Genetic Variants Associated with Life Expectancy in Patients with Chagas Disease

Single nucleotide polymorphisms (SNPs), as common genetic variations, can influence biological processes. Identifying these variations is crucial for recognizing high-risk subgroups, guiding preventive strategies, and enabling personalized management. Objective: This study aimed to determine the relationship between SNPs and survival, thereby identifying genetic profiles associated with increased risk. Methods: We included seropositive patients with Chagas disease who had a disease duration of >20 years and no comorbidities. DNA was extracted. A SNP panel focusing on genes involved in cardiac structure was created from the GnomAD database. Patients were followed for 8 years to assess survival. The association between SNPs and survival was evaluated, and a genetic risk score was generated. Univariate and multivariate Cox regression models assessed the association between SNPs (coded as ordinal variables) and survival time. SNPs with p < 0.05 were selected to construct a risk score, which was then assessed using Kaplan-Meier curves and median survival times. Results: A total of 182 patients were included, with 96.7% completing follow-up for a median of 5.1 years (interquartile range: 3.4-6.5). The median age was 62 years; 39.6% of patients were male, and 31% had reduced left ventricular ejection fraction. Univariate analysis showed that 3 of the 68 SNPs studied were associated with survival. Variant rs3755863 (PPARGC1A gene) was significantly associated with an increased risk of death (hazard ratio, HR = 1.94; p = 0.022). Conversely, two variants, rs7310615 (SH2B3 gene) and rs7405731 (JUP gene), showed a protective effect with significantly reduced mortality risk (HR = 0.45; p = 0.006 and HR = 0.48; p = 0.006, respectively). In multivariate analysis, rs7310615 and rs7405731 remained significantly associated with survival. A genetic risk score was constructed, assigning 0 points for homozygous wild-type, 1 point for heterozygotes, and 2 points for homozygous alternative alleles. Individual scores were calculated, and survival was estimated for each score category using Kaplan-Meier analysis and median survival times. Conclusions: Two SNPs were identified as significantly associated with survival. These findings require confirmation in larger and more diverse populations. Their validation could enable the identification of a subgroup of patients at particularly high risk.