BLK – Systemic Lupus Erythematosus

Multiple genome-wide association studies (GWAS) have established BLK as a susceptibility locus for systemic lupus erythematosus (SLE). In an initial GWAS of 1,311 SLE cases and 1,783 controls, a promoter-region allele (rs13277113) upstream of BLK was associated with increased disease risk (OR 1.39; P=1×10⁻¹⁰) and reduced BLK transcript levels ([PMID:18204098]). Replication in 793 cases and 857 controls from Sweden confirmed this finding ([PMID:18204098]).

Subsequent GWAS in Asian populations reinforced the association: a Chinese Han study of 1,047 cases and 1,205 controls (replicated in 3,152 cases and 7,050 controls) confirmed BLK among seven previously reported loci (P10,000 SLE cases) consistently implicated BLK variants (rs13277113, rs2736340) with ORs ranging 1.29–1.60 (P<2.33×10⁻⁸) ([PMID:20169177], [PMID:19180478], [PMID:31134304]).

Deep sequencing and fine mapping identified both common regulatory and rare coding variants in BLK. A low-frequency missense variant c.211G>A (p.Ala71Thr) (OR 2.31) was discovered in European SLE patients ([PMID:22696686]). Rare and low-frequency BLK alleles, absent in controls, were shown to impair suppression of IRF5 and type-I interferon in B-cell lines and to augment pathogenic lymphocytes in lupus-prone mice ([PMID:31101814]).

Functional studies demonstrated that promoter variants rs922483 and rs1382568 modulate BLK transcription in a cell-type and developmental-stage–specific manner, reducing promoter activity in B-lineage cells ([PMID:24702955]). The p.Ala71Thr substitution within the SH3 domain markedly decreases BLK protein half-life, enhances ubiquitin-mediated degradation, and severely reduces binding to the adaptor protein BANK1, thereby perturbing B-cell signaling ([PMID:22696686], [PMID:26821283]).

Together, these data support a mechanism of BLK haploinsufficiency in SLE: both regulatory and coding variants converge to lower BLK expression and function in B cells, leading to dysregulated autoantibody production and interferon signaling. No major conflicting genetic or experimental evidence has been reported to date.

Key Take-home: BLK promoter and coding variants confer moderate SLE risk through B-cell–specific expression defects and impaired kinase stability, providing a potential biomarker and therapeutic target for stratified management.

References

• N Engl J Med • 2008 • Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. PMID:18204098
• Nat Genet • 2009 • Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. PMID:19838193
• Nat Commun • 2019 • Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus. PMID:31101814
• Am J Hum Genet • 2014 • Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription. PMID:24702955
• Ann Rheum Dis • 2012 • 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. PMID:22696686
• Genes Immun • 2016 • The SLE variant Ala71Thr of BLK severely decreases protein abundance and binding to BANK1 through impairment of the SH3 domain function. PMID:26821283

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