An influence of HLA-A, B, DR, DQ, and MICA on the occurrence of Celiac disease in patients with type 1 diabetes

Abstract

Celiac disease (CD) is more common in individuals with insulin dependent diabetes mellitus (T1D) than in the general population. HLA class II molecules DQ8 (DQB1*0302-DQA1*0301) and DQ2 (DQB1*0201-DQA1*0501) have been identified as key genetic risk factors in both diseases. While DQ8 conveys a higher risk for T1D, DQ2 is more frequent in CD. Less is known about the contribution of HLA class I. The gut immune system has been implicated in the pathogenesis of both diseases. The MICA, which is mainly expressed in the gastrointestinal epithelium and recognized by gammadeltaT lymphocytes and natural killer (NK) cells via the NKG2D, might play a role. The aim of our study was to identify possible HLA class I and MICA alleles and conserved extended haplotypes as risk factors for the development of CD in T1D. Three groups consisting of 37 individuals with T1D and CD, 67 individuals with only T1D and 70 controls were analyzed. HLA class I and MICA alleles were determined using Luminex technology. An occurrence of CD in individuals with T1D was most significantly associated with B*08 (P = 7.3 x 10(-13)), contributing more than any of the HLA class II alleles (DRB1*0301, P = 5.00 x 10(-10); DQB1*0201, P = 7.65 x 10(-8)). Moreover, the association with CD became stronger when B*08(B*08-DQA*0501-DQB1*0201-DRB1*0301, P = 5.07 x 10(-12)) was present in the DRB1*0301-DQB1*0201-DQA1*0501 (P = 5.00 x 10(-10)) extended haplotype. We suggest a combined influence of alleles present in the MICA*008-B*08-A1-DR3-DQ2 extended haplotype on the development of CD in Slovenian individuals with T1D, where B*08 or/and a gene located close to it may play an important role, independently of HLA class II.