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Pharmacogenomic landscape of VIP genetic variants in Jordanian Arabs and comparison with worldwide populations
Journal Pre-proofs Research paper Pharmacogenomic landscape of VIP genetic variants in Jordanian Arabs and comparison with worldwide populations Laith N. AL-Eitan PII: DOI: Reference:
S0378-1119(20)30077-9 https://doi.org/10.1016/j.gene.2020.144408 GENE 144408
To appear in:
Gene Gene
Received Date: Revised Date: Accepted Date:
16 December 2019 23 January 2020 27 January 2020
Please cite this article as: L.N. AL-Eitan, Pharmacogenomic landscape of VIP genetic variants in Jordanian Arabs and comparison with worldwide populations, Gene Gene (2020), doi: https://doi.org/10.1016/j.gene.2020.144408
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Pharmacogenomic landscape of VIP genetic variants in Jordanian Arabs and comparison with worldwide populations Laith N. AL-Eitan Department of Applied Biological Sciences, Jordan University of Science and Technology, Irbid 22110, Jordan Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid 22110, Jordan Correspondence: Dr. Laith N AL-Eitan at Department of Applied Biological Sciences, Jordan University of Science and Technology. P.O. Box 3030, Irbid 22110, Jordan. Tel: + (962) -2 7201000. Fax: + (962)-2-7201071. Email: [email protected].
Abstract The pharmacogenomics has lately become a focal field of research that investigates the influence of genetic variations of drug-metabolizing enzymes and their receptors and downstream proteins on the interindividual variability in response to medications and adverse drug reactions. Therefore, it is significantly important to study and analyze the variations in drug response between different ethnic groups and populations. The current study aimed to detect the distribution of the genotype and allele frequencies in several very important pharmacogenetic (VIP) gene polymorphisms in the Jordanian population of Arab descent. This study involved 500 unrelated Jordanian individuals of Arab descent. A total of 65 VIP variants located within 33 candidate genes were randomly selected from the PharmGKB database and genotyped using the MassARRAY (iPLEX GOLD) system. The chi-square test was used to evaluate the significant differences of minor allele and genotype frequencies between the Jordanian and other populations including CHE, ASW, CEU, CHB, CDX, GIH, GBR, JPT, LWK, MXL, TSI, YRI, CAR, and ACB. This study revealed six variants were not in Hardy Weinberg equilibrium (HWE) (P-value > 0.05) and ten SNPs showed monomorphic features. Most of the remaining forty-nine variant frequencies were significantly different from the compared ethnic groups (P-value < 0.05). The results of this study may be helpful to develop safer treatment by applying the concept of personalized medicine based on the profile of VIP pharmacogene variants of the Jordanian population of Arab descent. Key Words: Pharmacogenomics; Pharmacogenes; SNPs; Jordanian; Arab
1. Introduction: The genomic variations between individuals due to various types of single nucleotide polymorphisms play an important and vital role in drug pharmacokinetics (absorption, distribution, metabolism and excretion) and pharmacodynamics which significantly influence the dose and response of the treatment medications (1-4). Therefore, a better understanding of the variations in genetic material, drug response, efficacy, and toxicity for the same dose of medication will improve the effectiveness of drug therapy (3, 5-7). One of the main public health problems in the world is the variability in drug response between individuals which represents about 2.5% to 10% of all admissions in the hospitals (8-10). It has been reported that various cases of adverse drug reactions due to the variation in drug response which lead to many adverse effects on the patient’s health and the economic status for the individual and society (11-13). It is worth to mention that pharmacogenetics or pharmacogenomics is the study of drug response due to the effect of individual genes or total genomic expression, respectively (14, 15). Over 7 million common variants that affect drug metabolism have been identified worldwide in the last decade (16). A total of 0.2% to 4 % of these common SNPs are responsible for distinguishing the variation in responding to medications among different individuals and populations (7). Therefore, this fact provides the basis for the development and enhancement of personalized treatment (17). In total, there are more than 100 very important pharmacogenes (VIP) which control an individual’s response to drug treatments (18). These genes are translated into products that are involved in drug metabolism (19). Cytochromes P450 (CYPs) or CYP450 is a family of enzymes that are important for the clearance of various compounds, in addition to hormone synthesis and breakdown (20, 21). CYPs are the main enzymes involved in drug metabolism which account for about 75% of the total metabolism (22, 23). The Human Genome Project has identified more than 50 human genes coding for the various cytochrome P450 enzymes (24). Classical examples of this family are CYP1A2, CYP2C9, CYP2C19, and CYP3A4 (21). In addition to other significant variants that have been identified within VIPs as MTHFR, DPYD, PACERR, SCN5A, NR1I2, P2RY1, P2RY1, ADH1A, ADH1B, ADH1C, ABCB1, HMGCR, KCNH2, ADRB2, and others are clinically functional and involved in drug metabolism and excretion (25-28).
The genetic diversity of the pharmacogenes exhibits the variable response to drug treatments for an individual through different ethnic groups (1, 9). Studying and identifying the polymorphisms of VIPs also helps in designing personalized medications profile for the patients in any population and matching individuals to different treatment options. Therefore, the prevalence of 65 variants located within 33 VIPs were investigated for the first time in the Jordanian population of Arab ethnicity. 2. Materials and Method 2.1. Study Subjects This study involved 500 unrelated Jordanian participants. The studied participants were 320 males (64%) and 180 females (36%). The average age (±SD) of individuals was 38.16 (±9.7) and 35.34 (±7.14) for males and females, respectively. A total of 10 ml from whole blood was collected from each participant for molecular analyses. This study was conducted in agreement with the Human ethics committee at Jordan University of Science and Technology (JUST). Written informed consent was obtained from all volunteers in the study. 2.2. DNA Extraction and Genotyping Genomic DNA was extracted from each blood sample using the Wizard® Genomic DNA Purification Kit (Promega Corporation, USA) according to the manufacturer’s instructions. The quality and quantity of the purified DNA were ascertained via agarose gel electrophoresis and the Nano-Drop ND-1000 UV-Vis Spectrophotometer (BioDrop, UK), respectively. A total of 65 single nucleotide polymorphisms (SNPs) were analyzed within 33 candidate genes using the MassARRAY (iPLEX GOLD) system (Sequenom, San Diego, CA, USA) following the manufacturer’s recommendation at the Australian Genome Research Facility (AGRF). In brief, Multiplex PCR was used to amplify Loci of candidate SNPs followed by a primer extension process (Mass EXTEND) resulting in allele-specific DNA products. Mass spectrometry was used for minisequencing reaction product analysis. Afterward, the extension PCR products were separated onto a 384 well spectroCHIP and placed into the MALDI-TOF (Matrix Assisted Laser Desorption/Ionization Time-of-Flight) mass spectrometer. Finally, a software system (SpectroTYPER-RT (RT for real-time) was used to analyze the results. 2.3. Basic characteristics of selected Pharmacogenomic VIP variants Genetic variants were chosen based on their clinical significance from previously published VIP variants associated with responsiveness to different drug treatments both at pharmacokinetic and
pharmacodynamic levels. For example, Table S1 shows a list of examples on VIP biomarkers and their associations with some therapeutic products from Drugs@FDA and their pharmacogenomics information
(https://www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomic-
biomarkers-drug-labeling). Table 1 shows the details of 65 candidate SNPs within 33 genes in addition to the quality control of the genotyping with genotype call rates ranging from 96.5% to 100%. Other data about the included SNPs such as chromosomal position, minor allele and location are also illustrated in Table 1. 2.4. Population variation data The allele counts variation data for other populations were obtained from Hap Map Project web site (https://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/): CHE: Chechens from Jordan, ASW: African ancestry in Southwest USA, CEU: Utah, USA residents with Northern and Western European ancestry from the CEPH collection, CHB: Han Chinese in Beijing, China, CDX: Chinese Dai in Xishuangbanna, China, GIH: Gujarati Indians in Houston, Texas, USA, GBR: British in England and Scotland, JPT: Japanese in Tokyo, Japan, LWK: Luhya in Webuye, Kenya, MXL: Mexican ancestry in Los Angeles, California, USA, TSI: Toscani in Italy, YRI: Yoruba in Ibadan, Nigeria, CAR: Circassian from Jordan (unpublished data), .ACB; African Caribbean’s in Barbados. In addition, the allele count data of populations around the world were obtained from the Exome Aggregation Consortium (ExAC) at http://exac.broadinstitute.org: African, East Asian, Latino, European (Non Finnish), and South Asian and European (Finnish). 2.5. Statistical analysis Statistical analyses were conducted using the Statistical Package for Social Sciences SPSS (version 25). The genotype and allele frequency was calculated and tested by performing the HardyWeinberg equilibrium equation (HWE).
Table 1: Basic characteristics of 65 variants within 33 pharmacogenes with their allele and genotype frequencies. Gene
SNP_ID
Positiona
SNP
SNP Location
Assay pass rateb
MTHFR
rs1801131
1:11794419
A>CMA
Missense Variant
97%
1:11796321
C>TMA
Missense Variant
99%
1:97450058
C>TMA
Splice Donor Variant
98%
2KB Upstream Variant
99%
rs1801133 DPYD
rs3918290
PTGS2
rs689466
1:186681619
G>AMA
