title: Genome wide association study (GWAS) of Chagas cardiomyopathy in Trypanosoma cruzi seropositive subjects.
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 between 1996 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(-8)) associated with cardiomyopathy. The two mostly highly associated SNPs for cardiomyopathy (rs4149018 and rs12582717; P-values <10(-6)) 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.
  
  
  CONCLUSIONS
  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 resistance to T. cruzi infection and non-Chagas cardiomyopathy.
authors: Blood Systems Research Institute, San Francisco, California, United States of America.
authors: Xutao
authors: X
authors: Deng
authors: Ester C
authors: EC
authors: Sabino
authors: Edecio
authors: E
authors: Cunha-Neto
authors: Antonio L
authors: AL
authors: Ribeiro
authors: Barbara
authors: B
authors: Ianni
authors: Charles
authors: C
authors: Mady
authors: Michael P
authors: MP
authors: Busch
authors: Mark
authors: M
authors: Seielstad
mesh_terms: D002598:Chagas Cardiomyopathy / Q000235:genetics* / Q000469:parasitology; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012189:Retrospective Studies; D014349:Trypanosoma cruzi / Q000472:pathogenicity*