Evaluating Single-Nucleotide Polymorphisms in Inflammasome Proteins and Serum Levels of IL-18 and IL-1β in Kidney Interstitial Damage in Anti-Neutrophilic Cytoplasmic Antibody-Associated Vasculitis
Abstract
:1. Introduction
2. Results
2.1. Characteristics of the Study Population
2.2. Serum and Urinary IL-18 and IL-1β Levels
2.3. Allele and Genotype Distribution
2.4. IL-18 SNPs, sIL-18 Levels, and Lesions in the Kidney Biopsy
2.5. The IL-18 rs187238 G Allele Is Associated with Lower sIL-18, More Severe Fibrosis, and Higher Mortality
2.6. The IL-18 rs1946518 T Allele Is Associated with Lower sIL-18, Lower eGFR Levels during Follow-Up, and a Higher Risk of Relapse within the First Year after Diagnosis
2.7. Association of SNPs and Organ Involvement in AAV
3. Discussion
4. Methods
4.1. Study Population
4.2. Clinical and Laboratory Data
4.3. Sampling, Genotyping Assays, and Cytokine Assessment
4.4. Selection of SNPs
4.5. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Gender (% male) | 44.56 |
Median age (IQR) (years) | 68 (60–76.75) |
Organ involvement (%) | 65.51 |
ANCA type (%MPO) | 74.70 |
Median ANCA titer (IQR) (karbU/L) | 13 (1.70–54) |
Median serum creatinine IQR (µmol/L) | 145 (104.51–180) |
Mean eGFR ± SD (mL/min) | 38.5 ± 18.63 |
Mean proteinuria ± SD (g/mol) | 0.53 ± 0.60 |
Median serum CRP (IQR) mg/L | 4 (1.40–11.92) |
Berden Histopathologic Classification (% patients) | |
Focal | 18.47 |
Crescentic | 26.08 |
Mixed | 31.52 |
Sclerotic | 11.95 |
N/A | 10.86 |
Induction treatment (% patients) | |
Methylprednisolone pulses | 40.21 |
Plasma exchange | 34.78 |
Cyclophosphamide | 42.39 |
Rituximab | 28.26 |
sIL-18 (pg/mL) | sIL-1β (pg/mL) | |||||
---|---|---|---|---|---|---|
Absent–Mild (Grades 0–1) | Moderate–Severe (Grades 2–3) | p-Value | Absent–Mild (Grades 0–1) | Moderate–Severe (Grades 2–3) | p-Value | |
Fibrosis | 567.93 ± 599.11 | 191.34 ± 250.34 | 0.013 | 1.36 ± 1.34 | 0.42 ± 0.59 | 0.002 |
Atrophy | 474.78 ± 523.43 | 166.25 ± 268.31 | 0.062 | 1.38 ± 1.49 | 0.2 ± 0.25 | 0.004 |
Inflammatory Infiltrate | 507.80 ± 513.59 | 370.27 ± 487.39 | 0.20 | 3.27 ± 8.64 | 0.95 ± 1.29 | 0.18 |
Gene | SNP | Hardy–Weinberg Equilibrium | Minor Allele in the Study Population | MAF in the Study Population | MAF (European Ancestry) | |
---|---|---|---|---|---|---|
Chi-Square | p-Value | |||||
IL-1β | rs1143634 | 0.237 | 0.88 | A | 0.19 | A allele, 0.24 |
NLRP3 | rs4612666 | 0.096 | 0.853 | T | 0.27 | T allele, 0.24 |
IL-18 | rs1946518 | 2.51 | 0.285 | G | 0.48 | T allele, 0.42 |
IL-18 | rs187238 | 1.152 | 0.562 | G | 0.32 | G allele, 0.28 |
NLRP1 | rs878329 | 0.509 | 0.775 | C | 0.44 | C allele, 0.46 |
CARD8 | rs2043211 | 0.182 | 0.913 | T | 0.33 | T allele, 0.33 |
NLRP3 | rs10754558 | 1.872 | 0.392 | G | 0.36 | G allele, 0.46 |
CASP1 | rs530537 | 0.163 | 0.922 | C | 0.48 | C allele, 0.44 |
IL-18 rs187238 | IL-18 rs1946518 | |||||
---|---|---|---|---|---|---|
GG n = 7 (7.6%) | C-Carriers n = 85 (92.4%) | p-Value | T-Carriers n = 67 (72.8%) | GG n = 25 (27.2%) | p-Value | |