SCN5A
rs7626962
3:38579416
G>A / G>T
Missense variant
99%
3:38603929
T>CMA
Missense variant
99%
rs6791924
3:38633208
G>AMA
Missense variant
99%
NR1I2
rs3814055
3:119781188
C>TMA
5 Prime UTR Variant
99%
P2RY12
rs2046934
3:151339854
GMA>A
Intron Variant
96%
P2RY1
rs1065776
3:152835839
C>TMA
Synonymous Variant
99%
3:152836568
A>GMA
Synonymous Variant
98%
Intron Variant
94%
rs1805124
rs701265 ADH1A
rs975833
4:99280582
G>CMA
ADH1B
rs2066702
4:99307860
G>AMA
Missense Variant
99%
rs1229984
4:99318162
TMA>C
Missense Variant
99%
rs698
4:99339632
T>CMA
Missense Variant
98%
rs17244841
5:75347030
A>TMA
Intron Variant
96%
rs3846662
5:75355259
AMA>G
Intron Variant
99%
5:75359673
T>GMA
Intron Variant
99%
rs1042713
5:148826877
G>AMA
Missense Variant
99%
rs1042714
5:148826910
GMA>C
Stop Gained
99%
rs1800888
5:148827322
C>TMA
Missense Variant
99%
Missense Variant
90%
ADH1C HMGCR
rs17238540 ADRB2
AHR
rs2066853
7:17339486
G>AMA
KCNH2
rs3815459
7:150947306
C>TMA
Intron Variant
95%
rs3807375
7:150970122
C>TMA
Intron Variant
99%
11:17388025
TMA>C
Stop Gained
98%
Missense Variant
99%
KCNJ11
rs5219
SLCO1B1
rs4149056
12:21178615
T>CMA
VKORC1
rs7294
16:31091000
C>TMA
3 Prime UTR Variant
99%
rs9934438
16:31093557
G>AMA
Intron Variant
99%
rs12659
21:45531642
AMA>G
Synonymous Variant
99%
rs1051266
21:45537880
T>CMA
Missense Variant
99%
rs1131596
21:45538002
G>AMA
Missense Variant
96%
Upstream Variant
99%
SLC19A1
CYP2J2
rs890293
1:59926822
C>AMA
CYP3A4
rs4986913
7:99760836
G>AMA
Missense Variant
97%
rs4986910
7:99760901
A>GMA
Missense Variant
99%
Missense Variant
99%
rs4986909
7:99762047
G>A
MA
rs12721634
7:99784038
A>G
Missense Variant
99%
7:99784473
CMA>T
Upstream Variant
99%
rs4986893
10:94780653
G>AMA
Stop Gained
99%
rs4244285
10:94781859
G>AMA
Synonymous Variant
97%
rs1799853
10:94942290
C>TMA
Missense Variant
99%
rs28399454
19:40845362
C>TMA
Missense Variant
99%
rs1801272
19:40848628
A>TMA
Missense Variant
99%
rs28399433
19:40850474
A>CMA
Upstream Variant
98%
19:41006936
G>TMA
Missense Variant
66%
rs28399499
19:41012316
T>CMA
Missense Variant
99%
rs59421388
22:42127608
C>TMA
Missense Variant
99%
rs28371725
22:42127803
C>TMA
Intron Variant
95%
rs61736512
22:42129132
C>TMA
Missense Variant
99%
rs28371706
22:42129770
G>AMA
Missense Variant
99%
rs5030656
22:4212817442128178
delTCT
Inframe Deletion
99%
rs4124874
2:233757013
TMA>G
Intronic variant
99%
rs10929302
2:23375713
G>AMA
Intronic variant
99%
rs4148323
2:233760498
G>AMA
Missense variant
99%
rs2740574 CYP2C19
CYP2C9 CYP2A6
CYP2B6
CYP2D6
UGT1A
rs3745274
COMT GSTP1
rs4680
22:19963748
G>AMA
Missense variant
99%
rs1695
11:67585218
A>GMA
Missense variant
99%
CYP3A5
rs1138272
11:67586108
C>TMA
Missense variant
99%
rs1045642
7:87509329
AMA>G / AMA>T
Synonymous Variant
99%
rs1128503
7:87550285
AMA>G
Synonymous Variant
97%
Missense Variant
99%
Missense Variant
99%
ABCB1
TPMT KCNH2 VDR
T>CMA
/ T>G G>AMA / G>C
rs1142345
6:18130687
rs12720441
7:150950216
rs7975232
12:47845054
CMA>A
Intron Variant
99%
rs3782905
12:47872384
G>CMA
Intron Variant
99%
rs1540339
12:47863543
C>TMA
Intron Variant
97%
12:47846052
C>A / C>G / C>TMA
Intron Variant
99%
rs1544410
Single Nucleotide 98% Variation a.Chromosome positions are based on NCBI Human Genome Assembly Build. b. Ratio of the number of discordant genotypes to the number of duplicates. MA: minor allele. rs11568820
12:47908762
C>TMA
3. Results 3.1. Allelic and genotypic frequencies of VIP pharmacogenomic variants Allele and genotype frequencies of the selected variants among 500 Jordanian participants are listed in table 2. In addition, polymorphisms were tested for Hardy-Weinberg Equilibrium (HWE), six SNPs (P2RY12 rs2046934, P2YRY1 rs701265, HMGCR rs3846662, ADRB2 rs1042713 and UGT1A1 rs4124874 and rs10929302) were found not fulfill the HWE equation (P-value <0.05) and were excluded from this study. In addition to ten monomorphic polymorphisms (DPYD rs3918290, CYP2D6 rs5030656 and CYP3A4 rs4986913, rs4986910, rs4986909 and rs12721634) were found in the Jordanian population and were excluded from the current study. Table 2: The minor allele frequencies and HWE p values for genes variants in Jordanian. Gene SNP_ID Alleles Allelic Frequency Genotypes Genotypic Frequency AA 0.47 C 0.33 rs1801131 CA 0.40 A 0.67 CC 0.13 MTHFR CC 0.51 T 0.29 rs1801133 CT 0.40 C 0.71 TT 0.09 CC 0.99 DPYD rs3918290 C 1.0 CT 0.01 CC 0.01 T 0.99 PTGS2 rs689466 CT 0.2 C 0.11 TT 0.79 G 0.99 GG 0.98 rs7626962 T 0.01 GT 0.02 CC 0.05 T 0.79 SCN5A rs1805124 CT 0.32 C 0.21 TT 0.63 G 0.98 GG 0.97 rs6791924 A 0.02 GT 0.03 CC 0.38 C 0.62 NR1I2 rs3814055 CT 0.47 T 0.38 TT 0.15 AA 0.89 A 0.94 P2RY12 rs2046934 AG 0.10 G 0.06 GG 0.01 C 0.95 CC 0.90 rs1065776 T 0.01 CT 0.1 P2RY1 AA 0.63 A 0.78 rs701265 AG 0.29 G 0.22 GG 0.08 CC 0.06 G 0.76 ADH1A rs975833 CG 0.36 C 0.24 GG 0.58 G 0.99 GA 0.03 rs2066702 A 0.01 GG 0.97 ADH1B CC 0.63 C 0.79 rs1229984 CT 0.32 T 0.21 TT 0.06
P- value 0.12 0.58 1 1 1 0.73 1 1 0.02 1 0.004 1 1 0.31
ADH1C
rs698 rs17244841
C T A T
0.24 0.76 0.92 0.08
rs3846662
G A
0.52 0.48
rs17238540
G T
0.08 0.92
rs1042713
G A
0.57 0.43
rs1042714
C G
0.76 0.24
rs1800888
C T
0.98 0.02
rs2066853
G A
0.86 0.14
rs3815459
C T
0.71 0.29
rs3807375
C T
0.53 0.47
KCNJ11
rs5219
C T
0.72 0.28
SLCO1B1
rs4149056
C T
rs7294
C T
0.66 0.34
rs9934438
G A
0.53 0.47
rs12659
G A
0.52 0.48
rs1051266
C T
0.48 0.52
rs1131596
A G
0.49 0.51
rs890293
C A
0.91 0.09
rs10264272
C T
0.97 0.03
HMGCR
ADRB2
AHR
KCNH2
0.22 0.78
VKORC1
SLC19A1
CYP2J2
CC CT TT AA AT TT AA GA GG TT GT GG GG GA AA CC CG GG CC CT GG GA AA CC CT TT CC CT TT CC CT TT CC CT TT CC CT TT GG GA AA GG GA AA CC CT TT AA AG GG AA CA CC CC CT
0.08 0.34 0.59 0.86 0.13 0.01 0.27 0.43 0.3 0.85 0.14 0.01 0.37 0.40 0.23 0.58 0.35 0.07 0.96 0.04 0.75 0.22 0.03 0.51 0.39 0.1 0.27 0.5 0.22 0.51 0.42 0.07 0.06 0.32 0.62 0.43 0.45 0.12 0.29 0.48 0.23 0.25 0.53 0.21 0.23 0.51 0.27 0.24 0.52 0.25 0.01 0.16 0.83 0.95 0.05
0.12 0.23 0.002 0.42 0.001 0.44 1 0.31 0.32 0.91 0.39 0.19
1
0.49 0.25 0.82 0.56 0.49 0.21
CYP3A5
rs776746
C T
0.88 0.12
CYP3A4
rs4986913 rs4986910 rs4986909 rs12721634
G A G A
1.0 1.0 1.0 1.0
rs2740574
T C
0.93 0.07
rs4986893
G
1.0
rs4244285
G A
0.91 0.09
rs1799853
C T
0.87 0.13
C T A A C G T T C T
0.99 0.01 1.0 0.96 0.04 0.87 0.13 1.0 0.99 0.01
C T
0.87 0.13
C T G A C/T/T
0.99 0.01 0.98 0.02 1.0
rs4124874
G T
0.51 0.49
rs10929302
G A
0.70 0.30
rs4148323
G
1.0
rs4680
G A
0.51 0.49
rs1695
A G
0.67 0.33
rs1138272
C T
0.92 0.08
rs1045642
G A
0.59 0.41
rs1128503
G
0.58
CYP2C19
CYP2C9
rs28399454 CYP2A6
rs1801272 rs28399433 rs3745274
CYP2B6
rs28399499 rs59421388 rs28371725
CYP2D6
rs61736512 rs28371706 rs5030656
UGT1A1
COMT
GSTP1 CYP3A5
ABCB1
CC CT TT GG AA GG AA CC TC TT GG AA GA GG CC CT TT CC CT AA AA AC GG GT TT CC TT CC CT TT CC CT GG GA GG GT TT GG GA AA GG GG GA AA AA AG GG CC CT TT GG GA AA GG
0.77 0.21 0.02 1.0 1.0 1.0 1.0 0.01 0.11 0.87 1.0 0.02 0.15 0.83 0.77 0.21 0.03 0.97 0.03 1.0 0.92 0.0.8 0.74 0.26 1.0 0.97 0.03 0.76 0.22 0.02 0.97 0.03 0.96 0.04 1.0 0.29 0.44 0.27 0.51 0.37 0.12 1.0 0.24 0.54 0.22 0.44 0.45 0.11 0.85 0.15 0.01 0.35 0.48 0.17 0.34
0.42 N/A N/A N/A N/A 0.04 N/A 0.09 0.13 1 N/A 1 0.05 N/A 1 0.44 1 1 N/A 0.04 0.04 N/A 0.21 1.0 1 0.91 1.0
TPMT KCNH2 VDR
A
0.42
T C G
0.99 0.01 1.0
rs1540339
C T
0.66 0.34
rs1544410
C T
0.62 0.38
rs2228570
C T
0.72 0.28
rs3782905
G C
0.69 0.31
rs7975232
A C
0.60 0.40
rs1142345 rs12720441
N/A: not applicable. HWE: HWE: Hardy-Weinberg equilibrium.
GA AA TT TC GG CC CT TT CC CT TT CC CT TT GG GC CC AA AC CC
0.49 0.34 0.98 0.02 1.0 0.45 0.42 0.12 0.39 0.45 0.16 0.52 0.39 0.08 0.50 0.39 0.11 0.37 0.47 0.17
1.0 NA 0.44 0.47 0.67 0.14 0.63
3.2. Pharmacogenomic VIP variants of Jordanian population compared to the eleven HapMap populations Using the χ2 test results of the chosen VIP variants, Jordanians showed a number of similarities and differences compared to the HapMap population. The comparison of minor allele frequencies (MAF) and the allelic distribution of the studied polymorphisms between Jordanian population and other populations as shown in Table 3. For example; rs689466 was distributed among Jordanian significantly different from CEU, GBR, LWK, MXL, and TSI populations (P-value < 0.05), but similar to the remaining studied populations.
Table 3: Significant variants within several genes in Jordanian compared to HapMap populations. Populations SNP ID JOR rs689466
0.11a
rs1805124
0.21a
rs3814055
0.38a
rs1065776
0.01a
rs1045642
0.41a
rs975833
0.24a
rs2066702
0.01a
rs1229984
0.21a 0.24
rs698
a
rs17244841
0.08a
ASW
CEU
CHB
CDX
GBR
GIH
JPT
LWK
MXL
TSI
YRI
ACB
0.13a 0.35b 0.55c 0.26a 1.8b 0.17c 0.29a 3.2b 0.07c 0.20a 21.4b 4e-6c 0.80a 21.4b 4e-6c 0.25a 0.18b 0.67c 0.20a N/Ab N/Ac 0.00a 31.9b 2e-8c 0.14a 6.4b 0.01c 0.10a 0.65b 0.42c
0.19a 8.2b 0.004c 0.18a 0.58b 0.44c 0.34a 1.2b 0.27c 0.05a 3.4b 0.03c 0.43a 14.4b 1e-4c 0.24a 0.03b 0.85c 0.00a 2.6b 0.10c 0.02a N/Ab N/Ac 0.47a N/Ab N/Ac 0.01a 9.7b 0.001c
0.47a N/Ab N/Ac 0.12a 6.6b 0.01c 0.27a 8.0b 0.004c 0.03a 1.0b 0.32c 0.63a 0.66b 0.41c 0.79a N/Ab N/Ac 0.00a 5.6b 0.02c 0.71a N/Ab N/Ac 0.05a N/Ab N/Ac 0.00a 16.7b 4e-5c
0.52a N/Ab N/Ac 0.07a 18.5b 3e-4c 0.15a 32.7b 1e-8c 0.02a 0.1b 0.81c 0.42a 0.11b 0.33c 0.75a N/Ab N/Ac 0.00a 2.9b 0.1c 0.63a N/Ab N/Ac 0.11a 12.7b 1e-3c 0.00a 15.1b 1e-4c
0.20a 8.9b 0.004c 0.22a 0.28b 0.60c 0.40a 0.23b 0.63c 0.02a 0.04b 0.84c 0.52a 7.7b 0.005c 0.24a 0.03b 0.87c 0.00a 2.5b 0.11c 0.01a N/Ab N/Ac 0.44a 25.6b 4.2e-7c 0.03a 5.5b 0.02c
0.13a 0.29b 0.59c 0.20a 0.01b 0.92c 0.42a 0.85b 0.35c 0.10a 14.9b 1e-4c 0.42a 15.3b 1e-4c 0.49a N/Ab N/Ac 0.00a 2.4b 0.12c 0.02a N/Ab N/Ac 0.28a 0.4b 0.50c 0.00a 16.7b 4e-5c
0.44a N/Ab N/Ac 0.13a 5.3b 0.02c 0.25a 11.0b 0.001c 0.07a 7.9b 5e-3c 0.42a 3.1b 0.8c 0.80a N/Ab N/Ac 0.00a 2.5b 0.11c 0.73a N/Ab N/Ac 0.07a 28.7b 8e-8c 0.02a 8.7b 0.003c
0.03a 12.0b 0.001c 0.30a 7.7b 0.005c 0.30a 3.9b 0.05c 0.21a N/Ab N/Ac 0.14a N/Ab N/Ac 0.19a 1.6b 0.20c 0.14a 2.8b 0.1c 0.00a N/Ab N/Ac 0.14a 28.7b 0.002c 0.08a 0.17b 0.67c
0.26a 18.5b 2e-5c 0.16a 1.2b 0.27c 0.33a 1.0b 0.34c 0.05a 2.4b 0.12c 0.47a 1.8b 0.17c 0.13a 6.5b 0.01c 0.03a N/Ab N/Ac 0.08a 11.0b 0.001c 0.28a 0.7b 0.39c 0.04a 2.3b 0.13c
0.20a 9.6b 0.002c 0.23a 0.66b 0.41c 0.36a 0.30b 0.58c 0.03a 0.9b 0.35c 0.53a 2.0b 0.15c 0.27a 1.0b 0.30c 0.00a 2.8b 01c 0.05a 29.5b 5e-8c 0.31a 3.2b 0.1c 0.03a 0.001b 0.97c
