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Background: STAT4 polymorphisms have been consistently associated with susceptibility to systemic lupus erythematosus (SLE) across multiple ethnic groups. However, their clinical impact on lupus nephritis phenotypes, disease severity, and renal outcomes remains poorly defined. This highlights the need to evaluate the role of STAT4 variants in renal response and damage in lupus nephritis.
Objectives: To determine the association between STAT4 gene polymorphisms (rs11889341 and rs7568275) and renal response as well as renal damage in patients with proliferative lupus nephritis.
Methods: This cross-sectional study included patients with biopsy-proven proliferative lupus nephritis treated at Hospital Canselor Tuanku Muhriz (HCTM), Universiti Kebangsaan Malaysia. Genotyping of STAT4 variants (rs11889341 and rs7568275) was performed using TaqMan SNP genotyping assays on the Applied Biosystems 7500 Fast Real-Time PCR System. Baseline clinical characteristics, treatment details, and outcomes were extracted from medical records. Early complete remission (CR) was defined as a complete renal response (urine protein/creatinine ratio <50 mg/mmol and within 10% of baseline glomerular filtration rate) at 12 months while receiving prednisolone ≤10 mg daily. Renal damage was defined as irreversible kidney impairment with a glomerular filtration rate <50%. Associations between STAT4 polymorphisms and renal remission were analyzed using generalized estimating equations (GEE), while associations with renal damage were assessed using multivariable logistic regression.
Results: A total of 106 patients with 149 episodes of active lupus nephritis were included. The mean age at active lupus nephritis was 28.2 ± 8.0 years. The cohort comprised predominantly Malay patients (65.4%, n=70), followed by Chinese (29.0%, n=31) and Indian (5.6%, n=6) ethnicities. In the GEE model analysis, carriers of the STAT4 rs11889341 T allele were significantly associated with delayed achievement of CR (OR 2.51; 95% CI 1.01-6.21) after adjustment for age, lupus nephritis duration, ethnicity, delayed induction therapy, hydroxychloroquine use, mycophenolate mofetil maintenance therapy, relapse episodes, and hypertension (Table 1). Conversely, in the multivariable logistic regression model analysis, the STAT4 rs11889341 C allele was associated with a reduced risk of renal damage (OR 0.26; 95% CI 0.07–0.94) after adjustment for disease duration, sex, ethnicity, presence of global sclerosis, baseline acute kidney injury, delayed CR, and antiphospholipid syndrome (Table 2).
Conclusions: STAT4 rs11889341 gene variants appear to influence renal response and damage in proliferative lupus nephritis within a Malaysian multi-ethnic cohort. Larger prospective studies are warranted to confirm these findings and further elucidate the role of STAT4 in lupus nephritis outcomes.
| Factors | B | OR (95% CI) | p value |
|---|---|---|---|
| STAT s11889341 allele T | 0.92 | 2.51 (1.01-6.21) | 0.04 |
| Delayed in induction | 1.76 | 5.82 (1.83-18.52) | 0.003 |
| Malay ethnicity | 1.23 | 3.43 (1.52-7.75) | 0.003 |
| Mycophenolate Mofetil maintanence | -1.16 | 0.31 (0.14-0.69) | 0.004 |
| Hypetension at baseline | 0.92 | 2.51 (1.09-5.74) | 0.03 |
| Hydroxychloroquin | -0.59 | 0.55 (0.24-1.27) | 0.16 |
| Age at induction | 0.04 | 1.04 (0.98-1.09) | 0.18 |
| LN duration | -0.02 | 0.98 (0.89-1.09) | 0.69 |
| Relapse LN episode | 0.67 | 1.95 (0.76-5.02) | 0.16 |
| Factors | B | OR (95% CI) | p value |
| STAT 4 rs11889341 allele C | -1.33 | 0.26 (0.07-0.94) | 0.04 |
| Delayed CR (any episode ever) | 1.64 | 5.16 (1.32-20.07) | 0.02 |
| Acute kidney injury (any episode ever) | 2.18 | 8.85 (2.34-33.5) | 0.001 |
| Male gender | 1.26 | 3.53 (0.86-14.45) | 0.08 |
| Malay ethnicity | 1.56 | 4.77 (1.09-20.83) | 0.04 |
| SLE duration | -0.03 | 0.97 (0.87-1.07) | 0.53 |
| Presence of global sclerosis | 1.10 | 3.01 (0.81-11.09) | 0.10 |
| Antiphospholipid syndrome | 0.67 | 1.95 (0.36-10.57) | 0.44 |
REFERENCES: [1] Reid S et al, Interaction between the STAT4 rs11889341(T) risk allele and smoking confers increased risk of myocardial infarction and nephritis in patients with systemic lupus erythematosus. Ann Rheum Dis. 2021 Sep;80(9):1183-1189. doi: 10.1136/annrheumdis-2020-219727.
[2] Bolin K, et al. Association of STAT4 polymorphism with severe renal insufficiency in lupus nephritis. PLoS One. 2013 Dec 27;8(12):e84450. doi: 10.1371/journal.pone.0084450.
Acknowledgments: NIL.
Disclosure of Interests: None declared.