Influence of Atg5 mutation in SLE depends on functional IL-10 genotype

Patricia López, Elisa Alonso-Pérez, Javier Rodríguez-Carrio, Ana Suárez, Patricia López, Elisa Alonso-Pérez, Javier Rodríguez-Carrio, Ana Suárez

Abstract

Increasing evidence supports the involvement of autophagy in the etiopathology of autoimmune diseases. Despite the identification of autophagy-related protein (Atg)-5 as one of the susceptibility loci in systemic Lupus erythematosus (SLE), the consequences of the carriage of these mutations for patients remain unclear. The present work analyzed the association of Atg5 rs573775 single nucleotide polymorphism (SNP) with SLE susceptibility, IFNα, TNFα and IL-10 serum levels, and clinical features, in 115 patients and 170 healthy individuals. Patients who where carriers of the rs573775 T* minor allele presented lower IFNα levels than those with the wild genotype, whereas the opposite result was detected for IL-10. Thus, since IL-10 production was regulated by rs1800896 polymorphisms, we evaluated the effect of this Atg5 mutation in genetically high and low IL-10 producers. Interestingly, we found that the rs573775 T* allele was a risk factor for SLE in carriers of the high IL-10 producer genotype, but not among genetically low producers. Moreover, IL-10 genotype influences SLE features in patients presenting the Atg5 mutated allele. Specifically, carriage of the rs573775 T* allele led to IL-10 upregulation, reduced IFNα and TNFα production and a low frequency of cytopenia in patients with the high IL-10 producer genotype, whereas patients with the same Atg5 allele that were low IL-10 producers presented reduced amounts of all these cytokines, had a lower prevalence of anti-dsDNA antibodies and the latest onset age. In conclusion, the Atg5 rs573775 T* allele seems to influence SLE susceptibility, cytokine production and disease features depending on other factors such as functional IL-10 genotype.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Atg5 rs573775 SNP influences cytokine…
Figure 1. Atg5 rs573775 SNP influences cytokine levels in SLE patients.
IFNα, TNFα and IL-10 serum levels were quantified by ELISA techniques in individuals previously genotyped for rs573775 SNP. A) IFNα serum levels in SLE patients and controls are shown on the basis of the Atg5 rs573775 alleles. B) IL-10 and TNFα serum levels depending on Atg5 alleles in SLE patients. Data are shown as box plots, where the lines in the boxes represent the median, the boxes represent the 25th to 75th centiles, and the lines outside the boxes represent the 10th and 90th centiles. Differences in cytokine serum concentration among genotypes were analyzed by the Kruskal-Wallis test (K-W test). Significant differences between one group and the rest were evaluated by Mann-Whitney U test (*p<0.05).
Figure 2. Effects of Atg5 and IL-10…
Figure 2. Effects of Atg5 and IL-10 SNPs on SLE risk, cytokine levels and clinical features.
The diagram represents a model of the effects of Atg5 rs573775 and the functional IL-10 polymorphisms (low/high genetic producers) on SLE, which were supported by our results. A significant influence of both SNPs was detected, however, Atg5 rs573775 showed a dominant role.

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