title: Contribution of IKBKE and IFIH1 gene variants to SLE susceptibility.
abstract: The type I interferon system genes IKBKE and IFIH1 are associated with the risk of systemic lupus erythematosus (SLE). To identify the sequence variants that are able to account for the disease association, we resequenced the genes IKBKE and IFIH1. Eighty-six single-nucleotide variants (SNVs) with potentially functional effect or differences in allele frequencies between patients and controls determined by sequencing were further genotyped in 1140 SLE patients and 2060 controls. In addition, 108 imputed sequence variants in IKBKE and IFIH1 were included in the association analysis. Ten IKBKE SNVs and three IFIH1 SNVs were associated with SLE. The SNVs rs1539241 and rs12142086 tagged two independent association signals in IKBKE, and the haplotype carrying their risk alleles showed an odds ratio of 1.68 (P-value=1.0 × 10(-5)). The risk allele of rs12142086 affects the binding of splicing factor 1 in vitro and could thus influence its transcriptional regulatory function. Two independent association signals were also detected in IFIH1, which were tagged by a low-frequency SNV rs78456138 and a missense SNV rs3747517. Their joint effect is protective against SLE (odds ratio=0.56; P-value=6.6 × 10(-3)). In conclusion, we have identified new SLE-associated sequence variants in IKBKE and IFIH1, and proposed functional hypotheses for the association signals.
authors.affiliation: Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.forename: A
authors.initials: A
authors.lastname: Ahlford
authors.forename: N
authors.initials: N
authors.lastname: Laxman
authors.forename: G
authors.initials: G
authors.lastname: Nordmark
authors.forename: M-L
authors.initials: ML
authors.lastname: Eloranta
authors.forename: I
authors.initials: I
authors.lastname: Gunnarsson
authors.forename: E
authors.initials: E
authors.lastname: Svenungsson
authors.forename: L
authors.initials: L
authors.lastname: Padyukov
authors.forename: G
authors.initials: G
authors.lastname: Sturfelt
authors.forename: A
authors.initials: A
authors.lastname: Jönsen
authors.forename: A A
authors.initials: AA
authors.lastname: Bengtsson
authors.forename: L
authors.initials: L
authors.lastname: Truedsson
authors.forename: S
authors.initials: S
authors.lastname: Rantapää-Dahlqvist
authors.forename: C
authors.initials: C
authors.lastname: Sjöwall
authors.forename: J K
authors.initials: JK
authors.lastname: Sandling
authors.forename: L
authors.initials: L
authors.lastname: Rönnblom
authors.forename: A-C
authors.initials: AC
authors.lastname: Syvänen
mesh_terms: D016022:Case-Control Studies; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics* / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D000072260:RNA Splicing Factors; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D000072260:RNA Splicing Factors; C107467:SF1 protein, human; D014157:Transcription Factors; D051550:I-kappa B Kinase; C496565:IKBKE protein, human; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1