title: Fine-mapping and transethnic genotyping establish IL2/IL21 genetic association with lupus and localize this genetic effect to IL21.
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)).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: Travis
authors.initials: T
authors.lastname: Hughes
authors.forename: Xana
authors.initials: X
authors.lastname: Kim-Howard
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kelly
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Kaufman
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.forename: Julie
authors.initials: J
authors.lastname: Ziegler
authors.forename: Elena
authors.initials: E
authors.lastname: Sanchez
authors.forename: Robert P
authors.initials: RP
authors.lastname: Kimberly
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Edberg
authors.forename: Rosalind
authors.initials: R
authors.lastname: Ramsey-Goldman
authors.forename: Michelle
authors.initials: M
authors.lastname: Petri
authors.forename: John D
authors.initials: JD
authors.lastname: Reveille
authors.forename: Javier
authors.initials: J
authors.lastname: Martín
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Brown
authors.forename: Luis M
authors.initials: LM
authors.lastname: Vilá
authors.forename: Graciela S
authors.initials: GS
authors.lastname: Alarcón
authors.forename: Judith A
authors.initials: JA
authors.lastname: James
authors.forename: Gary S
authors.initials: GS
authors.lastname: Gilkeson
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Moser
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Gaffney
authors.forename: Joan T
authors.initials: JT
authors.lastname: Merrill
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Vyse
authors.forename: Marta E
authors.initials: ME
authors.lastname: Alarcón-Riquelme
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Nath
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.forename: Amr H
authors.initials: AH
authors.lastname: Sawalha
mesh_terms: D044383:Black People / Q000235:genetics; D002874:Chromosome Mapping; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D015331:Cohort Studies; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics*; D007378:Interleukins / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000453:epidemiology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics; D001741:Black or African American; D000098546:Interleukin-21
chemical_list: D007376:Interleukin-2; D007378:Interleukins; D000098546:Interleukin-21