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The genetics of systemic lupus erythematosus and implications for targeted therapy
  1. Andrea L Sestak1,
  2. Barbara G Fürnrohr2,
  3. John B Harley3,4,
  4. Joan T Merrill5,
  5. Bahram Namjou6
  1. 1Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
  2. 2Department of Internal Medicine 3, Institute for Clinical Immunology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
  3. 3Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  4. 4US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA
  5. 5Department of Clinical Pharmacology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  6. 6Department of Arthritis and Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  1. Correspondence to Dr Andrea L Sestak, Rheumatology Division, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Andrea-sestak{at}


Observations of familial aggregation (λs=8–29) and a 40% identical twin concordance rate prompted recent work towards a comprehensive genetic analysis of systemic lupus erythematosus (SLE). Since 2007, the number of genetic effects known to be associated with human lupus has increased by fivefold, underscoring the complexity of inheritance that probably contributes to this disease. Approximately 35 genes associated with lupus have either been replicated in multiple samples or are near the threshold for genome-wide significance (p>5×10−8). Some are rare variants that convincingly contribute to lupus only in specific subgroups. Strong associations have been found with a large haplotype block in the human leucocyte antigen region, with Fcγ receptors, and with genes coding for complement components, in which a single gene deletion may cause SLE in rare familial cases and copy number variation is more common in the larger population of SLE patients. Examples of newly discovered genes include ITGAM, STAT4 and MECP2/IRAK1. Ongoing studies to build models in which combinations of associated genes might contribute to specific disease manifestations should contribute to improved understanding of disease pathology. In addition, pharmacogenomic components of ongoing clinical trials are likely to provide insights into fundamental disease pathology as well as contributing to informed patient selection for targeted treatments and biomarkers to guide dosing and gauge responsiveness. Besides these potentially valuable new insights into the pathophysiology of an enigmatic, potentially deadly, and, as yet, unsolved disease, genetic studies are likely to suggest novel molecular targets for strategic development of safer and more effective therapeutics.

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  • Competing interests JTM serves as a consultant for Genentech/Roche, UCB, Immunomedics, Human Genome Sciences/Glaxo Smith Kline, Bristol Myers Squibb, Cephalon and MedImmune/Astra Zeneca; all other authors have no competing interests.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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