Date Published: March 7, 2019
Publisher: Public Library of Science
Author(s): Maëva Veyssiere, Javier Perea, Laetitia Michou, Anne Boland, Christophe Caloustian, Robert Olaso, Jean-François Deleuze, François Cornelis, Elisabeth Petit-Teixeira, Valérie Chaudru, Obul Reddy Bandapalli.
The triggering and development of Rheumatoid Arthritis (RA) is conditioned by environmental and genetic factors. Despite the identification of more than one hundred genetic variants associated with the disease, not all the cases can be explained. Here, we performed Whole Exome Sequencing in 9 multiplex families (N = 30) to identify rare variants susceptible to play a role in the disease pathogenesis. We pre-selected 77 genes which carried rare variants with a complete segregation with RA in the studied families. Follow-up linkage and association analyses with pVAAST highlighted significant RA association of 43 genes (p-value < 0.05 after 106 permutations) and pinpointed their most likely causal variant. We re-sequenced the 10 most significant likely causal variants (p-value ≤ 3.78*10−3 after 106 permutations) in the extended pedigrees and 9 additional multiplex families (N = 110). Only one SNV in SUPT20H: c.73A>T (p.Lys25*), presented a complete segregation with RA in an extended pedigree with early-onset cases. In summary, we identified in this study a new variant associated with RA in SUPT20H gene. This gene belongs to several biological pathways like macro-autophagy and monocyte/macrophage differentiation, which contribute to RA pathogenesis. In addition, these results showed that analyzing rare variants using a family-based approach is a strategy that allows to identify RA risk loci, even with a small dataset.
Rheumatoid Arthritis (RA) is one of the most frequent autoimmune disease, affecting 0.3 to 1% of the worldwide population. Since the discovery of HLA locus as a risk factor for autoimmune diseases  and specifically HLA-DRB1 for RA, more than 100 RA genetic factors were identified by Genome Wide Association Studies (GWASs) [2,3]. However, the effect of these genetic risk factors is too weak to explain the entire RA genetic component. Indeed, the heritability attributed to HLA-DRB1 shared-epitope (SE) alleles was estimated between 11%  and 37% . While GWASs loci identified outside the HLA locus only explain an additional five percent of RA heritability .
In this study, we identified a novel SNV associated with RA, SUPT20H: c.73A>T(p.Lys25*), by performing WES in 9 multiplex RA pedigrees associated with HLA-DRB1 SE risk alleles. This nonsense variant had a complete penetrance in a family with rather young age at RA onset (meanonset-age = 31 years old). In addition, we showed with the RVAT pVAAST, that this variant was significantly associated with RA (pVAASTp-value = 3.78*10−3).