Background/Purpose: Rare variants provide important opportunity for mechanistic insight as they carry substantial effect sizes and provide deep insight into disease etiopathogenesis. To date, several pathways have been identified as monogenic causes of SLE or similar syndromes of systemic autoimmunity, particularly with the severe manifestations of childhood onset SLE. In several other disease phenotypes, such as autism spectrum disorders, with severe presentation in childhood, exome-wide sequencing approaches of both unaffected parents and affected children have identified causal de novo mutations and thus identified novel genes that were not amenable to the GWAS approach. With this approach, we identified a novel SLE candidate gene, ACACB, which encodes the acetyl-CoA carboxylase beta subunit (ACC-beta) (see below). This enzyme functions in many tissues as a regulator of fatty acid oxidation and was previously defined as a key modulator of innate immune response through its role supporting the anabolic demands of activated dendritic cells.

Methods: In order to define de novo mutations in SLE, we performed an exome-wide sequencing study in a trio consisting of an SLE proband and her parents. Quality control and Mendelian errors were filtered using a validated analysis pipeline (CASSI) as previously described [1]. Functional studies of a gene containing a de novo variant, ACACB, were then performed using 5-(Tetradecyloxy)-2-furoic acid (TOFA), an inhibitor of ACACB. THP1-Blue ISG cells that have stable integration of an interferon regulatory factor (IRF)-inducible secreted alkaline phosphatase reporter construct were treated with TOFA to confirm a role for ACACB in type I interferon response (Invivogen). P-values presented were adjusted for multiple comparisons using the Holm-Sidak method with alpha = 0.05.

Results: Inhibition studies with TOFA revealed that type I interferon activity in response to several nucleic acid ligands was impaired in the setting of ACC-beta inhibition as measured by secreted alkaline phosphatase activity. Specifically, in comparison to vehicle treatment, TOFA treated cells demonstrated 10-20% dose-dependent reduction of type I interferon activity in response to the STING ligand cGAMP (P < 0.01), 10-15% dose-dependent reduction of type I interferon activity in response to the transfection of the cytosolic DNA and RNA sensor ligand poly(dA:dT) (P< 0.01) and non-significant trend towards dose-dependent reduction of type I interferon activity in response to the TLR-7/TLR-8 ligand R848 (resiquimod).

Conclusion: ACACB is a candidate SLE susceptibility gene for childhood onset SLE. Inhibition of the activity of ACC-beta, its product, modulates type I interferon response to several SLE autoantigen relevant pattern recognition receptor ligands. By defining ACACB as a candidate mutation in SLE, fatty acid beta-oxidation is defined as a potential novel druggable target for SLE therapy. ACC inhibitors in development to treat non-alcoholic steatohepatitis may find utility if repurposed to treat human SLE.

[1] Front Genet. 2014 Feb 12;5:16. doi: 10.3389/fgene.2014.00016. eCollection 2014.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/de-novo-mutation-in-%ce%b1c%ce%b1c%ce%b2-in-childhood-onset-sle-highlights-a-novel-role-as-modulator-of-nucleic-acid-sensor-driven-type-i-interferon-responses/