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A nonsynonymous functional variant in integrin-αM (encoded by ITGAM) is associated with systemic lupus erythematosus

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Abstract

We identified and replicated an association between ITGAM (CD11b) at 16p11.2 and risk of systemic lupus erythematosus (SLE) in 3,818 individuals of European descent. The strongest association was at a nonsynonymous SNP, rs1143679 (P = 1.7 × 10−17, odds ratio = 1.78). We further replicated this association in two independent samples of individuals of African descent (P = 0.0002 and 0.003; overall meta-analysis P = 6.9 × 10−22). The genetic association between ITGAM and SLE implicates the αMβ2-integrin adhesion pathway in disease development.

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Figure 1: ITGAM gene structure and association with SLE.

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Acknowledgements

We are grateful to the affected individuals and their families for their cooperation and blood samples. This work would also not have been possible without the support of the all the LFRR staff, headed by LFRR director G. Bruner. We also acknowledge the contributions of sample from our collaborators, especially P. Gregersen, L. Barcelos, J. Oksenberg, J. Edberg, the PROFILE cohort (G. Alarcon, M. Petri, R. Ramsey-Goldman and J. Reveille), P. Gaffney and K. Moser. This work was supported by supported by the US National Institutes of Health (grants AR048928, AI063622, RR020143, AR049084, AI24717, AR42460, AR048940, HL 34363, AI053747, AR12253, DE15223, RR01577, RR14467, AI31584 and AI044902), the Alliance for Lupus Research, a Mary Kirkland Scholarship and the US Department of Veterans Affairs.

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Author notes

  1. Joel M Guthridge and John B Harley: These authors contributed equally to this work.

Authors and Affiliations

  1. Genetic Epidemiology Unit, Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City,, 73104, Oklahoma, USA

    Swapan K Nath, Shizhong Han, Xana Kim-Howard & Parvathi Viswanathan

  2. Arthritis & Immunology Program, Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, 73104, Oklahoma, USA

    Swapan K Nath, Shizhong Han, Xana Kim-Howard, Jennifer A Kelly, Parvathi Viswanathan, Judith A James, Kenneth M Kaufman, Joel M Guthridge & John B Harley

  3. Department of Medicine, Division of Rheumatology, Medical University of South Carolina, 135 Rutledge Ave, Charleston, 29403, South Carolina, USA

    Gary S Gilkeson

  4. George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, 801 Ferst Drive,. Atlanta, Georgia 30332, USA.,

    Wei Chen & Cheng Zhu

  5. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, 313 Ferst Drive, Suite 2127, Atlanta, Georgia 30332, USA.,

    Cheng Zhu

  6. Cardiovascular Biology Program, Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, 73104, Oklahoma, USA

    Rodger P McEver

  7. Department of Medicine, Division of Clinical Immunology and Rheumatology, The University of Alabama at Birmingham, 1900 University Blvd., Birmingham, 35294, Alabama, USA

    Robert P Kimberly

  8. Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, P.O. Box 256, Uppsala, SE-751 05, Sweden

    Marta E Alarcón-Riquelme

  9. Rheumatology Section, Imperial College, Hammersmith Hospital, London, W12 0NN, UK

    Timothy J Vyse

  10. Department of Immunology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, 75235, Texas, USA

    Quan-Zhen Li & Edward K Wakeland

  11. Department of Clinical Pharmacology, Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, 73104, Oklahoma, USA

    Joan T Merrill

  12. Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center, 1100 N. Lindsey, Oklahoma City, 73104, Oklahoma, USA

    Judith A James & John B Harley

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

    Kenneth M Kaufman & John B Harley

Authors
  1. Swapan K Nath
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  2. Shizhong Han
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  3. Xana Kim-Howard
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  4. Jennifer A Kelly
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  5. Parvathi Viswanathan
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  6. Gary S Gilkeson
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  7. Wei Chen
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  8. Cheng Zhu
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  9. Rodger P McEver
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  10. Robert P Kimberly
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  11. Marta E Alarcón-Riquelme
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  12. Timothy J Vyse
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  13. Quan-Zhen Li
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  14. Edward K Wakeland
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  15. Joan T Merrill
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  16. Judith A James
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  17. Kenneth M Kaufman
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  18. Joel M Guthridge
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  19. John B Harley
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Contributions

S.K.N. participated in the conception, design and coordination of the study, directed the whole project and drafted the manuscript. S.H. and X.K.-H. managed the genotyping data and analyzed the data. P.V. did the genotyping for the trio data. G.S.G., R.P.K., M.E.A.-R., J.T.M. and T.J.V. provided samples used in this study. J.M.G., R.P.M., C.Z. and W.C. provided protein structural analysis and functional predictions. K.M.K., E.K.W., J.A.K. and Q.-Z.L. were responsible for overseeing the genotyping and quality control of the actual genotype data. J.A.J. and J.M.G. participated in collecting samples and designing experiments and helped in drafting the manuscript. J.B.H. was responsible for making the DNA available and supervising the overall genotyping project. All authors contributed to the final manuscript.

Corresponding author

Correspondence to Swapan K Nath.

Supplementary information

Supplementary Text and Figures

Supplementary Methods, Supplementary Tables 1–6 and Supplementary Figure 1 (PDF 612 kb)

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Nath, S., Han, S., Kim-Howard, X. et al. A nonsynonymous functional variant in integrin-αM (encoded by ITGAM) is associated with systemic lupus erythematosus. Nat Genet 40, 152–154 (2008). https://doi.org/10.1038/ng.71

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  • DOI: https://doi.org/10.1038/ng.71

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