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Association of genetic variations in PTPN2 and CD122 with ocular Behcet's disease
Qi Zhang1, Hua Li2, Shengping Hou1
1Ophthalmology Department, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, People's Republic of China.
Background:
Protein tyrosine phosphatases (PTPs) play critical roles in human autoimmunity. Previous studies found that PTPN2 may be the key regulatory factor in the T-cell-mediated immune response. PTPN2 regulates the Janus kinase/signal transducers and activators of transcription pathway by inhibiting signalling via the interleukin (IL)-2 receptor (CD122). An association between genetic variations in PTPN2 and CD122 with ocular Behcet's disease (BD) has not yet been addressed and was therefore the purpose of this study.
Methods:
A two-stage case-control study was performed in 906 patients with ocular BD and 2178 healthy controls. Genotyping analysis of 11 single nucleotide polymorphisms was carried out. The expression of PTPN2 in peripheral blood mononuclear cells (PBMCs) was quantified by real-time PCR and cytokine production was measured by ELISA.
Results:
The frequency of the GG genotype of PTPN2-rs7234029 was significantly lower in patients with ocular BD (p=1.94×10-5, pc=8.34×10-4, OR=0.466). Stratification according to gender showed that rs7234029 was significantly associated with BD in men. A stratified analysis according to the main clinical features showed that rs7234029 was significantly associated with genital ulcers, skin lesions and a positive pathergy test. No association could be detected between BD and CD122 gene polymorphisms. Functional studies showed that rs7234029 GG genotype carriers had a higher PNPT2 mRNA expression level than those which carrying the AA or AG genotype, and a decreased secretion of IL-17 and tumour necrosis factor-alpha was seen by PBMCs from GG carriers. No significant difference could be detected concerning IL-1β or IL-6 production by stimulated PBMCs between the different genotype groups.
Conclusions:
This study shows that a PTPN2-rs7234029 polymorphism is associated with ocular BD and is strongly influenced by gender. In addition, our results suggest that the genetic association with PTPN2 may involve the regulation of PTPN2 mRNA expression and cytokine secretion.
Insights
Genetic variations in PTPN2, specifically the rs7234029 polymorphism, are linked to ocular Behcet's disease (BD) in men. This finding suggests a role for PTPN2 in regulating immune responses relevant to BD pathogenesis.
Area of Science:
- Immunology
- Genetics
- Autoimmunity
Background:
- Protein tyrosine phosphatases (PTPs) are crucial in autoimmunity.
- PTPN2 is a key regulator of T-cell-mediated immunity, influencing the JAK/STAT pathway via IL-2 receptor signaling.
- The association between PTPN2/CD122 genetic variations and ocular Behcet's disease (BD) was unexplored.
Purpose of the Study:
- To investigate the association between genetic variations in PTPN2 and CD122 and ocular Behcet's disease (BD).
Main Methods:
- A two-stage case-control study involving 906 ocular BD patients and 2178 healthy controls.
- Genotyping of 11 single nucleotide polymorphisms (SNPs) in PTPN2 and CD122.
- Quantification of PTPN2 mRNA expression in PBMCs and measurement of cytokine production (IL-17, TNF-α, IL-1β, IL-6).
Main Results:
- A significant association was found between the PTPN2-rs7234029 GG genotype and lower risk of ocular BD (p=1.94×10-5), particularly in men.
- The rs7234029 polymorphism was linked to genital ulcers, skin lesions, and a positive pathergy test in BD patients.
- GG genotype carriers exhibited higher PTPN2 mRNA expression and decreased IL-17 and TNF-α secretion from PBMCs.
Conclusions:
- The PTPN2-rs7234029 polymorphism is associated with ocular BD, with a notable gender influence.
- The genetic association may involve altered PTPN2 mRNA expression and subsequent cytokine secretion, impacting BD pathogenesis.