Jeremy E. Adler

2nd Year Medical Student

Department: School of Medicine

Graduate Program: TBD

Advisor: Dr. Anthony Zador (rotating)

Abstract (undergraduate):

Advisor:

Title:  Lupus Families Reveal Age-and Sex-Related Patterns of Interferon Alpha Expression

Author Block: Timothy B. Niewold¹, Jeremy E. Adler² , Thomas J.A. Lehman², John B. Harley³, Mary K. Crow². ¹University of Chicago, Chicago, IL; ²Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, New York, NY; ³Oklahoma Medical Research Foundation, Oklahoma City, OK

Purpose: Interferon alpha (IFN-α) levels are elevated in many patients with systemic lupus erythematosus (SLE), and IFN-α may play a primary role in disease pathogenesis. Given the marked 9:1 female to male differential in SLE disease, we examined two large SLE family cohorts and a diverse cohort of healthy donors for age- or sex-related patterns of IFN-α expression.

Patients and Methods: Serum samples from the Hospital for Special Surgery Family Lupus Registry (160 SLE, 115 first degree relatives), the Lupus Multiplex Registry and Repository (155 SLE, 230 first degree relatives), and 141 healthy unrelated donors were assayed for IFN-α activity using a functional reporter cell assay. Serum IFN-α activity data was correlated with age using Spearman’s R. Sub-groups are detected within the large data sets using a Mann-Whitney sliding window with a width of 15 years, and all sub-groups with nominal p value of ≤0.05 are recorded. All possible segmentations of IFN-α expression by age are generated, and then segmentations with non-significant adjacent subgroups are removed. Kruskal-Wallis testing is used to rank the significance of each segmentation.

Results: Age was inversely correlated with serum IFN-α activity in female SLE patients (r= -0.20, p=0.001) as well as healthy first degree female relatives (r= -0.16, p=0.023). In female healthy unrelated donors, highest IFN-α expression was also seen in 20-30 year old women, however there was no significant overall negative correlation. In male SLE patients, relatives, and unrelated donors, there were no significant correlations between age and serum IFN-α activity, although there was a trend toward an inverse correlation in the male SLE patients (r= -0.12, p=0.16). The data did not fit a monotonic function well, evidenced by the low r values despite significant p values. Therefore, a Mann-Whitney/Kruskal-Wallis pattern-finding algorithm was used to analyze the large complex data sets. This analysis revealed a significant increase in IFN-a expression between the ages of 12 and 22 for female SLE patients and between the ages 15 and 29 for male SLE patients. Both male and female healthy first degree relatives had significantly decreased IFN-α expression after age 50 (p=0.018 and p=0.042 respectively). No significant sub-groups were seen in the healthy unrelated donors.

Conclusions: IFN-α expression is inversely correlated with age in both female SLE patients and their female healthy first degree relatives. These data suggest a disease-independent increase in IFN-α expression in young women, which is accentuated in the female SLE patients. The peak of IFN-α expression observed in male SLE patients is later than in female SLE patients. These age- and sex-related patterns of IFN-α expression may underlie some of the increased SLE incidence and earlier onset of disease in women.

Author Disclosure Block: T.B. Niewold, Arthritis Foundation Post-doctoral Fellowship Grant, NIAID Clinical Research LRP, 2; J.E. Adler, None; T.J. Lehman, None; J.B. Harley, None; M.K. Crow, NIH R01 AI05983-01, Research Grants from Alliance for Lupus Research and Lupus Research Institute, 2; patent pending for interferon assay, 9.