Overexpression of the Cytokine BAFF and Autoimmunity Risk

TLDR

Genome‑wide association studies have identified hundreds of autoimmune disease loci, yet few causal genes, variants, or mechanisms have been pinpointed. The study sought to uncover disease‑causal variants and mechanisms by exploiting coincident associations of DNA variants with autoimmune disease risk and immune traits, focusing on multiple sclerosis and systemic lupus erythematosus in Sardinia. Researchers performed fine‑mapping, cross‑population and cross‑phenotype analyses, extensive immune phenotyping, gene‑expression studies, and examined positive‑selection signatures to identify the causal variant and its mechanism. An indel (GCTGT→A) in TNFSF13B that escapes microRNA inhibition increases soluble BAFF, up‑regulates humoral immunity, and associates with multiple sclerosis and systemic lupus erythematosus, with population‑genetic evidence of positive selection likely linked to malaria resistance. Funding was provided by the Italian Foundation for Multiple Sclerosis and other organizations.

Abstract

Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways.Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated.A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion-deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria.A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.).