Abstract
Several microRNAs (miRNAs) are associated with autoimmune disease susceptibility and phenotype, including systemic lupus erythematosus (SLE). We aimed to explore for the first time the role of the miRNA-34a gene (MIR34A) rs2666433A > G variant in SLE risk and severity. A total of 163 adult patients with SLE and matched controls were recruited. Real-Time allelic discrimination PCR was applied for genotyping. Correlation with disease activity and clinic-laboratory data was done. The rs2666433 variant conferred protection against SLE development under heterozygous [A/G vs. G/G; OR = 0.57, 95%CI = 0.34–0.95], homozygous [A/A vs. G/G; OR = 0.52, 95%CI = 0.29–0.94], dominant [A/G + A/A vs. GG; OR = 0.55, 95%CI = 0.35–0.88], and log-additive [OR = 0.71, 95%CI = 0.53–0.95] models. Data stratification by sex revealed a significant association with SLE development in female participants under heterozygous/homozygous models (p-interaction = 0.004). There was no clear demarcation between SLE patients carrying different genotypes regarding the disease activity index or patients stratified according to lupus nephritis. Enrichment analysis confirmed the implication of MIR34A in the SLE pathway by targeting several genes related to SLE etiopathology. In conclusion, although the MIR34A rs2666433 variant conferred protection against developing SLE disease in the study population, it showed no association with disease activity. Replication studies in other populations are warranted.
Highlights
According to the SLEDAI score, patients were divided into four groups: 7.4% Grade 1, 30% Grade 2, 34%
The microRNA family of non-coding RNAs has been implicated in immune system homeostasis, and its genetic variants and gene signature deregulation are associated with several immunological disorders, including systemic lupus erythematosus (SLE) [32,39,40,41,42]
On searching “HaploReg V4.1: an online tool for exploring annotations of the noncoding genome [43] to predict the impact of rs2666433 SNP, we found that it is in linkage disequilibrium (r2 ≥ 0.8) with other variants present in chromosome 1, and can influence the Ets, peroxisome proliferator-activated receptor (PPAR), and the paired box-4 (Pax-4) DNA
Summary
The systemic lupus erythematosus (SLE) (OMIM: 152700) is a complex autoimmune disease characterized by a loss of tolerance against nuclear autoantigens and complex dysfunction of innate and adaptive immunity [1]. The worldwide overall incidence rates of SLE range from 1 to 10 per 100,000 person-years, affecting predominantly females (the female/male ratio is 9:1) of a reproductive age [2]. The major pathogenic mechanisms of SLE include an inappropriate immune response to the nucleic acid-containing cellular particles, which impact different organ systems [3,4]. Clinical and epidemiological studies suggest genetic factors, in addition to environmental insults, play an important role in SLE pathogenesis [5,6,7,8]
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