An original Eurasian haplotype, HLA-DRB1*14:54-DQB1*05:03, influences the susceptibility to idiopathic achalasia

Abstract

Idiopathic achalasia is a relatively infrequent esophageal motor disorder for which major histocompatibility complex (MHC) genes are well-identified risk factors. However, no information about HLA-achalasia susceptibility in Mexicans has previously been reported. We studied a group of 91 patients diagnosed with achalasia and 234 healthy controls with Mexican admixed ancestry. HLA alleles and conserved extended haplotypes were analyzed using high-resolution HLA typing based on Sanger and next-generation sequencing technologies. Admixture estimates were determined using HLA-B and short tandem repeats. Results were analyzed by non-parametric statistical analysis and Bonferroni correction. P-values < 0.05 were considered significant. Patients with achalasia had 56.7% Native American genes, 24.7% European genes, 16.5% African genes and 2.0% Asian genes, which was comparable with the estimates in the controls. Significant increases in the frequencies of alleles DRB1*14:54 and DQB1*05:03 and the extended haplotypes DRB1*14:54-DQB1*05:03 and DRB1*11:01-DQB1*03:01, even after Bonferroni correction (pC<0.05), were found in the achalasia group compared to those in the controls. Concluding, the HLA class II alleles HLA-DRB1*14:54:01 and DQB1*05:03:01 and the extended haplotype are risk factors for achalasia in mixed-ancestry Mexican individuals. These results also suggest that the HLA-DRB1*14:54-DQB1*05:03 haplotype was introduced by admixture with European and/or Asian populations.

Infectious agents as potential triggers for autoimmunity in achalasia

“…The association of achalasia with antinuclear antibodies (ANAs) has been reported 75,76 . ANAs are present in 56-68% of the patients with achalasia.…”

“…Moreover, unusual staining patterns in the nuclei, such as cytoplasmic staining as in anti-Jo-1 (histidyl tRNA synthetase) positive polymyositis/dermatomyositis, and antimitochondrial antibodies have been determined 75 . At present, cytoplasmic structure has become highly relevant due to a critical role in the functions of siRNA and miRNAs 12,[72][73][74][75][76][77] .…”

“…Finally, it has determined that MHC Class II genes (HLA-DRB1*14:54 and DQB1*05:03) and the conserved haplotype DRB1*14:54-DQB1*05:03 confers risk for the development of achalasia in mixed ancestry Mexicans. These achalasia-associated MHC Class II genes are possibly of Eurasian origin, and they could be important in the development of aberrant immune responses against triggering factors, such as viral, bacterial, or parasitic infections, that may lead to the development of this autoimmune condition 76 .…”

Esophagogastric junction outflow obstruction: Characterization of a new entity? Clinical, manometric, and neuroimmunological description

“…In addition, autoimmune comorbidities (thyroidopathies, rheumatoid arthritis, Sjögren's syndrome, ankylosing spondylitis, etc) are more frequent in achalasia patients 9,10 . The haplotype DRB1*14:54 and DQB1*05:03 and the extended haplotypes DRB1*14:54‐DQB1*05:03 and DRB1*11:01‐DQB1*03:01 influence the susceptibility to the disease 11‐13 . Nonetheless, until now there is no evidence of circulating antinuclear antibodies, antimyenteric plexus autoantibodies, and local or systemic inflammation in EGJOO patients, because most of the studies have focused on manometric characterization.…”

Triosephosphate isomerase, carbonic anhydrase, and creatinine kinase‐brain isoform are possible antigen targets in patients with achalasia

“…The proposed pathogens in triggering the inflammatory response in achalasia, include herpes simplex virus (HSV), varicella‐zoster, measles, and human papillomavirus . On the other hand, the autoimmune etiology of achalasia is supported by association with class‐two major histocompatibility complex haplotypes (HLA‐DQ and HLA‐DR), the presence gelatinase B/Matrix Metalloproteinase‐9 as immune effector molecule, antimyenteric antibodies, and inflammatory T cell infiltrates in the myenteric plexus, which are associated with damage to nerve plexus/ganglia, degeneration of neurons and ganglion cell loss . Furthermore, there is evidence of an association of the diverse autoimmune diseases with achalasia.…”