0.07a 2.5b 0.11c 0.32a 13b 3e-4c 0.27a 8.1b 0.004c 0.22a N/Ab N/Ac 0.90a N/Ab N/Ac 0.30a 3.4b 0.06c 0.28a N/Ab N/Ac 0.00a N/Ab N/Ac 0.07a 30.7b 3e-8c 0.09a 0.55b 0.46c
0.10a 0.1b 0.76c 0.28a 4.6b 0.03c 0.39a 0.1b 0.7c 0.20a N/Ab N/Ac 0.15a N/Ab N/Ac 0.28a 1.2b 0.37c 0.19a N/Ab N/Ac 0.01a N/Ab N/Ac 0.11a 16b 6e-5c 0.10a 1.4b 0.23c
rs1128503 rs17238540
0.42a 0.08 a
rs1142345
0.01a
rs1042714
0.24a
rs1800888
0.02a
rs2066853
0.14a
rs3815459
0.29a
rs3807375
0.53 a
rs5219
0.28a
rs4149056
0.22a
rs7294
0.34a
rs9934438
0.47a
rs12659
0.48a
0.80a 26.3b 2.9e-7c 0.10a 0.46b 0.49c 0.09a N/Ab N/Ac 0.12a 8.3b 0,004c 0.00a 2.5b 0.12c 0.34a 30.0b 4e-8c 0.42a 7.5b 0.001c 0.27a 26.6b 2.5e-7c 0.14a 10.3b 1e-3c 0.06a 15.9b 1e-4c 0.48a 7.8b 0.005c 0.15a N/Ab N/Ac 0.40a 2.4b 0.12c
0.55a 0.43b 0.51c 0.01a 10.4b 0.001c 0.03a 5.3b 0.02c 0.46a N/Ab N/Ac 0.02a 0.18b 0.67c 0.09a 2.8b 0.1c 0.20a 6.7b 0.01c 0.65a 9.5b 0.002c 0.38a 7.8b 0.005c 0.15a 5.3b 0.02c 0.31a 0.54b 0.46c 0.43a 1.0b 0.31c 0.42a 2.1b 0.14c
0.31a N/Ab N/Ac 0.00a 17.5b 3e-5c 0.005a 0.24b 0.62c 0.11a 17b 4e-5c 0.00a 4.1b 0.04c 0.37a N/Ab N/Ac 0.71a N/Ab N/Ac 0.25a N/Ab N/Ac 0.38a 7.3b 0.007c 0.14a 8.7b 3e-3c 0.04a N/Ab N/Ac 0.96a N/Ab N/Ac 0.49a 0.03b 0.86c
0.62a 23.8b 1e-6c 0.00a 15.8b 1e-4c 0.03a 5.9b 0.01c 0.10a 16,7b 4e-5c 0.00a 3.7b 0.05c 0.26a 14.8b 1e-4c 0.56a 4.6b 0.03c 0.26a N/Ab N/Ac 0.23a 2.0b 0.16c 0.14a 6.0b 0.01c 0.17a 20.7b 5e-6c 0.82a N/Ab N/Ac 0.53a 1.6b 0.20c
0.42a 0.01b 0.99c 0.02a 7.5b 0.01c 0.03a 6.1b 0.01c 0.39a 16.5b 4e-5c 0.02a 0.03b 0.85c 0.09a 1.7b 0.19c 0.15a 13.7b 2e-4c 0.70a 17.8b 2e-5c 0.26a 0.15b 0.70c 0.14a 5.5b 0.01c 0.42a 3.5b 0.06c 0.36a 7.2b 0.01c 0.39a 4.4b 0.04c
0.41a 13.6b 2e-4c 0.00a 17.5b 3e-5c 0.02a 3.2b 0.07c 0.23a 0.16b 0.69c 0.00a 4.1b 0.04c 0.12a 0.52b 0.47c 0.35a 1.7b 0.19c 0.61a 4.5b 0.03c 0.42a 13.8b 2e-4c 0.02a N/Ab N/Ac 0.67a N/Ab N/Ac 0.17a N/Ab N/Ac 0.36a 8.1b 0.004c
0.42a 20.4b 1e-5c 0.00a 17.5b 3e-5c 0.02a 1.4b 0.2c 0.06a 33.4b 1e-8c 0.00a 4.1b 0.04c 0.46a N/Ab N/Ac 0.80a N/Ab N/Ac 0.20a N/Ab N/Ac 0.33a 2.1b 0.14c 0.12a 10.3b 1e-3c 0.09a N/Ab N/Ac 0.90a N/Ab N/Ac 0.54a 2.6b 0.11c
0.89a N/Ab N/Ac 0.09a 0.25b 0.62c 0.11a N/Ab N/Ac 0.21a 0.72b 0.39c 0.00a 3.9b 0.05c 0.48a N/Ab N/Ac 0.39a 6.5b 0.01c 0.20a N/Ab N/Ac 0.01a N/Ab N/Ac 0.02a N/Ab N/Ac 0.43a 4.9b 0.02c 0.04a N/Ab N/Ac 0.53a 1.6b 0.21c
0.46a 1.0b 0.30c 0.04a 2.6b 0.11c 0.04a 10.3b 1e-3c 0.14a 6.2b 0.01c 0.00a 2.6b 0.11c 0.13a 0.01b 0.9c 0.39a 5.6b 0.02c 0.43a 3.9b 0.05c 0.41a 8.2b 4e-3c 0.08a 13.9b 2e-4c 0.35a 0.04b 0.83c 0.47a 0.00b 0.97c 0.34a 7.7b 0.005c
0.57a 0.01b 0.99c 0.03a 5.6b 0.02c 0.01a 0.53b 0.46c 0.14a 17.8b 2e-5c 0.01a 0.30b 0.59c 0.09a 2.1b 0.15c 0.23a 2.6b 0.11c 0.66a 11.3b 1e-3c 0.29a 0.03b 0.85c 0.21a 0.12b 0.72c 0.34a 0.02b 0.89c 0.48a 0.02b 0.85c 0.44a 0.76b 0.38c
0.88a N/Ab N/Ac 0.10a 0.63b 0.43c 0.06a 20.06b 7e-6c 0.12a 15.0b 1e-4c 0.00a 4.3b 0.04c 0.45a N/Ab N/Ac 0.33a 1.3b 0.25c 0.23a N/Ab N/Ac 0.00a N/Ab N/Ac 0.01a 18.8b 1e-5c 0.51a 20.0b 1e-5c 0.03a N/Ab N/Ac 0.48a 0.01b 0.94c
0.13a N/Ab N/Ac 0.09a 0.38b 0.54c 0.05a 15.1b 1e-4c 0.16a 5.4b 0.01c 0.00a 3.9b 0.05c 0.47a N/Ab N/Ac 0.31a 0.46b 0.50c 0.26a N/Ab N/Ac 0.06a N/Ab N/Ac 0.02a N/Ab N/Ac 0.46a 8.5b 0.003c 0.06a N/Ab N/Ac 0.55a 3.1b 0.07c
rs1051266
0.48a
rs1131596
0.49a
rs890293
0.09a
rs10264272
0.03a
rs776746
0.12a
rs2032582
0.39a
0.43a 0.8b 0.35c 0.38a 5.6b 0.02c 0.16a 6.6b 0.01c 0.05a 1.4b 0.23 c 0.68a N/Ab N/Ac 0.09a N/Ab N/Ac 0.22a 3.5b 0.05c
0.57a 4.9b 0.02c 0.57a 3.4b 0.06c 0.05a 2.8b 0.1c 0.00a 5.7b 0.01c 0.04a 11.0b 0.002c 0.42a 0.93b 0.33c 0.36a 16.2b 5e-5c
0.52a 1.2b 0.27c 0.52a 0.5b 0.46c 0.04a 4.1b 0.04C 0.00a 5.9b 0.01c 0.31a N/Ab N/Ac 0.41a 4.3b 0.03c 0.14a 20.5b 6e-6c
0.46a 0.18b 0.67c 0.46a 0.60b 0.44c 0.02a 11.0b 0.001c 0.00a 5.3b 0.02c 0.31a N/Ab N/Ac 0.46a 8.5b 0.003c 0.13a 23.1b 1e-6c
0.60a 7.9b 0.005c 0.60a 6.0b 0.01c 0.05a 2.8b 0.09 c 0.00a 5.2b 0.02c 0.05a 6.9b 0.01c 0.41a 0.22b 0.63c 0.22a04 .5b 0.03c
0.60a 9.9b 0.002c 0.61a 7.6b 0.005c 0.05a 2.4b 0.12c 0.00a 6.0b 0.01c 0.28a 26.2b 3e-7c 0.58a 29.7b 5e-8c 0.25a 2.2b 0.14c
0.46a 0.27b 0.60c 0.46a 0.77b 0.37c 0.02a 9.4b 0.002 c 0.0a 6.0b 0.01c 0.25a 20.0b 1e-5c 0.41a 4.6b 0.03c 0.09a N/Ab N/Ac
0.31a 18.0b 2e-5c 0.24a N/Ab N/Ac 0.14a 3.9b 0.04c 0.24a N/Ab N/Ac 0.88a N/Ab N/Ac 0.01a N/Ab N/Ac 0.23a 4.6b 0.03c
0.65a 15.0b 5e-4c 0.65a 10.0b 0.002c 0.03a 4.7b 0.03c 0.02a 0.1b 0.75c 0.23a 10.5b 1e-3c 0.40a 0.42b 0.52c 0.21a 4.7b 0.02c
0.55a 3.2b 0.07c 0.55a 0.2b 0.16c 0.05a 2.8b 0.1 c 0.01a 4.0b 0.04c 0.05a 8.8b 3e-3c 0.40a N/Ab N/Ac 0.33a 0.11b 0.73c 0.41a 0.12b 0.72c
0.33a 14.8b 1e-4c 0.28a 30.0b 4e-8c 0.15a 7.2b 0.01 c 0.17a N/Ab N/Ac 0.83a N/Ab N/Ac 0.0a 0.18b 0.66c 0.22a 6.2b 0.01c
0.31a 16.6b 5e-5c 0.28a 28.1b 1.2e-7c 0.10a 0.49b 0.48c 0.11a 23.0b 1e-6c 0.75a N/Ab N/Ac 0.04a N/Ab N/Ac 0.23a 3.7b 0.05c
0.40a N/Ab N/Ac
0.33a 3.0b 0.03c
rs3782905
0.31a
rs7975232
0.40a
0.37a 0.35b 0.55c
0.40a 0.02b 0.87c
0.72a N/Ab N/Ac
0.65a N/Ab N/Ac
0.54a 11.3b 7e-4c
0.48a 4.8b 0.03c
0.66a N/Ab N/Ac
0.28a 8.2b 0.003c
0.59a 16.6b 5e-5c
rs4244285
0.09a
0.14a 2.4b 0.12c
0.14a 3.7b 0.03c
0.33a N/Ab N/Ac
0.32a N/Ab N/Ac
0.21a 19.7b 1e-5c
0.17a 8.7b 0.003c
0.15a 5.2b 0.02c
0.04a 7.7b 0.005c
0.0a 266b 2.4e-7c
0.08a 2.2b 0.13c
0.05a 10.0b 0.001c
0.0a 29.7b 5e-8c
0.0a 28.3b 1e-7c
0.12a 1.2b 0.26c 0.10a 0.73b 0.39c
0.09a 0.001b 0.97c
0.13a
0.33a N/Ab N/Ac 0.0a 29.4b 6e-8c
0.26a N/Ab N/Ac
rs1799853
0.13a 2.4b 0.12c 0.15a 0.64b 0.42c
0.15a 0.84b 0.35c
0.0a 30.8b 3e-8c
0.03a 16.6b 4e-5c
rs28399454
0.01a
0.07a 8.7b 3e-3c
0.0a 3.9b 0.04c
0.0a 4.1b 0.04c
0.0a 3.7b 0.05c
0.0a 3.7b 0.05c
0.0a 4.1b 0.04c
0.0a 4.1b 0.04c
0.06a 5.6b 0.02c
0.0a 2.5b 0.1c
0.0a 4.3b 0.03c
0.13a N/Ab N/Ac
0.15a N/Ab N/Ac
rs28399433
0.04a
0.06a 7.4b 0.006c
0.05a 0.40b 0.52c
0.27a N/Ab N/Ac
0.18a N/Ab N/Ac
0.04a 0.1b 0.81c
0.19a N/Ab N/Ac
0.28a N/Ab N/Ac
0.09a 7.7b 0.005c
0.10a 8.3b 0.004c
0.06a 2.3b 0.13c
0.10a 11.4b 7e-3c
0.06a 1.7b 0.19c
0.05a 15.1b 1e-4c 0.06a 7.4b 0.006c 0.04a 1.7b 0.81c
0.00a 1.6b 0.20c 0.00a 3.3b 0.06c 0.0a 3.9b 0.04c
0.00a 1.7b 0.19c 0.00a 3.4b 0.06c 0.0a 4.1b 0.04c
0.00a 1.5b 0.21c 0.00a 3.1b 0.07c 0.0a 3.7b 0.05c
0.00a 1.5b 0.22c 0.005a 1.2b 0.26c 0.0a 3.6b 0.05c
0.00a 1.7b 0.19c 0.00a 3.4b 0.06c 0.0a 4.1b 0.04c
0.00a 1.7b 0.19c 0.00a 3.4b 0.06c 0.0a 3.9b 0.04c
0.03a 5.3b 0.02c 0.16a N/Ab N/Ac 0.09a N/Ab N/Ac
0.00a 1.1b 0.30c 0.19a N/Ab N/Ac 0.0a 2.6b 0.11c
0.00a 1.8b 0.18c 0.00a 3.5b 0.06c 0.0a 4.2b 0.04c
0.08a 33.0b 1e-8c 0.09a 23.9b 1e-6c 0.11a 22.0b 2e-6c
0.02a 14.0b 1e-4c
0.12a 0.23b 0.63c
0.03a 16.0b 6e-5c
0.08a 3.8b 0.05c
0.07a 5.2b 0.02c
0.15a 0.16b 0.70c
0.01a 28.5b 9e-8c
0.03a 16.6b 4e-5c
0.02a 14.8b 1e-4c
0.14a 0.14b 0.70c
0.01a 27.0b 1.7e-7c
0.04a 4.5b 0.03c 0.15a N/Ab N/Ac 0.72a N/Ab N/Ac 0.24a 3.8b 0.05c
0.0a 2.6b 0.10c 0.0a 3.6b 0.05c 0.22a 2.0b 0.15c 0.32a 0.23b 0.63c
0.0a 2.7b 0.1c 0.0a 3.8b 0.05c 0.42a 14.8b 1e-4c 0.73a N/Ab N/Ac
0.0a 2.5b 0.11c 0.0a 3.4b 0.06c 0.34a 3.0b 0.08c 0.70a N/Ab N/Ac
0.0a 2.4b 0.12c 0.0a 3.3b 0.06c 0.21a 2.5b 0.11c 0.41a 3.5b 0.06c
0.0a 2.7b 0.1c 0.0a 3.8b 0.05c 0.39a 9.6b 2e-3c 0.35a 0.11b 0.73c
0.0a 2.8b 0.1c 0.0a 3.8b 0.05c 0.45a 23.8b 1e-6c 0.75a N/Ab N/Acc
0.17a N/Ab N/Ac 0.19a N/Ab N/Ac 0.85a N/Ab N/Ac 0.13a 30.7b 3e-8c
0.0a 1.7b 0.19c 0.0a 2.3b 0.12c 0.15a 8.7b 0.003c 0.38a 0.9b 0.31c
0.0a 2.8b 0.1c 0.0a 4.0b 0.05c 0.25a 0.53b 0.46c 0.35a 0.23b 0.62 c
0.11a N/Ab N/Ac 0.25a N/Ab N/Ac 0.97a N/Ab N/Ac 0.20a 14.3b 1e-4c
0.06a N/Ab N/Ac
0.34a 1.7b 0.18 c
0.43a 0.44b 0.50c
0.12a N/Ab N/Acc
0.25a 14.2 b 1e-4c
0.19a 19.3b 1e-5c
0.41a 0.15b 0.70 c
0.29a 7.5b 0.006c
c
0.52a 0.85b 0.35c
0.43a 1.6b 0.20c
0.28a 26.4b 2.8e-7c
0.28a 24.3b 8e-7c
0.39a 3.4b 0.06c
0.45a 0.78b 0.37c
0.30a 21.6b 3e-6 c
0.36a 16.1b 1e-4 c
0.18a 8.5b 3e-3c
0.22a 0.13b 0.71c
0.31a 0.36b 0.55c
0.31a N/Ab N/Ac
0.10a 19.8b 1e-5c
0.51a 23.7b 1e-6 c
0.56a 1.1b 0.30c
0.29a 2.9b 0.081 c
0.39a 6.9b 0.008c
rs7626962
0.01a
rs6791924
0.02a
rs59421388
0.01a
rs28371725
0.13a
rs61736512
0.01a
rs28371706
0.02a
rs11568820
0.27a
rs154033900
0.34a
rs1544410
0.38a
0.27a 7.4b 0.006c
0.47a 2.9b 0.08c
0.04a N/Ab N/Ac
0.49a
0.27a 19.4b 1e-5 c
0.46a 0.33b 0.56c
0.31a 18.5b 2e-5c
rs4680
rs1695
0.33a
0.30a 7.0b 0.01c
0.45a 2.4b 0.12c
0.39a 16.4b 5e-5c
0.26a 27.8b 1.3e-7
0.11a N/Ab N/Ac 0.12a N/Ab N/Ac 0.08a 15.4b 1e-4c 0.05a 11.1b 1e-3c 0.09a 20.0b 4e-8c 0.20a N/Ab N/Ac 0.85a N/Ab N/Ac 0.38a 14.2b 1e-4c 0.31a 4.8b 0.04c
0.10a 0.02a 0.09a 0.00a 0.00a 0.05a 0.08a 0.00a 0.01a 0.05a 0.05a 0.00a b b a b b b b b b b 4.7 0.53 17.4 15.7 1.2 1.2 17.5 10.4 3.7b 1.8 18.2 13.9b rs1138272 c c c c c c c c c c c 0.03 0.47 3e-5 7e-5 0.27 0.26 3e-5 1e-3 0.05 0.17 2e-5 2e-4c aminor allele frequency, bChi-square value, cp-value. N/A: Not Applicable. ASW: African ancestry in Southwest USA, CEU: Utah, USA residents with Northern and Western European ancestry from the CEPH collection, CHB: Han Chinese in Beijing, China, CDX: Chinese Dai in Xishuangbanna, China, GIH: Gujarati Indians in Houston, Texas, USA, GBR: British in England and Scotland, JPT: Japanese in Tokyo, Japan, LWK: Luhya in Webuye, Kenya, MXL: Mexican ancestry in Los Angeles, California, USA, TSI: Toscani in Italy, YRI: Yoruba in Ibadan, Nigeria, ACB: African Caribbean’s in Barbados. 0.08a
3.3. Pharmacogenomic VIP variants of Jordanian population compared to six Exome Aggregation Consortium (ExAC) populations χ2 test were also applied to compare the allelic frequencies of the selected VIP variants in Jordanians and six ExAC populations. Table 4 shows the frequencies of the studied VIP variants within the selected genes among Jordanians and their comparison to the available frequency variants among six populations listed in the Exome Aggregation Consortium (ExAC) database. The results of this study revealed that various polymorphisms among Jordanian had significantly different frequencies compared to other populations. It is very clear from this study as shown in tables 3 and 4 that each studied variant has its own genotypic and allelic distribution among Jordanian population differs from other polymorphisms and these frequencies could either differ significantly from the certain population or similar to others. Table 4: Significant variants within the pharmacogenes in Jordanians compared to six ExAC populations worldwide. ExAC Populations SNP ID JOR
rs1805124
0.21a
rs7626962
0.01a
rs6791924
0.02a
