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

• Published in: Cytokine (Philadelphia, Pa.) Vol. 132; p. 154631
• Main Authors: Ghodke-Puranik, Yogita, Imgruet, Molly, Dorschner, Jessica M., Shrestha, Prakriti, McCoy, Kaci, Kelly, Jennifer A., Marion, Miranda, Guthridge, Joel M., Langefeld, Carl D., Harley, John B., James, Judith A., Sivils, Kathy L., Niewold, Timothy B.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2020
• Subjects: Autoimmunity; Genetics; Interferon; Autoimmunity; Genetics; Interferon
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2018.12.014

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.