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\begin{document}

\title{Pharmacogenetic variability of tuberculosis biomarkers in native and
mestizo Peruvian populations}



\author[1]{Luis Jaramillo-Valverde}%
\author[1]{Kelly S. Levano}%
\author[1]{David D. Tarazona}%
\author[1]{Silvia Capristano}%
\author[1]{Cesar Sanchez}%
\author[2]{Julio A. Poterico}%
\author[3]{Eduardo Tarazona-Santos}%
\author[1]{Heinner Guio}%
\affil[1]{Instituto Nacional de Salud}%
\affil[2]{INBIOMEDIC Research and Technological Center}%
\affil[3]{Universidade Federal de Minas Gerais}%


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  \date{June 18, 2024}


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\begin{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 (INH) is the main drug responsible for
the appearance of DILI. In liver, INH is metabolized by
N-acetyltransferase-2 ( \emph{NAT2}) and cytochrome P450 2E1 (
\emph{CYP2E1}). Limited information exists on genetic risk factors
associated with the presence of drug-induced liver injury (DILI) to
anti-tuberculosis 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 \emph{NAT2} and
\emph{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 in south of Peru from the
EPIGEN - Brazil project. \emph{NAT2} acetylator genotype was determined
as fast, intermediate and slow, and \emph{CYP2E1} genotypes were
classified as c1/c1, c1/c2 and c2/c2, from molecular tests and
bioinformatic analyses. Of the 472 participants, 36 haplotypes were
identified in the mestizo population and 6 haplotypes in native
population paired with \emph{NAT2}. In mestizo population, the most
frequent \emph{NAT2}*5B and \emph{NAT2}*7B haplotypes were associated
with DILI risk; while in natives, \emph{NAT2}*5G and \emph{NAT2}*13A
haplotypes were the most frequent and associated with decreased risk of
DILI. For \emph{CYP2E1}, c1/c1 and c1/c2 genotypes are the most frequent
in native and mestizo populations, respectively. The linkage
disequilibrium of \emph{NAT2} and CYP2E1 SNPs was estimated using the
solid spine method, detecting a block between all SNPs native
population. In addition, a block between rs1801280 and rs1799929 for
\emph{NAT2} was detected in the mestizo population. Despite the
limitations of a secondary study, it was possible to report associations
between \emph{NAT2} and \emph{CYP2E} alleles with Peruvian native and
mestizo population by prevalence ratios. The results of this study will
help the development of new therapeutic strategies for a Tuberculosis
efficient control between populations.%
\end{abstract}%



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