rs7975232
0.40a
rs2032582
0.39a
rs1800888
0.02a
rs1142345
0.01a
rs1065776
0.01a
rs1045642
0.41a
African
East Asian
Latino
0.29a 18.3b 1e-5c 0.09a N/Ab N/Ac 0.1a N/Ab N/Ac 0.62a N/Ab N/Ac 0.91a N/Ab N/Ac 0.002a N/Ab N/Ac 0.05a 24.5b 7e-7c 0.19a N/Ab N/Ac 0.80a N/Ab N/Ac
0.1a N/Ab N/Ac 0.00a N/Ab N/Ac 0.00a N/Ab N/Ac 0.27a N/Ab N/Ac 0.46a 11.2b 8e-4c 0.00a N/Ab N/Ac 0.01a 1.1b 0.30c 0.04a 0.7b 0.38c 0.62a N/Ab N/Ac
0.21a 0.16b 0.68c 0.004a 1.9b 0.16c 0.006a 8.1b 0.004c 0.39a 0.11b 0.73c 0.54a N/Ab N/Ac 0.006a 16.7b 4e-5c 0.05a 20.1b 5e-6c 0.05a 0.01b 0.89c 0.54a N/Ab N/Ac
European ( Non Finnish)
South Asian
European (Finnish)
0.22a N/Ab N/Ac 0.0003a N/Ab N/Ac 0.001a N/Ab N/Ac 0.53a N/Ab N/Ac 0.55a N/Ab N/Ac 0.01a 25.5b 4e-7c 0.04a 15.6b 1e-4c 0.04a 1.5b 0.21c 0.47a 8.9b 0.002c
0.25a N/Ab N/Ac 0.00a N/Ab N/Ac 0.0003a N/Ab N/Ac 0.58a N/Ab N/Ac 0.35a 5.1b 0.02c 0.004a N/Ab N/Ac 0.02a 3.1b 0.07c 0.11a 21.6b 3e-6c 0.40a 0.40b 0.52c
0.20a 0.1b 0.79c 0.00a N/Ab N/Ac 0.0001a N/Ab N/Ac 0.55a N/Ab N/Ac 0.47a 12.5b 4e-4c 0.004a 1.2b 0.26c 0.03a 11.8b 6e-4c 0.06a 2.3b 0.12c 0.39a 1.0b 0.30c
rs2066702
0.01a
rs1229984
0.21a
rs698
0.24a
rs1128503
0.42a
rs1042714
0.24a
rs2066853
0.14a
rs3815459
0.29a
rs5219
0.28a
rs4149056
0.22a
rs12659
0.48a
rs1051266
0.48a
rs1131596
0.49a
rs10264272
0.03a
rs4244285
0.09a
rs1799853
0.13a
rs28399454
0.01a
rs28399433
0.04a
0.19a N/Ab N/Ac
0.0001a N/Ab N/Ac
0.01a 1.4b 0.23c
0.002a N/Ab N/Ac
0.002a N/Ab N/Ac
0.00a N/Ab N/Ac
0.99a N/Ab N/Ac 0.15a N/Ab N/Ac 0.80a N/Ab N/Ac 0.82a N/Ab N/Ac 0.45a N/Ab N/Ac 0.37a 7.9b 0.004c 0.94a N/Ab N/Ac 0.03a N/Ab N/Ac
0.27a 7.9b 0.004c 0.08a N/Ab N/Ac 0.36a 8.7b 0.003c 0.91a N/Ab N/Ac 0.37a N/Ab N/Ac 0.72a N/Ab N/Ac 0.64a N/Ab N/Ac 0.13a N/Ab N/Ac
0.94a N/Ab N/Ac 0.33a 19.5b 1e-5c 0.50a 13.5b 2e-4c 0.83a N/Ab N/Ac 0.12a 1.1b 0.29c 0.38a 3.9b 0.05c 0.61a N/Ab N/Ac 0.11a N/Ab N/Ac
0.95a N/Ab N/Ac 0.40a N/Ab N/Ac 0.57a N/Ab N/Ac 0.58a N/Ab N/Ac 0.10a 8.5b 0.003c 0.33a 3.0b 0.08c 0.63a N/Ab N/Ac 0.16a 17.3b 3e-5c
0.95a N/Ab N/Ac 0.32a 17.1b 3e-5c 0.39a 1.6b 0.20c 0.79a N/Ab N/Ac 0.14a 0.001b 0.97c 0.39a 22.4b 2e-6c 0.63a N/Ab N/Ac 0.05a N/Ab N/Ac
0.99a N/Ab N/Ac 0.51a N/Ab N/Ac 0.51a 18.4b 1e-5c 0.63a N/Ab N/Ac 0.11a 2.5b 0.11c 0.44a 1.5b 0.21c 0.53a N/Ab N/Ac 0.21a 0.27b 0.60c
0.55a 10.5b 1e-3c
0.49a 0.22b 0.63c
0.56a’ 0.03b 0.85c
0.58a 26.3b 2.9e-7c
0.64a N/Ab N/Ac
0.56a 13.9 1e-4c
0.42a 24.9b 5.8e-7c 0.36a N/Ab N/Ac
0.52a 0.03b 0.86c 0.51a 0.20b 0.64c
0.59a 11.5b 1e-3c 0.56a 6.2b 0.01c
0.60a 14.4b 1e-5c 0.59a 22.3b 2e-6c
0.61a 18.1b 2e-5c 0.58a 13.7b 2e-4c
0.60a 14.8b 1e-4c 0.61a 11.1b 1e-3c
0.12a N/Ab N/Ac
0.0a N/Ab N/Ac
0.01a 26.5b 2.6e-7c
0.001a N/Ab N/Ac
0.0002a N/Ab N/Ac
0.0a N/Ab N/Ac
0.18a 30.2b 4e-8c 0.02a N/Ab N/Ac
0.31a N/Ab N/Ac 0.0003a N/Ab N/Ac
0.10a 0.42b 0.52c 0.07a N/Ab N/Ac
0.15a 14.2b 1e-4c 0.13a 0.03b 0.86c
0.34a N/Ab N/Ac 0.05a N/Ab N/Ac
0.18a 30.5b 3e-8c 0.12a 0.78b 0.37c
0.11a 34.1b 1e-8c
0.0a N/Ab N/Ac
0.006a 11.7b 6e-4c
0.0004a N/Ab N/Ac
0.0a N/Ab N/Ac
0.0a N/Ab N/Ac
0.08a 2.7b 0.09c
0.23a N/Ab N/Ac
0.14a 27.2b 1e-7c
0.07a N/Ab N/Ac
0.14a 1.3b 0.25c
0.11a N/Ab N/Ac
rs59421388
0.01a
0.092a 24.2b 5e-7c
0.0001a N/Ab N/Ac
0.004a 23.3b 1e-6c
0.0003a N/Ab N/Ac
0.0001a N/Ab N/Ac
0.0a N/Ab N/Ac
rs28371725
0.13a
0.03a N/Ab N/Ac
0.03a N/Ab N/Ac
0.03a N/Ab N/Ac
0.09a 10.7b 0.001c
0.15a 0.004b 0.91c
0.03a N/Ab N/Ac
rs61736512
0.01a
0.10a N/Ab N/Ac
0.0005a N/Ab N/Ac
0.004a 11.3a 1e-3c
0.0003a N/Ab N/Ac
0.0002a 0.06a 0.80c
0.0a N/Ab N/Ac
rs28371706
0.02a
0.197a N/Ab N/Ac 0.32a N/Ab N/Ac 0.44a 28.4b 9e-8c
0.0a N/Ab N/Ac 0.28a N/Ab N/Ac 0.18a N/Ab N/Ac
0.007a 8.9b 0.003c 0.41a 15.5b 8e-5c 0.53a N/Ab N/Ac
0.002a N/Ab N/Ac 0.53a 3.8b 0.05c 0.31a 0.55b 0.45c
0.001a N/Ab N/Ac 0.45a 3.8b 0.05c 0.29a 5.6b 0.01c
0.0002a N/Ab N/Ac 0.57a 15.7b 7e-5c 0.27a 9.3b 0.002c
0.02a N/Ab N/Ac
0.0003a N/Ab N/Ac
0.03a N/Ab N/Ac
0.08a 0.01b 0.91c
0.07a 0.9b 0.34c
0.08a 0.11b 0.73c
rs4680 rs1695
0.33a
rs1138272
0.08a
aMinor
`
0.49a
allele frequency, bChi-square value, cp-value. N/A: Not Applicable
4. Discussion Recent advances in pharmacogenomics in the last few years will help the patients to be treated more efficiently with better response to medications (29, 30). The current study was conducted in the Jordanian population of Arab descent included 500 unrelated individuals to detect the allelic and genotypic distribution of 65 variants among 33 VIPs (table 1) and compared to other populations and different ethnic groups. One of the main large and diverse enzyme superfamily involved in the oxidative metabolism of various chemical substances like drugs is the cytochrome P450 (CYP) (31). The current study analyzed the following variants from CYP superfamily: CYP2J2 (rs890293, rs10264272), CYP3A5 (rs776746), CYP3A4 (rs4986913, rs4986910, rs4986909, rs12721634, rs2740574), CYP2C19 (rs4986893, rs4244285), CYP2C9 (rs1799853), CYP2A6 (rs28399454, rs1801272, rs28399433), CYP2B6 (rs3745274, rs28399499, rs59421388), CYP2D6 (rs28371725, rs61736512, rs28371706, rs5030656). The following SNPs rs4986913, rs4986910, rs4986909, rs12721634, rs4986893, rs1801272, rs28399499, and rs5030656have been found monomorphic polymorphisms. Two polymorphisms within UGT1A1 gene have been found from the current study (rs2740574, and rs10929302) did not fulfill the HWE (P- value < 0.05). It was found from the current study that the minor allele the frequency for these variants was almost the same with ASW (African ancestry in Southwest USA) and TSI (Toscani in Italy), but the frequency was significantly different from other compared populations with P-value < 0.05. One important member of this CYP superfamily is the CYP2C9 which approximately constitutes around 20 % of the total CYP protein with more than 60 variants have been reported for its gene (31, 32). CYP2C9 metabolizes about one-fourth of the clinically administrated medications (31, 33). Many studies reported that the rs4244285 variant was found at a high allelic frequency in south India (30%) and the lowest frequency was in Faroese (2.9%) (13), but the minor allele frequency (A) was 12% in Jordanian population which was the same allele frequency as rs689466, rs2066853, rs776746, rs1799853, and rs28371725 SNPs (Table 3). In contrast, rs4986893 was
monomorphic alleles in Jordanian population compared to the result of other studies on other populations that found that the rs4986893 at higher allelic frequencies in the Japanese (about 13%) but lower (0) among the European-Americans, South Africans, Greeks, Italians, and other populations (17, 26). Another important and abundant CYP enzyme that has a great effect on the metabolism of the drug within the different populations is the CYP3A4 (31). It has been identified more than 25 variants of CYP3A4 (1, 31). It was observed from different studies that the rs55785340 and rs4986910 allele frequencies of the CYP3A4 gene at a high rate at Caucasians population in comparison to rs12721627and rs28371759 that were observed at a high rate in the Chinese population (17, 20). In spite of this, all studied SNPs of CYP3A4 in the current study were found at a monomorphic feature in the Jordanian population. In addition to rs2740574 polymorphism that did not fulfill the HWE equation with P-value < 0.05. The current Jordanian study revealed that these variants: KCNH2 (rs3807375), VKORC1 (rs9934438), SLC19A1 (rs12659, rs1051266), UGT1A1 (rs4124874), COMT (s4680) were at a high level of allele frequency in the Jordanian population (approximately 50%) which differs from other frequencies in different populations because of many factors such as different mutations rate, natural selection, and migration (34, 35, 36, 37). Despite many studies reported that the rs8175347 and rs10929302 polymorphisms within UGT1A1 gene were associated with increased risk of diarrhea neutropenia for patients who treated with irinotecan from colorectal neoplasms (15, 38). The presented study revealed that two of the UGT1A1 variants (rs4124874 and rs10929302) were not in HWE and the third one (rs4148323) was at a monomorphic feature in the Jordanian population.
In conclusion, this study analyzed 65 variants among 33 various important pharmacogenes in 500 participants in the Jordanian population. Considering the results above, ethnicity is a significant factor for the distribution of allele and genotype frequencies between populations which can be used as great resources for future pharmacogenomic studies. Therefore, the presented study will enhance personalized medicine in clinical settings and choose the appropriate dose of drugs to increase the safety and efficacy of the medications for Jordanian individuals. Finally, this study could be used to match Jordanian individuals to different treatments potions based on the genetic profile of VIP pharmacogenomic variants. Funding This study was funded by the Deanship of Research (RN: 20180328), Jordan University of Science and Technology. References: 1. Jin T.; Xun X.; Shi X.; Yuan D.; Feng T.; Geng T.; et al. Genetic polymorphisms in very important pharmacogenomic (VIP) variants in the Tibetan population. Genet Mol Res. 2015; 14, 12497-504. 2. Tishkoff S.A.; Kidd K.K. Implications of biogeography of human populations for 'race' and medicine. Nature genetics. 2004; 36(11s), S21. 3. Giacomini K.M.; Brett C.M.; Altman R.B.; Benowitz N.; Dolan M.; Flockhart D.; et al. The pharmacogenetics research network: from SNP discovery to clinical drug response. Clinical Pharmacology & Therapeutics. 2007; 81(3), 328-45. 4. Ortega V.E.; Meyers D.A. Pharmacogenetics: implications of race and ethnicity on defining genetic profiles for personalized medicine. Journal of Allergy and Clinical Immunology. 2014; 133(1), 16-26. 5. Kim J.Y.; Cheong H.S.; Park T.J.; Shin H.J.; Seo D.W.; Na H.S.; et al. Screening for 392 polymorphisms in 141 pharmacogenes. Biomedical reports. 2014; 2(4), 463-76. 6. Burroughs V.J.; Maxey R.W.; Levy R.A. Racial and ethnic differences in response to medicines: towards individualized pharmaceutical treatment. Journal of the National Medical Association. 2002; 94(10 Suppl), 1. 7. Bulayeva K.B. Overview of genetic-epidemiological studies in ethnically and demographically diverse isolates of Dagestan, Northern Caucasus, Russia. Croatian medical journal. 2006; 47(4), 641-8.
