Systemic lupus erythematosus (SLE) patients frequently have high circulating tumor necrosis factor alpha (TNF-α) levels. We explored circulating TNF-αlevels in SLE families to determine whether high levels of TNF-αwere clustered in a heritable pattern. We measured TNF-αin 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-αtrait were assessed. SLE-affected individuals had the highest TNF-αlevels, and TNF-αwas 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-αlevels, resulting in a first degree relative recurrence risk of 4.48(P=2.9×10-5). Interestingly, the median TNF-αvalue in spouses was similar to that of the first degree relatives. Concordance of the TNF-αtrait (high versus low) in SLE patients and their spouses was strikingly high at 78.2%. These data support a role for TNF-αin SLE pathogenesis, and TNF-αlevels 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.
Heritable major histocompatibility complex class II-associated differences in production of tumor necrosis factor alpha: relevance to genetic predisposition to systemic lupus erythematosus.
