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

Nature Genetics volume 40, pages 204–210 (2008)Cite this article

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 < 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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Acknowledgements

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.

Author information

Author notes

  1. Broad Institute, 7 Cambridge Center, Boston, Massachusetts 02142 USA.

  2. Feinstein Institute for Medical Research, North Shore LIJ Health System, 350 Community Drive, Manhasset, New York 11030, USA.

  3. Genentech, Inc.,1 DNA Way, South San Francisco, California 94080, USA.

  4. University of California at Riverside, 900 University Avenue, Riverside, California 92521, USA.

  5. Université de Montréal, 5000 rue Belanger, Montréal H1T 1C8, Canada.

  6. Medical University of South Carolina, 135 Rutledge Avenue, Charleston, South Carolina 29403, USA.

  7. University of California at Davis, 1 Shields Avenue, Davis, California 95616, USA.

  8. University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, Texas 75235, USA.

Authors and Affiliations

  1. Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, 73104, Oklahoma, USA

    John B Harley & Kathy L Moser

  2. US Department of Veterans Affairs Medical Center, 921 NE 13th Street, Oklahoma City, 73104, Oklahoma, USA

    John B Harley

  3. University of Oklahoma Health Sciences Center, 1100 N Lindsey, Oklahoma City, 73104, Oklahoma, USA

    John B Harley

  4. University of Uppsala, Olofsgatan St 10B, Uppsala, SE-751 05, Sweden

    Marta E Alarcón-Riquelme

  5. University of California at San Francisco, 374 Parnassus Ave, San Francisco, 94143, California, USA

    Lindsey A Criswell

  6. University of Southern California, 2011 Zonal Avenue, Los Angeles, 90033, California, USA

    Chaim O Jacob

  7. University of Alabama at Birmingham, 1900 University Blvd., Birmingham, 35294, Alabama, USA

    Robert P Kimberly

  8. University of Minnesota, 312 Church Street, Minneapolis, 55455, Minnesota, USA

    Kathy L Moser

  9. University of California at Los Angeles, 1000 Veterans Avenue, Los Angeles, 90095, California, USA

    Betty P Tsao

  10. Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK

    Timothy J Vyse

  11. Wake Forest University Health Sciences, Medical Center Blvd., Winston-Salem, 27157, North Carolina, USA

    Carl D Langefeld

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  1. John B Harley
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Consortia

The International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN)

Contributions

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.

Supplementary information

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). https://doi.org/10.1038/ng.81

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