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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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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.
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fig1: 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.

Mentions: Linkage disequilibrium (LD) analysis was performed using Haploview 4.1 [24] (http://www.broad.mit.edu/mpg/haploview), and diagrams showing haplotype structures in each ancestral background studied are shown in Figure 1. Minor allele frequency <0.05 was used as a cutoff in each population as well as P-value for departure from Hardy-Weinberg equilibrium <.001 [23]. Association analysis was performed using the additive genetic model as the primary inference using PLINK v1.07 [25] (http://pngu.mgh.harvard.edu/~purcell/plink/) in each ancestral background and sex category separately. Association analyses were performed as logistic regressions using either SLE affected versus unaffected or SLE subphenotypes as outcome variables and the IFNK SNPs as predictor variables. The first four principal components which were informative for ancestry as described above [23] were incorporated as covariates in all association and subphenotype analyses to control for potential confounding related to population structure. SLE subphenotypes analyzed include the presence or absence of ACR clinical criteria for skin (discoid rash, malar rash, or photosensitivity), high versus low serum type I IFN activity defined as 2SD above healthy donors, as well as presence or absence of positive autoantibody response as determined by positive reactivities against dsDNA or select lupus-associated extractable nuclear antigens. P-values shown are not corrected for multiple comparisons. SNPs were screened for potential influence on serum IFN by logistic regression as above, and then quantitative serum IFN levels were plotted with respect to the SNPs which showed evidence for association in EA and AA, respectively. Two column nonparametric t-tests were performed comparing serum IFN levels in major allele homozygotes versus heterozygotes and minor allele homozygotes combined in each sex in both ancestral backgrounds.


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)

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

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

fig1: 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.
Mentions: Linkage disequilibrium (LD) analysis was performed using Haploview 4.1 [24] (http://www.broad.mit.edu/mpg/haploview), and diagrams showing haplotype structures in each ancestral background studied are shown in Figure 1. Minor allele frequency <0.05 was used as a cutoff in each population as well as P-value for departure from Hardy-Weinberg equilibrium <.001 [23]. Association analysis was performed using the additive genetic model as the primary inference using PLINK v1.07 [25] (http://pngu.mgh.harvard.edu/~purcell/plink/) in each ancestral background and sex category separately. Association analyses were performed as logistic regressions using either SLE affected versus unaffected or SLE subphenotypes as outcome variables and the IFNK SNPs as predictor variables. The first four principal components which were informative for ancestry as described above [23] were incorporated as covariates in all association and subphenotype analyses to control for potential confounding related to population structure. SLE subphenotypes analyzed include the presence or absence of ACR clinical criteria for skin (discoid rash, malar rash, or photosensitivity), high versus low serum type I IFN activity defined as 2SD above healthy donors, as well as presence or absence of positive autoantibody response as determined by positive reactivities against dsDNA or select lupus-associated extractable nuclear antigens. P-values shown are not corrected for multiple comparisons. SNPs were screened for potential influence on serum IFN by logistic regression as above, and then quantitative serum IFN levels were plotted with respect to the SNPs which showed evidence for association in EA and AA, respectively. Two column nonparametric t-tests were performed comparing serum IFN levels in major allele homozygotes versus heterozygotes and minor allele homozygotes combined in each sex in both ancestral backgrounds.

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