A putative functional variant within the UBAC2 gene is associated with increased risk of Behçet's disease

Abstract

Objectives Using a genome-wide association scan and DNA pooling, we previously identified 5 novel genetic susceptibility loci for Behçet’s disease. Herein, we establish the genetic effect within the UBAC2 gene, replicate this genetic association, and identify a functional variant within this locus. Methods A total of 676 Behçet’s disease patients and 1,096 controls were studied. The discovery set included 156 patients and 167 controls from Turkey, and the replication sets included 376 patients and 369 controls, and 144 patients and 560 controls, from Turkey and Italy, respectively. Genotyping of 14 SNPs within and around UBAC2 was performed using TaqMan SNP genotyping assays. Results The genetic association between Behçet’s disease and UBAC2 was established, replicated and confirmed (Meta-analysis OR= 1.84, meta-analysis P= 1.69X10−7). Haplotype analysis identified both a disease risk and a protective haplotype (P= 0.00014 and 0.0075, respectively). Using conditional haplotype analysis we identified the SNP rs7999348 (A/G) within UBAC2 as the most likely SNP with a genetic effect independent of the haplotypic effect formed by the remaining associated SNPs in this locus. Indeed, we demonstrate that rs7999348 tags a functional variant associated with increased mRNA expression of a UBAC2 transcript variant in PBMCs of individuals homozygous for the Behçet’s disease-associated “G” allele. Further, our data suggest the possibility of multiple genetic effects that increase susceptibility to Behçet’s disease in the UBAC2 locus. Conclusion We established and confirmed the genetic association between UBAC2 and Behçet’s disease in three independent sets of patients and controls. We identified the minor allele in rs7999348 as a disease-risk allele that tags altered UBAC2 expression.

Replication study confirms the association between UBAC2 and Behçet's disease in two independent Chinese sets of patients and controls

“…The UBAC2 gene encodes an ubiquitination related structural domain. The study reported by Fei et al [19] and their subsequent replication showed the association of UBAC2 gene with Behçet's disease and revealed the possible contribution of UBAC2 in the pathogenesis of BD [20]. Our present study successfully replicated the association between UBAC2 and BD in a Chinese cohort.…”

Inactive rhomboid proteins: New mechanisms with implications in health and disease

“…However, the respective metabolic pathways controlled by human versus S. pombe UBAC2 orthologs appear distinct, and precisely how UBAC2 and Dsc2 interplay with their clients remains to be investigated. Notably, UBAC2 has been identified, in genome-wide association studies, as a candidate gene for Behçets syndrome, a complex inflammatory condition of unknown etiology [82]. It is difficult to reconcile this with the cell biological observations mentioned above.…”

Identification of a susceptibility locus in STAT4 for Behçet's disease in Han Chinese in a genome‐wide association study

“…These findings indicate that additional genetic risks remain to be discovered. Many approaches to searching for genetic risk have been used to identify additional risk loci for BD, such as genome‐wide linkage scans in multiplex families (14) and candidate gene association studies (15–33). Recently, genome‐wide association studies (GWAS) for BD have identified several risk loci at IL23R – IL12RB2 , IL10 , KIAA1529 , CPVL , LOC100129342 , UBASH3B , and UBAC2 in Turkish and Japanese patients (34–36).…”