rs61751629 — CARD14 Glu422Lys

CARD14 Glu422Lys — A Rare Variant That May Guide Biologic Selection in Psoriasis

CARD14¹¹ CARD14
Caspase Recruitment Domain family member 14; also called CARMA2; the gene responsible for the PSORS2 psoriasis susceptibility locus on chromosome 17q25 encodes a scaffold protein expressed primarily in keratinocytes — the cells that form the outer skin barrier. In response to inflammatory signals, CARD14 recruits BCL10 and MALT1²² BCL10 and MALT1
These proteins form the CBM signalosome; MALT1 also functions as a protease that cleaves NF-κB inhibitors, amplifying the inflammatory cascade to assemble a signaling complex that activates NF-κB³³ NF-κB
Nuclear Factor kappa-B; a master transcription factor that switches on dozens of pro-inflammatory genes including TNF-α, IL-17, IL-36γ, and chemokines like CXCL8. Gain-of-function mutations in CARD14 cause psoriasis and the related condition pityriasis rubra pilaris⁴⁴ pityriasis rubra pilaris
CAPE — CARD14-Associated Papulosquamous Eruption; a spectrum of inflammatory skin disease driven by constitutive NF-κB activation in keratinocytes by disrupting normal autoinhibition and locking the protein in an active state. The rare Glu422Lys substitution lies in the coiled-coil/LATCH linker region where most psoriasis-associated CARD14 mutations cluster, and was identified by Coto-Segura et al.⁵⁵ Coto-Segura et al.
A Spanish group studying pharmacogenomics of anti-TNF therapy in psoriasis as a variant enriched among patients who respond favorably to anti-TNF biologic treatment.

The Mechanism

Wild-type CARD14 maintains a self-inhibited conformation through its linker region (LR), which suppresses spontaneous BCL10 binding and NF-κB activation. Studies by Howes et al.⁶⁶ Howes et al.
Howes A, et al. Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation. Biochem J. 2016;473:1759-68 showed that psoriasis mutations in this region — including E138A and G117S — abrogate the linker's inhibitory function by enabling constitutive BCL10 binding. Position 422 falls within the coiled-coil domain region (roughly residues 200–600) where autoinhibitory contacts are maintained. The Glu422Lys substitution replaces a negatively charged glutamate with a positively charged lysine, potentially disrupting the electrostatic environment that keeps the protein in its closed, autoinhibited state. No functional NF-κB reporter assay data specific to p.Glu422Lys exists in the published literature; the clinical association with anti-TNF response is the primary evidence for its functional relevance.

The mechanistic implication of an anti-TNF response association is that CARD14 Glu422Lys likely represents a partial gain-of-function variant⁷⁷ partial gain-of-function variant
Rather than fully constitutively active like E138A, the E422K mutation may lower the activation threshold without fully ablating autoinhibition — producing a keratinocyte NF-κB environment that is modestly TNF-α-overdriven and therefore preferentially responsive to TNF blockade. This parallels the mechanism seen with the common rs11652075 (Arg820Trp) variant at the same gene: both variants appear to mark a psoriasis subtype that is NF-κB/TNF-α-pathway-dominant and biologically matched to anti-TNF blockade.

The Evidence

The primary evidence comes from Coto-Segura et al. 2016⁸⁸ Coto-Segura et al. 2016
Coto-Segura P, et al. Common and rare CARD14 gene variants affect the antitumour necrosis factor response among patients with psoriasis. Br J Dermatol. 2016;175:134-41, which next-generation sequenced the entire CARD14 gene in 116 psoriasis patients treated with TNF inhibitors (79 responders, 37 non-responders; response defined as PASI 75 at week 24). Among responders, six patients were heterozygous p.Glu422Lys carriers versus zero non-responders (P=0.04). The effect is based on small numbers — six carriers across 116 patients — so while statistically significant, the confidence interval is wide and independent replication is essential.

The biological context strengthens the signal. Jordan et al. 2012⁹⁹ Jordan et al. 2012
Jordan CT, et al. Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis. Am J Hum Genet. 2012;90:796-808 established that rare CARD14 missense variants are enriched in psoriasis cases (burden test p=0.0015 across >6,000 cases and >4,000 controls), with functional assays confirming NF-κB activation >2.5-fold above wild-type for the most pathogenic variants. The Glu422Lys variant predating its identification in the treatment cohort is consistent with it belonging to this class of functionally relevant rare alleles.

Practical Actions

Most carriers of this rare variant will have — or develop — some degree of plaque psoriasis or related CARD14-spectrum skin disease. The clinical signal from the Coto-Segura study is that if anti-TNF therapy (adalimumab, etanercept, infliximab) is being considered for moderate-to-severe psoriasis, Glu422Lys heterozygosity is a supporting biomarker for trial of these agents. No functional study has established the optimal dosing adjustment, and response is not guaranteed — PASI 75 response was observed in 6 out of a small cohort.

CARD14-associated psoriasis is also responsive to IL-17 inhibitors (secukinumab, ixekizumab) and IL-23 inhibitors (guselkumab, risankizumab), which target the downstream Th17 inflammatory output of the NF-κB cascade CARD14 activates. Case reports of CARD14-associated papulosquamous eruption show strong responses to both anti-IL-17 and anti-IL-23 therapy.

Interactions

This variant sits in the same gene as rs11652075 (Arg820Trp), the common CARD14 psoriasis pharmacogenomics marker. The two variants appear to tag the same biological theme — NF-κB overactivation in keratinocytes — from two different positions: one common (rs11652075, ~50% heterozygote frequency), one rare (Glu422Lys, <1% carrier frequency). The Coto-Segura study examined both variants in the same cohort, and the rare variant carriers contributed independently to anti-TNF response prediction. These are candidates for a compound action when larger cohorts confirm the combined signal.