Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus

Travis Hughes, Adam Adler, Joan T. Merrill, Jennifer A. Kelly, Kenneth M. Kaufman, Adrienne Williams, Carl D. Langefeld, Gary S. Gilkeson, Elena Sanchez, Javier Martin, Susan A. Boackle, Anne M. Stevens, Graciela S. Alarcón, Timothy B. Niewold, Elizabeth E. Brown, Robert P. Kimberly, Jeffrey C. Edberg, Rosalind Ramsey-Goldman, Michelle Petri, John D. ReveilleLindsey A. Criswell, Luis M. Vilá, Chaim O. Jacob, Patrick M. Gaffney, Kathy L. Moser, Timothy J. Vyse, Marta E. Alarcón-Riquelme, Judith A. James, Betty P. Tsao, R. Hal Scofield, John B. Harley, Bruce C. Richardson, Amr H. Sawalha, Johan Frostegård, Lennart Truedsson, Enrique De Ramón, José M. Sabio, María F. González-Escribano, Norberto Ortego-Centeno, José Luis Callejas, Julio Sánchez-Román, Sandra D'Alfonso, Sergio Migliarese, Gian Domenico Sebastiani, Mauro Galeazzi, Torsten Witte, Bernard R. Lauwerys, Emoke Endreffy, László Kovács, Carlos Vasconcelos, Berta Martins Da Silva

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

Objectives: Systemic lupus erythematosus (SLE) is a sexually dimorphic autoimmune disease which is more common in women, but affected men often experience a more severe disease. The genetic basis of sexual dimorphism in SLE is not clearly defined. A study was undertaken to examine sex-specific genetic effects among SLE susceptibility loci. Methods: A total of 18 autosomal genetic susceptibility loci for SLE were genotyped in a large set of patients with SLE and controls of European descent, consisting of 5932 female and 1495 male samples. Sex-specific genetic association analyses were performed. The sex-gene interaction was further validated using parametric and non-parametric methods. Aggregate differences in sex-specific genetic risk were examined by calculating a cumulative genetic risk score for SLE in each individual and comparing the average genetic risk between male and female patients. Results: A significantly higher cumulative genetic risk for SLE was observed in men than in women. (P=4.52x10 -8) A significant sex-gene interaction was seen primarily in the human leucocyte antigen (HLA) region but also in IRF5, whereby men with SLE possess a significantly higher frequency of risk alleles than women. The genetic effect observed in KIAA1542 is specific to women with SLE and does not seem to have a role in men. Conclusions: The data indicate that men require a higher cumulative genetic load than women to develop SLE. These observations suggest that sex bias in autoimmunity could be influenced by autosomal genetic susceptibility loci.

Original languageEnglish (US)
Pages (from-to)694-699
Number of pages6
JournalAnnals of the rheumatic diseases
Volume71
Issue number5
DOIs
StatePublished - May 1 2012

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

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    Hughes, T., Adler, A., Merrill, J. T., Kelly, J. A., Kaufman, K. M., Williams, A., Langefeld, C. D., Gilkeson, G. S., Sanchez, E., Martin, J., Boackle, S. A., Stevens, A. M., Alarcón, G. S., Niewold, T. B., Brown, E. E., Kimberly, R. P., Edberg, J. C., Ramsey-Goldman, R., Petri, M., ... Da Silva, B. M. (2012). Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus. Annals of the rheumatic diseases, 71(5), 694-699. https://doi.org/10.1136/annrheumdis-2011-200385