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Abbreviations list ABCB1: ATP binding cassette subfamily B member 1 ADR: Adverse drug reactions ExAC: Exome Aggregation Consortium HapMap: Haplotype Map HWE: Hardy-Weinberg equilibrium NIH: National Institute of Health PharmGKB: Pharmacogenomics Knowledge Base PDs: Pharmacodynamics PKs: Drug pharmacokinetics QC: Quality control SNPs: Single nucleotide polymorphisms TPMT: Thiopurine S-methyltransferase VIP: Very important pharmacogene VDR: Vitamin D receptor COMT: Catechol O-Methyltransferase UGTs: Glucuronosyltransferases GSTs: Glutathione S-Transferases NATs: N-acetyltransferases SULTs: Sulfotransferases TPMT: Thiopurine S-Methyltransferase
Author contribution L.N.A.-E contributed to all research aspects from the design and implementation of the research, to the analysis of the results and to the writing of the manuscript.
Declaration of Interest The authors declare that they have no competing interests.
Resaerch Highlight
A total of 65 VIP variants located within 33 candidate genes were genotyped in Jordan for the first time. This study aimed to identify the allele frequencies of VIP variants in the Jordanian population. The difference in allele frequencies between the Jordanians and other populations was determined. This study will enhance personalized medicine in clinical settings.
S0378-1119(20)30077-9 https://doi.org/10.1016/j.gene.2020.144408 GENE 144408
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Please cite this article as: L.N. AL-Eitan, Pharmacogenomic landscape of VIP genetic variants in Jordanian Arabs and comparison with worldwide populations, Gene Gene (2020), doi: https://doi.org/10.1016/j.gene.2020.144408
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Pharmacogenomic landscape of VIP genetic variants in Jordanian Arabs and comparison with worldwide populations Laith N. AL-Eitan Department of Applied Biological Sciences, Jordan University of Science and Technology, Irbid 22110, Jordan Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid 22110, Jordan Correspondence: Dr. Laith N AL-Eitan at Department of Applied Biological Sciences, Jordan University of Science and Technology. P.O. Box 3030, Irbid 22110, Jordan. Tel: + (962) -2 7201000. Fax: + (962)-2-7201071. Email: [email protected].
Abstract The pharmacogenomics has lately become a focal field of research that investigates the influence of genetic variations of drug-metabolizing enzymes and their receptors and downstream proteins on the interindividual variability in response to medications and adverse drug reactions. Therefore, it is significantly important to study and analyze the variations in drug response between different ethnic groups and populations. The current study aimed to detect the distribution of the genotype and allele frequencies in several very important pharmacogenetic (VIP) gene polymorphisms in the Jordanian population of Arab descent. This study involved 500 unrelated Jordanian individuals of Arab descent. A total of 65 VIP variants located within 33 candidate genes were randomly selected from the PharmGKB database and genotyped using the MassARRAY (iPLEX GOLD) system. The chi-square test was used to evaluate the significant differences of minor allele and genotype frequencies between the Jordanian and other populations including CHE, ASW, CEU, CHB, CDX, GIH, GBR, JPT, LWK, MXL, TSI, YRI, CAR, and ACB. This study revealed six variants were not in Hardy Weinberg equilibrium (HWE) (P-value > 0.05) and ten SNPs showed monomorphic features. Most of the remaining forty-nine variant frequencies were significantly different from the compared ethnic groups (P-value < 0.05). The results of this study may be helpful to develop safer treatment by applying the concept of personalized medicine based on the profile of VIP pharmacogene variants of the Jordanian population of Arab descent. Key Words: Pharmacogenomics; Pharmacogenes; SNPs; Jordanian; Arab
1. Introduction: The genomic variations between individuals due to various types of single nucleotide polymorphisms play an important and vital role in drug pharmacokinetics (absorption, distribution, metabolism and excretion) and pharmacodynamics which significantly influence the dose and response of the treatment medications (1-4). Therefore, a better understanding of the variations in genetic material, drug response, efficacy, and toxicity for the same dose of medication will improve the effectiveness of drug therapy (3, 5-7). One of the main public health problems in the world is the variability in drug response between individuals which represents about 2.5% to 10% of all admissions in the hospitals (8-10). It has been reported that various cases of adverse drug reactions due to the variation in drug response which lead to many adverse effects on the patient’s health and the economic status for the individual and society (11-13). It is worth to mention that pharmacogenetics or pharmacogenomics is the study of drug response due to the effect of individual genes or total genomic expression, respectively (14, 15). Over 7 million common variants that affect drug metabolism have been identified worldwide in the last decade (16). A total of 0.2% to 4 % of these common SNPs are responsible for distinguishing the variation in responding to medications among different individuals and populations (7). Therefore, this fact provides the basis for the development and enhancement of personalized treatment (17). In total, there are more than 100 very important pharmacogenes (VIP) which control an individual’s response to drug treatments (18). These genes are translated into products that are involved in drug metabolism (19). Cytochromes P450 (CYPs) or CYP450 is a family of enzymes that are important for the clearance of various compounds, in addition to hormone synthesis and breakdown (20, 21). CYPs are the main enzymes involved in drug metabolism which account for about 75% of the total metabolism (22, 23). The Human Genome Project has identified more than 50 human genes coding for the various cytochrome P450 enzymes (24). Classical examples of this family are CYP1A2, CYP2C9, CYP2C19, and CYP3A4 (21). In addition to other significant variants that have been identified within VIPs as MTHFR, DPYD, PACERR, SCN5A, NR1I2, P2RY1, P2RY1, ADH1A, ADH1B, ADH1C, ABCB1, HMGCR, KCNH2, ADRB2, and others are clinically functional and involved in drug metabolism and excretion (25-28).
The genetic diversity of the pharmacogenes exhibits the variable response to drug treatments for an individual through different ethnic groups (1, 9). Studying and identifying the polymorphisms of VIPs also helps in designing personalized medications profile for the patients in any population and matching individuals to different treatment options. Therefore, the prevalence of 65 variants located within 33 VIPs were investigated for the first time in the Jordanian population of Arab ethnicity. 2. Materials and Method 2.1. Study Subjects This study involved 500 unrelated Jordanian participants. The studied participants were 320 males (64%) and 180 females (36%). The average age (±SD) of individuals was 38.16 (±9.7) and 35.34 (±7.14) for males and females, respectively. A total of 10 ml from whole blood was collected from each participant for molecular analyses. This study was conducted in agreement with the Human ethics committee at Jordan University of Science and Technology (JUST). Written informed consent was obtained from all volunteers in the study. 2.2. DNA Extraction and Genotyping Genomic DNA was extracted from each blood sample using the Wizard® Genomic DNA Purification Kit (Promega Corporation, USA) according to the manufacturer’s instructions. The quality and quantity of the purified DNA were ascertained via agarose gel electrophoresis and the Nano-Drop ND-1000 UV-Vis Spectrophotometer (BioDrop, UK), respectively. A total of 65 single nucleotide polymorphisms (SNPs) were analyzed within 33 candidate genes using the MassARRAY (iPLEX GOLD) system (Sequenom, San Diego, CA, USA) following the manufacturer’s recommendation at the Australian Genome Research Facility (AGRF). In brief, Multiplex PCR was used to amplify Loci of candidate SNPs followed by a primer extension process (Mass EXTEND) resulting in allele-specific DNA products. Mass spectrometry was used for minisequencing reaction product analysis. Afterward, the extension PCR products were separated onto a 384 well spectroCHIP and placed into the MALDI-TOF (Matrix Assisted Laser Desorption/Ionization Time-of-Flight) mass spectrometer. Finally, a software system (SpectroTYPER-RT (RT for real-time) was used to analyze the results. 2.3. Basic characteristics of selected Pharmacogenomic VIP variants Genetic variants were chosen based on their clinical significance from previously published VIP variants associated with responsiveness to different drug treatments both at pharmacokinetic and
pharmacodynamic levels. For example, Table S1 shows a list of examples on VIP biomarkers and their associations with some therapeutic products from Drugs@FDA and their pharmacogenomics information
(https://www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomic-
biomarkers-drug-labeling). Table 1 shows the details of 65 candidate SNPs within 33 genes in addition to the quality control of the genotyping with genotype call rates ranging from 96.5% to 100%. Other data about the included SNPs such as chromosomal position, minor allele and location are also illustrated in Table 1. 2.4. Population variation data The allele counts variation data for other populations were obtained from Hap Map Project web site (https://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/): CHE: Chechens from Jordan, ASW: African ancestry in Southwest USA, CEU: Utah, USA residents with Northern and Western European ancestry from the CEPH collection, CHB: Han Chinese in Beijing, China, CDX: Chinese Dai in Xishuangbanna, China, GIH: Gujarati Indians in Houston, Texas, USA, GBR: British in England and Scotland, JPT: Japanese in Tokyo, Japan, LWK: Luhya in Webuye, Kenya, MXL: Mexican ancestry in Los Angeles, California, USA, TSI: Toscani in Italy, YRI: Yoruba in Ibadan, Nigeria, CAR: Circassian from Jordan (unpublished data), .ACB; African Caribbean’s in Barbados. In addition, the allele count data of populations around the world were obtained from the Exome Aggregation Consortium (ExAC) at http://exac.broadinstitute.org: African, East Asian, Latino, European (Non Finnish), and South Asian and European (Finnish). 2.5. Statistical analysis Statistical analyses were conducted using the Statistical Package for Social Sciences SPSS (version 25). The genotype and allele frequency was calculated and tested by performing the HardyWeinberg equilibrium equation (HWE).
