Genetic Analysis of Complex Inflammatory Disorders

National Human Genome Research Institute

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Abstract

VEXAS Syndrome Given the high mortality rate and significant clinical heterogeneity of VEXAS syndrome, we participated in a collaborative effort to determine independent predictors of survival in VEXAS and to understand the mechanistic basis for these factors. We analyzed 83 patients with somatic pathogenic variants in UBA1 at p.Met41 (p.Met41Leu/Thr/Val), the start codon for translation of the cytoplasmic isoform of UBA1 (UBA1b). Patients with the p.Met41Val genotype were most likely to have an undifferentiated inflammatory syndrome. Multivariate analysis showed ear chondritis was associated with increased survival, while transfusion dependence and the p.Met41Val variant were independently associated with decreased survival. Using in vitro models and patient-derived cells, we demonstrated that the p.Met41Val variant supports less UBA1b translation than either p.Met41Leu or p.Met41Thr, providing a molecular rationale for decreased survival. In addition, we showed that these three canonical VEXAS variants produce more UBA1b than any of the six other possible single nucleotide variants within this codon. Finally, we found that a patient, clinically diagnosed with VEXAS syndrome, had two novel mutations in UBA1 occurring in cis on the same allele. One mutation (c.121 A>T; p.Met41Leu) caused severely reduced translation of UBA1b in a reporter assay, but co-expression with the second mutation (c.119 G>C; p.Gly40Ala) rescued UBA1b levels to those of canonical mutations. We concluded that regulation of residual UBA1b translation is fundamental to the pathogenesis of VEXAS syndrome and contributes to disease pathogenesis. A manuscript reporting these findings was electronically published in Blood during the current reporting period. Systemic Onset Juvenile Idiopathic Arthritis (sJIA; Stills Disease) As part of the INCHARGE Consortium led by former fellow Michael Ombrello, we participated in the analysis of a case/control study of 66 patients with sJIA who exhibited features of drug reaction with eosinophilia and systemic symptoms (DRESS) to inhibitors of interleukin 1 (IL-1) or IL-6, compared with 65 drug-tolerant sJIA controls. Clinical data from all sJIA subjects were retrospectively analyzed and 94/131 were typed for HLA. European sJIA-DRESS cases were ancestry matched to International Childhood Arthritis Genetics Consortium (INCHARGE) pediatric sJIA cases (n=550) and compared for HLA allele frequencies. HLA association was also analyzed using sJIA-DRESS cases (n=64) compared with drug-tolerant sJIA (n=30). Kawasaki disease subjects (n=19) were similarly studied. sJIA-DRESS features included eosinophilia (89%), AST-ALT elevation (75%), and non-evanescent rash (95%). Macrophage activation syndrome during treatment was frequent in sJIA-DRESS (64%) versus drug-tolerant sJIA (3%; p=1.2x10e-14). There was striking enrichment for HLA-DRB1*15 haplotypes in sJIA-DRESS cases versus INCHARGE sJIA controls (p=7.5x10e-13) and versus self-identified, ancestry matched sJIA controls (p=6.3x10e-10). In the Kawasaki disease cohort, DRB*15:01 was present only in those with suspected anakinra reactions. We concluded that DRESS-type reactions occur among patients treated with IL-1/IL-6 inhibitors and strongly associate with common HLA-DRB1*15 haplotypes, and we suggested consideration of preprescription HLA typing and vigilance for serious reactions. A manuscript reporting these findings was published in the Annals of the Rheumatic Diseases during the current reporting period.