Linkage between HLA-B8 and HLA-DQ2.5 Contributes to Ancestry-Dependent Genetic Risk for Celiac Disease

Area of Science:

• Genetics
• Immunology
• Population Health

Background:

• Celiac disease (CeD) genetic studies predominantly focus on European populations, with limited data on Hispanic and black individuals.
• Understanding genetic risk factors across diverse ancestries is crucial for equitable CeD diagnosis and management.

Purpose of the Study:

• To investigate the genetic and clinical risk factors for celiac disease (CeD) across diverse ancestries using the All of Us Research Program data.
• To determine if the well-established HLA-DQ2.5 haplotype's association and penetrance differ among European, Admixed American, and African populations.

Main Methods:

• Whole-genome sequencing, electronic health records (EHR), and laboratory results from the All of Us Research Program were analyzed.
• Identified 3,481 individuals with CeD and compared genetic risk factors (e.g., HLA haplotypes) and clinical data with matched controls across different ancestries.

Main Results:

• An enrichment of the DQB1*02:01 allele was observed in CeD patients across all ancestries, with the strongest association in Europeans.
• Linkage disequilibrium between HLA-B8 and the DQ2.5 haplotype varied significantly by ancestry, impacting CeD risk.
• A polygenic risk score combined with clinical factors (family history, hypothyroidism, diarrhea, vitamin D deficiency, anemia) achieved 92% accuracy in predicting CeD.

Conclusions:

• The linkage between HLA-B8 and DQ2.5 differs significantly across European, Admixed American, and African ancestries, contributing to ancestry-dependent genetic risk for CeD.
• These findings highlight the importance of considering ancestry in genetic risk assessments for celiac disease.