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NLRP3 and CARD8 Polymorphisms Influence Higher Disease Activity in Rheumatoid Arthritis
Barbara Jenko1, Sonja Praprotnik2, Matija Tomšic2
1Pharmacogenetics Laboratory, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Insights
Genetic variations in NLRP3 and CARD8 inflammasome components are linked to increased rheumatoid arthritis (RA) disease activity, but not susceptibility. These findings may inform new RA treatment strategies.
Area of Science:
- Immunology
- Genetics
- Rheumatology
Background:
- NLRP3-inflammasome activation is implicated in rheumatoid arthritis (RA) pathogenesis.
- Specific gene polymorphisms in NLRP3 and CARD8 have been linked to pro-inflammatory responses.
Purpose of the Study:
- To investigate the impact of NLRP3 rs35829419 and CARD8 rs2043211 polymorphisms on RA susceptibility.
- To assess the association of these polymorphisms with RA disease activity at diagnosis and after six months of methotrexate treatment.
Main Methods:
- Genotyping of 128 RA patients and 122 healthy controls for NLRP3 rs35829419 and CARD8 rs2043211 polymorphisms.
- Disease activity was assessed using DAS28 scores at diagnosis and after treatment.
Main Results:
- No significant influence of the investigated polymorphisms on RA susceptibility was found.
- NLRP3 and CARD8 polymorphisms were associated with higher DAS28 scores at diagnosis (p=0.003 and p=0.022, respectively).
- The CARD8 rs2043211 TT genotype correlated with higher DAS28 scores after six months of treatment (p=0.033).
Conclusions:
- Genetic variability in inflammasome components (NLRP3, CARD8) may contribute to higher disease activity in RA patients.
- These findings suggest potential for novel therapeutic approaches targeting pro-inflammatory phenotypes in RA.
Background:
The activation of NLRP3-inflammasome may contribute to inflammatory processes in rheumatoid arthritis (RA). Functional polymorphisms in the genes coding for its components NLRP3 and CARD8 were associated with a proinflammatory phenotype. Our aim was to investigate the influence of these polymorphisms on RA susceptibility and disease activity at the time of diagnosis and after six months of treatment.
Methods:
A group of 128 RA patients treated with methotrexate and 122 healthy controls were genotyped for NLRP3 rs35829419 (p. Q705K) and CARD8 rs2043211 (p. C10X) polymorphisms.
Results:
RA susceptibility was not influenced by the investigated polymorphisms or their interaction. The investigated polymorphisms explained 8% of variability in DAS28 at the time of diagnosis. Carriers of NLRP3 rs35829419 or CARD8 rs2043211 polymorphisms had significantly higher DAS28 at the time of diagnosis (p=0.003; p=0.022; respectively). Polymorphic CARD8 rs2043211 TT genotype was also associated with higher DAS28 after six months of treatment (p=0.033).
Conclusions:
Genetic variability of inflammasome components may contribute to higher disease activity at the time of diagnosis and after 6 months of methotrexate treatment in RA patients. Better understanding of the immunological mechanisms behind a more active course of RA may suggest novel treatment approaches in a subset of patients with a proinflammatory phenotype.