Genetic Polymorphisms of N-acetyl Transferase 2 and the Risk of Hepatotoxicity in Patients on Isoniazid Preventive Therapy at Kenyatta National Hospital
Abstract
BACKGROUND
Isoniazid preventive therapy (IPT) is an important intervention to prevent activation of latent
tuberculosis (TB) infection. Genetic variations associated with N-acetyl transferase (NAT2) are
closely associated with isoniazid-induced hepatotoxicity in IPT. This occurs as a result of the
patient's unique acetylation phenotype, which can affect clinical outcomes of patients on IPT
therapy.
OBJECTIVES
The main objective was to characterize the distribution of selected single nucleotide
polymorphisms (SNPs) of NAT2 in patients on IPT at the Comprehensive Care Centre (CCC) of
Kenyatta National Hospital (KNH) and to investigate for a relationship between acetylator status
and isoniazid induced hepatotoxicity as indicated by elevated alanine amino transferase (ALT)
levels.
METHODS
This was a cross-sectional study of human immunodeficiency virus (HIV) patients on IPT at
KNH CCC. Convenient sampling was employed during routine patient visits at the CCC,
following which inclusion and exclusion criteria were applied to recruit patients. Data was
extracted from patient records using a data collection form. Blood samples were taken from
patients. The QIAamp ® DNA Mini-Kit was used at the University of Nairobi's Institute of
Tropical Infectious Diseases (UNITID) for DNA extraction and purification of genomic DNA,
followed by DNA sequencing. Data analysis included both descriptive and inferential statistical
methods which were used to summarize the data, this was done in SPSS version 25.
RESULTS
Output data were summarized as follows: Mean, BMI (basal metabolic index) and age were 25.75
kg/m2 and 46.7 years, respectively. As a proxy indicator for hepatotoxicity, the cut-off for ALT
levels was 40 UI/L (units per liter). The median ALT level was 22 UI/L and the mean CD4 level
was 492 cells/mm3. The prevalence of the homozygous NAT2 genotype was 19% and that of the
heterozygous genotype was 50%. The proportion of the population with slow acetylator alleles
was 56% and the proportion of fast acetylator alleles was 44%. Fisher's exact test showed no
significant association between ALT levels and NAT2 genotype (P = 0.330). Similarly, NAT2
genotype and ethnolinguistic group (P = 1.0), alcohol consumption (P = 0.577), smoking status (P = 0.751), comorbidities (P = 0.127), and gender (P = 0.346). NAT2*5 and NAT2*6 alleles
were more frequent in this population compared to NAT2*7 and NAT2*14. On multivariate
regression analysis, the independent predictors. Smoking status, alcohol status, comorbidities,
and gender were not significant in predicting elevated ALT levels (P > 0.05).
CONCLUSION
The study found no significant association between NAT2 genotypes and ALT levels (P = 0.33).
However it found that there was a high frequency of NAT2*5 and NAT2*6 alleles compared to
NAT2*7 and NAT2*14 alleles among the 41 genotyped sequences in this study population. In
addition, the study also found that, there was no significant differences in the distribution of
NAT2 genotypes and the Ethno-linguistic groups (P = 1.00). Similarly, there was no association
between ALT levels and factors such as age, BMI, smoking status, alcohol status, gender and
comorbidities. More studies on the effect of NAT2 genotypes on Anti-tuberculosis drug induced
hepatoxicity in the Kenyan population with a larger sample size is recommended
Publisher
University of Nairobi
Rights
Attribution-NonCommercial-NoDerivs 3.0 United StatesUsage Rights
http://creativecommons.org/licenses/by-nc-nd/3.0/us/Collections
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