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Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription.

ABSTRACT: Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter activity and modulated alternative promoter usage. Allelic differences at rs1382568 resulted in altered promoter activity in B progenitor cell lines. Thus, our results demonstrated that both lupus-associated functional variants contribute to the autoimmune disease association by modulating transcription of BLK in B cells and thus potentially altering immune responses.

SUBMITTER: Guthridge JM

PROVIDER: S-EPMC3980411 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription.

Guthridge Joel M JM Lu Rufei R Sun Harry H Sun Celi C Wiley Graham B GB Dominguez Nicolas N Macwana Susan R SR Lessard Christopher J CJ Kim-Howard Xana X Cobb Beth L BL Kaufman Kenneth M KM Kelly Jennifer A JA Langefeld Carl D CD Adler Adam J AJ Harley Isaac T W IT Merrill Joan T JT Gilkeson Gary S GS Kamen Diane L DL Niewold Timothy B TB Brown Elizabeth E EE Edberg Jeffery C JC Petri Michelle A MA Ramsey-Goldman Rosalind R Reveille John D JD Vilá Luis M LM Kimberly Robert P RP Freedman Barry I BI Stevens Anne M AM Boackle Susan A SA Criswell Lindsey A LA Vyse Tim J TJ Behrens Timothy W TW Jacob Chaim O CO Alarcón-Riquelme Marta E ME Sivils Kathy L KL Choi Jiyoung J Joo Young Bin YB Bang So-Young SY Lee Hye-Soon HS Bae Sang-Cheol SC Shen Nan N Qian Xiaoxia X Tsao Betty P BP Scofield R Hal RH Harley John B JB Webb Carol F CF Wakeland Edward K EK James Judith A JA Nath Swapan K SK Graham Robert R RR Gaffney Patrick M PM

American journal of human genetics 20140401 4

Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter ...[more]

PMID: 24702955

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Project description:ObjectiveAlthough the number of convincingly established genetic associations with systemic lupus erythematosus (SLE) has increased sharply over the last few years, refinement of these associations is required, and their potential roles in gene-gene interactions need to be further investigated. Recent genome-wide association studies (GWAS) in SLE have produced renewed interest in B cell/T cell responses and the NF-κB signaling pathway. The aim of this study was to search for possible gene-gene interactions based on identified single-nucleotide polymorphisms (SNPs), in using an approach based on the role of signaling pathways.MethodsThe SNPs in BLK, TNFSF4, TRAF1, TNFAIP3, and REL were replicated in order to evaluate genetic associations with SLE. TaqMan genotyping was conducted in 804 Chinese patients with SLE and 722 matched control subjects. A multiple logistic regression model was used to estimate the multiplicative interaction effect of the SNPs, and additive interactions were analyzed by 2×2 factorial designs. Data from a previously published GWAS conducted by the International Consortium on the Genetics of Systemic Lupus Erythematosus were derived for comparison and validation.ResultsSingle-marker analysis validated the association of BLK rs2736340 (P=4.25×10(-6)) as well as TNFSF4 rs2205960 (P=2.82×10(-5)) and TNFAIP3 rs5029939 (P=1.92×10(-3)) with SLE susceptibility in Chinese. Multiplicative interaction analysis indicated that BLK had an interactive effect with TNFSF4 in Chinese patients with SLE (P=6.57×10(-4)). Additive interaction analysis revealed interactions between TRAF1 and TNFAIP3 in both Chinese (P=2.18×10(-3)) and Caucasians (P=2.86×10(-4)). In addition, multiple tendencies toward interactions were observed, and an additive effect was observed as the number of risk genotypes increased.ConclusionThe results of this study provide evidence of the possible gene-gene interactions of BLK, TNFSF4, TRAF1, TNFAIP3, and REL in SLE, which may represent a synergic effect of T cells and B cells through the NF-κB pathway in determining immunologic aberration.

Project description:UnlabelledTo explore the potential influence of the polymorphic 8p23.1 inversion on known autoimmune susceptibility risk at or near BLK locus, we validated a new bioinformatics method that utilizes SNP data to enable accurate, high-throughput genotyping of the 8p23.1 inversion in a Caucasian population.MethodsPrincipal components analysis (PCA) was performed using markers inside the inversion territory followed by k-means cluster analyses on 7416 European derived and 267 HapMaP CEU and TSI samples. A logistic regression conditional analysis was performed.ResultsThree subgroups have been identified; inversion homozygous, heterozygous and non-inversion homozygous. The status of inversion was further validated using HapMap samples that had previously undergone Fluorescence in situ hybridization (FISH) assays with a concordance rate of above 98%. Conditional analyses based on the status of inversion were performed. We found that overall association signals in the BLK region remain significant after controlling for inversion status. The proportion of lupus cases and controls (cases/controls) in each subgroup was determined to be 0.97 for the inverted homozygous group (1067 cases and 1095 controls), 1.12 for the inverted heterozygous group (1935 cases 1717 controls) and 1.36 for non-inverted subgroups (924 cases and 678 controls). After calculating the linkage disequilibrium between inversion status and lupus risk haplotype we found that the lupus risk haplotype tends to reside on non-inversion background. As a result, a new association effect between non-inversion status and lupus phenotype has been identified ((p = 8.18×10(-7), OR = 1.18, 95%CI = 1.10-1.26).ConclusionOur results demonstrate that both known lupus risk haplotype and inversion status act additively in the pathogenesis of lupus. Since inversion regulates expression of many genes in its territory, altered expression of other genes might also be involved in the development of lupus.

Dataset Information

Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription.

Publications

Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription.

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