1. Evidence for gene???gene epistatic interactions among susceptibility loci for systemic lupus erythematosus
- Author
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University of Michigan and Ann Arbor VA Medical Center, Ann Arbor, University of Puerto Rico, San Juan, Puerto Rico, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma Medical Research Foundation, University of Oklahoma Health Sciences Center, and Oklahoma City VA Medical Center, Oklahoma City, Wake Forest University Health Sciences Center, Winston???Salem, North Carolina, University of Alabama at Birmingham, Northwestern University Feinberg School of Medicine, Chicago, Illinois, Johns Hopkins University School of Medicine, Baltimore, Maryland, University of Colorado Denver School of Medicine, Aurora, University of Washington and Seattle Children's Research Institute, Seattle, University of Texas Health Science Center at Houston, Instituto de Parasitolog??a y Biomedicina L??pez???Neyra, CSIC, Granada, Spain, University of Chicago, Chicago, Illinois, Medical University of South Carolina, Charleston, University of California, San Francisco, Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center, Oklahoma City, University of Southern California, Los Angeles, University of California, Los Angeles, King's College London and Guy's Hospital, London, UK, Cincinnati Children's Hospital Medical Center and Cincinnati VA Medical Center, Cincinnati, Ohio, Center for Genomics and Oncological Research Pfizer???University of Granada???Junta de Andalucia, Granada, Spain, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, MS#24, Oklahoma City, OK 73104, Hughes, Travis, Adler, Adam, Kelly, Jennifer A., Kaufman, Kenneth M., Williams, Adrienne H., Langefeld, Carl D., Brown, Elizabeth E., Alarc??n, Graciela S., Kimberly, Robert P., Edberg, Jeffrey C., Ramsey???goldman, Rosalind, Petri, Michelle, Boackle, Susan A., Stevens, Anne M., Reveille, John D., Sanchez, Elena, Mart??n, Javier, Niewold, Timothy B., Vil??, Luis M., Scofield, R. Hal, Gilkeson, Gary S., Gaffney, Patrick M., Criswell, Lindsey A., Moser, Kathy L., Merrill, Joan T., Jacob, Chaim O., Tsao, Betty P., James, Judith A., Vyse, Timothy J., Alarc??n???riquelme, Marta E., Harley, John B., Richardson, Bruce C., Sawalha, Amr H., University of Michigan and Ann Arbor VA Medical Center, Ann Arbor, University of Puerto Rico, San Juan, Puerto Rico, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma Medical Research Foundation, University of Oklahoma Health Sciences Center, and Oklahoma City VA Medical Center, Oklahoma City, Wake Forest University Health Sciences Center, Winston???Salem, North Carolina, University of Alabama at Birmingham, Northwestern University Feinberg School of Medicine, Chicago, Illinois, Johns Hopkins University School of Medicine, Baltimore, Maryland, University of Colorado Denver School of Medicine, Aurora, University of Washington and Seattle Children's Research Institute, Seattle, University of Texas Health Science Center at Houston, Instituto de Parasitolog??a y Biomedicina L??pez???Neyra, CSIC, Granada, Spain, University of Chicago, Chicago, Illinois, Medical University of South Carolina, Charleston, University of California, San Francisco, Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center, Oklahoma City, University of Southern California, Los Angeles, University of California, Los Angeles, King's College London and Guy's Hospital, London, UK, Cincinnati Children's Hospital Medical Center and Cincinnati VA Medical Center, Cincinnati, Ohio, Center for Genomics and Oncological Research Pfizer???University of Granada???Junta de Andalucia, Granada, Spain, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, MS#24, Oklahoma City, OK 73104, Hughes, Travis, Adler, Adam, Kelly, Jennifer A., Kaufman, Kenneth M., Williams, Adrienne H., Langefeld, Carl D., Brown, Elizabeth E., Alarc??n, Graciela S., Kimberly, Robert P., Edberg, Jeffrey C., Ramsey???goldman, Rosalind, Petri, Michelle, Boackle, Susan A., Stevens, Anne M., Reveille, John D., Sanchez, Elena, Mart??n, Javier, Niewold, Timothy B., Vil??, Luis M., Scofield, R. Hal, Gilkeson, Gary S., Gaffney, Patrick M., Criswell, Lindsey A., Moser, Kathy L., Merrill, Joan T., Jacob, Chaim O., Tsao, Betty P., James, Judith A., Vyse, Timothy J., Alarc??n???riquelme, Marta E., Harley, John B., Richardson, Bruce C., and Sawalha, Amr H.
- Abstract
Objective Several confirmed genetic susceptibility loci for lupus have been described. To date, no clear evidence for genetic epistasis in lupus has been established. The aim of this study was to test for gene???gene interactions in a number of known lupus susceptibility loci. Methods Eighteen single???nucleotide polymorphisms tagging independent and confirmed lupus susceptibility loci were genotyped in a set of 4,248 patients with lupus and 3,818 normal healthy control subjects of European descent. Epistasis was tested by a 2???step approach using both parametric and nonparametric methods. The false discovery rate (FDR) method was used to correct for multiple testing. Results We detected and confirmed gene???gene interactions between the HLA region and CTLA4 , IRF5 , and ITGAM and between PDCD1 and IL21 in patients with lupus. The most significant interaction detected by parametric analysis was between rs3131379 in the HLA region and rs231775 in CTLA4 (interaction odds ratio 1.19, Z = 3.95, P = 7.8 ?? 10 ???5 [FDR ???0.05], P for multifactor dimensionality reduction = 5.9 ?? 10 ???45 ). Importantly, our data suggest that in patients with lupus, the presence of the HLA lupus risk alleles in rs1270942 and rs3131379 increases the odds of also carrying the lupus risk allele in IRF5 (rs2070197) by 17% and 16%, respectively ( P = 0.0028 and P = 0.0047, respectively). Conclusion We provide evidence for gene???gene epistasis in systemic lupus erythematosus. These findings support a role for genetic interaction contributing to the complexity of lupus heritability.
- Published
- 2012