ArticleAnnals of the rheumatic diseases2012
Fine mapping and conditional analysis identify a new mutation in the autoimmunity susceptibility gene BLK that leads to reduced half-life of the BLK protein.
Article in Annals of the rheumatic diseases, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 40 citations in OpenAlex.
- Systemic lupus erythematosus: updated insights on the pathogenesis, diagnosis, prevention and therapeutics.Signal transduction and targeted therapy · 2025Review
- Haplotype-specific chromatin looping reveals genetic interactions of regulatory regions modulating gene expression in 8p23.1.Frontiers in genetics · 2022Article
- The Immunogenetics of Systemic Sclerosis.Advances in experimental medicine and biology · 2022Article
- Immunogenetics of Lupus Erythematosus.Advances in experimental medicine and biology · 2022Article
- BLK polymorphisms and expression level in neuromyelitis optica spectrum disorder.CNS neuroscience & therapeutics · 2021Article
- Emerging roles of rare and low-frequency genetic variants in type 1 diabetes mellitus.Journal of medical genetics · 2021Review
- Review
- Incompatibility of chemical protein synthesis inhibitors with accurate measurement of extended protein degradation rates.Pharmacology research & perspectives · 2017Article
- Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus.Journal of medical genetics · 2017Article
- BLK pathway-associated rs13277113 GA genotype is more frequent in SLE patients and associated with low gene expression and increased flares.Clinical rheumatology · 2017Article
- Genetic association study of systemic lupus erythematosus and disease subphenotypes in European populations.Clinical rheumatology · 2016Article
- The SLE variant Ala71Thr of BLK severely decreases protein abundance and binding to BANK1 through impairment of the SH3 domain function.Genes and immunity · 2016Article
- Solving the genetic puzzle of systemic lupus erythematosus.Pediatric nephrology (Berlin, Germany) · 2015Review
- Concordance of increased B1 cell subset and lupus phenotypes in mice and humans is dependent on BLK expression levels.Journal of immunology (Baltimore, Md. : 1950) · 2015Article
- Natural Selection and Functional Potentials of Human Noncoding Elements Revealed by Analysis of Next Generation Sequencing Data.PloS one · 2015Article
- The plasmacytoid dendritic cell as the Swiss army knife of the immune system: molecular regulation of its multifaceted functions.Journal of immunology (Baltimore, Md. : 1950) · 2014Review
- Clinical perspectives on lupus genetics: advances and opportunities.Rheumatic diseases clinics of North America · 2014Review
- Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription.American journal of human genetics · 2014Article
- The effect of inversion at 8p23 on BLK association with lupus in Caucasian population.PloS one · 2014Article
- Reduced B lymphoid kinase (Blk) expression enhances proinflammatory cytokine production and induces nephrosis in C57BL/6-lpr/lpr mice.PloS one · 2014Article
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Authors and funding
24 authors at 16 institutions in 8 countries.
Funding
Abstract
objectivesTo perform fine mapping of the autoimmunity susceptibility gene BLK and identify functional variants involved in systemic lupus erythematosus (SLE).
methodsGenotyping of 1163 European SLE patients and 1482 controls and imputation were performed covering the BLK gene with 158 single-nucleotide polymorphisms. Logistic regression analysis was done using PLINK and conditional analyses using GENABEL's test score. Transfections of BLK constructs on HEK293 cells containing the novel mutation or the wild type form were analysed for their effect on protein half-life using a protein stability assay, cycloheximide and western blot. CHiP-qPCR for detection of nuclear factor κ B (NFkB) binding.
resultsFine mapping of BLK identified two independent genetic effects with functional consequences: one represented by two tightly linked associated haplotype blocks significantly enriched for NFκB-binding sites and numerous putative regulatory variants whose risk alleles correlated with low BLK mRNA levels. Binding of NFkBp50 and p65 to an associated 1.2 Kb haplotype segment was confirmed. A second independent genetic effect was represented by an Ala71Thr, low-frequency missense substitution with an OR=2.31 (95% CI 1.38 to 3.86). The 71Thr decreased BLK protein half-life.
conclusionsThese results show that rare and common regulatory variants in BLK are involved in disease susceptibility and both, albeit independently, lead to reduced levels of BLK protein.
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