RNAseq-Based Prioritization Revealed COL6A5, COL8A1, COL10A1 and MIR146A as Common and Differential Susceptibility Biomarkers for Psoriasis and Psoriatic Arthritis: Confirmation from Genotyping Analysis of 1417 Italian Subjects

Abstract

Psoriasis (Ps) and Psoriatic Arthritis (PsA) are characterized by a multifactorial etiology, involving genetic and environmental factors. The present study aimed to investigate polymorphisms (SNPs) within genes involved in extracellular matrix and cell homeostasis and microRNA genes as susceptibility biomarkers for Ps and PsA. Bioinformatic analysis on public RNA-seq data allowed for selection of rs12488457 (A/C, COL6A5), rs13081855 (G/T, COL8A1), rs3812111 (A/T, COL10A1) and rs2910164 (C/G, MIR146A) as candidate biomarkers. These polymorphisms were analyzed by Real-Time PCR in a cohort of 1417 Italian patients (393 Ps, 424 PsA, 600 controls). Statistical and bioinformatic tools were utilized for assessing the genetic association and predicting the effects of the selected SNPs. rs12488457, rs13081855 and rs2910164 were significantly associated with both Ps (p = 1.39 × 10−8, p = 4.52 × 10−4, p = 0.04, respectively) and PsA (p = 5.12 × 10−5, p = 1.19 × 10−6, p = 0.01, respectively). rs3812111, instead, was associated only with PsA (p = 0.005). Bioinformatic analysis revealed common and differential biological pathways involved in Ps and PsA. COL6A5 and COL8A1 take part in the proliferation and angiogenic pathways which are altered in Ps/PsA and contribute to inflammation together with MIR146A. On the other hand, the exclusive association of COL10A1 with PsA highlighted the specific involvement of bone metabolism in PsA.

Overview of the molecular determinants contributing to the expression of Psoriasis and Psoriatic Arthritis phenotypes

“…However, the expression of COL6A5 in the papillary dermis 42 suggested a potential association with Ps and PsA, given the fact that the papillary dermis can be affected in both disorders. Supporting this hypothesis, we found a significant association of rs12488457 (A/C) variant located in COL6A5 with Ps and PsA in a recent study on the Italian population 48 …”

“…In this context, mutations in these genes have been associated with different forms of chondrodysplasia 36 and increased levels of collagen X have been found in the serum of PsA patients 52 . On this subject, we found that the COL10A1 ‐rs3812111 (T/A) variant was exclusively associated with PsA, suggesting the possible contribution of bone metabolism‐related factors in the differential etiopathogenesis of PsA compared to Ps 48 . Given these data and considering the role of collagen genes in the maintenance of bone homeostasis, their investigation may provide interesting insights into different etiopathogenetic pathways underlying Ps and PsA 53 …”

“…Moreover, the genomic analysis of miRNAs genes and 3’UTR‐target genes as well as lncRNAs genes may reveal the presence of polymorphisms (SNPs, indels) that may alter the affinity binding or interaction with the expected target mRNAs and, ultimately, modify the transcriptional profile of the target genes 95,98 . On this subject, we reported the association of rs2910164 (C/G) variant within MIR146A sequence with both Ps and PsA in the Italian population, suggesting that the potential effect on the miRNA expression and post‐transcriptional regulation of target genes involved in skin homeostasis might contribute to the exacerbation of inflammation in Ps and PsA 48 . Therefore, further research on variants in miRNA genes will be critical for proving the existence of a ‘genetics of epigenetics’ contributing to the onset and progression of complex disorders such as Ps and PsA.…”

“…52 On this subject, we found that the COL10A1-rs3812111 (T/A) variant was exclusively associated with PsA, suggesting the possible contribution of bone metabolism-related factors in the differential etiopathogenesis of PsA compared to Ps. 48 Given these data and considering the role of collagen genes in the maintenance of bone homeostasis, their investigation may provide interesting insights into different etiopathogenetic pathways underlying Ps and PsA. 53 54 However, the microbial load may also be influenced by age, gender and lifestyle, suggesting that individuals may be stratified according to their microbiome profile.…”

“…47 Moreover, we recently reported the association of this variant with both Ps and PsA in the Italian population, highlighting a contribution of COL8A1 to ECM remodelling and activation of VEGFA-related pathways in psoriatic diseases. 48 COL2A1, COL9A1, COL10A1, COL11A1 and COL11A2 (Table 1) TA B L E 1 Overview of the genes potentially contributing to the etiopathogenesis of Psoriasis and Psoriatic Arthritis discussed throughout the manuscript encode important components of cartilage and are known to play an important role in joints maintenance and bone formation. 36,37 In this context, mutations in these genes have been associated with different forms of chondrodysplasia 36 and increased levels of collagen X have been found in the serum of PsA patients.…”