Genetics of Celiac Disease in Southern Brazil: High‐Resolution HLA Haplotypes and Non‐ HLA Polymorphisms

ABSTRACT

Celiac disease (CeD) is an autoimmune enteropathy triggered by gluten ingestion in genetically predisposed individuals, who frequently present HLA‐DQ2 or HLA‐DQ8 haplotypes. To examine the genetic architecture of CeD in the admixed South Brazilian population, we sequenced the HLA alleles to high resolution and genotyped 16 non‐HLA polymorphisms, previously identified through genome‐wide association studies of Europeans in 171 CeD diagnosed patients and 195 controls. Controls had no CeD diagnosis, no first‐degree affected relatives, and were negative for anti‐TTg autoantibodies. As expected, we observed a predominance of HLA ‐ DQA1*05:01:01~DQB1*02:01:01 (DQ2.5) and HLA ‐ DQA1*02:01:01~DQB1*02:02:01 (DQ2.2) haplotypes among patients (51.7% and 40.2%, respectively). The ancestral 8.1 haplotype of HLA Class I and II alleles presented the highest odds of developing CeD (OR = 6.54, pcorr = 0.000065). By contrast, HLA ‐ DQA1*01:02:01 , HLA ‐ DQB1*05:01:01 , HLA ‐ DRB1*08:02:01 and HLA ‐ DRB1*13:01:01 were more frequent among controls (OR < 0.4, pcorr < 0.01). In contrast to results obtained in populations of predominantly European origin, HLA‐DQ8 frequencies did not differ between patients and controls. Among non‐HLA loci, rs6691768*G (g.61326191G > A) in NFIA was associated with protection (OR = 0.32, pcorr = 0.039) and rs653178*C ( g.111569952C > T ) (OR = 1.49, pcorr = 0.042) in ATXN2 was associated with susceptibility. This is the first high‐resolution HLA genotyping study of CeD in Brazil, providing a comprehensive overview of genetic susceptibility in an admixed population and highlighting new potential modulatory variants beyond the classical HLA loci.