Genetic association study of NLRP1, CARD, and CASP1 inflammasome genes with chronic Chagas cardiomyopathy among Trypanosoma cruzi seropositive patients in Bolivia.

Steven J Clipman,Robert H Gilman,Caryn Bern,Katherine Y Fu,Josephine Henderson-Frost,Jorge Flores,David M Ojcius

doi:10.1371/journal.pone.0192378

Abstract

About 20–30% of people infected with Chagas disease present with chronic Chagas cardiomyopathy (CCC), the most serious and frequent manifestation of the disease, while others remain asymptomatic and often do not experience Chagas-specific mortality. It is not currently well understood what causes these differential disease outcomes, but a genetic predisposition within the host could play an important role. This study examined variants in the NLRP1, CARD, and CASP1 inflammasome genes among 62 T. cruzi seropositive patients from Bolivia (38 cases with CCC and 24 asymptomatic controls) to uncover associations with CCC. All subjects underwent a complete medical examination including electrocardiogram (EKG) and echocardiogram. After genotype calling and quality control filtering with exclusion of 3 cases and 3 controls, association analysis was performed across 76 directly genotyped SNPs in NLRP1, CARD, and CASP1 genes, adjusting for age, sex, and population stratification. One SNP (rs11651270; Bonferroni-corrected p = 0.036) corresponding to a missense mutation in NLPR1 was found to be significant after adjustment for multiple testing, and a suggestive association was seen in CARD11 (rs6953573; Bonferroni-corrected p = 0.060). Although limited by sample size, the study results suggest variations in the inflammasome, particularly in NLRP1 and CARD11, may be associated with CCC.

Highlights

Chagas disease as it is more commonly known, is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi (T. cruzi)
This study was designed as a nested case-control study within a larger cross-sectional study of Chagas cardiomyopathy patients enrolled from hospital-based settings in Bolivia
Association analysis was run under an additive model across 76 SNPs in the NLRP1, caspase activation and recruitment domain (CARD), and CASP1 genes using multivariate unconditional logistic regressions adjusting for age, sex, and genetic admixture using the first four within-sample components calculated from EIGENSTRAT smartpca

Summary

Introduction

Chagas disease as it is more commonly known, is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi (T. cruzi). Endemic to areas of Latin America, Chagas disease leads to more morbidity and mortality in the Americas than any other parasitic disease [1, 2]. It is currently estimated that 8 million people are infected worldwide with over 70 million at risk [2, 3]. Genetic association study of chronic Chagas cardiomyopathy decision to publish, or preparation of the manuscript

Objectives

Methods

Results