Structural Insights into HLA-DQ-Associated Susceptibility to Celiac Disease Through an Integrated Genetic and In Silico Approach in a Sardinian Population.

BACKGROUND

Celiac disease (CD) is a multifactorial autoimmune disorder strongly associated with specific HLA class II molecules, particularly HLA-DQ-encoding haplotypes. Although the genetic contribution of these loci is well established, the structural features accompanying allele-specific disease susceptibility remain incompletely explored.

METHODS

In this study, molecular HLA typing was integrated with in silico secondary structure analysis to examine the relationship between genetic predisposition and structural organization of HLA class II molecules in a Sardinian population. A total of 100 patients with CD and 100 healthy controls were genotyped for HLA-DR and HLA-DQ alleles, and allelic and haplotypic distributions were compared between groups. Secondary structure predictions were performed using PSIPRED on selected HLA class II alleles, focusing on groove-forming domains of HLA-DRB1 and HLA-DQA1.

RESULTS

CD patients showed a marked enrichment of the DR3-DQ2.5 haplotype, together with a population-specific predominance of DQ2.5 and a reduced contribution of DQ8. Secondary structure analysis of the HLA-DRB1 β1 domain revealed a largely conserved organization, with only modest allele-dependent variations. In contrast, comparative analysis of HLA-DQA1 identified localized differences within the α1 domain, with the DQ2.5 molecule displaying a more coherent secondary structure organization compared with the lower-risk DQ2.2 variant.

CONCLUSIONS

By integrating genetic and in silico structural analyses, this study highlights that HLA-associated susceptibility to celiac disease reflects not only allele and haplotype distribution but also subtle, allele-specific features in the structural organization of peptide-binding regions. These findings provide a refined framework for interpreting HLA-DQ-mediated genetic risk and support the relevance of structural coherence as a complementary dimension in the assessment of disease susceptibility.