Mean sCreatinine ± SD (µmol/L) | 363.68 ± 288.19 | 206.71 ± 110.35 | 0.16 | 360.04 ± 238.12 | 347.82 ± 296.61 | 0.90 |
Mean eGFR ± SD (mL/min) | 23.37 ± 18.99 | 33 ± 21.15 | 0.20 | 20.93 ± 18.70 | 25.17 ± 19.44 | 0.38 |
Mean proteinuria ± SD (g/day) | 0.78 ± 1.15 | 0.53 ± 0.78 | 0.64 | 0.69 ± 0.58 | 0.79 ± 1.28 | 0.75 |
Mean sCRP ± SD (mg/mL) | 68.3 ± 77.98 | 61.17 ± 73.90 | 0.83 | 67.37 ± 66.37 | 67.80 ± 81.35 | 0.98 |
Mean ANCA titer (KarbU/L) | 494.58 ± 882.16 | 469.58 ± 611.73 | 0.47 | 809.88 ± 1197.76 | 371.74 ± 668.78 | 0.12 |
Gene | SNP | Chromosome Location | Functional Consequence | Alleles | MAF (European Ancestry) |
---|---|---|---|---|---|
IL-1β | rs1143634 | chr2:112832813 | Coding sequence variant, synonymous variant | G/A, transition substitution | A allele, 0.24 |
NLRP3 | rs4612666 | chr1:247435768 | Intron variant | C/T, transition substitution | T allele, 0.24 |
IL-18 | rs1946518 | chr11:112164735 | Upstream transcript variant | T/G, transversion substitution | T allele, 0.42 |
IL-18 | rs187238 | chr11:112164265 | Upstream transcript variant | C/G, transversion substitution | G allele, 0.28 |
NLRP1 | rs878329 | chr17:5649930 | None | G/C, transversion substitution | C allele, 0.46 |
CARD8 | rs2043211 | chr19:48234449 | Stop gained variant | A/T, transversion substitution | T allele, 0.33 |
NLRP3 | rs10754558 | chr1:247448734 | 3′UTR variant | C/G, transversion substitution | G allele, 0.46 |
CASP1 | rs530537 | chr11:105027786 | Intron variant | C/T, transition substitution | C allele, 0.44 |
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Martinez Valenzuela, L.; Vidal-Alabró, A.; Rubio, B.; Antón-Pàmpols, P.; Gómez-Preciado, F.; Fulladosa, X.; Cruzado, J.M.; Torras, J.; Lloberas, N.; Draibe, J. Evaluating Single-Nucleotide Polymorphisms in Inflammasome Proteins and Serum Levels of IL-18 and IL-1β in Kidney Interstitial Damage in Anti-Neutrophilic Cytoplasmic Antibody-Associated Vasculitis. Int. J. Mol. Sci. 2024, 25, 6479. https://doi.org/10.3390/ijms25126479
Martinez Valenzuela L, Vidal-Alabró A, Rubio B, Antón-Pàmpols P, Gómez-Preciado F, Fulladosa X, Cruzado JM, Torras J, Lloberas N, Draibe J. Evaluating Single-Nucleotide Polymorphisms in Inflammasome Proteins and Serum Levels of IL-18 and IL-1β in Kidney Interstitial Damage in Anti-Neutrophilic Cytoplasmic Antibody-Associated Vasculitis. International Journal of Molecular Sciences. 2024; 25(12):6479. https://doi.org/10.3390/ijms25126479
Chicago/Turabian StyleMartinez Valenzuela, Laura, Anna Vidal-Alabró, Belén Rubio, Paula Antón-Pàmpols, Francisco Gómez-Preciado, Xavier Fulladosa, Josep Maria Cruzado, Juan Torras, Nuria Lloberas, and Juliana Draibe. 2024. "Evaluating Single-Nucleotide Polymorphisms in Inflammasome Proteins and Serum Levels of IL-18 and IL-1β in Kidney Interstitial Damage in Anti-Neutrophilic Cytoplasmic Antibody-Associated Vasculitis" International Journal of Molecular Sciences 25, no. 12: 6479. https://doi.org/10.3390/ijms25126479