What information is obtained by testing an individual for a CARD8 mutation?

CARD8 Mutation Testing: Clinical Information and Implications

Testing for CARD8 mutations identifies individuals at risk for inflammasome-mediated inflammatory conditions, particularly Crohn's disease with anti-TNF-α resistance, and provides critical information for targeted IL-1β inhibitor therapy selection. 1

Primary Clinical Information Obtained

Crohn's Disease Risk and Phenotype

• Loss-of-function CARD8 mutations (particularly the V44I mutation in the T60 isoform) cause NLRP3 inflammasome activation leading to Crohn's disease that is characteristically resistant to anti-TNF-α therapy but responsive to IL-1β inhibitors. 1
• The V44I mutation prevents CARD8 from binding to NLRP3 and inhibiting its oligomerization, resulting in excessive IL-1β production. 1
• This mutation exerts a dominant-negative effect by forming oligomers with unmutated CARD8 isoforms, further impairing inflammasome regulation. 1
• Serum IL-1β levels are elevated in affected individuals, and their peripheral monocytes produce increased IL-1β when stimulated by NLRP3 activators. 1

Inflammatory Bowel Disease-Associated Arthritis

• CARD8 mutations can manifest as juvenile idiopathic arthritis with associated inflammatory bowel disease, presenting with sacroiliitis, elevated inflammatory markers, and progression to Crohn's disease with severe gastrointestinal symptoms. 2
• These patients typically respond to combination therapy with methotrexate and adalimumab. 2

Anti-Glycan Antibody Response Profile

• The p.C10X mutation (rs2043211) in CARD8 associates with significantly lower levels of anti-mannan antibodies (ASCA) and anti-glucan antibodies (ALCA), but not anti-chitin antibodies (ACCA), in Crohn's disease patients. 3
• This association is independent of NOD2 and NOD1 genetic backgrounds. 3
• Lower antibody responses may reflect altered inflammasome-mediated immune regulation. 3

Genetic Interaction Effects

CARD8-NALP3 Interaction

• The presence of the minor allele of rs2043211 with the major allele of NALP3 rs35829419 confers protection against Crohn's disease (OR=0.66,95% CI 0.48-0.90, p=0.009). 4
• This protective effect intensifies in the absence of NOD2 mutations. 4
• These genotype combinations likely protect against gut inflammation by preventing excessive IL-1β production from the NALP3 inflammasome. 4

Diabetic Nephropathy Risk Modification

• Three common CARD8 variants (rs11665831, rs11083925, rs2043211) confer decreased risk for diabetic nephropathy in type 2 diabetes mellitus patients (OR range 0.62-0.66). 5
• These variants may alter the cross-talk between CARD8, NF-κB, and NLRP3, affecting the pro-inflammatory environment in T2DM. 5

Therapeutic Implications

Treatment Selection

• Patients with CARD8 mutations and Crohn's disease who fail anti-TNF-α therapy should be prioritized for IL-1β inhibitor treatment rather than escalating TNF-α blockade. 1
• This represents a precision medicine approach based on the underlying inflammasome dysfunction mechanism. 1

Cascade Testing Recommendations

• When a pathogenic CARD8 mutation is identified in a proband with Crohn's disease, first-degree relatives should undergo mutation-specific genetic testing to identify similarly affected individuals who may benefit from early intervention and targeted therapy. 6, 7
• Genetic counseling should precede testing to discuss implications for inflammatory disease risk and treatment options. 6

Critical Pitfalls to Avoid

• Do not assume all Crohn's disease patients will respond to anti-TNF-α therapy; CARD8 mutation carriers may require IL-1β-targeted treatment from the outset. 1
• Do not overlook extra-intestinal manifestations such as arthritis in CARD8 mutation carriers, as these may precede gastrointestinal symptoms. 2
• Variants of uncertain significance in CARD8 should not guide treatment decisions until their pathogenicity is established through functional studies or reclassification. 6, 7
• The protective effects of certain CARD8 variants depend on genetic context (NALP3 and NOD2 status), requiring comprehensive genetic evaluation rather than isolated CARD8 testing. 4