rs11652075 — CARD14 CARD14 Arg820Trp (R820W)

Missense variant in the keratinocyte NF-κB scaffold protein CARD14 that modestly elevates psoriasis susceptibility and strongly predicts favorable response to anti-TNF biologic therapy (adalimumab, etanercept, infliximab)

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CARD14 Arg820Trp — The Psoriasis Biologic Response Predictor

CARD14 is a scaffold protein11 scaffold protein
A non-enzymatic protein that organizes signaling complexes at cellular membranes expressed primarily in keratinocytes — the epidermal cells that form the skin barrier. Under inflammatory conditions, CARD14 recruits BCL10 and MALT1 to form an activation complex that triggers NF-κB22 NF-κB
Nuclear Factor kappa-light-chain-enhancer of activated B cells; a master regulator of inflammation that switches on dozens of proinflammatory genes signaling, producing TNF-α, IL-17, IL-23, and other cytokines that drive skin inflammation. The rs11652075 variant changes arginine to tryptophan at position 820 (p.Arg820Trp). This SNP carries two clinically distinct pieces of information: it slightly raises the odds of developing psoriasis, and it strongly predicts whether anti-TNF biologic therapy will achieve remission.

The Mechanism

The arginine-to-tryptophan substitution replaces a positively charged, hydrophilic residue with a bulky aromatic one.

The Evidence

The Jordan et al. 2012 study in American Journal of Human Genetics established the foundational evidence: across seven psoriasis cohorts with more than 6,000 cases and 4,000 controls33 more than 6,000 cases and 4,000 controls, rs11652075 is associated with psoriasis (p=2.1×10⁻⁶). Notably, adjustment for the major HLA-Cw*0602 psoriasis risk allele strengthened the CARD14 signal.

A subsequent meta-analysis by Shi et al. pooled five studies totaling 32,807 cases and 45,458 controls44 five studies totaling 32,807 cases and 45,458 controls
Ancestry breakdown: European and East Asian populations both represented and confirmed the T allele is protective against psoriasis (pooled OR=0.877, 95%CI 0.834–0.922, P<0.001), with consistent effects in both European (OR=0.883) and Asian (OR=0.872) populations. The effect is modest per allele — the primary clinical utility of this variant lies in pharmacogenomics, not risk stratification.

The pharmacogenomic evidence is more striking. Coto-Segura et al. sequenced the entire CARD14 gene in 116 psoriasis patients treated with TNF inhibitors55 116 psoriasis patients treated with TNF inhibitors
79 responders, 37 non-responders; response defined as PASI 75 reduction at week 24; anti-TNF agents included adalimumab, etanercept, and infliximab. The CC genotype (no T allele) was significantly enriched among responders (OR=3.71, 95%CI 1.30–10.51, P=0.01). Patients with CC genotype were nearly four times more likely to achieve PASI 75 response by week 24. The mechanistic interpretation is straightforward: if CARD14-mediated NF-κB activity is the dominant driver of a patient's psoriasis, TNF-α blockade more effectively disrupts that pathway; patients with the protective T allele may have psoriasis driven by other mechanisms less responsive to anti-TNF therapy.

Practical Actions

For people without psoriasis, the CC genotype conveys only modest susceptibility — well under 1% absolute lifetime risk increase from this variant alone. For those who do develop psoriasis and are considering biologic therapy, CC status is meaningful: it identifies them as likely responders to adalimumab, etanercept, or infliximab before a single injection is given. For CT and TT carriers who develop psoriasis, anti-TNF therapy remains an option but response is less reliably predicted by this variant; IL-17 or IL-23 inhibitors may be comparably or more effective choices depending on other clinical factors.

Interactions

CARD14 rs11652075 operates in the PSORS2 psoriasis susceptibility locus and interacts with the major PSORS1 locus (HLA-Cw*0602). The Jordan 2012 data showed that conditioning on HLA-Cw*0602 status actually increased the CARD14 signal. For pharmacogenomics purposes, rs61751629 (another CARD14 coding variant) has been examined alongside rs11652075; the combination of CARD14 rare variants also predicted favorable anti-TNF response in the Coto-Segura dataset. These interactions are candidates for compound action assessment pending larger pharmacogenomic study replication.

Drug Interactions

adalimumab dose_adjustment literature
etanercept dose_adjustment literature
infliximab dose_adjustment literature

Genotype Interpretations

What each possible genotype means for this variant.

CC Reference Genotype Normal

Common reference genotype with modest psoriasis susceptibility and favorable anti-TNF response profile

The CC genotype means both copies of your CARD14 gene encode arginine at position 820 — the wild-type configuration by GRCh38 reference.

TT Protective Genotype Beneficial

Two copies of the protective T allele with meaningfully reduced psoriasis susceptibility

Both copies of your CARD14 gene encode tryptophan at position 820, replacing the reference arginine with a bulky aromatic residue. The protective effect was established in a meta-analysis by Shi et al. pooling five studies (32,807 cases, 45,458 controls): the T allele showed OR=0.877 (95%CI 0.834–0.922) for psoriasis, with consistent effects in both European (OR=0.883) and Asian (OR=0.872) subgroups.

CT One Protective Allele Intermediate

One protective T allele; mildly reduced psoriasis susceptibility with intermediate anti-TNF response prediction

The T allele at position 820 changes arginine to tryptophan in CARD14, replacing a charged amino acid with a bulky aromatic one. The protective effect of T is codominant: one copy provides partial protection, two copies provide more.

For the pharmacogenomics: the Coto-Segura et al. study found the CC vs non-CC distinction to be most significant for anti-TNF response prediction, suggesting heterozygotes fall in an intermediate prediction zone where additional clinical and molecular factors (disease severity, HLA-Cw*0602 status, IL-17 pathway activity) should guide biologic selection.