Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55-IL6ST Gene Region in Immature Dendritic Cells.

Jorge Mena,Javier Díez García,Xavier Montalban,Koen Vandenbroeck,Ane Aldekoa,Ane Villanueva Etxebarria,Manuel Comabella,Cecilia Lindskog,Iraide Alloza,Raquel Tulloch Navarro,Alfredo Antigüedad,Luisa María Villar,Sunny Malhotra,José Luis Sánchez Menoyo,Amaya Álvarez De Arcaya,María Del Mar Mendibe-Bilbao,Noelia Villarrubia,Luciana Midaglia,Sabas Boyero

doi:10.3389/fimmu.2021.816930

Abstract

Intronic single-nucleotide polymorphisms (SNPs) in the ANKRD55 gene are associated with the risk for multiple sclerosis (MS) and rheumatoid arthritis by genome-wide association studies (GWAS). The risk alleles have been linked to higher expression levels of ANKRD55 and the neighboring IL6ST (gp130) gene in CD4+ T lymphocytes of healthy controls. The biological function of ANKRD55, its role in the immune system, and cellular sources of expression other than lymphocytes remain uncharacterized. Here, we show that monocytes gain capacity to express ANKRD55 during differentiation in immature monocyte-derived dendritic cells (moDCs) in the presence of interleukin (IL)-4/granulocyte-macrophage colony-stimulating factor (GM-CSF). ANKRD55 expression levels are further enhanced by retinoic acid agonist AM580 but downregulated following maturation with interferon (IFN)-γ and lipopolysaccharide (LPS). ANKRD55 was detected in the nucleus of moDC in nuclear speckles. We also analyzed the adjacent IL6ST, IL31RA, and SLC38A9 genes. Of note, in healthy controls, MS risk SNP genotype influenced ANKRD55 and IL6ST expression in immature moDC in opposite directions to that in CD4+ T cells. This effect was stronger for a partially correlated SNP, rs13186299, that is located, similar to the main MS risk SNPs, in an ANKRD55 intron. Upon analysis in MS patients, the main GWAS MS risk SNP rs7731626 was associated with ANKRD55 expression levels in CD4+ T cells. MoDC-specific ANKRD55 and IL6ST mRNA levels showed significant differences according to the clinical form of the disease, but, in contrast to healthy controls, were not influenced by genotype. We also measured serum sgp130 levels, which were found to be higher in homozygotes of the protective allele of rs7731626. Our study characterizes ANKRD55 expression in moDC and indicates monocyte-to-dendritic cell (Mo–DC) differentiation as a process potentially influenced by MS risk SNPs.

Highlights

The ANKRD55 gene, located on chromosome 5q11.2, contains single-nucleotide polymorphisms (SNPs) that emerged from genome-wide association studies (GWAS) as risk variants for disorders with predominantly autoimmune or chronic inflammatory etiopathogenesis
The three soluble gp130 isoforms were highly expressed in CD4+ T helper lymphocytes but less so in the other subpopulations studied, similar to the patterns seen for IL6ST (Supplementary Figure S2)
The influence of homozygosity for MS risk SNPs rs6859219 and rs7731626 and of the correlated SNP rs13186299 on the expression in healthy control (HC) CD4+ T cells of ANKRD55, IL6ST, and the three sgp130 isoforms is shown in Supplementary Figure S3

Summary

Introduction

The ANKRD55 gene, located on chromosome 5q11.2, contains single-nucleotide polymorphisms (SNPs) that emerged from genome-wide association studies (GWAS) as risk variants for disorders with predominantly autoimmune or chronic inflammatory etiopathogenesis. Among these SNPs, rs7731626 (Chr 5: 56148856) is the variant displaying the strongest association with both rheumatoid arthritis [RA; P < 2 × 10-22; ref [1, 2]] and multiple sclerosis [MS; P = 4 × 10-15; ref [3]]. Other SNPs in ANKRD55, located like rs7731626 in intronic areas next to exon 6 (Figure 1), have, as well, been associated with the risk for autoimmune disease with genome-wide significance levels. The IL6ST gene codes for the interleukin (IL)-6 receptor b unit, known as glycoprotein

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Conclusion