Genetic Architecture of Heart Disease in Rural Brazil
Condition: Chagas Disease; Heart Diseases; Arrhythmia; Heart Failure, Congestive
MeSH terms: Chagas Disease; Heart Failure; Heart Diseases
Study type: Observational

Summary: 
      To examine the genetics of human susceptibility to Chagas' disease, a leading cause of heart
      disease throughout Latin America.
    

Detailed description: 
      BACKGROUND:

      Chagas' disease is a leading cause of heart disease throughout Latin America, affecting
      between 16 and 18 million individuals. The disease, named after the Brazilian physician
      Carlos Chagas who first described it in 1909, exists only on the American Continents. It is
      caused by a flagellate protozoan parasite, Trypanosoma cruzi, transmitted to humans by
      blood-sucking triatomine insects known popularly in the different countries as "vinchuca",
      "barbeiro", "chipo" etc. The geographical distribution of the human T.cruzi infection extends
      from Mexico to the south of Argentina. In Brazil alone, approximately 10 percent of the
      population is seropositive for T. cruzi. Given the large pool of primary hosts for this
      zoonotic disease, complete eradication of Chagas' disease through control of the arthropod
      vector is unlikely. Research with humans and animal models indicates that there is variation
      in susceptibility to infection, and disease outcome, and that this variation may be due to
      genetic factors. Thus, this form of heart disease represents a complex phenotype with
      potential genetic determinants to both susceptibility to infection and differential disease
      pathogenesis.

      DESIGN NARRATIVE:

      The genetic epidemiology project studies an estimated 1,125 Black individuals age 18 years or
      older from a small community in Posse, Brazil in which the study population may be drawn from
      as few as four to five large pedigrees with varying blood relationships. Preliminary pilot
      data appear very promising regarding the primary hypothesis that specific genetic factors
      influence the susceptibility to this complex zoonotic disease. The investigation will be
      divided into three parts involving phenotypic characterization, statistical genetic analyses
      to determine the relative proportion of the phenotypic variance due to additive genetic
      effects, and localization of genes influencing the development of Chagas' disease.

      The phenotypic characterization will involve clinical history, infection status, immunologic
      studies, and cardiac status. The chronic phase of T. cruzi infection results in Chagas'
      disease manifest as a cardiomyopathy with heart block, conduction disturbance, ventricular
      tachyarrhythmia, heart failure, and sudden arrhythmic death. The cardiac phenotyping will
      involve electrocardiographic time intervals (PR interval, QRS duration, QT interval duration)
      as well as abnormal patterns (left anterior fascicular block, left ventricular hypertrophy,
      right bundle branch block), and possibly some measure of heart failure in terms of New York
      Heart Association functional classification. Right bundle branch block is probably the most
      frequent early manifestation of chronic cardiac involvement.

      The genetic linkage studies will attempt to localize genes influencing susceptibility to T.
      cruzi infection, ECG parameters (e.g., right bundle branch block), and immunologic factors
      using markers placed approximately every 10 centimorgans (cM) throughout the genome.

      About 375 individuals will be sampled per year. Each subject will donate two 10 ml samples of
      blood which will be used for immunoassays for seropositivity for T. cruzi, and for genotyping
      with 382 polymorphic short tandem repeats. During the initial visits, the population subjects
      will also be interviewed to gather information on demographic, pedigree, and socioeconomic
      makeup. Additionally, questions on pregnancy status, household ecology (years in the house,
      rooms shared, pets, rodents, food storage, triatomid bug history, etc) and residence history
      will be determined during the survey. In the fourth year, the investigators will return to
      the collection site and administer ECGs on 375 individuals per year.

      The blood collected in Brazil will be sent to San Antonio for high-throughput genotyping
      using 382 polymorphic short tandem repeats (STRs) spread throughout the genome. A population
      specific 10cM map is expected to be useful for linkage analysis.