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. 2020 Jul 14;13:199–215. doi: 10.2147/PGPM.S254677

Analysis of Comprehensive Pharmacogenomic Profiling of VIP Variants Among the Genetically Isolated Chechen Subpopulation from Jordan

Laith N AL-Eitan 1,2,✉, Doaa M Rababa’h 1, Nancy M Hakooz 3, Mansour A Alghamdi 4,5, Rana B Dajani 6,7,8
PMCID: PMC7368587  PMID: 32765042

Abstract

Background

Profiling rare variants in isolated populations can significantly clarify and understand the development of a clinically relevant process. Therefore, leading to a better identifying novel targeted treatment.

Objective

This study aimed to determine the allele frequencies of 56 single nucleotide polymorphisms (SNPs) within several important pharmacogenes.

Methods

This study consisted of 166 unrelated subjects from a genetically isolated group (Chechen) who were living in Jordan. In this study, the distribution of the variants among Chechen was compared to other ethnic groups available at two databases (Genome 1000 and (ExAC)). The frequency of genotypes and alleles was calculated and tested using the chi-square test and the Hardy–Weinberg equilibrium equation (HWE).

Results

Our results revealed that the distribution of allele frequencies within different pharmacogenes among Chechen showed different similarities with other populations. The CEU and TSI showed the highest resemblance with the Chechen population (75% similarity), in contrast to LWK which had the lowest similarity (30%).

Conclusion

This study sheds light on clinically relevant SNPs to enhance medical research and apply pharmacogenomics in clinical settings.

Keywords: pharmacogenomics, VIP polymorphism, Phase I enzymes, Phase II enzymes, metabolizing

Introduction

Pharmacogenomics has become a promising future to enhance individuals’ response to treatment.1 Single nucleotide polymorphisms (SNPs) are one of the most common variants among populations that affect enzyme activity as well as drug metabolism.2 Consequently, clinical significant SNPs have been studied and screened extensively in different genes in different ethnic backgrounds and given the term very important pharmacogenomic (VIP) variants.3

These VIP variants help in drug dose optimization for patients relevant to their genetic makeup and lead to enhanced therapy outcomes and maintain the efficacy of drug treatment.4 Remarkably, the frequency distribution of these VIP variants varies among different ethnic groups.5 The importance of the VIP variants depends on their presence within critical genes including drug-metabolizing genes.6 However, the underlying mechanism of the correlation between the genetic variants and drug response is still beyond clinical practice.7 Rare variants that impact gene function may account for some uncovered differences in the pharmacological response and metabolism process.8 Genetic variants in drug target enzymes; metabolizing, transporters, receptors help in predicting toxicity and treatment failure among patients.9

Genetically isolated populations, such as Chechen, can help medical research to overcome the extensive allelic heterogeneity which is a major cause of complex diseases.10 Chechen, a Caucasian ethnic group of the Nakh peoples, lived in the highlands of the North Caucasus region of Eastern Europe.11 In 1860 they immigrated to Ottoman lands; however, today, tens of thousands of Chechens live in Turkey, Jordan, Syria, Iraq, Egypt, Saudi Arabia and other Persian Gulf countries.12 Not many genetic studies have been conducted on Chechens and Circassians living in Jordan. As a genetically isolated population, they can provide a baseline for future studies to discover novel markers associated with diseases.13–16 Moreover, there is an urgent need for pharmacogenetic research as not many studies conducted in Jordan.17,18 Therefore, this study aimed to determine the allele frequencies of 52 SNPs within several pharmacogenes in Chechen living in Jordan in comparison to other ethnic groups.

Materials and Methods

Study Subjects

This study was subjected to and in agreement with the Human ethics committee at National Center for Diabetes, Endocrinology and Genetics (NCDEG) and Jordan University of Science and Technology (JUST). Details about subjects and written informed consent were obtained from all volunteers in the study. Ten milliliters of venous blood was collected from unrelated healthy 166 Chechen subjects living in Jordan.

This study was conducted in agreement with the Human ethics committee at National Center for Diabetes, Endocrinology and Genetics (NCDEG) and Jordan University of Science and Technology (JUST), policy number (GM7601). Written informed consent was obtained from all volunteers in the study. This research was also conducted in accordance with the Declaration of Helsinki.

DNA Extraction and Genotyping

Blood samples were drawn from subject and then stored at 4°C for 24 hours before the purification of the genetic material. The extracted DNA was then stored at −20°C.

