N-Acetyltransferase-2 (NAT2) phenotype is influenced by genotype-environment interaction in Ethiopians

Aklillu, Eleni; Carrillo, Juan Antonio Cabrera; Makonnen, Eyasu; Bertilsson, Leif; Djordjević, Nataša

doi:10.1007/s00228-018-2448-y

Cited by 23 publications

(21 citation statements)

References 51 publications

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“…Meanwhile, slow acetylation genotypes are more likely to lead to ATLI. It has been reported that 52%‐72% of Caucasians have slow acetylating phenotypes, while 34%‐61% of Africans carry slow acetylated phenotypes . In America, the rate of slow acetylation types ranges from 23% to 75%, while Asians only have 9%‐32% of the slow acetylation phenotype .…”

Section: Discussionmentioning

confidence: 99%

The role of NAT2 polymorphism and methylation in anti‐tuberculosis drug‐induced liver injury in Mongolian tuberculosis patients

et al. 2019

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What is known and objective: Anti-tuberculosis drug-induced liver injury (ATLI) is one of the most significant adverse reactions for this line of therapy. N-acetyltransferase 2 (NAT2) is an important metabolic enzyme involved in drug metabolism and detoxification. Genetic polymorphism and DNA methylation have been proven to be key factors that affect the expression of NAT2. Therefore, the objective of the study was to investigate the relationship between NAT2 gene polymorphism and DNA methylation in the promoter region with ATLI risk in Mongolian tuberculosis patients. Methods:Our study is a case-control design. Chi-square test, Mann-Whitney U nonparametric test and Pearson test were all used to analyse existing relationships. The association between NAT2 gene acetylation phenotype and the total methylation of the NAT2 promoter region was analysed by means of binary logistic regression analysis. The general situation of the patients was evaluated by questionnaire, and the NAT2 genotyping of the three major polymorphism loci of gene coding was carried out by a gene sequencing technique. The methylation status of the NAT2 gene promoter region was detected by bisulphite sequencing and mass spectrometry.Result and discussion: Our study found that the detection rate of ATLI in Mongolian tuberculosis patients was 27.6%. There were no significant differences in demographic characteristics and living habits amongst the two groups, while significant differences were observed in the polymorphism of the NAT2 genes 481 (rs1799929) and 590 (rs1799930) and the acetylation phenotype. Moreover, the composition and distribution of the NAT2*4/4 and NAT2*4/5 genotypes were found in the two groups. The risk of ATLI in the slow acetylation type was 3.56 times higher than that of the fast acetylation type. Compared with the control group, the CpG5, CpG10, CpG11.12 and total methylation of the NAT2 promoter region in the ATLI group showed a hypermethylated pattern (P < .05). However, on performing binary logistic regression, neither the slow acetylation, intermediate acetylation nor rapid acetylation were found to be associated with ATLI (P > .05). It was found that the total methylation of NAT2 gene promoter region was an independent influencing factor of ATLI in Mongolian tuberculosis How to cite this article: Zhang D, Hao J, Hou R, Yu Y, Hu B, Wei L. The role of NAT2 polymorphism and methylation in anti-tuberculosis drug-induced liver injury in Mongolian tuberculosis patients. J Clin Pharm Ther. 2020;45:561-569.

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Section: Discussionmentioning

confidence: 99%

The role of NAT2 polymorphism and methylation in anti‐tuberculosis drug‐induced liver injury in Mongolian tuberculosis patients

et al. 2019

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“…Finally, we investigated the correlation in gene frequencies for HLA and DMET between Somalia and Ethiopia, using the abovementioned 61 HLA alleles as well as a group of 15 DMET alleles previously studied in Ethiopia [41][42][43][44][45] . We found that DMET frequencies correlated better than HLA frequencies between the two populations ( Fig.…”

Section: Genotype Data Verificationmentioning

confidence: 99%

Genome-wide analyses disclose the distinctive HLA architecture and the pharmacogenetic landscape of the Somali population

