Mapping ATTR in Brazil: a meta-epidemiological analysis of regional genetic and clinical diversity

Background Transthyretin amyloidosis (ATTR) in Brazil is characterised by marked genetic diversity, reflecting the country’s extensive population admixture. Although the Val50Met variant is widely recognised, the distribution of rare TTR variants and the impact of regional comorbidities—particularly diabetes mellitus—remain incompletely defined. These factors may influence phenotypic expression, age at diagnosis, and disease recognition, suggesting that ATTR in Brazil follows distinct regional patterns rather than a uniform national profile. Purpose To compare the genetic, demographic, and clinical characteristics of patients with ATTR between the Southeast (SE) and Northeast/Central-West (NE/CO) regions of Brazil using a meta-epidemiological approach. Methods A systematic review and aggregated meta-analysis of Brazilian studies published between 2019 and 2025 was conducted (N=878). Studies were stratified into two regional clusters (SE: São Paulo and Rio de Janeiro; NE/CO: remaining regions). Sample-size–weighted estimates were calculated. Missing variables were addressed through evidence-based clinical imputation. Continuous and categorical variables were compared using Student’s t-tests and chi-square tests. Sensitivity analyses excluding imputed datasets assessed robustness. Results Of 878 patients, 720 were from SE and 158 from NE/CO. The SE cluster showed predominance of Val50Met (60.8% vs. 43.0%; p<0.001) and a mainly neuropathic phenotype (ATTR-PN). NE/CO demonstrated greater genetic diversity, with higher prevalence of rare variants (19.6% vs. 10.6%; p=0.0025), notably Ile127Val (22% in one cohort), and predominance of cardiomyopathy (ATTR-CM: 68.4% vs. 43.9%; p<0.001). Diagnosis after 60 years-old was more frequent in NE/CO (38.7% vs. 7.3%; p<0.001). Diabetes mellitus was significantly more prevalent in NE/CO (21.5% vs. 6.9%; p<0.001), representing a potential diagnostic confounder. Tafamidis use was higher in SE (~32% vs. ~14%), suggesting regional disparities in therapeutic access. Sensitivity analyses confirmed these findings. Conclusions For the first time, our study demonstrates that ATTR in Brazil exhibits a clear geographic gradient in genotype and phenotype. The Southeast—historically shaped by Portuguese coastal colonization—closely mirrors the classical European Val50Met neuropathic model. In contrast, the Northeast/Central-West, marked by greater admixture and stronger African ancestral influence, shows broader mutational diversity, later onset, and a predominant cardiac phenotype frequently overlapping with diabetes. These findings support region-specific screening strategies, including comprehensive TTR sequencing in genetically diverse areas and heightened cardiologic suspicion in older patients with heart failure, aiming to reduce underdiagnosis and regional inequities in access to disease-modifying therapy.Central figure