Genotyping was performed using Agena Bioscience MassARRAY® on a Compact Spectrometer iPLEX GOLD chemistry by Australian Genome Research Facility. 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.

Candidate genes polymorphisms were analyzed using Sequencing technique. Loci of candidate SNPs were amplified using Multiplex PCR followed by Mass EXTEND which is a primer extension process is resulting in allele-specific DNA products. The genotyping after the minisequencing reaction product analysis was reported by Mass spectrometry. After that, 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. Lastly, a software system (SpectroTYPER-RT (RT for real-time)) was used to analyze the results.

Variants Selection

The studied VIP variants were selected from the public databases including the PharmGKB database (https://www.pharmgkb.org/), the SNP database of the National Centre for Biotechnology Information (NCBI) (http://www.ncbi.nlm.nih.gov/SNP/), and the International HapMap Project (http://www.hapmap.org/). SNPs selected within significant genes that play roles in drug metabolism which make their variants clinically important variants. Finally, the primers were used to genotype these VIP variants were shown in the Supplementary Material.

Population’s Variation Data

The allele counts variation data for other populations were obtained from HapMap Project website: 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 Caribbeans in Barbados. Also, the allele count data of populations around the world were obtained from the Exome Aggregation Consortium (ExAC): African, East Asian, Latino, European (non-Finnish), South Asian and European (Finnish).

Statistical Analysis

Statistical Package for Social Sciences SPSS (version 19) was used to statistically analyze the data. The genotypes and alleles frequency was calculated and tested using the chi-square test and the Hardy–Weinberg equilibrium equation (HWE) and all p-values accepted as p-value <0.05. Fisher exact test was used for the correction of small sizes.

Results

Table 1 shows basic information about the selected variants within 28 studied genes, in addition to describe the quality control of samples’ genotyping. Genotype call rates ranged from 96.5% to 100%. Allele and genotype frequencies of the selected variants among 166 Chechen subjects are listed in Table 2. SNPs were tested for Hardy–Weinberg Equilibrium (HWE), all the studied polymorphisms met the HWE standards (P-value > 0.05) except for rs1801131 within MTHFR (P-value = 0.027) did not fulfil the HWE equation (Figure 1).

Table 1.

List of Genes, Their VIP Variants, Positions, and Genotyping Data Based on the Whole Cohort (N= 166)

