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. 2011 Nov;63(11):3607-12.
doi: 10.1002/art.30604.

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

Amr H Sawalha  1 , Travis Hughes, Ajay Nadig, Vuslat Yılmaz, Kenan Aksu, Gokhan Keser, Ayse Cefle, Ayten Yazıcı, Andaç Ergen, Marta E Alarcón-Riquelme, Carlo Salvarani, Bruno Casali, Haner Direskeneli, Güher Saruhan-Direskeneli
Affiliations

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

Amr H Sawalha et al. Arthritis Rheum. 2011 Nov.

Abstract

Objective: Using a genome-wide association scan and DNA pooling, we previously identified 5 novel genetic susceptibility loci for Behçet's disease. We undertook this study to establish the genetic effect within the UBAC2 gene, in the course of which we replicated this genetic association and identified a functional variant within this locus.

Methods: We studied a total of 676 Behçet's disease patients and 1,096 controls. The discovery set included 156 patients and 167 controls from Turkey, and the replication sets included 376 patients and 369 controls from Turkey and 144 patients and 560 controls from Italy. Genotyping of 14 single-nucleotide polymorphisms (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 odds ratio 1.84, P = 1.69 × 10(-7) ). Haplotype analysis identified both a disease-risk haplotype and a protective haplotype (P = 0.00014 and P = 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 demonstrated that rs7999348 tags a functional variant associated with increased messenger RNA expression of a UBAC2 transcript variant in peripheral blood mononuclear cells of individuals homozygous for the Behçet's disease-associated "G" allele. Further, our data suggested 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 3 independent sets of patients and controls. We identified the minor allele in rs7999348 as a disease-risk allele that tags altered UBAC2 expression.

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Conflict of interest statement

Conflict of Interest Statement

None of the authors has any financial conflict of interest with the work and results presented herein.

Figures

Figure 1
Figure 1
Linkage disequilibrium (LD) plot showing the 14 SNPs genotyped in the UBAC2 locus and pair-wise correlation coefficient (r2) values. The location of the newly-identified functional SNP rs7999348 is depicted with an arrow.
Figure 2
Figure 2
Relative mRNA expression of UBAC2 transcript variant 1 (NM_001144072.1) in PBMCs of healthy normal donors with homozygous risk (GG) (n= 4), heterozygous (AG) (n= 8), and homozygous protective (AA) (n= 8) rs7999348 genotypes.
See this image and copyright information in PMC

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