Are rs2187668 and rs7454108 linked to celiac gluten susceptibility?

Celiac disease is a complex autoimmune enteropathy strongly governed by the human leukocyte antigen (HLA) class II locus. Genetic testing often utilizes specific single nucleotide polymorphisms (SNPs) as efficient proxies to identify individuals carrying high-risk HLA haplotypes.

Genetic association and proxy markers

• HLA-DQ2.5 Tagging: The SNP rs2187668, located in the first intron of HLA-DQA1, serves as an exceptionally strong tag variant for the high-risk HLA-DQ2.5 haplotype (DQA1*05:01-DQB1*02:01) with a linkage disequilibrium of $r^2 = 0.97$.
• HLA-DQ8 Tagging: The SNP rs7454108, located near HLA-DQB1, is a highly linked tag proxy used to infer the HLA-DQ8 haplotype (DQA1*03-DQB1*0302).
• Clinical Prevalence: Together, the HLA-DQ2 and HLA-DQ8 haplotypes are present in approximately 95% of all individuals diagnosed with celiac disease, making these two tag SNPs highly sensitive genetic screening markers.

Mechanistic pathway of gluten susceptibility

• Deamidation: In the small intestine, the enzyme tissue transglutaminase deamidates gluten-derived gliadin peptides, introducing negative charges.
• Antigen Presentation: The HLA-DQ2.5 and HLA-DQ8 molecules encode MHC class II heterodimers with positively charged peptide-binding grooves that exhibit a high affinity for these deamidated gluten peptides.
• T-Cell Activation: Once bound, these complexes present the gluten peptides to gluten-specific CD4+ T cells in the lamina propria, triggering an inflammatory cascade, autoantibody production, and mucosal tissue damage.

Bottom line

• The rs2187668 and rs7454108 variants are highly validated, sensitive genetic proxies for the HLA-DQ2.5 and HLA-DQ8 celiac-risk haplotypes, which directly drive gluten immune susceptibility through MHC class II presentation of deamidated gluten to CD4+ T cells. However, because many healthy carriers of these alleles never develop the condition, these markers are necessary but not sufficient for clinical diagnosis.