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Title
GENETIC POLYMORPHISM OF CYTOCHROME P1-450A2 (CYP1A2) AND N-ACETYLTRANSFERASE2-
(NAT2) AMONG EMIRATIS
Faculty Advisor
Prof. Salim Bastaki
Defense Date
26 March 2017
Abstract
Brief introduction: There are limited studies on CYP1A2 and NAT2 polymorphisms among Emiratis. Aims:
This study aims to determine CYP1A2 and NAT2 alleles and genotypes and correlate these genotypes
with caffeine metabolism phenotypes among Emiratis. Methods: After obtaining informed consent, five
hundred and eighty one non-smoker subjects were given 300ml of caffeinated soft drink and were asked
to provide a buccal swab and a urine sample two hours later. TaqMan Real Time PCR, PCR-RFLP, DNA
sequencing were performed to determine CYP1A2 and NAT2 alleles and genotypes. Phenotyping was
carried out by analysing the caffeine metabolites using HPLC analysis. Results: We found that 1.4%,
16.3% and 82.3% of the recruited subjects were slow, intermediate and rapid CYP1A2 metabolisers,
respectively. Only 1.4% of the subjects were homozygotes for CYP1A2 mutant alleles while 16.1% were
heterozygotes and 82.5% were homozygotes for the CYP1A2 wild type genotype. Therefore, the frequency
of the wild type genotype CYP1A2*1A/*1A was 0.825 followed by CYP1A2*1A/*1C and CYP1A2*1A/*1K,
with frequencies of 0.102 and 0.058, respectively. The degree of phenotype/genotype concordance was
81.6%. The CYP1A2*1C/*1C and CYP1A2*3/*3 genotypes showed the lowest phenotype status. With
regards to NAT2, we found that 78.5%, 19.1% and 2.4% of the subjects were slow, intermediate and rapid
NAT2 acetylators, respectively, with 77.4% being homozygote or heterozygote for NAT2 mutant alleles and
18.4% and 4.2% were heterozygote and homozygote for the NAT2 wild type genotypes, respectively. The
most common genotypes found were NAT2*5B/*7B, NAT2*5B/*6A, NAT2*7B/*14B and NAT2*4/*5B with
frequencies of 0.255, 0.135, 0.105 and 0.09, respectively. The degree of phenotype/genotype concordance
was equal to 96.2%. The NAT2*6A/*6A, NAT2*6A/*7B, NAT2*7B/*7B, NAT2*5A/*5B and NAT2*5A/*5A
genotypes were found to be associated with the lowest 5-Acetylamino-6-Formylamino-3-Methyluracil/1-
Methylxanthine (AFMU/1X) ratios. Significant contributions: The majority of the studied Emiratis are
slow NAT2 acetylators with implications for the prescription of medications that are metabolised by this
enzyme. In addition, a small percentage of Emiratis have slow CYP1A2 enzyme activity which again should
be taken into consideration when prescribing medications that are partially metabolised by this enzyme.
In Emirati population, the frequency of the CYP1A2*1A and NAT2*5 alleles were the highest relative to
other alleles frequencies. Moreover, Individuals who carried NAT2*6A/*6A, NAT2*6A/*7B, NAT2*7B/*7B,
NAT2*5A/*5B, NAT2*5A/*5A, CYP1A2*1C/*1C or CYP1A2*3/*3 genotypes might be at high risk of toxicity
with some drugs and some diseases compared to others as these genotypes are associated with the
slowest phenotype status. Consequently, genetic testing is recommended prior to prescribing medications
that are largely metabolized by CYP1A2 or NAT2. Gap filled: This is the first detailed study of CYP1A2 and
NAT2 alleles and genotypes among Emiratis.
Dissertation
MOHAMMAD MAJED AL-AHMAD
Department of Pharmacology and therapeutics
College of Medicine and Health Sciences