Ali

Aalto²,

Jonasson

et al. 2020

Sci Rep

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African populations are underrepresented in medical genomics studies. for the Somali population, there is virtually no information on genomic markers with significance to precision medicine. Here, we analyzed nearly 900,000 genomic markers in samples collected from 95 unrelated individuals in the north eastern Somalia. ADMiXtURe program for estimation of individual ancestries revealed a homogenous Somali population. principal component analysis with pLinK software showed approximately 60% East African and 40% West Eurasian genes in the Somali population, with a close relation to the Cushitic and Semitic speaking Ethiopian populations. We report the unique features of human leukocyte antigens (HLA) in the Somali population, which seem to differentiate from all other neighboring regions compared. Current study identified high prevalence of the diabetes type 1 (T1D) predisposing HLA DR-DQ haplotypes in Somalia. This finding may explain the increased T1D risk observed among Somali children. In addition, ethnic Somalis were found to host the highest frequencies observed thus far for several pharmacogenetic variants, including UGT1A4*2. In conclusion, we report that the Somali population displays genetic traits of significance to health and disease. The Somali dataset is publicly available and will add more information to the few genomic datasets available for African populations. Africa harbors the largest human genetic variation in the world 1-5 and many human gene variants are found only in Africa 6 including those associated with drug response. Yet, many ethnic populations in Sub-Saharan Africa are not represented in medical genomics studies found in the literature, mainly because of the generally lower level of medical research conducted in Sub-Saharan Africa compared with developed countries due to insufficient research infrastructures or resources. As a result, most of the human genetic variation present in Africa is yet unexplored. Some efforts have been made in recent years to better understand African genetic variation. These include studies that examined genetic markers for diabetes 7,8 and those investigating the genetic selection in Africa as a result of disease exposure or environmental adaptation 4,9. However, the need for more genomic data from African populations still persists, notably for underrepresented ethnolinguistic groups, including the Somali population, where there is still lack of information on genetic markers for drug responses, immunity and diseases. Somalia is located in the Horn of Africa (Somalia, Djibouti, Ethiopia, Eritrea,), a historic site for human migrations into either direction of Africa or Eurasia 10-13. Rock art paintings in multiple sites of Northern Somalia show Neolithic human activities in this part of East Africa 14,15. Later Himyarite and Sabaean inscriptions found in the same Somali region suggest existence of socio-cultural mingling with the ancient Axumite-South Arabian sphere 15. Due to the geographic location of Somalia, the Somalis have both African and non-Africa...

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“…However, only one tagging SNP may lead to incorrect predictions because phenotypically slow acetylators are genotyped as intermediate or rapid, and a drawback of the current practice of solely discriminating between slow, intermediate and rapid genotypes for phenotypic inference is the limited resolution of the differences between slow acetylators . Furthermore, a recent study reported a high prevalence of NAT2 slow acetylators in Ethiopians and also that a conditional NAT2 genotype–phenotype discordance (implicating a partial phenotypic conversion and metabolic adaptation) and gene–environment interactions could regulate the NAT2 phenotype . Therefore, these issues and the clinical application of this tagging SNP may require further research.…”

Section: Discussionmentioning

confidence: 99%

“…32 Furthermore, a recent study reported a high prevalence of NAT2 slow acetylators in Ethiopians and also that a conditional NAT2 genotype-phenotype discordance (implicating a partial phenotypic conversion and metabolic adaptation) and gene-environment interactions could regulate the NAT2 phenotype. 33 Therefore, these issues and the clinical application of this tagging SNP may require further research.…”

Section: Discussionmentioning

confidence: 99%

Relevance of NAT2 genotype to anti‐tuberculosis drug‐induced hepatotoxicity in a Chinese Han population

Tao

Wei

et al. 2019

The Journal of Gene Medicine

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Background Anti‐tuberculosis drug‐induced hepatotoxicity (ATDH) is a serious adverse drug reaction. The slow acetylator status of N‐acetyl transferase 2 (NAT2) is a well‐established risk factor for ATDH. One novel tagging single nucleotide polymorphism (tagging SNP), rs1495741, in NAT2 has been found to be highly predictive of the NAT2 phenotype. The present study aimed to validate the relationships between tagging SNP rs1495741 and ATDH in a Chinese Han population. Methods A 1:2 matched case–control study was conducted using 235 ATDH cases and 470 controls. Conditional or unconditional logistic regression analysis was used to estimate the association between genotypes and the risk of ATDH according to the odds ratio (OR) with a 95% confidence interval (CI). Results Patients carrying the AA genotype of tagging SNP rs1495741 were at higher risk of ATDH than those carrying the GG genotype (OR = 1.653, 95% CI = 1.050–2.601; p = 0.030). Subgroup analysis suggested that the AA genotype was a risk factor for ATDH in patients aged older than 50 years (OR = 2.486, 95% CI = 1.313–4.706; p = 0.005), weighing over 50 kg (OR = 1.757, 95% CI = 1.016–3.038; p = 0.044) or using a hepatoprotectant (OR = 1.611, 95% CI = 1.009–2.572; p = 0.046). Tagging SNP rs1495741 was not a significant risk factor for moderate and severe hepatotoxicity but appears to be relevant to risk of mild hepatotoxicity specifically. Conclusions The present study is the first to validate the relationships between the tagging SNP rs1495741 and ATDH in a Chinese population. Based on this case–control study, the NAT2 rs1495741 polymorphism is a risk factor for mild but not more severe ATDH in Chinese Han patients.

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N-Acetyltransferase-2 (NAT2) phenotype is influenced by genotype-environment interaction in Ethiopians

Cited by 23 publications

References 51 publications

The role of NAT2 polymorphism and methylation in anti‐tuberculosis drug‐induced liver injury in Mongolian tuberculosis patients

The role of NAT2 polymorphism and methylation in anti‐tuberculosis drug‐induced liver injury in Mongolian tuberculosis patients

Genome-wide analyses disclose the distinctive HLA architecture and the pharmacogenetic landscape of the Somali population

Relevance of NAT2 genotype to anti‐tuberculosis drug‐induced hepatotoxicity in a Chinese Han population

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