Genetic and Functional Characterization of STAT4 in Rheumatoid Arthritis Patients with Distinct Disease Activity
Abstract
1. Introduction
2. Results
3. Discussion
4. Materials and Methods
4.1. Study Population
4.2. Serological and Immunological Parameters
4.3. Proinflammatory Cytokines
4.4. Genotyping of STAT4 Variants
4.5. STAT4 mRNA Expression
4.6. Semiquantitative Detection of pSTAT4
4.7. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
anti-CCP | Anti-cyclic citrullinated peptide antibodies |
BMI | Body mass index |
CI | Confidence interval |
CRP | C-reactive protein |
D′ | Linkage disequilibrium |
DAS28 | Disease Activity Score in 28 joints |
ESR | Erythrocyte sedimentation rate |
GWAS | Genome-wide association studies |
HAQ | Health Assessment Questionnaire |
HCQ | Hydroxychloroquine |
HLA | Human leukocyte antigen |
IFN-γ | Interferon gamma |
IL-12 | Interleukin-12 |
IL-23 | Interleukin-23 |
MCH | Mean corpuscular hemoglobin |
MCV | Mean corpuscular volume |
mRNA | Messenger RNA |
MTX | Methotrexate |
OR | Odds ratio |
PBMCs | Peripheral blood mononuclear cells |
PLT | Platelets |
pSTAT4 | Phosphorylated STAT4 |
r2 | Correlation between loci |
RA | Rheumatoid arthritis |
RF | Rheumatoid factor |
SSZ | Sulfasalazine |
STAT4 | Signal transducer and activator of transcription 4 |
VAS | Visual analogue scale |
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Variable | Remission-Low Group (n = 31) | Moderate-High Group (n = 32) | p-Value |
---|---|---|---|
Family history and lifestyle factors | |||
Rheumatoid arthritis + | 17 (54.8) | 14 (43.8) | 0.454 c |
Type 1 Diabetes + | 11 (35.5) | 9 (28.1) | 0.595 c |
Crohn’s disease | 2 (6.5) | 1 (3.1) | 0.613 c |
Systemic lupus erythematosus + | 2 (6.5) | 2 (6.3) | 1.00 c |
Multiple sclerosis | 0 (0) | 2 (6.3) | 0.492 c |
Sjögren’s syndrome + | 2 (6.5) | 0 (0) | 0.238 c |
Tobacco use | 5 (16.1) | 10 (31.3) | 0.237 c |
Years smoking | 0 (0–30) | 0 (0–62) | 0.224 b |
Cigarettes per day | 0 (0–7) | 0 (0–20) | 0.111 b |
Wood smoke exposure + | 15 (48.4) | 11 (34.4) | 0.311 c |
Years exposed | 0 (0–60) | 0 (0–42) | 0.183 b |
Anthropometric data | |||
Age | 47.80 ± 11.75 | 50.25 ± 10.54 | 0.389 a |
Female | 26 (83.9) | 31 (96.9) | 0.104 c |
Male | 5 (16.1) | 1 (3.1) | |
BMI (kg/m2) | 28.81 ± 6.55 | 27.40 ± 5.60 | 0.364 b |
Clinical evaluation | |||
Disease duration (years) | 5.0 (0.08–29) | 3 (1–16) | 0.566 b |
HAQ | 0.58 ± 0.64 | 1.14 ± 0.69 | <0.01 ** a |
Tender joints | 0 (0–3) | 2 (0–16) | <0.01 ** b |
Swollen joints | 0 (0–4) | 1 (0–7) | <0.01 ** b |
ESR (mm/h) | 23.29 ± 12.27 | 38.72 ± 8.29 | <0.01 ** a |
VAS (Patient) | 27.1 ± 19.87 | 61.25 ± 18.09 | <0.01 ** a |
DAS28 | 2.58 (1.64–3.2) | 4.29 (3.22–6.65) | <0.01 ** b |
Morning stiffness + | 15 (48.4) | 21 (65.6) | 0.207 c |
Duration of stiffness (min) | 0 (0–180) | 7.50 (0–120) | 0.206 b |
Movement limitation + | 4 (12.9) | 17 (53.1) | <0.01 ** c |
PBMCs | 4.43 × 106 ± 2.16 × 106 | 4.15 × 106 ± 1.79 × 106 | 0.580 a |
CRP (mg/dL) | 3.78 (0.65–24.32) | 7.38 (1.77–75.85) | 0.102 b |
RF (IU/mL) | 78.1 (0.0–287.60) | 113.63 (2.66–490.30) | 0.105 b |
Anti-CCP (U/mL) | 1076 (0.0–2445) | 1078 (0.0–2343) | 0.778 b |
Treatment type | |||
Celecoxib + | 22 (71) | 24 (75) | 0.782 c |
Celecoxib dose (mg) | 200 (0–400) | 200 (0–400) | 0.781 b |
Alendronate + | 5 (16.1) | 4 (12.5) | 0.732 c |
Alendronate dose (mg) | 0 (0–10) | 0 (0–10) | 0.683 b |
Folic acid + | 29 (93.5) | 30 (93.8) | 1.00 c |
Folic acid dose (mg) | 5 (0–5) | 5 (0–5) | 0.982 b |
Calcium + | 16 (51.6) | 10 (31.3) | 0.128 c |
