Recombinant human IFN- administered as a therapy for chronic viral hepatitis and malignancy is thought to cause em de novo /em SLE in some patients [6]

Recombinant human IFN- administered as a therapy for chronic viral hepatitis and malignancy is thought to cause em de novo /em SLE in some patients [6]. expert database review. The seven loci were: leucine-rich repeat containing 20 ( em LRRC20 /em ); protein phosphatase 1 H ( em PPM1H /em ); lysophosphatidic acid receptor 1 ( em LPAR1 /em ); ankyrin repeat and sterile alpha motif domain 1A ( em ANKS1A /em ); protein tyrosine phosphatase, receptor type M ( em PTPRM /em ); ephrin A5 ( em EFNA5 /em ); and V-set and immunoglobulin domain containing 2 ( em VSIG2 /em ). Results SNPs in the em LRRC20 /em , em PPM1H /em , em LPAR1 /em , em ANKS1A /em , and em VSIG2 /em loci each demonstrated strong association with a particular serologic profile (all odds ratios 2.2 and em P /em 3.5 10-4). Each of these serologic profiles was associated with increased serum IFN-. SNPs in both em PTPRM /em and em LRRC20 /em were associated with increased serum IFN- independent of serologic profile ( em P /em = 2.2 10-6 and em P /em = 2.6 10-3 respectively). None of the SNPs were strongly associated with SLE in case-control analysis, suggesting that the major impact of these variants will be upon subphenotypes in SLE. Conclusions This study demonstrates the power of using serologic and cytokine subphenotypes to elucidate genetic factors involved in complex autoimmune disease. The distinct associations observed emphasize the heterogeneity of molecular pathogenesis in SLE, and the need for stratification by subphenotypes in genetic studies. We hypothesize that these genetic variants play a role in disease manifestations and severity in SLE. Introduction Systemic lupus erythematosus ((SLE) OMIM #152700) is a complex disease characterized by multi-system involvement commonly affecting the skin, renal, musculoskeletal, and hematopoetic systems. SLE is caused by interactions between susceptibility genes and environmental factors resulting in an irreversible loss of immunologic self-tolerance [1]. Incidence is highest in women during the reproductive years [2]; however, people of all ages, genders, and ancestral backgrounds are susceptible. Disease features range from typically reversible manifestations such as rash or inflammatory arthritis to life-threatening end-organ damage such as glomerulonephritis or thrombosis, and it is difficult to predict which manifestations will affect an individual patient. Interferon alpha (IFN-) is a pleiotropic type I interferon with the potential to break immunologic self-tolerance by activating antigen-presenting cells after uptake of self material [3]. Serum IFN- is elevated in many SLE patients, and elevations often correlate with disease activity [4,5]. Recombinant human IFN- administered as a therapy for chronic viral hepatitis and malignancy is thought Amprolium HCl to cause em de novo /em SLE in some patients [6]. IFN–induced SLE typically resolves after the IFN- is discontinued [7,8], supporting the idea that IFN- Hepacam2 was causal. We have previously shown that serum IFN- is abnormally high in 20% of healthy first degree relatives of SLE patients as compared to 5% of healthy unrelated individuals [9]. Spouses of SLE patients did not have high serum IFN-. Taken together, these data suggest that high serum IFN- is a heritable risk factor for SLE. Additionally, serum IFN- activity is highest during the ages of peak SLE incidence in both patients and their healthy first degree relatives [10]. The high IFN- trait in SLE families is inherited in a complex fashion, suggesting polygenic inheritance which has not been fully characterized [11]. Autoantibodies directed at double-stranded Amprolium HCl DNA (dsDNA) and RNA binding proteins (anti-Ro, anti-La, anti-Sm, and Amprolium HCl anti-RNP, collectively anti-RBP) are characteristically found in SLE sera, and are the strongest known predictors of high serum IFN- in SLE patients [9]. The presence of anti-RBP and anti-dsDNA autoantibodies appears to be heritable in SLE families [12]. These autoantibodies are rare in healthy first degree relatives (one to three percent prevalence), and thus heritability of autoantibody traits is not sufficient to explain the heritability of high serum IFN- in SLE families [9]. Immune complexes formed by these SLE-associated autoantibodies can directly stimulate IFN- production em in vitro /em , likely via the endosomal Toll-like receptors [13]. In humans em in vivo /em , we find that while anti-RBP antibodies are associated with high serum.