A candidate gene study of the type i interferon pathway implicates IKBKE and IL8 as risk loci for SLE

Johanna K. Sandling, Sophie Garnier, Snaevar Sigurdsson, Chuan Wang, Gunnel Nordmark, Iva Gunnarsson, Elisabet Svenungsson, Leonid Padyukov, Gunnar Sturfelt, Andreas Jönsen, Anders A. Bengtsson, Lennart Truedsson, Catharina Eriksson, Solbritt Rantapää-Dahlqvist, Anders Mälarstig, Rona J. Strawbridge, Anders Hamsten, Lindsey A. Criswell, Robert R. Graham, Timothy W. BehrensMaija Leena Eloranta, Gunnar Alm, Lars Rönnblom, Ann Christine Syvänen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

52 Citations (Scopus)

Abstract

Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease in which the type I interferon pathway has a crucial role. We have previously shown that three genes in this pathway, IRF5, TYK2 and STAT4, are strongly associated with risk for SLE. Here, we investigated 78 genes involved in the type I interferon pathway to identify additional SLE susceptibility loci. First, we genotyped 896 single-nucleotide polymorphisms in these 78 genes and 14 other candidate genes in 482 Swedish SLE patients and 536 controls. Genes with P0.01 in the initial screen were then followed up in 344 additional Swedish patients and 1299 controls. SNPs in the IKBKE, TANK, STAT1, IL8 and TRAF6 genes gave nominal signals of association with SLE in this extended Swedish cohort. To replicate these findings we extracted data from a genomewide association study on SLE performed in a US cohort. Combined analysis of the Swedish and US data, comprising a total of 2136 cases and 9694 controls, implicates IKBKE and IL8 as SLE susceptibility loci (Pmeta 0.00010 and P meta 0.00040, respectively). STAT1 was also associated with SLE in this cohort (P meta 3.3 × 10-5), but this association signal appears to be dependent of that previously reported for the neighbouring STAT4 gene. Our study suggests additional genes from the type I interferon system in SLE, and highlights genes in this pathway for further functional analysis.

Original languageEnglish
Pages (from-to)479-484
Number of pages6
JournalEuropean Journal of Human Genetics
Volume19
Issue number4
DOIs
Publication statusPublished - Apr 2011

Bibliographical note

Funding Information:
This study was supported by a Target Identification in Lupus (TIL) grant from the Alliance for Lupus Research, US, the Swedish Research Council for Medicine, the Knut and Alice Wallenberg Foundation, the Swedish Rheumatism Foundation, the King Gustaf V 80-year Foundation, COMBINE, the European Community 6th Framework Program (LSHM-CT-2007-037273), the Swedish Heart-Lung Foundation, the Torsten and Ragnar Söderberg Foundation, the ‘Visare Norr’ Fund for Northern County Councils of Sweden, The Åke Wiberg Foundation, ALF funding from Stockholm County Council and Karolinska Institutet, the National Institutes of Health (R01 AR44804, K24 AR02175), the National Center for Research Resources (5 M01 RR00079), and a Kirkland Scholar Award to LAC. We thank Rezvan Kiani Dehkordi at the Rheumatology Clinic, Uppsala University Hospital, for assistance with DNA sample collection. Professor Göran Hallmans, Head of the Medical Biobank of Northern Sweden for providing blood samples. Ann-Christin Wiman, Caisa Pöntinen, Molecular Medicine, Department of Medical Sciences, Uppsala University, for assistance with genotyping. Genotyping was performed using equipment available at the SNP Technology Platform in Uppsala, Sweden (http://www.genotyping.se).

Other keywords

  • candidate gene study
  • IKBKE
  • IL8
  • single nucleotide polymorphism
  • systemic lupus erythematosus
  • type I interferon system

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