Table 1: Basic characteristics of 65 variants within 33 pharmacogenes with their allele and genotype frequencies. Gene
SNP_ID
Positiona
SNP
SNP Location
Assay pass rateb
MTHFR
rs1801131
1:11794419
A>CMA
Missense Variant
97%
1:11796321
C>TMA
Missense Variant
99%
1:97450058
C>TMA
Splice Donor Variant
98%
2KB Upstream Variant
99%
rs1801133 DPYD
rs3918290
PTGS2
rs689466
1:186681619
G>AMA
SCN5A
rs7626962
3:38579416
G>A / G>T
Missense variant
99%
3:38603929
T>CMA
Missense variant
99%
rs6791924
3:38633208
G>AMA
Missense variant
99%
NR1I2
rs3814055
3:119781188
C>TMA
5 Prime UTR Variant
99%
P2RY12
rs2046934
3:151339854
GMA>A
Intron Variant
96%
P2RY1
rs1065776
3:152835839
C>TMA
Synonymous Variant
99%
3:152836568
A>GMA
Synonymous Variant
98%
Intron Variant
94%
rs1805124
rs701265 ADH1A
rs975833
4:99280582
G>CMA
ADH1B
rs2066702
4:99307860
G>AMA
Missense Variant
99%
rs1229984
4:99318162
TMA>C
Missense Variant
99%
rs698
4:99339632
T>CMA
Missense Variant
98%
rs17244841
5:75347030
A>TMA
Intron Variant
96%
rs3846662
5:75355259
AMA>G
Intron Variant
99%
5:75359673
T>GMA
Intron Variant
99%
rs1042713
5:148826877
G>AMA
Missense Variant
99%
rs1042714
5:148826910
GMA>C
Stop Gained
99%
rs1800888
5:148827322
C>TMA
Missense Variant
99%
Missense Variant
90%
ADH1C HMGCR
rs17238540 ADRB2
AHR
rs2066853
7:17339486
G>AMA
KCNH2
rs3815459
7:150947306
C>TMA
Intron Variant
95%
rs3807375
7:150970122
C>TMA
Intron Variant
99%
11:17388025
TMA>C
Stop Gained
98%
Missense Variant
99%
KCNJ11
rs5219
SLCO1B1
rs4149056
12:21178615
T>CMA
VKORC1
rs7294
16:31091000
C>TMA
3 Prime UTR Variant
99%
rs9934438
16:31093557
G>AMA
Intron Variant
99%
rs12659
21:45531642
AMA>G
Synonymous Variant
99%
rs1051266
21:45537880
T>CMA
Missense Variant
99%
rs1131596
21:45538002
G>AMA
Missense Variant
96%
Upstream Variant
99%
SLC19A1
CYP2J2
rs890293
1:59926822
C>AMA
CYP3A4
rs4986913
7:99760836
G>AMA
Missense Variant
97%
rs4986910
7:99760901
A>GMA
Missense Variant
99%
Missense Variant
99%
rs4986909
7:99762047
G>A
MA
rs12721634
7:99784038
A>G
Missense Variant
99%
7:99784473
CMA>T
Upstream Variant
99%
rs4986893
10:94780653
G>AMA
Stop Gained
99%
rs4244285
10:94781859
G>AMA
Synonymous Variant
97%
rs1799853
10:94942290
C>TMA
Missense Variant
99%
rs28399454
19:40845362
C>TMA
Missense Variant
99%
rs1801272
19:40848628
A>TMA
Missense Variant
99%
rs28399433
19:40850474
A>CMA
Upstream Variant
98%
19:41006936
G>TMA
Missense Variant
66%
rs28399499
19:41012316
T>CMA
Missense Variant
99%
rs59421388
22:42127608
C>TMA
Missense Variant
99%
rs28371725
22:42127803
C>TMA
Intron Variant
95%
rs61736512
22:42129132
C>TMA
Missense Variant
99%
rs28371706
22:42129770
G>AMA
Missense Variant
99%
rs5030656
22:4212817442128178
delTCT
Inframe Deletion
99%
rs4124874
2:233757013
TMA>G
Intronic variant
99%
rs10929302
2:23375713
G>AMA
Intronic variant
99%
rs4148323
2:233760498
G>AMA
Missense variant
99%
rs2740574 CYP2C19
CYP2C9 CYP2A6
CYP2B6
CYP2D6
UGT1A
rs3745274
COMT GSTP1
rs4680
22:19963748
G>AMA
Missense variant
99%
rs1695
11:67585218
A>GMA
Missense variant
99%
CYP3A5
rs1138272
11:67586108
C>TMA
Missense variant
99%
rs1045642
7:87509329
AMA>G / AMA>T
Synonymous Variant
99%
rs1128503
7:87550285
AMA>G
Synonymous Variant
97%
Missense Variant
99%
Missense Variant
99%
ABCB1
TPMT KCNH2 VDR
T>CMA
/ T>G G>AMA / G>C
rs1142345
6:18130687
rs12720441
7:150950216
rs7975232
12:47845054
CMA>A
Intron Variant
99%
rs3782905
12:47872384
G>CMA
Intron Variant
99%
rs1540339
12:47863543
C>TMA
Intron Variant
97%
12:47846052
C>A / C>G / C>TMA
Intron Variant
99%
rs1544410
Single Nucleotide 98% Variation a.Chromosome positions are based on NCBI Human Genome Assembly Build. b. Ratio of the number of discordant genotypes to the number of duplicates. MA: minor allele. rs11568820
12:47908762
C>TMA
3. Results 3.1. Allelic and genotypic frequencies of VIP pharmacogenomic variants Allele and genotype frequencies of the selected variants among 500 Jordanian participants are listed in table 2. In addition, polymorphisms were tested for Hardy-Weinberg Equilibrium (HWE), six SNPs (P2RY12 rs2046934, P2YRY1 rs701265, HMGCR rs3846662, ADRB2 rs1042713 and UGT1A1 rs4124874 and rs10929302) were found not fulfill the HWE equation (P-value <0.05) and were excluded from this study. In addition to ten monomorphic polymorphisms (DPYD rs3918290, CYP2D6 rs5030656 and CYP3A4 rs4986913, rs4986910, rs4986909 and rs12721634) were found in the Jordanian population and were excluded from the current study. Table 2: The minor allele frequencies and HWE p values for genes variants in Jordanian. Gene SNP_ID Alleles Allelic Frequency Genotypes Genotypic Frequency AA 0.47 C 0.33 rs1801131 CA 0.40 A 0.67 CC 0.13 MTHFR CC 0.51 T 0.29 rs1801133 CT 0.40 C 0.71 TT 0.09 CC 0.99 DPYD rs3918290 C 1.0 CT 0.01 CC 0.01 T 0.99 PTGS2 rs689466 CT 0.2 C 0.11 TT 0.79 G 0.99 GG 0.98 rs7626962 T 0.01 GT 0.02 CC 0.05 T 0.79 SCN5A rs1805124 CT 0.32 C 0.21 TT 0.63 G 0.98 GG 0.97 rs6791924 A 0.02 GT 0.03 CC 0.38 C 0.62 NR1I2 rs3814055 CT 0.47 T 0.38 TT 0.15 AA 0.89 A 0.94 P2RY12 rs2046934 AG 0.10 G 0.06 GG 0.01 C 0.95 CC 0.90 rs1065776 T 0.01 CT 0.1 P2RY1 AA 0.63 A 0.78 rs701265 AG 0.29 G 0.22 GG 0.08 CC 0.06 G 0.76 ADH1A rs975833 CG 0.36 C 0.24 GG 0.58 G 0.99 GA 0.03 rs2066702 A 0.01 GG 0.97 ADH1B CC 0.63 C 0.79 rs1229984 CT 0.32 T 0.21 TT 0.06
P- value 0.12 0.58 1 1 1 0.73 1 1 0.02 1 0.004 1 1 0.31
ADH1C
rs698 rs17244841
C T A T
0.24 0.76 0.92 0.08
rs3846662
G A
0.52 0.48
rs17238540
G T
0.08 0.92
rs1042713
G A
0.57 0.43
rs1042714
C G
0.76 0.24
rs1800888
C T
0.98 0.02
rs2066853
G A
0.86 0.14
rs3815459
C T
0.71 0.29
rs3807375
C T
0.53 0.47
KCNJ11
rs5219
C T
0.72 0.28
SLCO1B1
rs4149056
C T
rs7294
C T
0.66 0.34
rs9934438
G A
0.53 0.47
rs12659
G A
0.52 0.48
rs1051266
C T
0.48 0.52
rs1131596
A G
0.49 0.51
rs890293
C A
0.91 0.09
rs10264272
C T
0.97 0.03
HMGCR
ADRB2
AHR
KCNH2
0.22 0.78
VKORC1
SLC19A1
CYP2J2
CC CT TT AA AT TT AA GA GG TT GT GG GG GA AA CC CG GG CC CT GG GA AA CC CT TT CC CT TT CC CT TT CC CT TT CC CT TT GG GA AA GG GA AA CC CT TT AA AG GG AA CA CC CC CT
0.08 0.34 0.59 0.86 0.13 0.01 0.27 0.43 0.3 0.85 0.14 0.01 0.37 0.40 0.23 0.58 0.35 0.07 0.96 0.04 0.75 0.22 0.03 0.51 0.39 0.1 0.27 0.5 0.22 0.51 0.42 0.07 0.06 0.32 0.62 0.43 0.45 0.12 0.29 0.48 0.23 0.25 0.53 0.21 0.23 0.51 0.27 0.24 0.52 0.25 0.01 0.16 0.83 0.95 0.05
0.12 0.23 0.002 0.42 0.001 0.44 1 0.31 0.32 0.91 0.39 0.19
1
0.49 0.25 0.82 0.56 0.49 0.21
CYP3A5
rs776746
C T
0.88 0.12
CYP3A4
rs4986913 rs4986910 rs4986909 rs12721634
G A G A
1.0 1.0 1.0 1.0
rs2740574
T C
0.93 0.07
rs4986893
G
1.0
rs4244285
G A
0.91 0.09
rs1799853
C T
0.87 0.13
C T A A C G T T C T
0.99 0.01 1.0 0.96 0.04 0.87 0.13 1.0 0.99 0.01
C T
0.87 0.13
C T G A C/T/T
0.99 0.01 0.98 0.02 1.0
rs4124874
G T
0.51 0.49
rs10929302
G A
0.70 0.30
rs4148323
G
1.0
rs4680
G A
0.51 0.49
rs1695
A G
0.67 0.33
rs1138272
C T
0.92 0.08
rs1045642
G A
0.59 0.41
rs1128503
G
0.58
CYP2C19
CYP2C9
rs28399454 CYP2A6
rs1801272 rs28399433 rs3745274
CYP2B6
rs28399499 rs59421388 rs28371725
CYP2D6
rs61736512 rs28371706 rs5030656
UGT1A1
COMT
GSTP1 CYP3A5
ABCB1
CC CT TT GG AA GG AA CC TC TT GG AA GA GG CC CT TT CC CT AA AA AC GG GT TT CC TT CC CT TT CC CT GG GA GG GT TT GG GA AA GG GG GA AA AA AG GG CC CT TT GG GA AA GG
0.77 0.21 0.02 1.0 1.0 1.0 1.0 0.01 0.11 0.87 1.0 0.02 0.15 0.83 0.77 0.21 0.03 0.97 0.03 1.0 0.92 0.0.8 0.74 0.26 1.0 0.97 0.03 0.76 0.22 0.02 0.97 0.03 0.96 0.04 1.0 0.29 0.44 0.27 0.51 0.37 0.12 1.0 0.24 0.54 0.22 0.44 0.45 0.11 0.85 0.15 0.01 0.35 0.48 0.17 0.34
0.42 N/A N/A N/A N/A 0.04 N/A 0.09 0.13 1 N/A 1 0.05 N/A 1 0.44 1 1 N/A 0.04 0.04 N/A 0.21 1.0 1 0.91 1.0
TPMT KCNH2 VDR
A
0.42
T C G
0.99 0.01 1.0
rs1540339
C T
0.66 0.34
rs1544410
C T
0.62 0.38
rs2228570
C T
0.72 0.28
rs3782905
G C
0.69 0.31
rs7975232
A C
0.60 0.40
rs1142345 rs12720441
N/A: not applicable. HWE: HWE: Hardy-Weinberg equilibrium.
GA AA TT TC GG CC CT TT CC CT TT CC CT TT GG GC CC AA AC CC
0.49 0.34 0.98 0.02 1.0 0.45 0.42 0.12 0.39 0.45 0.16 0.52 0.39 0.08 0.50 0.39 0.11 0.37 0.47 0.17
1.0 NA 0.44 0.47 0.67 0.14 0.63
3.2. Pharmacogenomic VIP variants of Jordanian population compared to the eleven HapMap populations Using the χ2 test results of the chosen VIP variants, Jordanians showed a number of similarities and differences compared to the HapMap population. The comparison of minor allele frequencies (MAF) and the allelic distribution of the studied polymorphisms between Jordanian population and other populations as shown in Table 3. For example; rs689466 was distributed among Jordanian significantly different from CEU, GBR, LWK, MXL, and TSI populations (P-value < 0.05), but similar to the remaining studied populations.
Table 3: Significant variants within several genes in Jordanian compared to HapMap populations. Populations SNP ID JOR rs689466
0.11a
rs1805124
0.21a
rs3814055
0.38a
rs1065776
0.01a
rs1045642
0.41a
rs975833
0.24a
rs2066702
0.01a
rs1229984
0.21a 0.24
rs698
a
rs17244841
0.08a
ASW
CEU
CHB
CDX
GBR
GIH
JPT
LWK
MXL
TSI
YRI
ACB
0.13a 0.35b 0.55c 0.26a 1.8b 0.17c 0.29a 3.2b 0.07c 0.20a 21.4b 4e-6c 0.80a 21.4b 4e-6c 0.25a 0.18b 0.67c 0.20a N/Ab N/Ac 0.00a 31.9b 2e-8c 0.14a 6.4b 0.01c 0.10a 0.65b 0.42c
0.19a 8.2b 0.004c 0.18a 0.58b 0.44c 0.34a 1.2b 0.27c 0.05a 3.4b 0.03c 0.43a 14.4b 1e-4c 0.24a 0.03b 0.85c 0.00a 2.6b 0.10c 0.02a N/Ab N/Ac 0.47a N/Ab N/Ac 0.01a 9.7b 0.001c
0.47a N/Ab N/Ac 0.12a 6.6b 0.01c 0.27a 8.0b 0.004c 0.03a 1.0b 0.32c 0.63a 0.66b 0.41c 0.79a N/Ab N/Ac 0.00a 5.6b 0.02c 0.71a N/Ab N/Ac 0.05a N/Ab N/Ac 0.00a 16.7b 4e-5c
0.52a N/Ab N/Ac 0.07a 18.5b 3e-4c 0.15a 32.7b 1e-8c 0.02a 0.1b 0.81c 0.42a 0.11b 0.33c 0.75a N/Ab N/Ac 0.00a 2.9b 0.1c 0.63a N/Ab N/Ac 0.11a 12.7b 1e-3c 0.00a 15.1b 1e-4c
0.20a 8.9b 0.004c 0.22a 0.28b 0.60c 0.40a 0.23b 0.63c 0.02a 0.04b 0.84c 0.52a 7.7b 0.005c 0.24a 0.03b 0.87c 0.00a 2.5b 0.11c 0.01a N/Ab N/Ac 0.44a 25.6b 4.2e-7c 0.03a 5.5b 0.02c
