1. Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study
- Author
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Lessard, Christopher J., Adrianto, Indra, Ice, John A., Wiley, Graham B., Kelly, Jennifer A., Glenn, Stuart B., Adler, Adam J., Li, He, Rasmussen, Astrid, Williams, Adrienne H., Ziegler, Julie, Comeau, Mary, Marion, Miranda, Wakeland, Benjamin E., Liang, Chaoying, Ramos, Paula S., Grundahl, Kiely M., Gallant, Caroline J., Alarcón-Riquelme, Marta E., Alarcón, Graciela S., Anaya, Juan-Manuel, Bae, Sang-Cheol, Boackle, Susan, Brown, Elizabeth E., Chang, Deh-Ming, Cho, Soo-Kyung, Criswel, Lindsey A., Edberg, Jeffrey C., Freedman, Barry I., Gilkeson, Gary S., Jacob, Chaim O., James, Judith A., Kamen, Diane L., Kimberly, Robert P., Kim, Jae-Hoon, Martin, Javier, Merrill, Joan T., Niewold, Timothy B., Park, So-Yeon, Petri, Michelle A., Pons-Estel, Bernardo A., Ramsey-Goldman, Rosalind, Reveille, John D., Scofield, Robert H., Song, Yeong Wook, Stevens, Anne M., Tsao, Betty P., Vila, Luis M., Vyse, Timothy J., Yu, Chack-Yung, Guthridge, Joel M., Kaufman, Kenneth M., Harley, John B., Wakeland, Edward K., Langefeld, Carl D., Gaffney, Patrick M., Montgomery, Courtney G., and Moser, Kathy L.
- Subjects
Male ,Chromosome 17Q ,Hispanic ,Ikzf3 Gene ,Genetic Susceptibility ,Gene ,Genetic Risk ,Or8D4 Gene ,Indians ,Lpp Gene ,Ethnicity ,Haplotype ,African American ,European American ,Membrane Protein ,Immune Response ,Irf8 Gene ,African Continental Ancestry Group ,Transmembrane Protein 39A ,Cadm2 Gene ,C1Orf64 Gene ,Chromosome Mapping ,Fam19A2 Gene ,Patología ,Single Nucleotide ,Slu7 Gene ,Tmem39A Gene ,Genetic Predisposition To Disease ,High Risk Population ,Interferon Consensus Sequence Binding Protein ,Gene Locus ,Zpbp2 Gene ,Genetic Variability ,American Indian ,Interferon Regulatory Factors ,Priority Journal ,Interferon ,Female ,Hispanic Americans ,Sequence Analysis ,Genetic Association ,North American ,Human ,Asian Continental Ancestry Group ,Gene Sequence ,Genotype ,Major Clinical Study ,European Continental Ancestry Group ,Protein Ikzf3 ,Il12A Gene ,Loc6392 Gene ,Systemic Lupus Erythematosus ,Article ,Heritability ,Ikaros Transcription Factor ,Unclassified Drug ,Autoantigen ,Lupus eritematoso sistémico ,Humans ,Zona Pellucida Binding Protein 2 ,Controlled Study ,Gene Identification ,Polymorphism ,Cfhr1 Gene ,Asian ,Environmental Factor ,Lupus Erythematosus ,Gene Mapping ,Egg Proteins ,Systemic ,Immunoregulation ,Membrane Proteins ,Dna ,Genome Analysis ,Genética ,Haplotypes ,Stxbp6 Gene ,Single Nucleotide Polymorphism ,Adamtsl1 Gene ,Immunological Tolerance - Abstract
Systemic lupus erythematosus (SLE) is a chronic heterogeneous autoimmune disorder characterized by the loss of tolerance to self-antigens and dysregulated interferon responses. The etiology of SLE is complex, involving both heritable and environmental factors. Candidate-gene studies and genome-wide association (GWA) scans have been successful in identifying new loci that contribute to disease susceptibility; however, much of the heritable risk has yet to be identified. In this study, we sought to replicate 1,580 variants showing suggestive association with SLE in a previously published GWA scan of European Americans; we tested a multiethnic population consisting of 7,998 SLE cases and 7,492 controls of European, African American, Asian, Hispanic, Gullah, and Amerindian ancestry to find association with the disease. Several genes relevant to immunological pathways showed association with SLE. Three loci exceeded the genome-wide significance threshold: interferon regulatory factor 8 (IRF8; rs11644034; p meta-Euro = 2.08 × 10 -10), transmembrane protein 39A (TMEM39A; rs1132200; p meta-all = 8.62 × 10 -9), and 17q21 (rs1453560; p meta-all = 3.48 × 10 -10) between IKAROS family of zinc finger 3 (AIOLOS; IKZF3) and zona pellucida binding protein 2 (ZPBP2). Fine mapping, resequencing, imputation, and haplotype analysis of IRF8 indicated that three independent effects tagged by rs8046526, rs450443, and rs4843869, respectively, were required for risk in individuals of European ancestry. Eleven additional replicated effects (5 × 10 -8 < p meta-Euro < 9.99 × 10 -5) were observed with CFHR1, CADM2, LOC730109/IL12A, LPP, LOC63920, SLU7, ADAMTSL1, C10orf64, OR8D4, FAM19A2, and STXBP6. The results of this study increase the number of confirmed SLE risk loci and identify others warranting further investigation. © 2012 The American Society of Human Genetics.
- Published
- 2012