Does the HLA-DQA1 rs2187668 CT genotype indicate celiac disease susceptibility?

The HLA-DQA1 rs2187668 variant is a highly characterized genomic marker that serves as a proxy for genetic susceptibility to celiac disease. This assessment outlines how the heterozygous CT genotype relates to the HLA-DQ2.5 risk haplotype and the downstream inflammatory processes driving mucosal damage.

Genomic tagging and clinical utility

• The single nucleotide polymorphism (SNP) rs2187668, located in the first intron of the HLA-DQA1 gene, is in tight linkage disequilibrium ($r^2 \approx 0.97$) with the HLA-DQ2.5 haplotype (DQA1*05:01/DQB1*02:01).
• A heterozygous CT genotype indicates the carriage of exactly one copy of this risk haplotype, which increases susceptibility to celiac-type gluten-reactive enteropathy, although the absolute risk is lower than in homozygous individuals.
• While the absence of this and related HLA-DQ alleles has an outstanding negative predictive value (>99%) to rule out celiac disease, carrying this risk allele is genetically permissive rather than individually diagnostic.

Mechanistic pathways of mucosal damage

• Structurally, the HLA-DQ2.5 heterodimer features a positively charged binding groove that binds negatively charged, deamidated gluten peptides with exceptionally high affinity.
• Tissue transglutaminase (TG2) deamidates gluten, allowing stable peptide-HLA-DQ2.5 presentation on antigen-presenting cells to activate pathogenic, Th1-polarized CD4+ T cells.
• Activated CD4+ T cells secrete high levels of pro-inflammatory cytokines, primarily interferon-gamma (IFN-$\gamma$), which mediate direct mucosal injury and drive the characteristic loss of the small-intestinal villous absorptive surface (villous atrophy).

Bottom line

• The HLA-DQA1 rs2187668 CT genotype reliably identifies individuals carrying one copy of the HLA-DQ2.5 haplotype, signifying a genetically driven susceptibility to gluten-induced Th1 inflammation and small-intestinal villous atrophy.