Conteduca G, Rossi A, Megiorni F, Parodi A, Ferrera F, Tardito S, Altosole T, Fausti V, Occella C, Kalli F, Negrini S, Pizzuti A, Marchese C, Rizza E, Indiveri F, Coviello D, Fenoglio D, Filaci G
Laboratory of Human Genetics IRCCS Istituto Giannina Gaslini Genoa Italy.
Department of Anesthesiology and Cardiovascular Clinical Internal Sciences "Sapienza" University of Rome Rome Italy.
Skin Health Dis. 2021 May 6;1(2):e34. doi: 10.1002/ski2.34. eCollection 2021 Jun.
Alopecia areata (AA) spares the stem cell compartment and attacks only the base of the hair follicle, which is surrounded by infiltrating lymphocytes. AA is associated with polymorphisms in immune-related genes and with decreased function of CD4+CD25+ T regulatory (Treg) cells. Treg function is modulated by the costimulatory molecules, like inducible costimulator (ICOS) that are crucial in orienting T cell differentiation and function so that they strongly impact on the immunologic decision between tolerance or autoimmunity development.
The aim of our study was to investigate the possible association of AA with single-nucleotide polymorphisms (SNP) present in the ICOS 3'-untranslated region (3'UTR) region and to elucidate how SNPs modulate ICOS gene expression by affecting miRNA binding sites.
This is a case-control study performed in 184 patients with AA and 200 controls. ICOS gene and miRNA expression were analyzed by real-time polymerase chain reaction.
The genotype carrying the rs4404254(C) [ = 0.012, OR (95% CI): 0.5 (0.3-0.8)] and rs4675379(C) [ = 0.015, OR (95% CI): 0.3 (0.1-0.8)] 3' UTR alleles was more frequently observed in AA patients than in controls and correlated with a reduced ICOS expression. miR-1276 significantly suppressed ICOS expression by binding to the 3'UTR of ICOS mRNA. Also, we observed that, miR-101 and miR-27b are upregulated, while miR-103 and miR-2355-3p are downregulated in peripheral blood mononuclear cells of AA patients compared to controls.
Our data show that rs4404254 and rs4675379 SNPs of ICOS gene are associated with AA and also reveal that the presence of rs4404254 polymorphism correlates with ICOS post-transcriptional repression by microRNA binding.
斑秃（AA）不累及干细胞区室，仅攻击毛囊底部，该部位被浸润的淋巴细胞所包围。AA与免疫相关基因的多态性以及CD4 + CD25 + T调节（Treg）细胞功能降低有关。Treg功能受共刺激分子调节，如诱导性共刺激分子（ICOS），其在引导T细胞分化和功能方面至关重要，因此对耐受或自身免疫发展之间的免疫决策有强烈影响。
我们研究的目的是调查AA与ICOS 3'非翻译区（3'UTR）区域存在的单核苷酸多态性（SNP）之间的可能关联，并阐明SNP如何通过影响miRNA结合位点来调节ICOS基因表达。
这是一项对184例AA患者和200例对照进行的病例对照研究。通过实时聚合酶链反应分析ICOS基因和miRNA表达。
携带rs4404254（C）[= 0.012，OR（95％CI）：0.5（0.3 - 0.8）]和rs4675379（C）[= 0.015，OR（95％CI）：0.3（0.1 - 0.8）] 3'UTR等位基因的基因型在AA患者中比在对照中更频繁地观察到，并且与ICOS表达降低相关。miR - 1276通过与ICOS mRNA的3'UTR结合而显著抑制ICOS表达。此外，我们观察到，与对照相比，AA患者外周血单核细胞中miR - 101和miR - 27b上调，而miR - 103和miR - 2355 - 3p下调。
我们的数据表明，ICOS基因的rs4404254和rs4675379 SNP与AA相关，并且还揭示了rs4404254多态性的存在与通过microRNA结合的ICOS转录后抑制相关。
