Title |
Genome‐Wide Association Study in an Amerindian Ancestry Population Reveals Novel Systemic Lupus Erythematosus Risk Loci and the Role of European Admixture
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Published in |
Arthritis & Rheumatology, March 2016
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DOI | 10.1002/art.39504 |
Pubmed ID | |
Authors |
Marta E Alarcón-Riquelme, Julie T Ziegler, Julio Molineros, Timothy D Howard, Andrés Moreno-Estrada, Elena Sánchez-Rodríguez, Hannah C Ainsworth, Patricia Ortiz-Tello, Mary E Comeau, Astrid Rasmussen, Jennifer A Kelly, Adam Adler, Eduardo M Acevedo-Vázquez, Jorge Mariano Cucho-Venegas, Ignacio García-De la Torre, Mario H Cardiel, Pedro Miranda, Luis J Catoggio, Marco Maradiaga-Ceceña, Patrick M Gaffney, Timothy J Vyse, Lindsey A Criswell, Betty P Tsao, Kathy L Sivils, Sang-Cheol Bae, Judith A James, Robert P Kimberly, Kenneth M Kaufman, John B Harley, Jorge A Esquivel-Valerio, José F Moctezuma, Mercedes A García, Guillermo A Berbotto, Alejandra M Babini, Hugo Scherbarth, Sergio Toloza, Vicente Baca, Swapan K Nath, Carlos Aguilar Salinas, Lorena Orozco, Teresa Tusié-Luna, Raphael Zidovetzki, Bernardo A Pons-Estel, Carl D Langefeld, Chaim O Jacob |
Abstract |
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a strong genetic component. Our aim was to perform the first genome-wide association study on individuals from the Americas enriched for Native American heritage. We analyzed 3,710 individuals from four countries of Latin America and the Unites States diagnosed with SLE and healthy controls. Samples were genotyped with the HumanOmni1 BeadChip. Data of out-of-study controls was obtained for the HumanOmni2.5. Statistical analyses were performed using SNPTEST and SNPGWA. Data was adjusted for genomic control and FDR. Imputation was done using IMPUTE2, and HiBAG for classical HLA alleles. The IRF5-TNPO3 region showed the strongest association and largest odds ratio (OR) (rs10488631, Pgcadj = 2.61x10(-29) , OR = 2.12, 95% CI: 1.88-2.39) followed by the HLA class II on the DQA2-DQB1 loci (rs9275572, Pgcadj = 1.11 x 10(-16) , OR = 1.62, 95% CI: 1.46-1.80; rs9271366, Pgcadj =6.46 x 10(-12) , OR = 2.06, 95% CI: 1.71-2.50). Other known SLE loci associated were ITGAM, STAT4, TNIP1, NCF2 and IRAK1. We identified a novel locus on 10q24.33 (rs4917385, Pgcadj =1.4x10(-8) ) with a eQTL effect (Peqtl =8.0 x 10(-37) at USMG5/miR1307), and describe novel loci. We corroborate SLE-risk loci previously identified in European and Asians. Local ancestry estimation showed that HLA allele risk contribution is of European ancestral origin. Imputation of HLA alleles suggested that autochthonous Native American haplotypes provide protection. Our results show the insight gained by studying admixed populations to delineate the genetic architecture that underlies autoimmune and complex diseases. This article is protected by copyright. All rights reserved. |
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