Open AccessFine‐mapping and transethnic genotyping establish IL2 / IL21 genetic association with lupus and localize this genetic effect to IL21
Author(s) -
Hughes Travis,
KimHoward Xana,
Kelly Jennifer A.,
Kaufman Kenneth M.,
Langefeld Carl D.,
Ziegler Julie,
Sanchez Elena,
Kimberly Robert P.,
Edberg Jeffrey C.,
RamseyGoldman Rosalind,
Petri Michelle,
Reveille John D.,
Martín Javier,
Brown Elizabeth E.,
Vilá Luis M.,
Alarcón Graciela S.,
James Judith A.,
Gilkeson Gary S.,
Moser Kathy L.,
Gaffney Patrick M.,
Merrill Joan T.,
Vyse Timothy J.,
AlarcónRiquelme Marta E.,
Nath Swapan K.,
Sawalha Amr H.
Publication year - 2011
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.30320
Subject(s) - linkage disequilibrium , single nucleotide polymorphism , genetics , imputation (statistics) , genetic association , systemic lupus erythematosus , odds ratio , locus (genetics) , genome wide association study , biology , genotype , medicine , gene , mathematics , disease , missing data , statistics
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.