0.13a 0.29b 0.59c 0.20a 0.01b 0.92c 0.42a 0.85b 0.35c 0.10a 14.9b 1e-4c 0.42a 15.3b 1e-4c 0.49a N/Ab N/Ac 0.00a 2.4b 0.12c 0.02a N/Ab N/Ac 0.28a 0.4b 0.50c 0.00a 16.7b 4e-5c
0.44a N/Ab N/Ac 0.13a 5.3b 0.02c 0.25a 11.0b 0.001c 0.07a 7.9b 5e-3c 0.42a 3.1b 0.8c 0.80a N/Ab N/Ac 0.00a 2.5b 0.11c 0.73a N/Ab N/Ac 0.07a 28.7b 8e-8c 0.02a 8.7b 0.003c
0.03a 12.0b 0.001c 0.30a 7.7b 0.005c 0.30a 3.9b 0.05c 0.21a N/Ab N/Ac 0.14a N/Ab N/Ac 0.19a 1.6b 0.20c 0.14a 2.8b 0.1c 0.00a N/Ab N/Ac 0.14a 28.7b 0.002c 0.08a 0.17b 0.67c
0.26a 18.5b 2e-5c 0.16a 1.2b 0.27c 0.33a 1.0b 0.34c 0.05a 2.4b 0.12c 0.47a 1.8b 0.17c 0.13a 6.5b 0.01c 0.03a N/Ab N/Ac 0.08a 11.0b 0.001c 0.28a 0.7b 0.39c 0.04a 2.3b 0.13c
0.20a 9.6b 0.002c 0.23a 0.66b 0.41c 0.36a 0.30b 0.58c 0.03a 0.9b 0.35c 0.53a 2.0b 0.15c 0.27a 1.0b 0.30c 0.00a 2.8b 01c 0.05a 29.5b 5e-8c 0.31a 3.2b 0.1c 0.03a 0.001b 0.97c
0.07a 2.5b 0.11c 0.32a 13b 3e-4c 0.27a 8.1b 0.004c 0.22a N/Ab N/Ac 0.90a N/Ab N/Ac 0.30a 3.4b 0.06c 0.28a N/Ab N/Ac 0.00a N/Ab N/Ac 0.07a 30.7b 3e-8c 0.09a 0.55b 0.46c
0.10a 0.1b 0.76c 0.28a 4.6b 0.03c 0.39a 0.1b 0.7c 0.20a N/Ab N/Ac 0.15a N/Ab N/Ac 0.28a 1.2b 0.37c 0.19a N/Ab N/Ac 0.01a N/Ab N/Ac 0.11a 16b 6e-5c 0.10a 1.4b 0.23c
rs1128503 rs17238540
0.42a 0.08 a
rs1142345
0.01a
rs1042714
0.24a
rs1800888
0.02a
rs2066853
0.14a
rs3815459
0.29a
rs3807375
0.53 a
rs5219
0.28a
rs4149056
0.22a
rs7294
0.34a
rs9934438
0.47a
rs12659
0.48a
0.80a 26.3b 2.9e-7c 0.10a 0.46b 0.49c 0.09a N/Ab N/Ac 0.12a 8.3b 0,004c 0.00a 2.5b 0.12c 0.34a 30.0b 4e-8c 0.42a 7.5b 0.001c 0.27a 26.6b 2.5e-7c 0.14a 10.3b 1e-3c 0.06a 15.9b 1e-4c 0.48a 7.8b 0.005c 0.15a N/Ab N/Ac 0.40a 2.4b 0.12c
0.55a 0.43b 0.51c 0.01a 10.4b 0.001c 0.03a 5.3b 0.02c 0.46a N/Ab N/Ac 0.02a 0.18b 0.67c 0.09a 2.8b 0.1c 0.20a 6.7b 0.01c 0.65a 9.5b 0.002c 0.38a 7.8b 0.005c 0.15a 5.3b 0.02c 0.31a 0.54b 0.46c 0.43a 1.0b 0.31c 0.42a 2.1b 0.14c
0.31a N/Ab N/Ac 0.00a 17.5b 3e-5c 0.005a 0.24b 0.62c 0.11a 17b 4e-5c 0.00a 4.1b 0.04c 0.37a N/Ab N/Ac 0.71a N/Ab N/Ac 0.25a N/Ab N/Ac 0.38a 7.3b 0.007c 0.14a 8.7b 3e-3c 0.04a N/Ab N/Ac 0.96a N/Ab N/Ac 0.49a 0.03b 0.86c
0.62a 23.8b 1e-6c 0.00a 15.8b 1e-4c 0.03a 5.9b 0.01c 0.10a 16,7b 4e-5c 0.00a 3.7b 0.05c 0.26a 14.8b 1e-4c 0.56a 4.6b 0.03c 0.26a N/Ab N/Ac 0.23a 2.0b 0.16c 0.14a 6.0b 0.01c 0.17a 20.7b 5e-6c 0.82a N/Ab N/Ac 0.53a 1.6b 0.20c
0.42a 0.01b 0.99c 0.02a 7.5b 0.01c 0.03a 6.1b 0.01c 0.39a 16.5b 4e-5c 0.02a 0.03b 0.85c 0.09a 1.7b 0.19c 0.15a 13.7b 2e-4c 0.70a 17.8b 2e-5c 0.26a 0.15b 0.70c 0.14a 5.5b 0.01c 0.42a 3.5b 0.06c 0.36a 7.2b 0.01c 0.39a 4.4b 0.04c
0.41a 13.6b 2e-4c 0.00a 17.5b 3e-5c 0.02a 3.2b 0.07c 0.23a 0.16b 0.69c 0.00a 4.1b 0.04c 0.12a 0.52b 0.47c 0.35a 1.7b 0.19c 0.61a 4.5b 0.03c 0.42a 13.8b 2e-4c 0.02a N/Ab N/Ac 0.67a N/Ab N/Ac 0.17a N/Ab N/Ac 0.36a 8.1b 0.004c
0.42a 20.4b 1e-5c 0.00a 17.5b 3e-5c 0.02a 1.4b 0.2c 0.06a 33.4b 1e-8c 0.00a 4.1b 0.04c 0.46a N/Ab N/Ac 0.80a N/Ab N/Ac 0.20a N/Ab N/Ac 0.33a 2.1b 0.14c 0.12a 10.3b 1e-3c 0.09a N/Ab N/Ac 0.90a N/Ab N/Ac 0.54a 2.6b 0.11c
0.89a N/Ab N/Ac 0.09a 0.25b 0.62c 0.11a N/Ab N/Ac 0.21a 0.72b 0.39c 0.00a 3.9b 0.05c 0.48a N/Ab N/Ac 0.39a 6.5b 0.01c 0.20a N/Ab N/Ac 0.01a N/Ab N/Ac 0.02a N/Ab N/Ac 0.43a 4.9b 0.02c 0.04a N/Ab N/Ac 0.53a 1.6b 0.21c
0.46a 1.0b 0.30c 0.04a 2.6b 0.11c 0.04a 10.3b 1e-3c 0.14a 6.2b 0.01c 0.00a 2.6b 0.11c 0.13a 0.01b 0.9c 0.39a 5.6b 0.02c 0.43a 3.9b 0.05c 0.41a 8.2b 4e-3c 0.08a 13.9b 2e-4c 0.35a 0.04b 0.83c 0.47a 0.00b 0.97c 0.34a 7.7b 0.005c
0.57a 0.01b 0.99c 0.03a 5.6b 0.02c 0.01a 0.53b 0.46c 0.14a 17.8b 2e-5c 0.01a 0.30b 0.59c 0.09a 2.1b 0.15c 0.23a 2.6b 0.11c 0.66a 11.3b 1e-3c 0.29a 0.03b 0.85c 0.21a 0.12b 0.72c 0.34a 0.02b 0.89c 0.48a 0.02b 0.85c 0.44a 0.76b 0.38c
0.88a N/Ab N/Ac 0.10a 0.63b 0.43c 0.06a 20.06b 7e-6c 0.12a 15.0b 1e-4c 0.00a 4.3b 0.04c 0.45a N/Ab N/Ac 0.33a 1.3b 0.25c 0.23a N/Ab N/Ac 0.00a N/Ab N/Ac 0.01a 18.8b 1e-5c 0.51a 20.0b 1e-5c 0.03a N/Ab N/Ac 0.48a 0.01b 0.94c
0.13a N/Ab N/Ac 0.09a 0.38b 0.54c 0.05a 15.1b 1e-4c 0.16a 5.4b 0.01c 0.00a 3.9b 0.05c 0.47a N/Ab N/Ac 0.31a 0.46b 0.50c 0.26a N/Ab N/Ac 0.06a N/Ab N/Ac 0.02a N/Ab N/Ac 0.46a 8.5b 0.003c 0.06a N/Ab N/Ac 0.55a 3.1b 0.07c
rs1051266
0.48a
rs1131596
0.49a
rs890293
0.09a
rs10264272
0.03a
rs776746
0.12a
rs2032582
0.39a
0.43a 0.8b 0.35c 0.38a 5.6b 0.02c 0.16a 6.6b 0.01c 0.05a 1.4b 0.23 c 0.68a N/Ab N/Ac 0.09a N/Ab N/Ac 0.22a 3.5b 0.05c
0.57a 4.9b 0.02c 0.57a 3.4b 0.06c 0.05a 2.8b 0.1c 0.00a 5.7b 0.01c 0.04a 11.0b 0.002c 0.42a 0.93b 0.33c 0.36a 16.2b 5e-5c
0.52a 1.2b 0.27c 0.52a 0.5b 0.46c 0.04a 4.1b 0.04C 0.00a 5.9b 0.01c 0.31a N/Ab N/Ac 0.41a 4.3b 0.03c 0.14a 20.5b 6e-6c
0.46a 0.18b 0.67c 0.46a 0.60b 0.44c 0.02a 11.0b 0.001c 0.00a 5.3b 0.02c 0.31a N/Ab N/Ac 0.46a 8.5b 0.003c 0.13a 23.1b 1e-6c
0.60a 7.9b 0.005c 0.60a 6.0b 0.01c 0.05a 2.8b 0.09 c 0.00a 5.2b 0.02c 0.05a 6.9b 0.01c 0.41a 0.22b 0.63c 0.22a04 .5b 0.03c
0.60a 9.9b 0.002c 0.61a 7.6b 0.005c 0.05a 2.4b 0.12c 0.00a 6.0b 0.01c 0.28a 26.2b 3e-7c 0.58a 29.7b 5e-8c 0.25a 2.2b 0.14c
0.46a 0.27b 0.60c 0.46a 0.77b 0.37c 0.02a 9.4b 0.002 c 0.0a 6.0b 0.01c 0.25a 20.0b 1e-5c 0.41a 4.6b 0.03c 0.09a N/Ab N/Ac
0.31a 18.0b 2e-5c 0.24a N/Ab N/Ac 0.14a 3.9b 0.04c 0.24a N/Ab N/Ac 0.88a N/Ab N/Ac 0.01a N/Ab N/Ac 0.23a 4.6b 0.03c
0.65a 15.0b 5e-4c 0.65a 10.0b 0.002c 0.03a 4.7b 0.03c 0.02a 0.1b 0.75c 0.23a 10.5b 1e-3c 0.40a 0.42b 0.52c 0.21a 4.7b 0.02c
0.55a 3.2b 0.07c 0.55a 0.2b 0.16c 0.05a 2.8b 0.1 c 0.01a 4.0b 0.04c 0.05a 8.8b 3e-3c 0.40a N/Ab N/Ac 0.33a 0.11b 0.73c 0.41a 0.12b 0.72c
0.33a 14.8b 1e-4c 0.28a 30.0b 4e-8c 0.15a 7.2b 0.01 c 0.17a N/Ab N/Ac 0.83a N/Ab N/Ac 0.0a 0.18b 0.66c 0.22a 6.2b 0.01c
0.31a 16.6b 5e-5c 0.28a 28.1b 1.2e-7c 0.10a 0.49b 0.48c 0.11a 23.0b 1e-6c 0.75a N/Ab N/Ac 0.04a N/Ab N/Ac 0.23a 3.7b 0.05c
0.40a N/Ab N/Ac
0.33a 3.0b 0.03c
rs3782905
0.31a
rs7975232
0.40a
0.37a 0.35b 0.55c
0.40a 0.02b 0.87c
0.72a N/Ab N/Ac
0.65a N/Ab N/Ac
0.54a 11.3b 7e-4c
0.48a 4.8b 0.03c
0.66a N/Ab N/Ac
0.28a 8.2b 0.003c
0.59a 16.6b 5e-5c
rs4244285
0.09a
0.14a 2.4b 0.12c
0.14a 3.7b 0.03c
0.33a N/Ab N/Ac
0.32a N/Ab N/Ac
0.21a 19.7b 1e-5c
0.17a 8.7b 0.003c
0.15a 5.2b 0.02c
0.04a 7.7b 0.005c
0.0a 266b 2.4e-7c
0.08a 2.2b 0.13c
0.05a 10.0b 0.001c
0.0a 29.7b 5e-8c
0.0a 28.3b 1e-7c
0.12a 1.2b 0.26c 0.10a 0.73b 0.39c
0.09a 0.001b 0.97c
0.13a
0.33a N/Ab N/Ac 0.0a 29.4b 6e-8c
0.26a N/Ab N/Ac
rs1799853
0.13a 2.4b 0.12c 0.15a 0.64b 0.42c
0.15a 0.84b 0.35c
0.0a 30.8b 3e-8c
0.03a 16.6b 4e-5c
rs28399454
0.01a
0.07a 8.7b 3e-3c
0.0a 3.9b 0.04c
0.0a 4.1b 0.04c
0.0a 3.7b 0.05c
0.0a 3.7b 0.05c
0.0a 4.1b 0.04c
0.0a 4.1b 0.04c
0.06a 5.6b 0.02c
0.0a 2.5b 0.1c
0.0a 4.3b 0.03c
0.13a N/Ab N/Ac
0.15a N/Ab N/Ac
rs28399433
0.04a
0.06a 7.4b 0.006c
0.05a 0.40b 0.52c
0.27a N/Ab N/Ac
0.18a N/Ab N/Ac
0.04a 0.1b 0.81c
0.19a N/Ab N/Ac
0.28a N/Ab N/Ac
0.09a 7.7b 0.005c
0.10a 8.3b 0.004c
0.06a 2.3b 0.13c
0.10a 11.4b 7e-3c
0.06a 1.7b 0.19c
0.05a 15.1b 1e-4c 0.06a 7.4b 0.006c 0.04a 1.7b 0.81c
0.00a 1.6b 0.20c 0.00a 3.3b 0.06c 0.0a 3.9b 0.04c
0.00a 1.7b 0.19c 0.00a 3.4b 0.06c 0.0a 4.1b 0.04c
0.00a 1.5b 0.21c 0.00a 3.1b 0.07c 0.0a 3.7b 0.05c
0.00a 1.5b 0.22c 0.005a 1.2b 0.26c 0.0a 3.6b 0.05c
0.00a 1.7b 0.19c 0.00a 3.4b 0.06c 0.0a 4.1b 0.04c
0.00a 1.7b 0.19c 0.00a 3.4b 0.06c 0.0a 3.9b 0.04c
0.03a 5.3b 0.02c 0.16a N/Ab N/Ac 0.09a N/Ab N/Ac
0.00a 1.1b 0.30c 0.19a N/Ab N/Ac 0.0a 2.6b 0.11c
0.00a 1.8b 0.18c 0.00a 3.5b 0.06c 0.0a 4.2b 0.04c
0.08a 33.0b 1e-8c 0.09a 23.9b 1e-6c 0.11a 22.0b 2e-6c
0.02a 14.0b 1e-4c
0.12a 0.23b 0.63c
0.03a 16.0b 6e-5c
0.08a 3.8b 0.05c
0.07a 5.2b 0.02c
0.15a 0.16b 0.70c
0.01a 28.5b 9e-8c
0.03a 16.6b 4e-5c
0.02a 14.8b 1e-4c
0.14a 0.14b 0.70c
0.01a 27.0b 1.7e-7c
0.04a 4.5b 0.03c 0.15a N/Ab N/Ac 0.72a N/Ab N/Ac 0.24a 3.8b 0.05c
0.0a 2.6b 0.10c 0.0a 3.6b 0.05c 0.22a 2.0b 0.15c 0.32a 0.23b 0.63c
0.0a 2.7b 0.1c 0.0a 3.8b 0.05c 0.42a 14.8b 1e-4c 0.73a N/Ab N/Ac
0.0a 2.5b 0.11c 0.0a 3.4b 0.06c 0.34a 3.0b 0.08c 0.70a N/Ab N/Ac
0.0a 2.4b 0.12c 0.0a 3.3b 0.06c 0.21a 2.5b 0.11c 0.41a 3.5b 0.06c
0.0a 2.7b 0.1c 0.0a 3.8b 0.05c 0.39a 9.6b 2e-3c 0.35a 0.11b 0.73c
0.0a 2.8b 0.1c 0.0a 3.8b 0.05c 0.45a 23.8b 1e-6c 0.75a N/Ab N/Acc
0.17a N/Ab N/Ac 0.19a N/Ab N/Ac 0.85a N/Ab N/Ac 0.13a 30.7b 3e-8c
0.0a 1.7b 0.19c 0.0a 2.3b 0.12c 0.15a 8.7b 0.003c 0.38a 0.9b 0.31c
0.0a 2.8b 0.1c 0.0a 4.0b 0.05c 0.25a 0.53b 0.46c 0.35a 0.23b 0.62 c
0.11a N/Ab N/Ac 0.25a N/Ab N/Ac 0.97a N/Ab N/Ac 0.20a 14.3b 1e-4c
0.06a N/Ab N/Ac
0.34a 1.7b 0.18 c
0.43a 0.44b 0.50c
0.12a N/Ab N/Acc
0.25a 14.2 b 1e-4c
0.19a 19.3b 1e-5c
0.41a 0.15b 0.70 c
0.29a 7.5b 0.006c
c
0.52a 0.85b 0.35c
0.43a 1.6b 0.20c
0.28a 26.4b 2.8e-7c
0.28a 24.3b 8e-7c
0.39a 3.4b 0.06c
0.45a 0.78b 0.37c
0.30a 21.6b 3e-6 c
0.36a 16.1b 1e-4 c
0.18a 8.5b 3e-3c
0.22a 0.13b 0.71c
0.31a 0.36b 0.55c
0.31a N/Ab N/Ac
0.10a 19.8b 1e-5c
0.51a 23.7b 1e-6 c
0.56a 1.1b 0.30c
0.29a 2.9b 0.081 c
0.39a 6.9b 0.008c
rs7626962
0.01a
rs6791924
0.02a
rs59421388
0.01a
rs28371725
0.13a
rs61736512
0.01a
rs28371706
0.02a
rs11568820
0.27a
rs154033900
0.34a
rs1544410
0.38a
0.27a 7.4b 0.006c
0.47a 2.9b 0.08c
0.04a N/Ab N/Ac
0.49a
0.27a 19.4b 1e-5 c
0.46a 0.33b 0.56c
0.31a 18.5b 2e-5c
rs4680
rs1695
0.33a
0.30a 7.0b 0.01c
0.45a 2.4b 0.12c
0.39a 16.4b 5e-5c
0.26a 27.8b 1.3e-7
0.11a N/Ab N/Ac 0.12a N/Ab N/Ac 0.08a 15.4b 1e-4c 0.05a 11.1b 1e-3c 0.09a 20.0b 4e-8c 0.20a N/Ab N/Ac 0.85a N/Ab N/Ac 0.38a 14.2b 1e-4c 0.31a 4.8b 0.04c
0.10a 0.02a 0.09a 0.00a 0.00a 0.05a 0.08a 0.00a 0.01a 0.05a 0.05a 0.00a b b a b b b b b b b 4.7 0.53 17.4 15.7 1.2 1.2 17.5 10.4 3.7b 1.8 18.2 13.9b rs1138272 c c c c c c c c c c c 0.03 0.47 3e-5 7e-5 0.27 0.26 3e-5 1e-3 0.05 0.17 2e-5 2e-4c aminor allele frequency, bChi-square value, cp-value. N/A: Not Applicable. ASW: African ancestry in Southwest USA, CEU: Utah, USA residents with Northern and Western European ancestry from the CEPH collection, CHB: Han Chinese in Beijing, China, CDX: Chinese Dai in Xishuangbanna, China, GIH: Gujarati Indians in Houston, Texas, USA, GBR: British in England and Scotland, JPT: Japanese in Tokyo, Japan, LWK: Luhya in Webuye, Kenya, MXL: Mexican ancestry in Los Angeles, California, USA, TSI: Toscani in Italy, YRI: Yoruba in Ibadan, Nigeria, ACB: African Caribbean’s in Barbados. 0.08a
