 patients with CD, 69 patients with both diseases (T1D+CD) and 130 controls. Statistical analysis was based on two tailed Fisher exact test with corrections for multiple testing. After stratification by DR3‐DQ2, an association of HLA class I part of the COX haplotype (A1‐B8‐Cw7‐DR3‐DQ2) was not observed with each of the studied diseases separately, but it could be shown in case of the co‐occurrence of T1D and CD. Only in the group of patients with coexisting diseases, the presence of HLA‐C*07 (P = 8.65×10−3) and HLA‐B*08 (P = 0.03) but not HLA‐A*01 increased the succeptibility. Our current data indicated that C*07, contributing C1 ligand (Pc = 3.67×10−5) rather than B*08, that possesses no KIR ligand, could have an impact on the innate immunity rout of this susceptibility. The significant combination of C1‐KIR2DL3 (Pc = 1.97×10−4) observed in patients with coexisting diseases supports this hypotesis. Interestingly, no association was observed when C1 in combination with its stronger inhibitory receptor KIR2DL2 was investigated. Predominantly, weak inhibition in patients with coexisting T1D and CD could lead to a natural killer cell response, making them vulnerable for developing more than one autoimmune disease.