Analysis of autosomal genes reveals gene–sex interactions and higher total genetic risk in men with systemic lupus erythematosus
- Travis Hughes1,
- Adam Adler1,
- Joan T Merrill2,3,
- Jennifer A Kelly1,
- Kenneth M Kaufman1,2,4,
- Adrienne Williams5,
- Carl D Langefeld5,
- Gary S Gilkeson6,
- Elena Sanchez1,
- Javier Martin7,
- Susan A Boackle8,
- Anne M Stevens9,10,
- Graciela S Alarcón11,
- Timothy B Niewold12,
- Elizabeth E Brown11,
- Robert P Kimberly11,
- Jeffrey C Edberg11,
- Rosalind Ramsey-Goldman13,
- Michelle Petri14,
- John D Reveille15,
- Lindsey A Criswell16,
- Luis M Vilá17,
- Chaim O Jacob18,
- Patrick M Gaffney1,
- Kathy L Moser1,
- Timothy J Vyse19,
- Marta E Alarcón-Riquelme1,20 BIOLUPUS Network,
- Judith A James1,2,
- Betty P Tsao21,
- R Hal Scofield1,2,4,
- John B Harley22,23,
- Bruce C Richardson24,25,
- Amr H Sawalha1,2,4
- 1Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
- 2Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
- 3Clinical Pharmacology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
- 4US Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA
- 5Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA
- 6Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, South Carolina, USA
- 7Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain
- 8Division of Rheumatology, School of Medicine, University of Colorado Denver, Aurora, Colorado, USA
- 9Department of Pediatrics, Division of Rheumatology, University of Washington, Seattle, Washington, USA
- 10Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington, USA
- 11Department of Medicine, University of Alabama, Birmingham, Alabama, USA
- 12Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois, USA
- 13Department of Medicine, Northwestern University, Chicago, Illinois, USA
- 14Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- 15Department of Medicine, University of Texas-Houston Health Science Center, Houston, Texas, USA
- 16Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco, San Francisco, California, USA
- 17Department of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico, USA
- 18Department of Medicine, University of Southern California, Los Angeles, California, USA
- 19Divisions of Genetics and Molecular Medicine and Immunology, Infection and Inflammatory Disease, King's College London, Guy's Hospital, London, UK
- 20Center for Genomics and Oncological Research Pfizer-University of Granada-Junta de Andalucia, Granada, Spain
- 21Department of Medicine, Division of Rheumatology, University of California, Los Angeles, Los Angeles, California, USA
- 22Rheumatology Division and Autoimmune Genomics Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- 23US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA
- 24Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, USA
- 25US Department of Veterans Affairs Medical Center, Ann Arbor, Michigan, USA
- Correspondence to Amr H Sawalha, Department of Medicine, University of Oklahoma Health Sciences Center, 825 NE 13th Street, MS#24, Oklahoma City, OK 73104, USA;
- Received 6 July 2011
- Accepted 25 September 2011
- Published Online First 21 November 2011
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.
BCR and AHS contributed equally to this work.
The BIOLUPUS network is composed of: Johan Frostegård (Huddinge, Sweden), Lennart Truedsson (Lund, Sweden), Enrique de Ramón (Málaga, Spain), José M Sabio (Granada, Spain), María F González-Escribano (Sevilla, Spain), Norberto Ortego-Centeno (Granada, Spain), José Luis Callejas (Granada, Spain), Julio Sánchez-Román (Sevilla, Spain), Sandra D'Alfonso (Novara, Italy), Sergio Migliarese (Napoli, Italy), Gian-Domenico Sebastiani (Rome, Italy), Mauro Galeazzi (Siena, Italy), Torsten Witte (Hannover, Germany), Bernard R Lauwerys, (Louvain, Belgium), Emoke Endreffy (Szeged, Hungary), László Kovács (Szeged, Hungary), Carlos Vasconcelos (Porto, Portugal) and Berta Martins da Silva (Porto, Portugal).
Funding This work was made possible by the Lupus Foundation of America, the NIH (R03AI076729, P20RR020143, P20RR015577, P30AR053483, R01AR042460, R37AI024717, R01AI031584, N01AR62277, P50AR048940, P01AI083194, RC1AR058554, U19AI082714, HHSN266200500026C, P30RR031152, P01AR049084, R01AR043274, R01AI063274, K24AR002138, P602AR30692, UL1RR025741, R01DE018209, R01AR043727, UL1RR025005, R01AR043814, K08AI083790, P30DK42086, L30AI071651, UL1RR024999, R01AR044804, M01RR000079, R21AI070304), Arthritis National Research Foundation, American College of Rheumatology/Research and Education Foundation, Lupus Research Institute, Kirkland Scholar awards, Alliance for Lupus Research, US Department of Veterans Affairs, US Department of Defense PR094002, European Science Foundation to the BIOLUPUS network (07-RNP-083), the Swedish Research Council and the Instituto de Salud Carlos III (PS09/00129), cofinanced partly through FEDER funds of the European Union and grant PI0012 from the Consejería de Salud de Andalucía.
Competing interests None.
Ethics approval Ethical approval was obtained from the Institutional Review Boards at Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center.
Provenance and peer review Not commissioned; externally peer reviewed.