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

Abstract

Interferon alpha (IFN-alpha) levels are elevated in many patients with systemic lupus erythematosus (SLE); however it is not known whether high serum IFN-alpha 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-alpha activity in both patients and healthy relatives as compared to healthy unrelated individuals. High IFN-alpha 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-alpha activity, concordance in affected sib pairs and frequent transmission of the high IFN-alpha activity trait from parents to offspring. Autoantibodies to RNA-binding proteins and double-stranded DNA were associated with high IFN-alpha 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-alpha activity was similar across all studied ethnic backgrounds. These data suggest that high serum IFN-alpha activity is a complex heritable trait, which plays a primary role in SLE pathogenesis.

Figure 1

Many healthy first-degree relatives of systemic lupus erythematosus (SLE) patients demonstrate abnormally high serum interferon α (IFN-α) activity. Quantitative IFN-α activity data are shown for SLE patients, first-degree relatives by type of relation and healthy unrelated donors. The y axis represents sum of number of s.d. above healthy unrelated donors for the three IFN-α-induced genes measured in the reporter cell assay (see ‘Patients and methods’), P-values by Mann–Whitney t-test, error bars represent standard error of the mean.

Figure 2

Familial aggregation and correlation of interferon α (IFN-α) activity in first-degree relatives of systemic lupus erythematosus (SLE) patients. Each box represents a person, with the solid bold line separating SLE affecteds from healthy first-degree relatives. White shading indicates no significant difference from healthy unrelated donors, increasing yellow to red shading indicates increasing quantitative IFN-α activity. SLE patients are ordered by quantitative IFN-α activity in ascending order, lowest at top left, highest at bottom right. The gap in the middle of the diagram represents the categorical cutoff for high vs low IFN activity in the SLE patients. Healthy relatives are then arrayed on the right side of the bold line ordered by the IFN-α activity value of their corresponding SLE-affected member to show the variance in familial IFN-α activity as it relates to the SLE affected in the same family. Boxes representing family members with high IFN-α activity are moved centrally within the same row to allow easier comparison of the relative proportion of high IFN-α family members between rows.

Figure 3

Anti-RNA-binding protein (anti-RBP) and anti-dsDNA autoantibodies are independently associated with high interferon α (IFN-α) activity in systemic lupus erythematosus (SLE) patients, and modulate IFN-α activity in an additive fashion. Quantitative IFN-α activity in SLE patients stratified by both types of autoantibodies shows an independent association for each type, and an additive interaction (mean for each single positive = 25–30, mean for double positive = 65). P-values by Mann–Whitney t-test corrected with Bonferroni's method for multiple comparisons. RBP, anti-RNA-binding protein antibodies; DNA, anti-dsDNA antibodies; + or −, present or absent in a particular patient, respectively.

Figure 4

Interferon α (IFN-α) activity and presence of anti-RNA-binding proteins (RBP) and anti-dsDNA autoantibodies are similar in all self-reported ethnic groups. Quantitative IFN-α activity data for systemic lupus erythematosus (SLE) patients (a) and healthy first-degree relatives (b) stratified by self-reported race. P-values <0.05 by Mann–Whitney t-test between all self-reported ethnic groups, uncorrected for multiple comparisons to be conservative. (c) Percentage of patients with various combinations of anti-RBP and anti-DNA autoantibodies stratified by self-reported ethnicity. *P-value <0.05, all P-values are nonsignificant when corrected by Bonferroni method. P-values by Fisher's exact test. Eur. Am., European American; Afr. Am., African-American; + or −, present or absent, respectively.

Figure 5

A two hit model for interferon α (IFN-α) in systemic lupus erythematosus (SLE) pathogenesis may apply as an inherent hereditary tendency toward increased IFN-α activity is modulated by autoantibodies. APCs, antigen-presenting cells; anti-RBP, anti-RNA binding protein antibodies.