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Cytokine. 2019 Jan 23. pii: S1043-4666(19)30002-X. doi: 10.1016/j.cyto.2018.12.014. [Epub ahead of print]

Novel genetic associations with interferon in systemic lupus erythematosus identified by replication and fine-mapping of trait-stratified genome-wide screen.

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Colton Center for Autoimmunity, New York University School of Medicine, New York, NY, USA.
Division of Rheumatology, Mayo Clinic, Rochester, MN, USA.
Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine and Cincinnati VA Medical Center, Cincinnati, OH, USA.
Colton Center for Autoimmunity, New York University School of Medicine, New York, NY, USA. Electronic address:



High serum interferon alpha (IFN-α) is an important heritable phenotype in systemic lupus erythematosus (SLE) which is involved in primary disease pathogenesis. High vs. low levels of IFN-α are associated with disease severity and account for some of the biological heterogeneity between SLE patients. The aim of the study was to replicate and fine-map previously detected genetic associations with serum IFN-α in SLE.


We previously undertook a case-case genome-wide association study of SLE patients stratified by ancestry and extremes of phenotype in serum IFN-α. Single nucleotide polymorphisms (SNPs) in seven loci identified in this screen were selected for follow up in a large independent cohort of 1370 SLE patients (703 European-ancestry, 432 African ancestry, and 235 Amerindian ancestry). Each ancestral background was analyzed separately, and ancestry-informative markers were used to control for ancestry and admixture.


We find a rare haplotype spanning the promoter region of EFNA5 that is strongly associated with serum IFN-α in both African-American and European-American SLE patients (OR = 3.0, p = 3.7 × 10-6). We also find SNPs in the PPM1H, PTPRM, and NRGN regions associated with IFN-α levels in European-American, Amerindian, and African-American SLE patients respectively. Many of these associations are within regulatory regions of the gene, suggesting an impact on transcription.


This study demonstrates the power of molecular sub-phenotypes to reveal genetic factors involved in complex autoimmune disease. The distinct associations observed in different ancestral backgrounds emphasize the heterogeneity of molecular pathogenesis in SLE.


Autoimmunity; Genetics; Interferon


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