3.3. Pharmacogenomic VIP variants of Jordanian population compared to six Exome Aggregation Consortium (ExAC) populations χ2 test were also applied to compare the allelic frequencies of the selected VIP variants in Jordanians and six ExAC populations. Table 4 shows the frequencies of the studied VIP variants within the selected genes among Jordanians and their comparison to the available frequency variants among six populations listed in the Exome Aggregation Consortium (ExAC) database. The results of this study revealed that various polymorphisms among Jordanian had significantly different frequencies compared to other populations. It is very clear from this study as shown in tables 3 and 4 that each studied variant has its own genotypic and allelic distribution among Jordanian population differs from other polymorphisms and these frequencies could either differ significantly from the certain population or similar to others. Table 4: Significant variants within the pharmacogenes in Jordanians compared to six ExAC populations worldwide. ExAC Populations SNP ID JOR
rs1805124
0.21a
rs7626962
0.01a
rs6791924
0.02a
rs7975232
0.40a
rs2032582
0.39a
rs1800888
0.02a
rs1142345
0.01a
rs1065776
0.01a
rs1045642
0.41a
African
East Asian
Latino
0.29a 18.3b 1e-5c 0.09a N/Ab N/Ac 0.1a N/Ab N/Ac 0.62a N/Ab N/Ac 0.91a N/Ab N/Ac 0.002a N/Ab N/Ac 0.05a 24.5b 7e-7c 0.19a N/Ab N/Ac 0.80a N/Ab N/Ac
0.1a N/Ab N/Ac 0.00a N/Ab N/Ac 0.00a N/Ab N/Ac 0.27a N/Ab N/Ac 0.46a 11.2b 8e-4c 0.00a N/Ab N/Ac 0.01a 1.1b 0.30c 0.04a 0.7b 0.38c 0.62a N/Ab N/Ac
0.21a 0.16b 0.68c 0.004a 1.9b 0.16c 0.006a 8.1b 0.004c 0.39a 0.11b 0.73c 0.54a N/Ab N/Ac 0.006a 16.7b 4e-5c 0.05a 20.1b 5e-6c 0.05a 0.01b 0.89c 0.54a N/Ab N/Ac
European ( Non Finnish)
South Asian
European (Finnish)
0.22a N/Ab N/Ac 0.0003a N/Ab N/Ac 0.001a N/Ab N/Ac 0.53a N/Ab N/Ac 0.55a N/Ab N/Ac 0.01a 25.5b 4e-7c 0.04a 15.6b 1e-4c 0.04a 1.5b 0.21c 0.47a 8.9b 0.002c
0.25a N/Ab N/Ac 0.00a N/Ab N/Ac 0.0003a N/Ab N/Ac 0.58a N/Ab N/Ac 0.35a 5.1b 0.02c 0.004a N/Ab N/Ac 0.02a 3.1b 0.07c 0.11a 21.6b 3e-6c 0.40a 0.40b 0.52c
0.20a 0.1b 0.79c 0.00a N/Ab N/Ac 0.0001a N/Ab N/Ac 0.55a N/Ab N/Ac 0.47a 12.5b 4e-4c 0.004a 1.2b 0.26c 0.03a 11.8b 6e-4c 0.06a 2.3b 0.12c 0.39a 1.0b 0.30c
rs2066702
0.01a
rs1229984
0.21a
rs698
0.24a
rs1128503
0.42a
rs1042714
0.24a
rs2066853
0.14a
rs3815459
0.29a
rs5219
0.28a
rs4149056
0.22a
rs12659
0.48a
rs1051266
0.48a
rs1131596
0.49a
rs10264272
0.03a
rs4244285
0.09a
rs1799853
0.13a
rs28399454
0.01a
rs28399433
0.04a
0.19a N/Ab N/Ac
0.0001a N/Ab N/Ac
0.01a 1.4b 0.23c
0.002a N/Ab N/Ac
0.002a N/Ab N/Ac
0.00a N/Ab N/Ac
0.99a N/Ab N/Ac 0.15a N/Ab N/Ac 0.80a N/Ab N/Ac 0.82a N/Ab N/Ac 0.45a N/Ab N/Ac 0.37a 7.9b 0.004c 0.94a N/Ab N/Ac 0.03a N/Ab N/Ac
0.27a 7.9b 0.004c 0.08a N/Ab N/Ac 0.36a 8.7b 0.003c 0.91a N/Ab N/Ac 0.37a N/Ab N/Ac 0.72a N/Ab N/Ac 0.64a N/Ab N/Ac 0.13a N/Ab N/Ac
0.94a N/Ab N/Ac 0.33a 19.5b 1e-5c 0.50a 13.5b 2e-4c 0.83a N/Ab N/Ac 0.12a 1.1b 0.29c 0.38a 3.9b 0.05c 0.61a N/Ab N/Ac 0.11a N/Ab N/Ac
0.95a N/Ab N/Ac 0.40a N/Ab N/Ac 0.57a N/Ab N/Ac 0.58a N/Ab N/Ac 0.10a 8.5b 0.003c 0.33a 3.0b 0.08c 0.63a N/Ab N/Ac 0.16a 17.3b 3e-5c
0.95a N/Ab N/Ac 0.32a 17.1b 3e-5c 0.39a 1.6b 0.20c 0.79a N/Ab N/Ac 0.14a 0.001b 0.97c 0.39a 22.4b 2e-6c 0.63a N/Ab N/Ac 0.05a N/Ab N/Ac
0.99a N/Ab N/Ac 0.51a N/Ab N/Ac 0.51a 18.4b 1e-5c 0.63a N/Ab N/Ac 0.11a 2.5b 0.11c 0.44a 1.5b 0.21c 0.53a N/Ab N/Ac 0.21a 0.27b 0.60c
0.55a 10.5b 1e-3c
0.49a 0.22b 0.63c
0.56a’ 0.03b 0.85c
0.58a 26.3b 2.9e-7c
0.64a N/Ab N/Ac
0.56a 13.9 1e-4c
0.42a 24.9b 5.8e-7c 0.36a N/Ab N/Ac
0.52a 0.03b 0.86c 0.51a 0.20b 0.64c
0.59a 11.5b 1e-3c 0.56a 6.2b 0.01c
0.60a 14.4b 1e-5c 0.59a 22.3b 2e-6c
0.61a 18.1b 2e-5c 0.58a 13.7b 2e-4c
0.60a 14.8b 1e-4c 0.61a 11.1b 1e-3c
0.12a N/Ab N/Ac
0.0a N/Ab N/Ac
0.01a 26.5b 2.6e-7c
0.001a N/Ab N/Ac
0.0002a N/Ab N/Ac
0.0a N/Ab N/Ac
0.18a 30.2b 4e-8c 0.02a N/Ab N/Ac
0.31a N/Ab N/Ac 0.0003a N/Ab N/Ac
0.10a 0.42b 0.52c 0.07a N/Ab N/Ac
0.15a 14.2b 1e-4c 0.13a 0.03b 0.86c
0.34a N/Ab N/Ac 0.05a N/Ab N/Ac
0.18a 30.5b 3e-8c 0.12a 0.78b 0.37c
0.11a 34.1b 1e-8c
0.0a N/Ab N/Ac
0.006a 11.7b 6e-4c
0.0004a N/Ab N/Ac
0.0a N/Ab N/Ac
0.0a N/Ab N/Ac
0.08a 2.7b 0.09c
0.23a N/Ab N/Ac
0.14a 27.2b 1e-7c
0.07a N/Ab N/Ac
0.14a 1.3b 0.25c
0.11a N/Ab N/Ac
rs59421388
0.01a
0.092a 24.2b 5e-7c
0.0001a N/Ab N/Ac
0.004a 23.3b 1e-6c
0.0003a N/Ab N/Ac
0.0001a N/Ab N/Ac
0.0a N/Ab N/Ac
rs28371725
0.13a
0.03a N/Ab N/Ac
0.03a N/Ab N/Ac
0.03a N/Ab N/Ac
0.09a 10.7b 0.001c
0.15a 0.004b 0.91c
0.03a N/Ab N/Ac
rs61736512
0.01a
0.10a N/Ab N/Ac
0.0005a N/Ab N/Ac
0.004a 11.3a 1e-3c
0.0003a N/Ab N/Ac
0.0002a 0.06a 0.80c
0.0a N/Ab N/Ac
rs28371706
0.02a
0.197a N/Ab N/Ac 0.32a N/Ab N/Ac 0.44a 28.4b 9e-8c
0.0a N/Ab N/Ac 0.28a N/Ab N/Ac 0.18a N/Ab N/Ac
0.007a 8.9b 0.003c 0.41a 15.5b 8e-5c 0.53a N/Ab N/Ac
0.002a N/Ab N/Ac 0.53a 3.8b 0.05c 0.31a 0.55b 0.45c
0.001a N/Ab N/Ac 0.45a 3.8b 0.05c 0.29a 5.6b 0.01c
0.0002a N/Ab N/Ac 0.57a 15.7b 7e-5c 0.27a 9.3b 0.002c
0.02a N/Ab N/Ac
0.0003a N/Ab N/Ac
0.03a N/Ab N/Ac
0.08a 0.01b 0.91c
0.07a 0.9b 0.34c
0.08a 0.11b 0.73c
rs4680 rs1695
0.33a
rs1138272
0.08a
aMinor
`
0.49a
allele frequency, bChi-square value, cp-value. N/A: Not Applicable
4. Discussion Recent advances in pharmacogenomics in the last few years will help the patients to be treated more efficiently with better response to medications (29, 30). The current study was conducted in the Jordanian population of Arab descent included 500 unrelated individuals to detect the allelic and genotypic distribution of 65 variants among 33 VIPs (table 1) and compared to other populations and different ethnic groups. One of the main large and diverse enzyme superfamily involved in the oxidative metabolism of various chemical substances like drugs is the cytochrome P450 (CYP) (31). The current study analyzed the following variants from CYP superfamily: CYP2J2 (rs890293, rs10264272), CYP3A5 (rs776746), CYP3A4 (rs4986913, rs4986910, rs4986909, rs12721634, rs2740574), CYP2C19 (rs4986893, rs4244285), CYP2C9 (rs1799853), CYP2A6 (rs28399454, rs1801272, rs28399433), CYP2B6 (rs3745274, rs28399499, rs59421388), CYP2D6 (rs28371725, rs61736512, rs28371706, rs5030656). The following SNPs rs4986913, rs4986910, rs4986909, rs12721634, rs4986893, rs1801272, rs28399499, and rs5030656have been found monomorphic polymorphisms. Two polymorphisms within UGT1A1 gene have been found from the current study (rs2740574, and rs10929302) did not fulfill the HWE (P- value < 0.05). It was found from the current study that the minor allele the frequency for these variants was almost the same with ASW (African ancestry in Southwest USA) and TSI (Toscani in Italy), but the frequency was significantly different from other compared populations with P-value < 0.05. One important member of this CYP superfamily is the CYP2C9 which approximately constitutes around 20 % of the total CYP protein with more than 60 variants have been reported for its gene (31, 32). CYP2C9 metabolizes about one-fourth of the clinically administrated medications (31, 33). Many studies reported that the rs4244285 variant was found at a high allelic frequency in south India (30%) and the lowest frequency was in Faroese (2.9%) (13), but the minor allele frequency (A) was 12% in Jordanian population which was the same allele frequency as rs689466, rs2066853, rs776746, rs1799853, and rs28371725 SNPs (Table 3). In contrast, rs4986893 was
monomorphic alleles in Jordanian population compared to the result of other studies on other populations that found that the rs4986893 at higher allelic frequencies in the Japanese (about 13%) but lower (0) among the European-Americans, South Africans, Greeks, Italians, and other populations (17, 26). Another important and abundant CYP enzyme that has a great effect on the metabolism of the drug within the different populations is the CYP3A4 (31). It has been identified more than 25 variants of CYP3A4 (1, 31). It was observed from different studies that the rs55785340 and rs4986910 allele frequencies of the CYP3A4 gene at a high rate at Caucasians population in comparison to rs12721627and rs28371759 that were observed at a high rate in the Chinese population (17, 20). In spite of this, all studied SNPs of CYP3A4 in the current study were found at a monomorphic feature in the Jordanian population. In addition to rs2740574 polymorphism that did not fulfill the HWE equation with P-value < 0.05. The current Jordanian study revealed that these variants: KCNH2 (rs3807375), VKORC1 (rs9934438), SLC19A1 (rs12659, rs1051266), UGT1A1 (rs4124874), COMT (s4680) were at a high level of allele frequency in the Jordanian population (approximately 50%) which differs from other frequencies in different populations because of many factors such as different mutations rate, natural selection, and migration (34, 35, 36, 37). Despite many studies reported that the rs8175347 and rs10929302 polymorphisms within UGT1A1 gene were associated with increased risk of diarrhea neutropenia for patients who treated with irinotecan from colorectal neoplasms (15, 38). The presented study revealed that two of the UGT1A1 variants (rs4124874 and rs10929302) were not in HWE and the third one (rs4148323) was at a monomorphic feature in the Jordanian population.
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Abbreviations list ABCB1: ATP binding cassette subfamily B member 1 ADR: Adverse drug reactions ExAC: Exome Aggregation Consortium HapMap: Haplotype Map HWE: Hardy-Weinberg equilibrium NIH: National Institute of Health PharmGKB: Pharmacogenomics Knowledge Base PDs: Pharmacodynamics PKs: Drug pharmacokinetics QC: Quality control SNPs: Single nucleotide polymorphisms TPMT: Thiopurine S-methyltransferase VIP: Very important pharmacogene VDR: Vitamin D receptor COMT: Catechol O-Methyltransferase UGTs: Glucuronosyltransferases GSTs: Glutathione S-Transferases NATs: N-acetyltransferases SULTs: Sulfotransferases TPMT: Thiopurine S-Methyltransferase
Author contribution L.N.A.-E contributed to all research aspects from the design and implementation of the research, to the analysis of the results and to the writing of the manuscript.
Declaration of Interest The authors declare that they have no competing interests.
Resaerch Highlight
A total of 65 VIP variants located within 33 candidate genes were genotyped in Jordan for the first time. This study aimed to identify the allele frequencies of VIP variants in the Jordanian population. The difference in allele frequencies between the Jordanians and other populations was determined. This study will enhance personalized medicine in clinical settings.