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Systemic lupus erythematosus (SLE) patients frequently have high circulating tumor necrosis factor alpha (TNF-  α  ) levels. We explored circulating TNF-  α   levels in SLE families to determine whether high levels of TNF-  α   were clustered in a heritable pattern. We measured TNF-  α   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-  α   trait were assessed. SLE-affected individuals had the highest TNF-  α   levels, and TNF-  α   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-  α   levels, resulting in a first degree relative recurrence risk of 4.48 ( P  = 2.9 × 10 −5 ). Interestingly, the median TNF-  α   value in spouses was similar to that of the first degree relatives. Concordance of the TNF-  α   trait (high versus low) in SLE patients and their spouses was strikingly high at 78.2%. These data support a role for TNF-  α   in SLE pathogenesis, and TNF-  α   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.

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