Abstract
Type I interferon (IFN-I) pathway plays a central role in the systemic lupus erythematosus (SLE) pathogenesis. Recent data suggest that SLE is associated with variants in IFN-I genes, such as tyrosine kinase 2 (TYK2), which is crucial in anti-viral immunity. Here, five TYK2 single nucleotide polymorphisms (SNPs) were genotyped in 368 childhood-onset SLE Mexican patients and 516 sex-matched healthy controls. Allele frequencies were also estimated in four indigenous groups. SLE protection was associated with TYK2 risk infection variants affecting residually its catalytic domain, rs12720356 (OR = 0.308; p = 0.041) and rs34536443 (OR = 0.370; p = 0.034), but not with rs2304256, rs12720270, and rs280500. This association was replicated in a 506 adult-onset SLE patients sample (OR = 0.250; p = 0.005, and OR = 0.277; p = 0.008, respectively). The minor alleles of both associated SNPs had a lower frequency in Mestizos than in Spaniards and were absent or rare in indigenous, suggesting that the presence of these alleles in the Mexican Mestizo population was derived from the Spaniards. For the first time, we report genetic variants with a protective effect in childhood- and adult-onset SLE Mexican population. Our results suggest that the frequency of IFN-I alleles associated with SLE, may have been shaped in populations exposed to infectious diseases for long periods, and this could be an explanation why Native American ancestry is associated with a higher SLE prevalence and an earlier onset.
Highlights
A haplotype located on IFN-regulatory factor 5 (IRF5) shows one of the strongest associations with SLE (OR = 10.46), and was identified in the Mexican Mestizo population
We compared these allele frequencies with those reported in the 1000 Genomes Project Database, and with those determined in the Mexican indigenous population in this study
These frequencies were significantly lower than those observed among the Mexican Mestizo healthy controls (Table 1, and Supplemental Table 1), suggesting that the presence of these alleles in the Mexican Mestizo population was derived from the Spaniards
Summary
Demonstrate that the type I interferon (IFN-I) pathway plays a central role in SLE pathogenesis, in agreement with the concurrence of elevated IFN-α serum levels in several SLE patients[9,10] Supporting this relationship, association studies in different populations indicate that IFN-I signaling genes contribute to SLE. In the Han Chinese population, a gene–gene interaction between TYK2 and IRF5 is associated with SLE susceptibility, suggesting that the combined effect of variants located in IFN genes may play a crucial role in SLE pathogenesis[12]. These varied observations may reflect differences that rely among populations[13]. We determined whether the gene–gene interaction of TYK2 with the risk haplotype of IRF5 was associated with this disease
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