Discovery of a novel genetic variant in the N-acetyltransferase2 (NAT2) gene that is associated with bladder cancer risk

Lina Elsalem; Ahmad Al Shatnawi; Mahmoud  A Alfaqih; Ayat Alshoh; Saddam Al Demour; Ali Al-Daghmin; Omar Halalsheh; Khalid Kheirallah; Mamoun Ahram

doi:10.18388/abp.2020_6590

Lina Elsalem Jordan University of Science and Technology, Faculty of Medicine, Department of Pharmacology, Irbid, Jordan https://orcid.org/0000-0002-3814-4865
Ahmad Al Shatnawi Jordan University of Science and Technology, Faculty of Medicine, Department of Pharmacology, Irbid, Jordan; 2Royal Medical Services, Department of Clinical Pharmacy, Irbid, Jordan
Mahmoud A Alfaqih 3Department of Biochemistry, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain; 4Department of Physiology and Biochemistry, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan https://orcid.org/0000-0002-6383-7014
Ayat Alshoh Jordan University of Science and Technology, Faculty of Medicine, Department of Pharmacology, Irbid, Jordan
Saddam Al Demour The University of Jordan, School of Medicine, Department of Special Surgery, Division of Urology, Amman, Jordan https://orcid.org/0000-0003-4044-0927
Ali Al-Daghmin 6King Hussein Cancer Center, Department of Surgery, Amman, Jordan; 7Abdali Medical Center, Amman, Jordan
Omar Halalsheh Jordan University of Science and Technology, Faculty of Medicine, Department of General Surgery and Urology, Irbid, Jordan
Khalid Kheirallah Jordan University of Science and Technology, Faculty of Medicine, Department of Public Health and Community Medicine, Irbid, Jordan
Mamoun Ahram The University of Jordan, School of Medicine, Department of Physiology and Biochemistry, Amman, Jordan

DOI: https://doi.org/10.18388/abp.2020_6590

Abstract

Smoking is a main risk factor for bladder cancer (BC). NAT2 is a drug-metabolizing enzyme that catalyses the detoxification of many xenobiotics and carcinogens. Single nucleotide polymorphism (SNP) in NAT2 results in different acetylation phenotypes (fast, intermediate or slow). Certain NAT2 SNPs were associated with BC and/or modified the association of BC with smoking. However, limited evidence is available among BC patients or smokers from Jordan. This study aimed to discover novel SNPs in NAT2 and to assess the association with BC. This was a case-control study among 120 BC patients and 120 controls. Amplification of a 446 bp fragment of NAT2 encoding the N-catalytic domain was conducted using a polymerase chain reaction. Gene sequencing was done using Sanger-based technology. A total of 40 SNPs were detected. Two variants were significantly associated with BC (p<0.05); namely a novel c.87G>A and the reported c.341T>C. Regarding c.87G>A, genotype distribution was significantly associated with BC and subgroup analysis confirmed that this was significant in both smokers (p=0.007) and non-smokers (p=0.001). Regression subgroup analysis suggested GA as a risk factor among smokers (AOR= 2.356). The frequencies of TC and CC genotypes of c.341T>C were significantly higher in BC (p<0.05). This was statistically significant among smokers only (p=0.044), upon subgroup analysis. Multivariate analysis showed that subjects with TC genotype are 6.15 more likely to develop BC and regression subgroup analysis revealed TC as a risk factor among smokers (AOR=5.47). This is the first study from Jordan to report the association of smoking and two NAT2 variants with BC. The data supports the use of GA and TC genotypes of the novel c.87G>A and the reported c.341T>C SNPs, respectively as potential biomarkers of BC, particularly among smokers. Future investigations with a larger population are required to support our findings.