Protective Human Leucocyte Antigen Haplotype, HLA-DRB1*01-B*14, against Chronic Chagas Disease in Bolivia

Abstract

BackgroundChagas disease, caused by the flagellate parasite Trypanosoma cruzi affects 8–10 million people in Latin America. The mechanisms that underlie the development of complications of chronic Chagas disease, characterized primarily by pathology of the heart and digestive system, are not currently understood. To identify possible host genetic factors that may influence the clinical course of Chagas disease, Human Leucocyte Antigen (HLA) regional gene polymorphism was analyzed in patients presenting with differing clinical symptoms.MethodologyTwo hundred and twenty nine chronic Chagas disease patients in Santa Cruz, Bolivia, were examined by serological tests, electrocardiogram (ECG), and Barium enema colon X-ray. 31.4% of the examinees showed ECG alterations, 15.7% megacolon and 58.1% showed neither of them. A further 62 seropositive megacolon patients who had undergone colonectomy due to acute abdomen were recruited. We analyzed their HLA genetic polymorphisms (HLA-A, HLA-B, MICA, MICB, DRB1 and TNF-alpha promoter region) mainly through Sequence based and LABType SSO typing test using LUMINEX Technology.Principal FindingsThe frequencies of HLA-DRB1*01 and HLA-B*14:02 were significantly lower in patients suffering from megacolon as well as in those with ECG alteration and/or megacolon compared with a group of patients with indeterminate symptoms. The DRB1*0102, B*1402 and MICA*011 alleles were in strong Linkage Disequilibrium (LD), and the HLA-DRB1*01-B*14-MICA*011haplotype was associated with resistance against chronic Chagas disease.ConclusionsThis is the first report of HLA haplotype association with resistance to chronic Chagas disease.

Chagas disease research and development: Is there light at the end of the tunnel?

“…Results from a Genome Wide Association Study (GWAS) using the well-established REDS-II cohort of Chagas patients suggested that both cardiovascular- and immune-related polymorphism in some genes of interest could be associated with the genetic predisposition to chronic Chagas cardiomyopathy [48]. Another study found an association between HLA haplotype and resistance to chronic Chagas disease [49]. In a retrospective cohort study of cardiomyopathy incidence among previously asymptomatic Chagas patients, factors such as male sex, history of ECG abnormalities, among others, were associated with prognostic markers for cardiomyopathy [50].…”

21-Hydroxylase gene mutant allele CYP21A2∗15 strongly linked to the resistant HLA haplotype B∗14:02-DRB1∗01:02 in chronic Chagas disease

“…After the detection of the mutant alleles by RFLP as shown in Figure 1, we observed a linkage between the CYP21A2*15 and the alleles B*1402 and DRB1*0102, in the subjects [12] (Table 1). Out of the 291 samples analyzed, we could obtain results in 285 of them, the CYP21A2*15 was present in a frequency of 5.96 % (17 out of 285)…”

“…The selection criteria, grouping and clinical manifestations were previously described by del Puerto et al 2012 [12]. Briefly, 229 seropositive Chagas outpatients in Santa Cruz, Bolivia, were examined by Electrocardiogram and Barium enema colon X-ray.…”

Significance and Distribution of the Mic a/B Alleles Among the Worldwide Populations

“…Such MIC variations are widely reported in worldwide populations such as Chinese [33,48,49,50], Indian [51], Iranian [52,53], Swedish [54], Finnish [55], Korean [56,57], Spanish [58], Bolivian [59], and Algerian [60]. …”

“…Interestingly, this current study does not indicate any presence of MICA/B allelic variations in Iranian population. The MICA *011 allele is reported [59] to be associated with protection against Chronic Chagas Disease among the Bolivian subjects. Even though, this study does not include Bolivian subjects, the neighbor communities could be considered for possible presence of this allele.…”