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

Autor: 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.

Publication year: 2020

Cytokine

issn:1096-0023 1043-4666

doi: 10.1016/j.cyto.2018.12.014

Abstract:

BACKGROUND/PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Language: eng

Pmid: 30685201

Tags: Humans; Polymorphism, Single Nucleotide; Genome-Wide Association Study; Genetics; Haplotypes; Autoimmunity; Ephrin-A5/genetics; Interferon; Interferon-alpha/*blood; Lupus Erythematosus, Systemic/blood/*genetics

Link: https://pubmed.ncbi.nlm.nih.gov/30685201/