Genome Wide Association Study (GWAS) of Chagas Cardiomyopathy in Trypanosoma cruzi Seropositive Subjects Xutao Deng 1 , Ester C. Sabino 2 , Edecio Cunha-Neto 3,4 , Antonio L. Ribeiro 5 , Barbara Ianni 6 , Charles Mady 6 , Michael P. Busch 1,7 , Mark Seielstad 1,7,8 *, the REDS II Chagas study group from the NHLBI Retrovirus Epidemiology Donor Study-II (REDS-II), International Component 1 Blood Systems Research Institute, San Francisco, California, United States of America, 2 Department of Infectious Disease/Institute of Tropical Medicine, University of Sa ˜o Paulo, Sa ˜o Paulo, Brazil, 3 Laboratory of Immunology, Heart Institute (InCor)/Division of Clinical Immunology and Allergy, University of Sa ˜o Paulo, Sa ˜o Paulo, Brazil, 4 Institute for Investigation in Immunology/Instituto Nacional de Cie ˆncia e Tecnologia, Sa ˜o Paulo, Brazil, 5 Hospital das Clı ´nicas and Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil, 6 Cardiomyopathy Unit of the Heart Institute (InCor) University of Sa ˜o Paulo Medical School, Sa ˜o Paulo, Brazil, 7 Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, United States of America, 8 Institute for Human Genetics, University of California San Francisco, San Francisco, California, United States of America Abstract Background: Familial aggregation of Chagas cardiac disease in T. cruzi–infected persons suggests that human genetic variation may be an important determinant of disease progression. Objective: To perform a GWAS using a well-characterized cohort to detect single nucleotide polymorphisms (SNPs) and genes associated with cardiac outcomes. Methods: A retrospective cohort study was developed by the NHLBI REDS-II program in Brazil. Samples were collected from 499 T. cruzi seropositive blood donors who had donated between1996 and 2002, and 101 patients with clinically diagnosed Chagas cardiomyopathy. In 2008–2010, all subjects underwent a complete medical examination. After genotype calling, quality control filtering with exclusion of 20 cases, and imputation of 1,000 genomes variants; association analysis was performed for 7 cardiac and parasite related traits, adjusting for population stratification. Results: The cohort showed a wide range of African, European, and modest Native American admixture proportions, consistent with the recent history of Brazil. No SNPs were found to be highly (P,10 28 ) associated with cardiomyopathy. The two mostly highly associated SNPs for cardiomyopathy (rs4149018 and rs12582717; P-values ,10 26 ) are located on Chromosome 12p12.2 in the SLCO1B1 gene, a solute carrier family member. We identified 44 additional genic SNPs associated with six traits at P-value ,10 -6 : Ejection Fraction, PR, QRS, QT intervals, antibody levels by EIA, and parasitemia by PCR. Conclusion: This GWAS identified suggestive SNPs that may impact the risk of progression to cardiomyopathy. Although this Chagas cohort is the largest examined by GWAS to date, (580 subjects), moderate sample size may explain in part the limited number of significant SNP variants. Enlarging the current sample through expanded cohorts and meta-analyses, and targeted studies of candidate genes, will be required to confirm and extend the results reported here. Future studies should also include exposed seronegative controls to investigate genetic associations with susceptibility or resitance to T. cruzi infection and non-Chagas cardiomathy. Citation: Deng X, Sabino EC, Cunha-Neto E, Ribeiro AL, Ianni B, et al. (2013) Genome Wide Association Study (GWAS) of Chagas Cardiomyopathy in Trypanosoma cruzi Seropositive Subjects. PLoS ONE 8(11): e79629. doi:10.1371/journal.pone.0079629 Editor: Herbert B. Tanowitz, Albert Einstein College of Medicine, United States of America Received May 17, 2013; Accepted September 24, 2013; Published November 20, 2013 Copyright: ß 2013 Deng et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study is supported by National Heart, Lung, and Blood Institute Retrovirus Epidemiology Donor Study-II (REDS-II), International Component Contract (HHSN268200417175C). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: Mark.Seielstad@ucsf.edu Introduction Chagas disease is caused by T. cruzi, a parasite which is naturally transmitted through several species of haematophagous reduviid bugs. The infection/disease is prevalent in most Latin American countries, where approximately 10 million people are infected with T. cruzi and at least 120 million are at risk [1,2]. In the recent decades, migration from endemic areas brought hundreds of thousands of T. cruzi-infected patients to the USA and Europe, turning Chagas disease into a global health concern [1,2]. Most untreated acute cases evolve into the so-called indeterminate stage of chronic Chagas disease (seropositive but no evidence of the PLOS ONE | www.plosone.org 1 November 2013 | Volume 8 | Issue 11 | e79629