Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci

John B. Harley, Marta E. Alarcón-Riquelme, Lindsey A. Criswell, Chaim O. Jacob, Robert P. Kimberly, Kathy L. Moser, Betty P. Tsao, Timothy J. Vyse, Carl D. Langefeld, Swapan K. Nath, Joel M. Guthridge, Beth L. Cobb, Daniel B. Mirel, Miranda C. Marion, Adrienne H. Williams, Jasmin Divers, Wei Wang, Summer G. Frank, Bahram Namjou, Stacey B. GabrielAnnette T. Lee, Peter K. Gregersen, Timothy W. Behrens, Kimberly E. Taylor, Michelle Fernando, Raphael Zidovetzki, Patrick M. Gaffney, Jeffrey C. Edberg, John D. Rioux, Joshua O. Ojwang, Judith A. James, Joan T. Merrill, Gary S. Gilkeson, Michael F. Seldin, Hong Yin, Emily C. Baechler, Quan Zhen Li, Edward K. Wakeland, Gail R. Bruner, Kenneth M. Kaufman, Jennifer A. Kelly

Research output: Contribution to journalArticlepeer-review

985 Scopus citations

Abstract

Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (λS = ∼30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 × 10-7 < P overall < 1.6 × 10-23; odds ratio = 0.82-1.62) in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 × 10 -5) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at ≥9 other loci (P < 2 × 10-7). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.

Original languageEnglish (US)
Pages (from-to)204-210
Number of pages7
JournalNature Genetics
Volume40
Issue number2
DOIs
StatePublished - Feb 2008

Bibliographical note

Funding Information:
SLEGEN appreciates the financial support of the Alliance for Lupus Research. Other support was obtained individually from the Alliance for Lupus Research (J.B.H., K.L.M., C.O.J.), the US National Institutes of Health (grants RR020278 (S.B.G.), AR62277 (J.B.H.), RR020143 (J.B.H.), AR24260 (J.B.H.), AI24717 (J.B.H.), AR22804 (L.A.C.), AR02175 (L.A.C.), AR052300 (L.A.C.), AR43815 (C.O.J.), AR49084 (R.P.K.), AR33062 (R.P.K.), AR43247 (K.L.M.) and AR43814 (B.P.T.)), the Mary Kirkland Awards (J.B.H., L.A.C.), the US Department of Veterans Affairs (J.B.H.), the Lupus Foundation of Minnesota (K.L.M.), the Knut and Alice Wallenberg Foundation (M.E.A.-R.), the Torsten & Ragnar Söderbergs Foundation (M.E.A.-R.), the Swedish Research Council (M.E.A.-R.) and a Wellcome Trust Senior Fellowship (T.J.V.). Additional acknowledgments are listed in the Supplementary Note online.

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