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


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 < Poverall < 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.

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Figure 1: Combined association results for the extended HLA region (chromosome 6, 26–34 Mb).


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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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J.B.H., C.D.L. and J.A.K. wrote the manuscript. M.E.A.-R., L.A.C., C.O.J., R.P.K., K.L.M., B.P.T., T.J.V. and J.C.E. evaluated the manuscript for content. S.B.G., D.B.M., K.M.K., Q.-Z.L., E.K.W., S.G.F., A.T.L., P.K.G., G.R.B., J.O.O., S.K.N., J.M.G., B.L.C. and B.N. collected or contributed data. C.D.L., M.C.M., A.H.W., W.W., J.A.K., J.D., K.E.T., R.Z. and M.F.S. performed analyses overseen by the data analysis committee (C.D.L., R.Z., P.M.G., J.C.E., J.D.R., K.M.K., M.E.A.-R., M.F., K.E.T. and B.P.T.). J.B.H., C.D.L., K.M.K., T.W.B., J.A.K., M.E.A.-R., L.A.C., C.O.J., R.P.K., K.L.M., B.P.T., T.J.V., S.K.N. and J.M.G. are responsible for the study design. J.B.H., M.E.A.-R., L.A.C., C.O.J., R.P.K., K.L.M., B.P.T., T.J.V., T.W.B., P.K.G., P.M.G., J.A.J., J.T.M., G.S.G., H.Y., E.C.B. and G.R.B. provided samples.

Other contributing authors are as follows:

Swapan K Nath1, Joel M Guthridge1, Beth L Cobb1, Daniel B Mirel12, Miranda C Marion10, Adrienne H Williams10, Jasmin Divers10, Wei Wang10, Summer G Frank1, Bahram Namjou1, Stacey B Gabriel12, Annette T Lee13, Peter K Gregersen13, Timothy W Behrens7,14, Kimberly E Taylor4, Michelle Fernando9, Raphael Zidovetzki15, Patrick M Gaffney1,7, Jeffrey C Edberg6, John D Rioux16, Joshua O Ojwang1, Judith A James1, Joan T Merrill1, Gary S Gilkeson17, Michael F Seldin18, Hong Yin3, Emily C Baechler7, Quan-Zhen Li19, Edward K Wakeland19, Gail R Bruner1, Kenneth M Kaufman1,2 & Jennifer A Kelly1

Corresponding authors

Correspondence to John B Harley or Carl D Langefeld.

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Competing interests

SLEGEN has submitted a patent application based upon these results.

Additional information

SLEGEN members are listed above; other contributing authors are listed at the end of the paper.

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Supplementary Text and Figures

Supplementary Note, Supplementary Methods, Supplementary Tables 1–3, Supplementary Figures 1–5 (PDF 813 kb)

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The International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN)., Harley, J., Alarcón-Riquelme, M. et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 40, 204–210 (2008).

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