Gene SNP_ID Positiona SNP SNP Location Assay Pass Rateb Call Ratec
MTHFR rs1801131 1:11794419 A>CMA Missense variant 100% 100%
rs1801133 1:11796321 C>TMA Missense variant 100% 99.7%
DPYD rs3918290 1:97450058 C>TMA Splice donor variant 100% 99.7%
PTGS2 rs689466 1:186681619 G>AMA 2KB Upstream variant 100% 100%
SCN5A rs7626962 3:38579416 G>A/G>T Missense variant 100% 100%
rs1805124 3:38603929 T>CMA Missense variant 100% 100%
rs6791924 3:38633208 G>AMA Missense variant 100% 100%
NR1I2 rs3814055 3:119781188 C>TMA 5 Prime UTR variant 100% 100%
P2RY12 rs2046934 3:151339854 GMA>A Intron variant 99% 99.2%
P2RY1 rs1065776 3:152835839 C>TMA Synonymous variant 100% 100%
rs701265 3:152836568 A>GMA Synonymous variant 100% 100%
ADH1A rs975833 4:99280582 G>CMA Intron variant 100% 99.7%
ADH1B rs2066702 4:99307860 G>AMA Missense variant 100% 100%
rs1229984 4:99318162 TMA>C Missense variant 100% 100%
ADH1C rs698 4:99339632 T>CMA Missense variant 99% 99.2%
HMGCR rs17244841 5:75347030 A>TMA Intron variant 99% 98.6%
rs3846662 5:75355259 AMA>G Intron variant 100% 99.7%
rs17238540 5:75359673 T>GMA Intron variant 100% 100%
ADRB2 rs1042713 5:148826877 G>AMA Missense variant 100% 100%
rs1042714 5:148826910 GMA>C Stop gained 100% 100%
rs1800888 5:148827322 C>TMA Missense variant 100% 99.7%
AHR rs2066853 7:17339486 G>AMA Missense variant 100% 99.7%
KCNH2 rs3815459 7:150947306 C>TMA Intron variant 100% 99.7%
rs3807375 7:150970122 C>TMA Intron variant 100% 100%
KCNJ11 rs5219 11:17388025 TMA>C Stop gained 100% 100%
SLCO1B1 rs4149056 12:21178615 T>CMA Missense variant 100% 100%
VKORC1 rs7294 16:31091000 C>TMA 3 Prime UTR variant 100% 100%
rs9934438 16:31093557 G>AMA Intron variant 100% 100%
SLC19A1 rs12659 21:45531642 AMA>G Synonymous variant 100% 100%
rs1051266 21:45537880 T>CMA Missense variant 99% 98.6%
rs1131596 21:45538002 G>AMA Missense variant 100% 99.7%
CYP2J2 rs890293 1:59926822 C>AMA Upstream variant 100% 100%
CYP3A4 rs4986913 7:99760836 G>AMA Missense variant 100% 100%
rs4986910 7:99760901 A>GMA Missense variant 100% 100%
rs4986909 7:99762047 G>A MA Missense variant 100% 100%
rs12721634 7:99784038 A>G Missense variant 100% 100%
rs2740574 7:99784473 CMA>T Upstream variant 100% 100%
CYP2C19 rs4986893 10:94780653 G>AMA Stop gained 100% 100%
rs4244285 10:94781859 G>AMA Synonymous variant 100% 99.7%
CYP2C9 rs1799853 10:94942290 C>TMA Missense variant 100% 100%
CYP2A6 rs28399454 19:40845362 C>TMA Missense variant 100% 100%
rs1801272 19:40848628 A>TMA Missense variant 100% 100%
rs28399433 19:40850474 A>CMA Upstream Variant 99% 99.2%
CYP2B6 rs3745274 19:41006936 G>TMA Missense variant 96% 96.5%
rs28399499 19:41012316 T>CMA Missense variant 100% 100%
CYP2D6 rs59421388 22:42127608 C>TMA Missense variant 100% 100%
rs28371725 22:42127803 C>TMA Intron variant 98% 98.4%
rs61736512 22:42129132 C>TMA Missense variant 100% 100%
rs28371706 22:42129770 G>AMA Missense variant 100% 100%
rs5030656 22:42128174–42128178 delTCT Inframe deletion 100% 100%
CYP3A5 rs776746 7:99672916 C>TMA Splice Acceptor Variant 100% 99%
UGT1A1 rs4124874 2:233757013 TMA>G Intronic variant 100% 100%
rs10929302 2:23375713 G>AMA Intronic variant 100% 100%
rs4148323 2:233760498 G>AMA Missense variant 100% 100%
COMT rs4680 22:19963748 G>AMA Missense variant 100% 99.7%
GSTP1 rs1695 11:67585218 A>GMA Missense variant 100% 100%
rs1138272 11:67586108 C>TMA Missense variant 100% 100%
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Notes: aChromosome positions are based on NCBI Human Genome Assembly Build. bRatio of the number of discordant genotypes to the number of duplicates. cRatio of the number of valid genotypes to the number of subjects genotyped. MA: Global minor allele <1.

Table 2.

The Minor Allele Frequencies and HWE p Values for the VIP Variants in Chechen (N= 166)

