Immunogenomics and Metabolic Diseases Laboratory, National Institute of Genomic Medicine, SS, Mexico City, Mexico.
Servicio de Reumatología del Hospital Juárez de México, Mexico City, Mexico.
Sci Rep. 2019 Aug 21;9(1):12165. doi: 10.1038/s41598-019-48451-3.
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.
I 型干扰素（IFN-I）通路在系统性红斑狼疮（SLE）发病机制中起着核心作用。最近的数据表明，SLE 与 IFN-I 基因的变异有关，如酪氨酸激酶 2（TYK2），它在抗病毒免疫中至关重要。在这里，对 368 名儿童发病的 SLE 墨西哥患者和 516 名性别匹配的健康对照者的 5 个 TYK2 单核苷酸多态性（SNP）进行了基因分型。还在四个土著群体中估计了等位基因频率。SLE 保护与 TYK2 风险感染变异有关，这些变异影响其催化结构域，rs12720356（OR=0.308；p=0.041）和 rs34536443（OR=0.370；p=0.034），但与 rs2304256、rs12720270 和 rs280500 无关。这一关联在 506 名成人发病的 SLE 患者样本中得到了复制（OR=0.250；p=0.005，和 OR=0.277；p=0.008）。这两个相关 SNP 的较小等位基因在梅斯蒂索人中的频率低于西班牙人，在土著人中不存在或罕见，这表明这些等位基因在墨西哥梅斯蒂索人群中的存在是由西班牙人衍生而来的。我们首次报告了在儿童和成人发病的墨西哥 SLE 人群中具有保护作用的遗传变异。我们的研究结果表明，与 SLE 相关的 IFN-I 等位基因的频率可能在长期暴露于传染病的人群中发生了变化，这可以解释为什么美洲原住民的血统与更高的 SLE 患病率和更早的发病有关。
