High serum IFN-α activity is a heritable risk factor for systemic lupus erythematosus

Interferon α (IFN- α ) levels are elevated in many patients with systemic lupus erythematosus (SLE); however it is not known whether high serum IFN- α activity is a cause or a result of the disease. We studied 266 SLE patients and 405 of their healthy relatives, and frequently found high serum IFN- α activity in both patients and healthy relatives as compared to healthy unrelated individuals. High IFN- α activity was clustered in specific families in both SLE patients and their healthy first-degree relatives, suggesting a heritable trait. Heritability was also supported by quantitative familial correlation of IFN- α activity, concordance in affected sib pairs and frequent transmission of the high IFN- α activity trait from parents to offspring. Autoantibodies to RNA-binding proteins and double-stranded DNA were associated with high IFN- α activity in SLE patients; however these autoantibodies were very uncommon in healthy family members and did not explain the observed familial correlations. The frequency of high IFN- α activity was similar across all studied ethnic backgrounds. These data suggest that high serum IFN- α activity is a complex heritable trait, which plays a primary role in SLE pathogenesis.