Gene SNP_ID Allele Allelic Frequency Genotype Genotypic Frequency P-value
MTHFR rs1801131 C 0.64 AA 0.37 0.027
A 0.36 CA 0.54
CC 0.08
rs1801133 T 0.18 CC 0.67 0.88
C 0.82 CT 0.3
TT 0.03
DPYD rs3918290 C 99.7 CC 0.99 0.96
T 0.003 CT 0.01
PTGS2 rs689466 T 0.89 CC 0.01 0.7
C 0.11 CT 0.21
TT 0.78
SCN5A rs7626962 G 1.0 GG 1.0 NA
rs1805124 T 0.75 CC 0.04 0.22
C 0.25 CT 0.42
TT 0.54
rs6791924 G 1.0 GG 1.0 NA
NR1I2 rs3814055 C 0.67 CC 0.46 0.39
T 0.33 CT 0.42
TT 0.13
P2RY12 rs2046934 A 0.85 AA 0.72 0.97
G 0.15 AG 0.26
GG 0.02
P2RY1 rs1065776 C 0.99 CC 0.98 0.90
T 0.01 CT 0.02
rs701265 A 0.83 AA 0.69 0.75
G 0.17 AG 0.28
GG 0.02
ADH1A rs975833 G 0.76 CC 0.05 0.78
C 0.24 CG 0.37
GG 0.57
ADH1B rs2066702 G 0.99 GA 0.02 0.87
A 0.01 GG 0.98
rs1229984 C 0.88 CC 0.75 0.14
T 0.12 CT 0.25
ADH1C rs698 C 0.27 CC 0.07 0.91
T 0.73 CT 0.39
TT 0.54
HMGCR rs17244841 A 0.97 AA 0.94 0.72
T 0.03 AT 0.06
rs3846662 G 0.43 AA 0.31 0.53
A 0.57 GA 0.52
GG 0.17
rs17238540 G 0.03 TT 0.93 0.65
T 0.97 GT 0.07
ADRB2 rs1042713 G 0.63 GG 0.4 0.62
A 0.37 GA 0.45
AA 0.15
rs1042714 C 0.69 CC 0.49 0.21
G 0.31 CG 0.39
GG 0.12
rs1800888 C 0.99 CC 0.99 0.97
T 0.003 CT 0.01
AHR rs2066853 G 0.87 GG 0.77 0.73
A 0.13 GA 0.22
AA 0.02
KCNH2 rs3815459 C 0.73 CC 0.52 0.37
T 0.27 CT 0.43
TT 0.05
rs3807375 C 0.63 CC 0.39 0.74
T 0.37 CT 0.48
TT 0.13
KCNJ11 rs5219 C 0.54 CC 0.31 0.35
T 0.46 CT 0.46
TT 0.23
SLCO1B1 rs4149056 C 0.04 CT 0.08 0.59
T 0.96 TT 0.92
VKORC1 rs7294 C 0.62 CC 0.36 0.33
T 0.38 CT 0.51
TT 0.13
rs9934438 G 0.59 GG 0.34 0.63
A 0.41 GA 0.51
AA 0.16
SLC19A1 rs12659 G 0.51 GG 0.27 0.54
A 0.49 GA 0.48
AA 0.25
rs1051266 C 0.48 CC 0.23 0.86
T 0.52 CT 0.51
TT 0.43
rs1131596 A 0.47 AA 0.22 0.88
G 0.53 AG 0.49
GG 0.28
CYP2J2 rs890293 C 0.93 CA 0.13 0.36
A 0.07 CC 0.87
CYP3A5 rs10264272 C 1.0 CC 1.0 N/A
rs776746 C 0.97 CC 0.95 0.13
T 0.03 CT 0.05
TT 0.01
CYP3A4 rs4986913 G 1.0 GG 1.0 N/A
rs4986910 A 1.0 AA 1.0 N/A
rs4986909 G 1.0 GG 1.0 N/A
rs12721634 A 1.0 AA 1.0 N/A
rs2740574 T 0.99 TC 0.01 0.96
C 0.004 TT 0.99
CYP2C19 rs4986893 G 1.0 GG 1.0 N/A
rs4244285 G 0.91 AA 0.02 0.13
A 0.09 GA 0.14
GG 0.84
CYP2C9 rs1799853 C 0.98 CC 0.96 0.083
T 0.02 CT 0.04
TT 0.01
CYP2A6 rs28399454 C 1.0 CC 1.0 N/A
rs1801272 A 1.0 AA 1.0 N/A
rs28399433 A 0.91 AA 0.82 0.37
C 0.09 AC 0.18
CYP2B6 rs3745274 G 0.69 GG 0.5 0.072
T 0.31 GT 0.37
TT 0.13
rs28399499 T 1.0 TT 1.0 N/A
CYP2D6 rs59421388 C 1.0 CC 1.0 N/A
rs28371725 C 0.86 CC 0.74 0.33
T 0.14 CT 0.23
TT 0.03
rs61736512 C 1.0 CC 1.0 N/A
rs28371706 G 1.0 GG 1.0 N/A
rs5030656 C/T/T 1.0 - 1.0 N/A
UGT1A1 rs4124874 G 0.54 GG 0.33 0.06
T 0.46 GT 0.41
TT 0.26
rs10929302 G 0.61 GG 0.37 0.90
A 0.39 GA 0.47
AA 0.16
rs4148323 G 0.97 GG 0.95 0.80
A 0.03 GA 0.05
COMT rs4680 G 0.59 GG 0.35 0.90
A 0.41 GA 0.47
AA 0.18
GSTP1 rs1695 A 0.67 AA 0.46 0.69
G 0.33 AG 0.43
GG 0.12
rs1138272 C 0.84 CC 0.71 0.50
T 0.16 CT 0.26
TT 0.02
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Note: *p-value > 0.05 is considered normally distributed.

