Familial Aggregation of High Tumor Necrosis Factor Alpha Levels in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) patients frequently have high circulating tumor necrosis factor alpha (TNF-alpha) levels. We explored circulating TNF-alpha levels in SLE families to determine whether high levels of TNF-alpha were clustered in a heritable pattern. We measured TNF-alpha in 242 SLE patients, 361 unaffected family members, 23 unaffected spouses of SLE patients, and 62 unrelated healthy controls. Familial correlations and relative recurrence risk rates for the high TNF-alpha trait were assessed. SLE-affected individuals had the highest TNF-alpha levels, and TNF-alpha was significantly higher in unaffected first degree relatives than healthy unrelated subjects (P = 0.0025). No Mendelian patterns were observed, but 28.4% of unaffected first degree relatives of SLE patients had high TNF-alpha levels, resulting in a first degree relative recurrence risk of 4.48 (P = 2.9 x 10(-5)). Interestingly, the median TNF-alpha value in spouses was similar to that of the first degree relatives. Concordance of the TNF-alpha trait (high versus low) in SLE patients and their spouses was strikingly high at 78.2%. These data support a role for TNF-alpha in SLE pathogenesis, and TNF-alpha levels may relate with heritable factors. The high degree of concordance in SLE patients and their spouses suggests that environmental factors may also play a role in the observed familial aggregation.