Sigurgeir Ólafsson

Significance We have previously demonstrated an increased autoantibody reactivity to Anoctamin 2 (ANO2), an ion channel expressed in the central nervous system (CNS), in multiple sclerosis (MS). We now show that ANO2 antibodies recognize a fragment of Epstein-Barr virus (EBV) nuclear antigen 1, thereby constituting an example of molecular mimicry. In this way, the immune response toward EBV may take part in and promote CNS inflammation, likely through T cells reactive with the same protein. In our very large case-control cohort, we demonstrate that the presence of ANO2 reactivity associates with a high MS risk, in particular together with HLA risk variants and high EBNA1 antibody titers, which we consider a strong argument for its relevance in MS ethiopathogenesis.

Abstract The human leukocyte antigen (HLA) haplotype DRB1*15 : 01 is the major risk factor for multiple sclerosis (MS). Here, we find that DRB1*15 : 01 is hypomethylated and predominantly expressed in monocytes among carriers of DRB1*15 : 01 . A differentially methylated region (DMR) encompassing HLA-DRB1 exon 2 is particularly affected and displays methylation-sensitive regulatory properties in vitro. Causal inference and Mendelian randomization provide evidence that HLA variants mediate risk for MS via changes in the HLA-DRB1 DMR that modify HLA-DRB1 expression. Meta-analysis of 14,259 cases and 171,347 controls confirms that these variants confer risk from DRB1*15 : 01 and also identifies a protective variant (rs9267649, p < 3.32 × 10 −8 , odds ratio = 0.86) after conditioning for all MS-associated variants in the region. rs9267649 is associated with increased DNA methylation at the HLA-DRB1 DMR and reduced expression of HLA-DRB1 , suggesting a modulation of the DRB1*15 : 01 effect. Our integrative approach provides insights into the molecular mechanisms of MS susceptibility and suggests putative therapeutic strategies targeting a methylation-mediated regulation of the major risk gene.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease associated with increased risk of gastrointestinal cancers. We whole-genome sequenced 446 colonic crypts from 46 IBD patients and compared these to 412 crypts from 41 non-IBD controls from our previous publication on the mutation landscape of the normal colon. The average mutation rate of affected colonic epithelial cells is 2.4-fold that of healthy colon, and this increase is mostly driven by acceleration of mutational processes ubiquitously observed in normal colon. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimeter-scale clonal expansions. We discovered non-synonymous mutations in ARID1A, FBXW7, PIGR, ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, under positive selection in IBD. These results suggest distinct selection mechanisms in the colitis-affected colon and that somatic mutations potentially play a causal role in IBD pathogenesis.