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

## TL;DR

This study explores how genetic and structural features of HLA-DQ molecules influence celiac disease risk in a Sardinian population.

## Contribution

The study integrates genetic data with in silico structural analysis to reveal structural differences in HLA-DQ alleles linked to celiac disease.

## Key findings

- CD patients showed a marked enrichment of the DR3–DQ2.5 haplotype.
- HLA-DQ2.5 displayed a more coherent secondary structure compared to DQ2.2.
- Structural coherence in HLA-DQ molecules is linked to disease susceptibility.

## Abstract

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.