Abbreviations: HWE, Hardy–Weinberg equilibrium; N/A, not applicable.

Figure 1.

Figure 1

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The number of single nucleotide polymorphisms (SNPs) in this study and their genotyping accuracy.

Table 3 compares minor allele frequencies (MAF) of the significant polymorphisms among Chechens and other populations. For example, the MAF of rs776746 (T) of the CYP3A5 gene within the Chechen group was similar to both CEU and GBR but different from ASW, CHB, CDX, GIH, and others. Also, Table 3 compares the allelic distribution of selected variants among Chechens and Circassians and other populations by estimating the P-value. We found that each studied variant distribution within Chechens in Jordan is significantly different from various populations. For example, Rs1229984 and rs28371725 had a highly different distribution with around 90% of the compared populations.

Table 3.

VIP Variants Within the Pharmacogenes in Chechen Compared to HapMap Populations

SNP ID Populations
CHE ASW CEU CHB CDX GBR GIH JPT LWK MXL TSI YRI ACB
rs3918290 0.003a 0.008a 0.005a 0.00a 0.00a 0.00a 0.146a 0.00a 0.00a 0.00a 0.005a 0.00a 0.00a
0.54b 0.13b 0.62b 0.56b 0.55b 2.3b 0.63b 0.60b 0.39b 0.09b 0.65b 0.57b
0.46c 0.71c 0.43c 0.45c 0.45c 0.13c 0.43c 0.44c 0.53c 0.75c 0.42c 0.45c
rs689466 0.11a 0.13a 0.19a 0.47a 0.52a 0.20a 0.13a 0.44a 0.03a 0.26a 0.20a 0.07a 0.10a
0.34b 6.6b N/Ab N/Ab 7.2b 0.26b N/Ab 10.9b 15.3b 7.5b 2.1b 0.1b
0.56c 0.01c N/Ac N/Ac 0.01c 0.60c N/Ac 1e-3c 1e-4c 0.01c 0.14c 0.79c
rs1805124 0.25a 0.26a 0.18a 0.12a 0.07a 0.22a 0.20a 0.13a 0.30a 0.16a 0.23a 0.32a 0.28a
0.04b 3.5b 12.5b 26.2b 0.49b 1.7b 10.9b 1.6b 4.1b 0.26b 3.7b 0.5b
0.84c 0.06c 4e-4c 3e-7c 0.48c 0.19c 1e-3c 0.21c 0.04c 0.61c 0.05c 0.47c
rs3814055 0.33a 0.29a 0.34a 0.27a 0.15a 0.40a 0.42a 0.25a 0.30a 0.33a 0.36a 0.27a 0.39a
0.62b 0.01b 2.3b 19.2b 33.2b 3.8b 3.8b 0.55b 0.001b 0.37b 2.2b 2.0b
0.42c 0.92c 0.12c 1e-5c 1e-8c 0.05c 0.05c 0.45c 0.97c 0.54c 0.13c 0.15c
rs1065776 0.01a 0.20a 0.05a 0.03a 0.02a 0.02a 0.10a 0.07a 0.21a 0.05a 0.03a 0.22a 0.20a
N/Ab 10.43b 4.3b 0.52b 1.4b 25.7b 15.7b N/Ab 6.9b 4.1b N/Ab N/Ab
N/Ac 0.001c 0.04c 0.46c 0.22c 3.9e-7c 7e-5c N/Ac 0.01c 0.04c N/Ac N/Ac
