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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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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.
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fig3: 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.

Mentions: When each ancestral background was analyzed separately in case-control analysis, there were no strong associations observed (Table 3). Given the precedent for sex differences in the association of type I IFN-pathway genes [13, 27], we also analyzed females and males separately in each background (Table 4). Surprisingly, there was evidence for association between the rs12553951 C allele and SLE in EA males [odds ratio (OR) =  1.93, 95% confidence interval (95% CI) =  1.36–2.74, P = 2.5 × 10−4], but no similar association in EA females. This association would withstand statistical correction for multiple hypothesis testing, such as a Bonferroni correction for the number of SNPs tested within the IFNK locus in this study (P-values < 2.6 × 10−2 would remain significant after this correction). This correction for multiple hypothesis testing is likely too conservative, as independence between the individual measurements is an assumption of this correction, and in fact many of the SNPs tested in this study showed some degree of correlation with other SNPs, as shown in Figure 1. The low number of male subjects tested relates to the low incidence of SLE in males and reduces our confidence to some degree that this will prove to be a robust association to independent replication. However, the observed OR of >1.9 is large for human complex diseases, and genotyping of an independent cohort in an effort to definitively confirm this association would be warranted. No significant effect was observed upon the case-control associations when age was used as a covariate or when analyzing cases separated into age strata as described in the study of the IFN pathway gene SPP1 in [13]. We also imputed SNPs using the IMPUTE program in the Genome-Wide Association Study Software suite by Marchini et al. Using this algorithm we did not observe any additional significant associations with the imputed SNPs which would exceed a Bonferroni correction for the number of SNPs genotyped in the study (Figure 3).


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)

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

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

fig3: 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.
Mentions: When each ancestral background was analyzed separately in case-control analysis, there were no strong associations observed (Table 3). Given the precedent for sex differences in the association of type I IFN-pathway genes [13, 27], we also analyzed females and males separately in each background (Table 4). Surprisingly, there was evidence for association between the rs12553951 C allele and SLE in EA males [odds ratio (OR) =  1.93, 95% confidence interval (95% CI) =  1.36–2.74, P = 2.5 × 10−4], but no similar association in EA females. This association would withstand statistical correction for multiple hypothesis testing, such as a Bonferroni correction for the number of SNPs tested within the IFNK locus in this study (P-values < 2.6 × 10−2 would remain significant after this correction). This correction for multiple hypothesis testing is likely too conservative, as independence between the individual measurements is an assumption of this correction, and in fact many of the SNPs tested in this study showed some degree of correlation with other SNPs, as shown in Figure 1. The low number of male subjects tested relates to the low incidence of SLE in males and reduces our confidence to some degree that this will prove to be a robust association to independent replication. However, the observed OR of >1.9 is large for human complex diseases, and genotyping of an independent cohort in an effort to definitively confirm this association would be warranted. No significant effect was observed upon the case-control associations when age was used as a covariate or when analyzing cases separated into age strata as described in the study of the IFN pathway gene SPP1 in [13]. We also imputed SNPs using the IMPUTE program in the Genome-Wide Association Study Software suite by Marchini et al. Using this algorithm we did not observe any additional significant associations with the imputed SNPs which would exceed a Bonferroni correction for the number of SNPs genotyped in the study (Figure 3).

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