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. 2010:2010:706825.
doi: 10.1155/2010/706825. Epub 2010 Jul 15.

The role of genetic variation near interferon-kappa in systemic lupus erythematosus

Isaac T W Harley  1 , Timothy B Niewold, Rebecca M Stormont, Kenneth M Kaufman, Stuart B Glenn, Beverly S Franek, Jennifer A Kelly, Jeffrey R Kilpatrick, David Hutchings, Jasmin Divers, Gail R Bruner, Jeffrey C Edberg, Gerald McGwin Jr, Michelle A Petri, Rosalind Ramsey-Goldman, John D Reveille, Luis M Vilá-Pérez, Joan T Merrill, Gary S Gilkeson, Timothy J Vyse, Marta E Alarcón-Riquelme, Soo-Kyung Cho, Chaim O Jacob, Graciela S Alarcón, Kathy L Moser, Patrick M Gaffney, Robert P Kimberly, Sang-Cheol Bae, Carl D Langefeld, John B Harley, Joel M Guthridge, Judith A James
Affiliations

The role of genetic variation near interferon-kappa in systemic lupus erythematosus

Isaac T W Harley et al. J Biomed Biotechnol. 2010.

Abstract

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by increased type I interferons (IFNs) and multiorgan inflammation frequently targeting the skin. IFN-kappa is a type I IFN expressed in skin. A pooled genome-wide scan implicated the IFNK locus in SLE susceptibility. We studied IFNK single nucleotide polymorphisms (SNPs) in 3982 SLE cases and 4275 controls, composed of European (EA), African-American (AA), and Asian ancestry. rs12553951C was associated with SLE in EA males (odds ratio = 1.93, P = 2.5 x 10(-4)), but not females. Suggestive associations with skin phenotypes in EA and AA females were found, and these were also sex-specific. IFNK SNPs were associated with increased serum type I IFN in EA and AA SLE patients. Our data suggest a sex-dependent association between IFNK SNPs and SLE and skin phenotypes. The serum IFN association suggests that IFNK variants could influence type I IFN producing plasmacytoid dendritic cells in affected skin.

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Figures

Figure 1
Figure 1
Haplotype diagrams showing LD structure between SNPs near the IFNK gene in each ancestral background. Generated using Haploview 4.1 software, the plots show pairwise comparisons between each SNP in each ancestral background as r-squared values. Increased dark shading indicates higher r-squared values between the two SNPs. Eur. European ancestry, Af-Am. African-American ancestry.
Figure 2
Figure 2
Stimulation of WISH reporter cells with IFN-α, IFN-κ, and SLE sera with and without anti-IFN-κ antibodies. WISH cells were assayed for type I IFN-induced gene expression as described in the methods, using the stimuli indicated on the graph. Anti-IFN-κ antibody was used at a concentration of 10 μg/mL, and anti-IFN-κ treated sera were preincubated with the antibody for 30 minutes before the sera was applied to the WISH cells. Y-axis shows the IFN-induced gene expression score calculated as described in the Methods.
Figure 3
Figure 3
Association analysis of imputed IFNK SNPs. Each symbol represents an SNP, with downward pointing triangles showing the SNPs directly genotyped and upward pointing triangles indicating the SNPs which were imputed (see methods for details of imputation). Y-axis shows the inverse log of the P value resulting from the case-control chi-square test statistic for each SNP. X-axis shows the location of each SNP in bases along chromosome 9. Each color represents a different ancestral background/sex included in this analysis. Due to low numbers, African-American (AA) males and Asian males were not included. EA: European ancestry, M: male, and F: female.
Figure 4
Figure 4
Serum type I IFN levels in SLE patients stratified by IFNK genotype. Serum type I IFN activity in European (a) and African-American (b) ancestry SLE patients is shown, stratified by genotype at the associated SNP in each ancestral background. Minor allele homozygotes are combined with the heterozygous state in each case due to low numbers. Serum type I IFN activity is reported in relative units (see methods for derivation of IFN activity). Data are nonnormally distributed, so the box-and-whiskers format is used, with lines indicating the median, boxes showing the interquartile range, and error bars showing the 10th and 90th percentiles. P values were calculated using a nonparametric Mann-Whitney U test.
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