rs701265 0.17a 0.67a 0.17a 0.28a 0.19a 0.13a 0.21a 0.27a 0.80a 0.20a 0.16a 0.81a 0.72a
N/Ab 0.001b 11.1b 0.42b 1.0b 1.6b 9.1b N/Ab 0.89b 0.004b N/Ab N/Ab
N/Ac 0.97c 0.001c 0.51c 0.31c 0.21c 0.002c N/Ac 0.34c 0.95c N/Ac N/Ac
rs975833 0.24a 0.25a 0.24a 0.79a 0.75a 0.24a 0.49a 0.80a 0.19a 0.13a 0.27a 0.30a 0.28a
0.08b 0.001b N/Ab N/Ab N/Ab N/Ab N/Ab 1.7b 6.5b 0.6b 2.4b 0.79b
0.77c 0.97c N/Ac N/Ac N/Ac N/Ac N/Ac 0.19c 0.01c 0.43c 0.12c 0.37c
rs2066702 0.01a 0.20a 0.00a 0.00a 0.00a 0.00a 0.00a 0.00a 0.14a 0.03a 0.00a 0.28a 0.19a
N/Ab 2.4b 2.5b 2.3b 2.2b 2.5b 2.5b N/Ab 1.9b 2.6b N/Ab N/Ab
N/Ac 0.12c 0.11c 0.13c 0.14c 0.11c 0.11c N/Ac 0.16c 0.11c N/Ac N/Ac
rs1229984 0.12a 0.00a 0.02a 0.71a 0.63a 0.01a 0.02a 0.73a 0.00a 0.08a 0.05a 0.00a 0.01a
16.5b
5e-5c 		19.1b
1e-5c 		N/Ab
N/Ac 		N/Ab
N/Ac 		21.8b
3e-6c 		16.0b
6e-5c 		N/Ab
N/Ac 		26.5b
2.6e-7c 		1.3b
0.25c 		7.8b
0.005c 		28.8b
8e-8c 		20.6b
6e-6c
rs698 0.27a 0.14a 0.47a 0.05a 0.11a 0.44a 0.28a 0.07a 0.14a 0.28a 0.31a 0.07a 0.11a
8.1b 23.7b N/Ab 16.9b 15.9b 0.14b 31.2b 11.3b 0.10b 1.1b 33.1b 18.1b
0.004c 1e-6c N/Ac 4e-5c 7e-5c 0.71c 2e-8c 0.001c 0.75c 0.29c 1e-8c 2e-5c
rs17244841 0.03a 0.10a 0.01a 0.00a 0.00a 0.03a 0.00a 0.02a 0.08a 0.04a 0.03a 0.09a 0.10a
9.8b 0.87b 5.8b 5.2b N/Ab 5.2b 0.39b 8.7b 0.38b 0.11b 10.7b 13.3b
0.002c 0.35c 0.02 0.02c N/Ac 0.02c 0.53c 0.003c 0.53c 0.74c 0.001c 3e-4c
rs3846662 0.43a 0.13a 0.57a 0.48 0.49a 0.55a 0.34a 0.47a 0.03a 0.56a 0.57a 0.04a 0.11a
N/Ab 0.04b 3.3b 2.5b 0.14b 26.1b 7.1b N/Ab 0.005b 0.008b N/Ab N/Ab
N/Ac 0.83c 0.06c 0.12c 0.17c 3.2e-7c 0.008c N/Ac 0.94c 0.93c N/Ac N/Ac
rs17238540 0.03a 0.10a 0.01a 0.00a 0.00a 0.02a 0.00a 0.00a 0.09a 0.04a 0.03a 0.10a 0.09a
7.9b 1.5b 6.9b 6.3b 0.5b 6.9b 7.0b 8.0b 0.09b 0.001b 9.7b 8.5b
0.005c 0.21c 0.008c 0.01c 0.47c 0.008c 0.008c 0.004c 0.76c 0.97c 0.002c 0.003c
rs1042713 0.37a 0.54a 0.35a 0.55a 0.58a 0.42a 0.43a 0.44a 0.49a 0.48a 0.37a 0.53a 0.51a
11.3a 0.33b 15.8b 20.7b 0.96b 1.8b 2.5b 7.0b 4.1b 0.01b 13.4b 9.3b
0.001c 0.56c 7e-5c 5e-6c 0.32 0.18c 0.11c 0.008c 0.04c 0.92c 0.0002c 0.002c
rs1042714 0.31a 0.12a 0.46a 0.11a 0.10a 0.39a 0.23a 0.06a 0.21a 0.14a 0.14a 0.12a 0.16a
16.7b 12.1b 30.2b 29.3b 3.5b 4.6b N/Ab 6.3b 14.1b 3.6b 27.0b 14.6b
4e-5c 5e-4c 4e-8c 6e-8c 0.06c 0.03c N/Ac 0.01c 2e-4c 0.06c 2.1e-7c 1e-4c
