Beyond Human Leukocyte Antigen Class I Antigens: Hereditary Hemochromatosis Gene Mutations in Recurrent Aphthous Oral Ulcers and Behçet Disease in the South of Tunisia

Abstract

Objective: The aim of this work was to establish human leukocyte antigen (HLA) class I and hereditary hemochromatosis gene (HFE) mutation associations with recurrent aphthous oral ulcers (RAOU) and Behçet disease (BD) in a cohort of Southern Tunisian patients. Subjects and Methods: A total of 232 patients with RAOU and 123 healthy controls (HCs) were enrolled in this study. The patients were divided into 2 groups based on the presence (BD+: n = 62) or absence of BD (BD−, n = 170). In the BD+ group, 28 patients had severe manifestations of BD. In the BD- group, RAOU was isolated in 81 patients, associated with mucocutaneous manifestations in 58 and with joint symptoms in 25. Complement-dependent microlymphocytotoxicity assay and polymerase chain reaction-restriction fragment length polymorphism were used to study HLA class I polymorphism and HFE mutations, respectively. Results: HLA-B51 was positively associated with BD, particularly in those with severe manifestations. No association was detected with HLA class I polymorphism among the BD group. Based on stratification to clinical manifestations, the isolated RAOU was negatively associated with HLA-A1 with a difference close to significance (12 [14.81%] vs. 32 [26.02%] in HCs; p = 0.06). Furthermore, patients with mucocutaneous features had a higher frequency of HLA-B51 (14, 24.14%) than patients without mucocutaneous involvement (11, 11.37%). Considering HFE mutations, patients with isolated RAOU had a higher frequency of H63D when compared with other subgroups, especially after limiting the comparison to 27 patients of at least 5 years of follow-up. Conclusion: This study showed that, unlike BD, RAOU were not associated with HLA-B51. Moreover, we suggest that H63D mutation was positively associated with isolated RAOU.