Association of tumor necrosis factor-alpha polymorphisms with susceptibility and clinical outcomes of rheumatic heart disease.

Objective: To examine the association of tumor necrosis factor-alpha (TNF-alpha) gene polymorphisms with rheumatic heart disease (RHD) and valve damage, and their influence on TNF-alpha production and disease outcome.

Methods: We performed this cross-sectional study at Kasr El-Aini Hospital, Cairo University, Cairo, Egypt, from December 2008 to October 2009. Eighty children with chronic RHD and valve affection, and 50 controls were included. Patients with any other diseases or complications were excluded. Blood samples (5 ml) were collected. Genotyping for TNF-alpha polymorphisms was performed by the polymerase chain reaction-restriction fragment length polymorphism method. Serum TNF-alpha was measured by enzyme-linked immunosorbent assay.

Results: Serum TNF-alpha was significantly increased in RHD compared with controls (p=0.00003). The TNF-alpha -238 adenine (AA) (p=0.036) and -308AA (p=0.003) genotypes were more frequent in RHD patients than in controls, and were associated with increased production of TNF-alpha (p=0.00001 for 238AA) and (p=0.001 for 308AA). Both polymorphisms contributed to increased susceptibility for RHD (-308AA and adenine guanine (AG), odds ratio [OR]=4.72 [95% confidence interval [CI] 2.03-11.05], p=0.0001); (-238 AA and AG, OR=2.33 [CI: 1.05-5.19], p=0.035). The presence of -308AA was associated with mitral (p=0.001) and multivalvular (p=0.003) lesions and was more prevalent in moderate (p=0.001), and severe (p<0.001) cases than in controls. The -238AA variant was associated with mitral lesions (p=0.04) and severe cases (p=0.05) as compared with controls.

Conclusion: The TNF-alpha-238G/A and -308G/A polymorphisms were associated with susceptibility to RHD and increased production of TNF-alpha. Both polymorphisms were related to valve damage, and a more severe outcome of RHD.