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

ABSTRACT: 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.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.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.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.

SUBMITTER: Sawalha AH

PROVIDER: S-EPMC3205238 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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

Sawalha Amr H AH Hughes Travis T Nadig Ajay A Yılmaz Vuslat V Aksu Kenan K Keser Gokhan G Cefle Ayse A Yazıcı Ayten A Ergen Andaç A Alarcón-Riquelme Marta E ME Salvarani Carlo C Casali Bruno B Direskeneli Haner H Saruhan-Direskeneli Güher G

Arthritis and rheumatism 20111101 11

<h4>Objective</h4>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.<h4>Methods</h4>We studied a total of 676 Behçet's disease patients and 1,096 controls. The discovery set included 156 patients and 167 controls from ...[more]

PMID: 21918955

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Project description:INTRODUCTION:The purpose of this study was to replicate genetic factors associated with the susceptibility to Behçet's disease (BD). We conducted a two-stage candidate genes association and functional study, involving 477 BD patients and 1,334 normal controls of Chinese Han descent. METHODS:The genotyping of five candidate genes/loci, including LOC100129342, KIAA1529, CPVL, UBASH3B and UBAC2, were performed using TaqMan single nucleotide polymorphism (SNP) assays. Real-time PCR and luciferase reporter assay were performed to test the function of the identified promoter polymorphism. The main outcome measures were genotype frequencies and expression levels in BD patients. RESULTS:The first-stage study results showed that UBAC2 (rs9513584, Pc = 0.018, OR = 1.4), but not LOC100129342, KIAA1529, CPVL, UBASH3B was associated with the susceptibility to BD in Chinese Han. The fine-mapping association study of UBAC2 identified six risk SNPs for BD in the Chinese cohort; three of them were verified in validation study (rs3825427, first-stage Pc = 2.2 × 10-3, second-stage Pc = 9.3 × 10-3, combined Pc = 6.9 × 10-6; rs9517668, first-stage Pc = 1.7 × 10-3, second-stage Pc = 0.03, combined Pc = 3.3 × 10-4; rs9517701, first-stage Pc = 5.1 × 10-3, second-stage Pc = 9.0 × 10-3, combined Pc = 2.9 × 10-5; respectively). Functional analysis showed that the risk T allele of the promoter polymorphism rs3825427 had a significantly lower promoter activity than the non-risk G allele (P = 0.002) and a decreased expression of UBAC2 transcript variant 1 in peripheral blood mononuclear cells (PBMCs) and skin of normal controls carrying the risk T allele than that in individuals with the G allele (P = 0.045, P = 0.025; respectively). The mRNA expression of UBAC2 transcript variant 1 was significantly decreased in PBMCs and skin of BD patients as compared with controls (P = 0.025; P = 0.047, respectively). The mRNA expression of UBAC2 transcript variant 2 was significantly increased in skin of BD patients as compared with controls (P = 0.004). CONCLUSIONS:This study replicates a predisposition gene to BD, UBAC2, and suggests that UBAC2 may be involved in the development of BD through its transcriptional modulation.

Project description:BackgroundsBone morphogenetic protein receptor type 2 (BMPR2) signaling is anti-inflammatory. Decreased BMPR2 expression was seen in lung tissue from chronic obstructive pulmonary disease (COPD) patients.MethodsThe selected single nucleotide polymorphisms (SNPs) in BMPR2 were genotyped with polymerase chain reaction (PCR) ligase detection reaction. The effects of SNPs on gene expression were analyzed with luciferase assays. The mRNA and protein expression levels of BMPR2 in peripheral blood mononuclear cells (PBMCs) from COPD patients were determined by quantitative PCR and western blotting, respectively.FindingsTwo SNPs, rs6435156C > T and rs1048829G > T in the 3'-untranslated region (3'UTR) of BMPR2 were selected and genotyped in COPD case and healthy control subjects from southern Chinese population. Both of them were found associated with significantly increased COPD risk (adjusted odds ratio [OR] = 1.58 with 95% confidence interval [CI] = 1.14-2.15, P = 0.0056 for rs6435156C > T; adjusted OR = 1.47 and 95% CI = 1.10-1.97, P = 0.0092 for rs1048829G > T). Older age, cigarette smoking, family history of cancer and COPD were all factors that interacted with rs6435156C > T and rs1048829G > T causing increased COPD risk. Cigarette smokers with rs6435156 (CT + TT) or rs1048829 (GT + TT) were more susceptible to COPD than that with the rs6435156CC or rs1048829GG genotypes. In A549 human alveolar epithelial cells, luciferase reporter assays revealed that introduction of 3'UTR of BMPR2 plasmids carrying rs6435156T allele but not rs1048829T led to lower luciferase activity than the wild-type C or G alleles. Comparing to rs6435156CC, treatment with hsa-miR-20a mimics deceased whereas hsa-miR-20a inhibitor restored the luciferase reporter activity in cells transfected with constructs carrying rs6435156TT. BMPR2 mRNA and protein expressions were significantly lower in PBMCs from COPD smokers than that in non-smokers. COPD patients carrying rs6435156T allele had less BMPR2 expression in PBMCs.InterpretationThis study demonstrated that both rs6435156C > T and rs1048829G > T variants in BMPR2 contributed to increased susceptibility to COPD. The T variants of rs6435156 increased COPD risk likely by binding with hsa-miR-20a, thus leading to downregulated BMPR2 expression in lung epithelial and immune cells.

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

Publications

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

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