Calcium dose (mg) | 500 (0–1000) | 0 (0–500) | 0.065 b |
Methotrexate + | 30 (96.8) | 31 (96.9) | 1.00 c |
Methotrexate dose (mg) | 15 (0–25) | 15 (0–25) | 0.736 b |
Hydroxychloroquine + | 11 (35.5) | 4 (12.5) | 0.04 * c |
Hydroxychloroquine dose (mg) | 0 (0–300) | 0 (0–300) | 0.056 b |
Sulfasalazine + | 21 (67.7) | 24 (75) | 0.585 c |
Sulfasalazine dose (mg) | 1000 (0–3000) | 1000 (0–3000) | 0.747 b |
Variable | Remission-Low Group (n = 31) | Moderate-High Group (n = 32) | p-Value |
---|---|---|---|
Inflammatory markers | |||
IL-12 | 87.2 (13.5–516.2) | 103.2 (23.8–1920.4) | 0.386 b |
IFN-ɣ | 12.8 (0–1153) | 12.9 (0–621.2) | 0.815 b |
IL-23 | 12.3 (0–1247.5) | 23 (0–1108.7) | 0.353 b |
pSTAT4 | 0.15 ± 0.1 | 0.15 ± 0.1 | 0.814 a |
Underexpression + | 19 (61.3) | 14 (43.8) | 0.210 c |
Overexpression + | 12 (38.7) | 18 (56.3) | |
STAT4 mRNA | 0.63 (0.07–17.91) | 0.63 (0.16–20.76) | 0.929 b |
Underexpression + | 19 (61.3) | 20 (62.5) | 0.921 c |
Overexpression + | 12 (38.7) | 12 (37.5) |
Western Mexico | |||||
---|---|---|---|---|---|
Remission-Low Group (n = 31) | Moderate-High Group (n = 32) | OR | 95% CI | p-Value | |
STAT4: rs7574865 G/T | |||||
GG 1 | 36.7 (11) | 28.1 (9) | Reference | ||
GT 2 | 48.4 (15) | 50 (16) | 1.397 | (0.449–4.35) | 0.564 |
TT 3 | 16.7 (5) | 21.9 (7) | 2.512 | (0.319–19.755) | 0.381 |
G 4 | 60 (36) | 53 (34) | Reference | ||
T 5 | 40 (24) | 47 (30) | 1.380 | (0.961–1.981) | 0.081 |
STAT4: rs11889341 C/T | |||||
CC 1 | 36.7 (11) | 28.1 (9) | Reference | ||
CT 2 | 48.4 (15) | 50 (16) | 1.397 | (0.449–4.35) | 0.564 |
TT 3 | 16.7 (5) | 21.9 (7) | 2.512 | (0.319–19.755) | 0.381 |
C 4 | 60 (36) | 53 (34) | reference | ||
T 5 | 40 (24) | 47 (30) | 1.380 | (0.961–1.981) | 0.081 |
Western Mexico | ||||||
---|---|---|---|---|---|---|
Haplotype | Remission-Low Group | Moderate-High Group | OR | 95% CI | D′ | r2 |
GC | 60 | 53.12 | 1.00 | - | 1.000 | 1.000 |
TT | 40 | 43.55 | 0.76 | 0.37–1.55 |
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Bravo-Villagra, K.M.; Hernández-Ruíz, R.G.; Landeros-Sáenz, A.; Baños-Hernández, C.J.; Cerpa-Cruz, S.; García-Arellano, S.; Muñoz-Valle, J.F.; López-Quintero, A. Genetic and Functional Characterization of STAT4 in Rheumatoid Arthritis Patients with Distinct Disease Activity. Int. J. Mol. Sci. 2025, 26, 10011. https://doi.org/10.3390/ijms262010011
Bravo-Villagra KM, Hernández-Ruíz RG, Landeros-Sáenz A, Baños-Hernández CJ, Cerpa-Cruz S, García-Arellano S, Muñoz-Valle JF, López-Quintero A. Genetic and Functional Characterization of STAT4 in Rheumatoid Arthritis Patients with Distinct Disease Activity. International Journal of Molecular Sciences. 2025; 26(20):10011. https://doi.org/10.3390/ijms262010011
Chicago/Turabian StyleBravo-Villagra, Karla Mayela, Rocio Guadalupe Hernández-Ruíz, Alejandra Landeros-Sáenz, Christian Johana Baños-Hernández, Sergio Cerpa-Cruz, Samuel García-Arellano, José Francisco Muñoz-Valle, and Andres López-Quintero. 2025. "Genetic and Functional Characterization of STAT4 in Rheumatoid Arthritis Patients with Distinct Disease Activity" International Journal of Molecular Sciences 26, no. 20: 10011. https://doi.org/10.3390/ijms262010011
APA StyleBravo-Villagra, K. M., Hernández-Ruíz, R. G., Landeros-Sáenz, A., Baños-Hernández, C. J., Cerpa-Cruz, S., García-Arellano, S., Muñoz-Valle, J. F., & López-Quintero, A. (2025). Genetic and Functional Characterization of STAT4 in Rheumatoid Arthritis Patients with Distinct Disease Activity. International Journal of Molecular Sciences, 26(20), 10011. https://doi.org/10.3390/ijms262010011