Format

Send to

Choose Destination
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.

Author information

1
Colton Center for Autoimmunity, New York University School of Medicine, New York, NY, USA.
2
Division of Rheumatology, Mayo Clinic, Rochester, MN, USA.
3
Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
4
Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
5
Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine and Cincinnati VA Medical Center, Cincinnati, OH, USA.
6
Colton Center for Autoimmunity, New York University School of Medicine, New York, NY, USA. Electronic address: Timothy.Niewold@nyulangone.org.

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.

KEYWORDS:

Autoimmunity; Genetics; Interferon

PMID:
30685201
DOI:
10.1016/j.cyto.2018.12.014

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center