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

Harley IT, Niewold TB, Stormont RM, Kaufman KM, Glenn SB, Franek BS, Kelly JA, Kilpatrick JR, Hutchings D, Divers J, Bruner GR, Edberg JC, McGwin G, Petri MA, Ramsey-Goldman R, Reveille JD, Vilá-Pérez LM, Merrill JT, Gilkeson GS, Vyse TJ, Alarcón-Riquelme ME, Cho SK, Jacob CO, Alarcón GS, Moser KL, Gaffney PM, Kimberly RP, Bae SC, Langefeld CD, Harley JB, Guthridge JM, James JA - J. Biomed. Biotechnol. (2010)

Bottom Line: 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.The serum IFN association suggests that IFNK variants could influence type I IFN producing plasmacytoid dendritic cells in affected skin.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Immunology and Graduate Program in Immunobiology, Cincinnati Children's Hospital Research Foundation, OH 45267, USA.

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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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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fig4: 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.

Mentions: We next analyzed serum type I IFN activity in subjects with data available for this phenotype, which included 230 European-American and 158 African-American SLE patients. We first used logistic regression models with ancestry covariates to detect associations with high serum type I IFN activity as a categorical trait (high IFN was defined as >2SD above healthy controls). In both EA and AA, there was a single SNP associated with high serum type I IFN activity in female patients. The rs12686452 A allele was associated with high serum IFN in EA females (OR = 2.79, 95% CI = 1.48–5.29, P = 1.6 × 10−3) and the rs2814707 G allele was associated with high serum IFN in AA females (OR = 2.69, 95% CI = 1.30–5.56, P = 7.6 × 10−3). Quantitative serum type I IFN activity in each ancestral background stratified by SNP genotype is shown in Figure 4.


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

Harley IT, Niewold TB, Stormont RM, Kaufman KM, Glenn SB, Franek BS, Kelly JA, Kilpatrick JR, Hutchings D, Divers J, Bruner GR, Edberg JC, McGwin G, Petri MA, Ramsey-Goldman R, Reveille JD, Vilá-Pérez LM, Merrill JT, Gilkeson GS, Vyse TJ, Alarcón-Riquelme ME, Cho SK, Jacob CO, Alarcón GS, Moser KL, Gaffney PM, Kimberly RP, Bae SC, Langefeld CD, Harley JB, Guthridge JM, James JA - J. Biomed. Biotechnol. (2010)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2914299&req=5

fig4: 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.
Mentions: We next analyzed serum type I IFN activity in subjects with data available for this phenotype, which included 230 European-American and 158 African-American SLE patients. We first used logistic regression models with ancestry covariates to detect associations with high serum type I IFN activity as a categorical trait (high IFN was defined as >2SD above healthy controls). In both EA and AA, there was a single SNP associated with high serum type I IFN activity in female patients. The rs12686452 A allele was associated with high serum IFN in EA females (OR = 2.79, 95% CI = 1.48–5.29, P = 1.6 × 10−3) and the rs2814707 G allele was associated with high serum IFN in AA females (OR = 2.69, 95% CI = 1.30–5.56, P = 7.6 × 10−3). Quantitative serum type I IFN activity in each ancestral background stratified by SNP genotype is shown in Figure 4.

Bottom Line: 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.The serum IFN association suggests that IFNK variants could influence type I IFN producing plasmacytoid dendritic cells in affected skin.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Immunology and Graduate Program in Immunobiology, Cincinnati Children's Hospital Research Foundation, OH 45267, USA.

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.

Show MeSH
Related in: MedlinePlus