Fine-mapping and transethnic genotyping establish IL2/IL21 genetic association with lupus and localize this genetic effect to IL21

Travis Hughes, Xana Kim-Howard, Jennifer A. Kelly, Kenneth M. Kaufman, Carl D. Langefeld, Julie Ziegler, Elena Sanchez, Robert P. Kimberly, Jeffrey C. Edberg, Rosalind Ramsey-Goldman, Michelle Petri, John D. Reveille, Javier Martín, Elizabeth E. Brown, Luis M. Vilá, Graciela S. Alarcón, Judith A. James, Gary S. Gilkeson, Kathy L. Moser, Patrick M. GaffneyJoan T. Merrill, Timothy J. Vyse, Marta E. Alarcón-Riquelme, Swapan K. Nath, B. Harley John, Amr H. Sawalha

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Objective Genetic association of the IL2/IL21 region at chromosome 4q27 has previously been reported in lupus and a number of autoimmune and inflammatory diseases. This study was undertaken to determine whether this genetic effect could be localized, using a very large cohort of lupus patients and controls. Methods We genotyped 45 tag single-nucleotide polymorphisms (SNPs) across the IL2/IL21 locus in 2 large independent lupus sample sets. We studied a set of subjects of European descent consisting of 4,248 lupus patients and 3,818 healthy controls, and an African American set of 1,569 patients and 1,893 healthy controls. Imputation in 3,004 additional controls from the Wellcome Trust Case Control Consortium was also performed. Genetic association between the genotyped markers was determined, and pairwise conditional analysis was performed to localize the independent genetic effect in the IL2/IL21 locus in lupus. Results We established and confirmed the genetic association between IL2/IL21 and lupus. Using conditional analysis and transethnic mapping, we localized the genetic effect in this locus to 2 SNPs in high linkage disequilibrium: rs907715 located within IL21 (odds ratio 1.16 [95% confidence interval 1.10-1.22], P = 2.17 × 10-8) and rs6835457 located in the 3′-untranslated flanking region of IL21 (odds ratio 1.11 [95% confidence interval 1.05-1.17], P = 9.35 × 10-5). Conclusion Our findings establish the genetic association between lupus and IL2/IL21 with a genome-wide level of significance. Further, our findings indicate that this genetic association within the IL2/IL21 linkage disequilibrium block is localized to IL21. If other autoimmune IL2/IL21 genetic associations are similarly localized, then the IL21 risk alleles would be predicted to operate by a fundamental mechanism that influences the course of a number of autoimmune disease processes.

Original languageEnglish (US)
Pages (from-to)1689-1697
Number of pages9
JournalArthritis and rheumatism
Volume63
Issue number6
DOIs
StatePublished - Jun 2011

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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