Pharmacogenetic variability of tuberculosis biomarkers in native and mestizo Peruvian populations

Abstract

In Peru, 29 292 people were diagnosed with tuberculosis in 2022. Although tuberculosis treatments are effective, 3.4%–13% are associated with significant adverse drug reactions, with drug‐induced liver injury (DILI) considered the most predominant. Among the first‐line antituberculosis drugs, isoniazid is the main drug responsible for the appearance of DILI. In liver, isoniazid (INH) is metabolized by N‐acetyltransferase‐2 (NAT2) and cytochrome P450 2E1 (CYP2E1). Limited information exists on genetic risk factors associated with the presence of DILI to antituberculosis drugs in Latin America, and even less is known about these factors in the native and mestizo Peruvian population. The aim of this study was to determine the prevalence of NAT2 and CYP2E1 genotypes in native and mestizo population. An analytical cross‐sectional analysis was performed using genetic data from mestizo population in Lima and native participants from south of Peru. NAT2 metabolizer was determined as fast, intermediate and slow, and CYP2E1 genotypes were classified as c1/c1, c1/c2 and c2/c2, from molecular tests and bioinformatic analyses. Of the 472 participants, 36 and 6 NAT2 haplotypes were identified in the mestizo and native population, respectively. In mestizo population, the most frequent NAT2*5B and NAT2*7B haplotypes were associated with DILI risk; while in natives, NAT2*5G and NAT2*13A haplotypes were associated with decreased risk of DILI. For CYP2E1, c1/c1 and c1/c2 genotypes are the most frequent in natives and mestizos, respectively. The linkage disequilibrium of NAT2 single nucleotide polymorphisms (SNPs) was estimated, detecting a block between all SNPs natives. In addition, a block between rs1801280 and rs1799929 for NAT2 was detected in mestizos. Despite the limitations of a secondary study, it was possible to report associations between NAT2 and CYP2E alleles with Peruvian native and mestizo by prevalence ratios. The results of this study will help the development of new therapeutic strategies for a Tuberculosis efficient control between populations.

The Peruvian Genome Project: expanding the global pool of genome diversity from South America

“…For instance, we found evidence of NAT25B and NAT2 7B being associated with DILI risk in mestizos, while no such association has been observed in natives. Additionally, haplotypes NAT25G and NAT2 13A have only been negatively associated with DILI in the studied native Peruvians 15 . Current research also suggests a greater prevalence of probable hepatotoxicity in the Amazonian population.…”

“…In 2018 and 2019 we then performed pharmacogenomics and transcriptomics investigations. This research allowed us to shed light on the susceptibility’s highlanders have in tuberculosis infections, together with their pharmacological responses 14,15 . During the COVID pandemic (2020-2022), we shifted our focus to collaborating with international research groups to incorporate ancient Peruvian DNA samples into the pool.…”