Abstract
Objective Macrophage activation syndrome (MAS), a life-threatening complication of SLE, resembles familial hemophagocytic lymphohistiocytosis (fHLH), an inherited disorder of hyperinflammation. We compared the proportion of childhood-onset SLE (cSLE) patients with and without MAS, who carried low-frequency HLH non-synonymous variants.
Methods We enrolled patients from the Lupus Clinic at SickKids, Toronto. Demographic and clinical features were extracted from the lupus database and ancestry was genetically inferred using multiethnic genotyping array data. Patients with MAS (based on expert diagnosis) underwent either paired-end whole exome sequencing (read-depth:70-118X) or whole-genome sequencing. Non-MAS patients had whole-genome sequencing (read-depth:37-40X). In 16 HLH genes we prioritized low-frequency (minor allele frequency (MAF) <0.05) exonic nonsynonymous variants. We compared the proportion of patients with and without MAS carrying HLH variants (Fisher's exact test, P<0.05). MAFs were compared to an ancestrally-matched general population (TOPMed and gnomAD).
Results The study included 81 patients, 19 with MAS. We identified 47 unique low-frequency non-synonymous HLH variants. There was no difference in the proportion of MAS and non-MAS patients carrying ≥1 HLH variants (37% versus 47%, P=0.44). The MAS cohort did not carry more HLH variants when compared to an ancestrally-matched general population.
Conclusion In a single-center multiethnic cSLE cohort, we found no difference in the proportion of MAS patients carrying non-synonymous HLH genetic variants compared to patients without MAS. This is the first study to examine the frequency of HLH genetic variants in relation to MAS among cSLE patients. Future studies are required to validate our findings.
