The Association of ATG16L1 Variations with Clinical Phenotypes of Adult-Onset Still's Disease.

Wei-Ting Hung,Shuen-Iu Hung,Yi-Ming Chen,Kuo-Tung Tang,Chia-Wei Hsieh,Der-Yuan Chen,Hsin-Hua Chen,Tsuo-Hung Lan

doi:10.3390/genes12060904

Abstract

Adult-onset Still’s disease (AOSD) is a rare autoinflammatory disease, which has elevated autophagosome levels regulated by autophagy-related gene (ATG) expression. We investigated the associations of ATG polymorphisms with AOSD susceptibility, clinical manifestations, and disease course. The six-candidate single-nucleotide polymorphisms (SNPs) involved in autophagy were genotyped using direct sequencing on samples from 129 AOSD patients and 129 healthy participants. The differentially expressed gene products were quantified using PCR and ELISA. Significant linkage disequilibrium was noted in three SNPs of autophagy-related 16-like 1 (ATG16L1) gene (rs10210302, rs2241880, and rs1045100). Although the AA/CC/TT haplotype of ATG16L1 was not associated with the susceptibility of our AOSD patients compared with other haplotypes, those carrying this haplotype had lower mRNA expression levels of LC3-II, reflecting by autophagosome formation (p = 0.026). Patients carrying AA/CC/TT haplotype also have a significantly higher proportion of skin rash and a lower proportion of arthritis compared with other haplotypes. The AA/CC/TT haplotype was significantly associated with systemic pattern (odds ratio, 3.25; 95% confidence interval, 1.15–9.14; p = 0.026). In summary, the AA/CC/TT haplotype encoded lower levels of autophagosome formation and was associated with a higher proportion of skin rash and systemic pattern of AOSD compared with other haplotypes.

Highlights

Adult-onset Still’s disease (AOSD) is characterized by spiking fever, skin rash, arthritis, lymphadenopathy, hepatosplenomegaly, variable multisystemic involvement, and increased acute phase reactants [1,2]
Taking the AA/CC/TT haplotype as the reference, we observed an increased odds ratios (ORs) (95% confidence interval) of the AG/CT/CT haplotype in patients with AOSD compared with the healthy controls (OR 1.74, CI (1.02–2.95), p = 0.04)
We identified a valuable genetic variant, the AA/CC/TT haplotype of the autophagy-related 16-like 1 (ATG16L1) gene composed of three single-nucleotide polymorphisms (SNPs), as a genetic factor that is significantly associated with the systemic pattern of AOSD by using direct sequencing

Summary

Introduction

Adult-onset Still’s disease (AOSD) is characterized by spiking fever, skin rash, arthritis, lymphadenopathy, hepatosplenomegaly, variable multisystemic involvement, and increased acute phase reactants [1,2]. Its pathogenesis remains elusive, AOSD is characterized by increased levels of proinflammatory cytokines, such as interleukin (IL)-1β and IL-18 [5,6,7]. We recently revealed that elevated levels of autophagosome formation and autophagy-related gene (ATG). Expression both positively correlated with disease activity, suggesting the involvement of autophagy in AOSD pathogenesis [8]. Autophagy is a genetically programmed process that requires ATG proteins. The genetic variants within or near ATG5, which are required for autophagosome formation, may participate in the pathogenesis of systemic lupus erythematosus at multiple levels [11,12]. ATG7 mediates the elongation of the isolation membrane, which culminates in the conversion of microtubule-associated protein one light chain three (LC3-I) to its phosphatidylethanolamineconjugated form (LC3-II), a process indicating active autophagy [13,14]. Autophagyrelated 16-like 1 (ATG16L1) is required to extend phagophores through the ATG5–ATG12–

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