MEFV variants as phenotypic modifiers in ankylosing spondylitis: a genetic interaction analysis with HLA-B27

Irmak Kaya Z., KAŞİFOĞLU T.

Acta Clinica Belgica: International Journal of Clinical and Laboratory Medicine, 2026 (SCI-Expanded, Scopus)

Abstract

Background: MEFV mutations are prevalent in Mediterranean populations, yet their potential role in modulating ankylosing spondylitis (AS) remains unclear. We investigated whether MEFV variants act as susceptibility factors or modify disease phenotype via interaction with HLA-B27. Methods: In this cross-sectional study, 129 AS patients meeting the modified New York criteria, 51 rheumatoid arthritis controls, and 58 healthy controls were genotyped for 11 MEFV mutations using pyrosequencing. Radiographic severity was assessed using the Bath Ankylosing Spondylitis Radiographic Index (BASRI), scored by a blinded radiologist. Multivariate linear regression identified independent predictors of structural involvement, incorporating a multiplicative interaction term (HLA-B27×MEFV). Bonferroni correction was applied to post-hoc analyses. Results: MEFV carrier frequencies were similar across groups (29.5% in AS, 29.4% in RA, 22.4% in controls; p = 0.582), indicating no primary role in susceptibility. In multivariate analysis without interaction, disease duration (β = 0.379, p < 0.001) and male sex (β = 0.214, p = 0.017) independently predicted BASRI scores, whereas HLA-B27 and MEFV alone were not significant. Including the interaction term revealed a significant HLA-B27×MEFV effect (β = 0.243, p = 0.012), improving model fit (ΔR2 = 0.034). Double-positive patients had higher BASRI scores than double-negatives (7.80 ± 4.15 vs. 4.80 ± 3.50; p = 0.008). Conclusion: MEFV variants do not increase AS susceptibility but are associated with greater structural involvement in HLA-B27-positive patients. This interaction identifies a high-risk genetic subgroup in endemic populations, highlighting implications for early identification and targeted monitoring.