rs2736340 — BLK

FAM167A-BLK region regulatory variant that reduces B-lymphoid tyrosine kinase expression and confers risk for the broadest autoimmune disease spectrum of any BLK locus SNP, including SLE, RA, SSc, primary Sjögren's syndrome, APS, myositis, and Kawasaki disease

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BLK rs2736340 — The Widest-Spectrum Autoimmune Tag at the B-Cell Kinase Locus

BLK (B-lymphoid tyrosine kinase)11 BLK (B-lymphoid tyrosine kinase)
A Src-family non-receptor tyrosine kinase expressed almost exclusively in B cells and plasmacytoid dendritic cells, essential for B-cell receptor signaling and central B-cell tolerance encodes a kinase that drives B-cell activation and, crucially, enforces the self-tolerance checkpoint that eliminates self-reactive B-cell clones before they can generate pathogenic autoantibodies. rs2736340 sits within the FAM167A-BLK regulatory locus on chromosome 8p23.1, approximately 5 kilobases upstream of the BLK transcription start site — slightly further from BLK than its locus partners rs13277113 (at position 11,491,677) and rs4840568 (at 11,493,510). The T risk allele reduces BLK mRNA in B cells, and carriers show impaired B-cell tolerance signaling. What distinguishes rs2736340 from its locus partners is its documented breadth: across all dedicated meta-analyses, it is consistently associated with the widest spectrum of autoimmune diseases of any single BLK tag SNP, spanning classical B-cell-driven conditions (SLE, primary Sjögren's syndrome), connective tissue diseases (systemic sclerosis, antiphospholipid syndrome), musculoskeletal autoimmunity (rheumatoid arthritis), muscle inflammation (myositis/dermatomyositis), and vasculitis (Kawasaki disease in children).

The Mechanism

rs2736340 maps to the shared FAM167A-BLK regulatory zone — a promoter/enhancer region upstream of BLK that contains transcription factor binding sites controlling BLK expression specifically in B cells. The T allele is associated with reduced BLK mRNA levels22 reduced BLK mRNA levels
Pamuk et al. 2017 (PMID 27864698): BLK expression approximately 0.52× that of controls in circulating immune cells of SLE patients carrying BLK risk alleles in B-cell lines, mirroring the functional effect of its locus partners rs13277113 and rs4840568. When BLK kinase levels fall, the central tolerance checkpoint33 central tolerance checkpoint
The bone-marrow editing process by which immature B cells that recognize self-antigens are normally clonally deleted or silenced before they can enter circulation as mature, potentially autoreactive B cells is partially impaired: autoreactive B cells escape deletion at an elevated rate and can subsequently produce autoantibodies against nuclear antigens (anti-dsDNA, anti-Smith in SLE), exocrine gland proteins (anti-SSA/SSB in Sjögren's), and other self-targets.

The rs2736340 locus sits within a region subject to a polymorphic inversion at chromosome 8p2344 polymorphic inversion at chromosome 8p23
A ~4 Mb inversion polymorphism at 8p23.1 present at ~20-40% frequency in Caucasians; BLK risk alleles are almost exclusively found on the non-inverted haplotype, explaining why LD patterns and effect sizes for BLK SNPs differ between populations. This structural variant context explains in part why rs2736340, rs13277113, and rs4840568 do not show perfectly uniform LD across all ethnic groups: the inversion reshuffles which SNPs most faithfully tag the risk haplotype in each ancestry background.

The Evidence

The most specific evidence comes from a dedicated rs2736340 meta-analysis55 dedicated rs2736340 meta-analysis
Yang et al. 2016 — 25 studies, 30,217 patients, 44,754 controls; searched databases from 1966 through October 2015, which is the only dedicated meta-analysis for this specific SNP across the full spectrum of autoimmune diseases. The T allele showed an overall OR of 1.36 (95% CI 1.28–1.44, p<0.001) in the combined analysis. Subgroup analyses found significant associations in Asia (OR 1.46), North America (OR 1.33), and Europe (OR 1.26), with no significant association in African populations — a pattern consistent with the lower T allele frequency in African ancestry groups (~14%) and smaller study representation.

A second three-SNP BLK meta-analysis66 three-SNP BLK meta-analysis
Zeng et al. 2017 — largest meta-analysis specifically comparing rs13277113, rs2736340, and rs4840568 simultaneously; rs2736340 covered in 21 studies, 26,388 cases, 40,635 controls confirmed T vs C OR=1.34 (95% CI 1.27–1.41, P<.01), virtually identical to the rs13277113 and rs4840568 effect sizes in the same paper (OR 1.33 and 1.32 respectively). This parallel effect size across all three BLK locus SNPs is consistent with them tagging the same underlying risk haplotype and similar functional effect on BLK expression.

The disease-specific breadth was catalogued across both meta-analyses and individual cohort studies: rheumatoid arthritis (the largest single contributor to the meta-analytic dataset), SLE, systemic sclerosis, Kawasaki disease, primary Sjögren's syndrome, primary antiphospholipid syndrome, and polymyositis/dermatomyositis77 polymyositis/dermatomyositis
Han Chinese myositis cohort finding significant rs2736340 association. A Han Chinese Sjögren's cohort88 Han Chinese Sjögren's cohort
Salgado et al. 2013 — 540 pSS cases, 577 controls found rs2736340 T allele significantly elevated in Sjögren's patients (p=0.034), with haplotype analysis with rs13277113 producing a stronger combined signal.