rs1800888 0.003a 0.00a 0.02a 0.00a 0.00a 0.02a 0.00a 0.00a 0.00a 0.00a 0.01a 0.00a 0.00a
0.36b 2.4b 0.62b 0.56b 4.3b 0.62b 0.62b 0.59b 0.38b 2.2b 0.65b 0.57b
0.54c 0.11c 0.43c 0.45c 0.04c 0.43c 0.42c 0.44c 0.53c 0.14c 0.42c 0.45c
rs2066853 0.13a 0.34a 0.09a 0.37a 0.26a 0.09a 0.12a 0.46a 0.48a 0.13a 0.09a 0.45a 0.47a
28.0b 1.5b N/Ab 14.4b 0.87b 0.11b N/Ab N/Ab 0.03b 1.02b N/Ab N/Ab
1.2e-7c 0.21c N/Ac 2e-4c 0.35c 0.73c N/Ac N/Ac 0.85c 0.31c N/Ac N/Ac
rs3815459 0.27a 0.42a 0.20a 0.71a 0.56a 0.15a 0.35a 0.80a 0.39a 0.39a 0.23a 0.33a 0.31a
9.5b 3.2b N/Ab 6.6b 8.5b 3.2b N/Ab 8.6b 7.6b 0.74b 2.8b 1.5b
0.002c 0.07c N/Ac 0.01c 0.003c 0.07c N/Ac 0.003c 0.006c 0.39c 0.09c 0.22c
rs3807375 0.63a 0.27a 0.65a 0.25a 0.26a 0.70a 0.61a 0.20a 0.20a 0.43a 0.66a 0.23a 0.26a
N/Ab 0.33b N/Ab N/Ab 3.1b 1.0b N/Ab N/Ab N/Ab 0.59b N/Ab N/Ab
N/Ac 0.56c N/Ac N/Ac 0.08c 0.31c N/Ac N/Ac N/Ac 0.44c N/Ac N/Ac
rs5219 0.46a 0.14a
N/Ab 		0.38a
3.2b 		0.38a
3.7b 		0.23a
28.7b 		0.26a
19.7b 		0.42a
1.1b 		0.33a
9.2b 		0.01a
N/Ab 		0.41a
1.24b 		0.29a
17.4b 		0.00a
N/Ab 		0.06a
N/Ab
N/Ac 0.07c 0.05c 8e-8c 1e-5c 0.29c 0.002c N/Ac 0.26c 3e-5c N/Ac N/Ac
rs4149056 0.04a 0.06a 0.15a 0.14a 0.14a 0.14a 0.02a 0.12a 0.02a 0.08a 0.21a 0.01a 0.02a
0.38b 3.0b 2.19b 2.4b 2.6b 8.5b 1.1b 7.9b 0.05b 11.0b 13.3b 7.6b
0.53c 0.08c 0.14c 0.12c 0.10c 0.004c 0.29c 0.004c 0.82c 0.001c 3e-4c 0.01c
rs7294 0.38a 0.48a 0.31a 0.04a 0.17a 0.42a 0.67a 0.09a 0.43a 0.35a 0.34a 0.51a 0.46a
N/Ab 14.5b 0.64b 0.98b 15.2b 0.02b 2.9b N/Ab 23.4b 10.7b N/Ab N/Ab
N/Ac 1e-4c 0.42c 0.32c 1e-4c 0.89c 0.09c N/Ac 1e-6c 0.001c N/Ac N/Ac
rs9934438 0.41a 0.15a 0.43a 0.96a 0.82a 0.36a 0.17a 0.90a 0.04a 0.47a 0.48a 0.03a 0.06a
27.3b 0.19b N/Ab N/Ab 1.4b 32.2b N/Ab N/Ab 1.3b 2.4b N/Ab N/Ab
1.7e-7c 0.65c N/Ac N/Ac 0.24c 1e-8c N/Ac N/Ac 0.25c 0.12c N/Ac N/Ac
rs12659 0.49a 0.40a 0.42a 0.49a 0.53a 0.39a 0.36a 0.54a 0.53a 0.34a 0.44a 0.48a 0.55a
2.8b 2.5b 0.02b 0.81b 4.8b 8.3b 1.4b 0.77b 8.1b 1.2b 0.05b 1.8b
0.09c 0.10c 0.90c 0.37c 0.03c 0.004c 0.23c 0.38c 0.004c 0.28c 0.83c 0.18c
rs1051266 0.48a 0.43a 0.57a 0.52a 0.46a 0.60a 0.60a 0.46a 0.31a 0.65a 0.55a 0.33a 0.31a
0.79b 3.9b 0.92b 0.17b 4.6b 7.9b 0.31b 15.2b 10.3b 2.5b 12.4b 14.1b
