TNF‐α promoter gene polymorphisms in Spanish children with persistent oligoarticular and systemic‐onset juvenile idiopathic arthritis

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Abstract
Objective: To explore the possible association/s of the first reported tumour necrosis factor (TNF‐αTNF‐) α promoter gene polymorphisms −308, −238, −376 and −163 (G→A) with systemic (SoJIA) and oligoarticular subtypes of juvenile idiopathic arthritis (JIA); and to test the association between these polymorphisms and the class I/class II HLA alleles in our population. Methods: The patient group comprised 29 oligoarticular and 26 systemic Caucasian Spanish children with JIA; 68 healthy volunteers from the same ethnic group and geographical region served as controls. HLA alleles were determined using low‐resolution polymerase chain reaction (PCR). TNF‐α promoter gene polymorphisms were screened using PCR denaturing gradient gel electrophoresis (PCR‐DGGE), followed, if positive, by restriction fragment length polymorphism (RFLP) analysis for identification. Results: No statistical association was found between the four polymorphisms studied and JIA. However, the −308 G→A polymorphism (TNF A2) tended to be more frequent in patients with SoJIA than in the oligoarticular group. TNF A2 was strongly associated with the extended haplotype A1B8DR3 (p = 0.003), and the tandem polymorphism −238/−376 in the presence of B18 and DR3. Conclusion: The TNF A2 allele was more frequent in SoJIA than in the oligoarticular group. TNF A2 can help to create a more inflammatory milieu in this JIA subtype, in combination with other polymorphisms involved in regulatory sequences of key molecules in the inflammatory response. The association of the −308 and −238/−376 polymorphisms with specific alleles of the HLA is reconfirmed.