Beyond main effects, a gene-gene interaction study in Chinese SLE99 gene-gene interaction study in Chinese SLE
Wang et al. 2011 — 806 SLE cases and 806 matched controls; multiplicative interaction model found a significant interaction between BLK rs2736340 and TNFSF4 (OX40L) in SLE susceptibility (P=6.57×10⁻⁴). TNFSF4 encodes OX40 ligand, a T-cell co-stimulatory molecule; its interaction with BLK points to cross-talk between B-cell intrinsic kinase deficiency and T-cell hyperactivation as compounding mechanisms in SLE pathogenesis.

Practical Implications

The T allele at rs2736340 confers a modestly elevated, replicated lifetime background risk for multiple B-cell-driven autoimmune diseases. The per-allele OR of ~1.34–1.36 is consistent across both large meta-analyses and translates to a meaningful risk shift when T alleles accumulate (TT homozygotes carry approximately OR² ≈ 1.8× baseline risk) or when co-occurring risk alleles at interacting loci (BANK1, PTPN22, TNFSF4) are also present.

The disease spectrum most practically relevant for surveillance is: SLE, primary Sjögren's syndrome, rheumatoid arthritis, systemic sclerosis, and autoimmune thyroid disease (the latter through association of the broader BLK locus). These are all diagnosable through available laboratory and clinical assessment, and all are significantly more manageable with early detection.

No supplements or dietary interventions are proven to counteract BLK-mediated B-cell dysregulation. The actionable response is symptom recognition and targeted monitoring.

Interactions

rs2736340, rs13277113, and rs4840568 are all within the FAM167A-BLK regulatory zone and are likely co-inherited on the same risk haplotype in most populations — especially in East Asian ancestry, where LD between these sites exceeds r²>0.9. Carrying T alleles at rs2736340 is in practice a marker for the broader BLK risk haplotype rather than an independent functional variant.

The most important trans-gene interactions are with BANK1 rs105164871010 BANK1 rs10516487
BANK1 R61H, a B-cell scaffold protein variant that amplifies BCR signaling; combined BLK × BANK1 risk allele OR=2.36 for primary Sjögren's syndrome (PMID 33756160) and TNFSF4 rs22059601111 TNFSF4 rs2205960
OX40 ligand variant that compounds BLK risk through T-cell co-stimulation; interactive OR with BLK rs2736340 in Chinese SLE P=6.57×10⁻⁴ (PMID 21905002). The PTPN22 rs2476601 R620W variant also overlaps mechanistically — both BLK and PTPN22 shift antigen receptor signaling thresholds, with BLK acting on B cells specifically and PTPN22 acting on both B cells and T cells.

Genotype Interpretations

What each possible genotype means for this variant.

CC Typical BLK Activity Normal

Common genotype — normal BLK expression, typical autoimmune background risk

You carry two copies of the common C allele at rs2736340. This is the reference genotype at this FAM167A-BLK regulatory position and is associated with normal BLK expression in B cells and typical self-tolerance signaling. Approximately 54% of people globally share this genotype. Your genetic background risk for BLK-associated autoimmune diseases (SLE, RA, Sjögren's, systemic sclerosis) from this variant is at or below the population average.

CT One Risk Allele Intermediate

One BLK locus risk allele — modestly elevated broad-spectrum autoimmune risk

rs2736340 sits approximately 5kb upstream of the BLK transcription start site in the FAM167A-BLK regulatory locus on chromosome 8p23.1. The T risk allele reduces BLK mRNA levels in B cells, impeding the central tolerance checkpoint that eliminates self-reactive B-cell clones. This is the same mechanism as the neighboring rs13277113 and rs4840568 variants — all three tag the same risk haplotype and carry comparable per-allele ORs of ~1.33–1.36 in meta-analyses.

The heterozygous CT state confers approximately half the per-allele risk of TT under the additive model, translating to roughly 1.15–1.18× elevated baseline risk for the autoimmune conditions in the meta-analytic dataset. The breadth of associations (7+ disease types) reflects the fundamental role of BLK in B-cell tolerance broadly, not specificity for any single condition. The T allele is considerably more common in East Asian populations (~71%) than in European (~25%) or African (~14%) populations, which accounts for the stronger statistical power in Asian studies.

TT Two Risk Alleles High Risk

Two BLK locus risk alleles — meaningfully elevated broad-spectrum autoimmune risk

TT homozygosity at rs2736340 represents the full-risk end of the BLK upstream regulatory spectrum at this position. The T allele reduces BLK mRNA in B cells — studies in SLE patients carrying BLK risk haplotypes show approximately 0.52-fold reduction in BLK expression in circulating immune cells. With two T alleles, B-cell tolerance signaling is most impaired, allowing the highest per-individual escape rate of self-reactive B-cell clones.

The disease-breadth documented for rs2736340 is especially relevant for TT homozygotes: the dedicated meta-analysis (PMID 27105348) found significant associations with seven distinct autoimmune diseases in this locus. This breadth reflects the upstream position of the variant — impairing BLK at the transcriptional level affects all B-cell-mediated tolerance decisions, not just those relevant to specific target antigens in individual diseases.

The documented gene-gene interaction with TNFSF4 (OX40L) in Chinese SLE (P=6.57×10⁻⁴) is particularly relevant for TT homozygotes: if TNFSF4 risk alleles are also present, the combined BLK-plus-TNFSF4 signaling defect may amplify SLE susceptibility beyond what either variant predicts alone. TNFSF4 drives T-cell co-stimulation of B cells; together with reduced BLK, this creates both a tolerance deficit (B cell intrinsic) and an activation surplus (T-cell co-stimulation), a mechanistically compounding combination.

TT homozygotes of East Asian descent may also carry the rs4840568 and rs13277113 risk alleles on the same haplotype, making comprehensive BLK locus genotyping informative for distinguishing haplotype-level cumulative risk.