0.37c 0.05c 0.33c 0.68c 0.01c 0.005c 0.58c 1e-4c 0.001c 0.11c 4e-4c 2e-4c
rs1131596 0.47a 0.38a 0.57a 0.52a 0.46a 0.60a 0.61a 0.46a 0.24a 0.65a 0.55a 0.28a 0.28a
3.1b 5.1b 1.5b 0.03b 7.8b 9.6b 0.09b 28.3b 11.8b 3.5b 201b 19.0b
0.08c 0.02c 0.22c 0.87c 0.005c 0.001c 0.77c 1.1e-7c 0.001c 0.06c 1e-5c 1e-5c
rs4124874 0.44a 0.22a 0.57a 0.72a 0.55a 0.62a 0.39a 0.69a 0.11a 0.48a 0.56a 0.09a 0.22a
47.3b 7.8b 42.7b 5.6b 15.4b 1.1b 31.5b 63.9b 0.74b 7.04b 74.6b 0.9b
N/Ac 0.005c N/AC 0.02c 9e−5 c 0.28c 2e−8 c N/Ac 0.38c 008e−3 c N/A c 0.3c
rs10929302 0.35a 0.33a 0.30a 0.11a 0.15a 0.23a 0.44a 0.18a 0.36a 0.34a 0.24a 0.64a 0.30a
0.183b 0.95b 37.5b 23.4b 7.7b 4.1b 18.5b 0.05 b 0.01b 7.7b 0.08b 0.9b
0.67c 0.33c N/Ac 2e−6 c 5e−3 c 0.04c 2e−5 c 0.83c 0.91c 6e−3 c 0.78c 0.32c
rs4148323 0.0a 0.01a 0.0a 0.23a 0.10a 0.0a 0.02a 0.13a 0.0a 0.02a 0.0a 0.0a 0.0a
2.7b N/Ab 82.9b 35.2b N/Ab 6.4b 45.3b N/Ab 7.8b N/Ab N/Ab N/Ab
0.09c N/Ac N/Ac N/Ac N/Ac 0.01c N/Ac N/Ab 5e−3 c N/Ac N/Ac N/Ac
rs4680 0.50a 0.27a 0.46a 0.31a 0.26a 0.52a 0.43a 0.28a 0.28a 0.39a 0.45a 0.30a 0.36a
19.0b 0.6b 17.6b 26.1b 0.3b 2.0b 24.5b 22.8b 3.8b 1.1b 20.2b 15.4b
1e−5 c 0.43c 3e-5 c 3.1e-7 c 0.55c 0.15c 7.2e-7 c 1e-6c 0.05c 0.28c 6e-6 c 8e-5 c
rs1695 0.30a 0.45a
10.2b 		0.39a
5.1b 		0.18a
8.6b 		0.22a
3.6b 		0.31a
0.2b 		0.31a
0.01b 		0.10a
28.7b 		0.51a
23.7b 		0.56a
27.6b 		0.29a
23.7b 		0.39a
5.8b 		0.43a
10.3b
0.001c 0.02c 0.003c 0.05c 0.62c 0.76c 8e-8 c 1e-6 c 1.5e-7c 1e-6 c 0.01c 0.001c
rs1138272 0.10a 0.00a 0.09a 0.00a 0.00a 0.05a 0.08a 0.00a 0.01a 0.05a 0.05a 0.00a 0.001a
6.4b N/A 21.1b 19.1b 2.6b 0.2b N/Ab 13.2b 2.07b 3.6b 22.1b 17.1b
0.01c N/A 4e-6c 1e-5c 0.1c 0.58c N/Ac 3e-4c 0.15c 0.05c 2e-6c 3e-5c
rs890293 0.07a 0.16a 0.05a 0.04a 0.02a 0.05a 0.05a 0.02a 0.14a 0.03a 0.05a 0.15a 0.10a
10.1b 0.5b 1.2b 6.5b 0.6b 0.4b 4.8b 7.3b 2.1b 0.5b 10.8b 2.3b
0.001c 0.46c 0.27C 0.01c 0.44 c 0.54c 0.02 c 0.007c 0.14c 0.47 c 0.001 c 0.12c
rs10264272 0.0a 0.05a 0.00a 0.00a 0.00a 0.00a 0.00a 0.0a 0.24a 0.02a 0.01a 0.17a 0.11a
16.5b N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab 7.8b 1.6b N/Ab N/Ab
5e−5 c N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac 0.005c 0.21c N/Ac N/Ac
rs776746 0.03a 0.68a 0.04a 0.31a 0.31a 0.05a 0.28a 0.25a 0.88a 0.23a 0.05a 0.83a 0.75a
N/Ab 0.4b N/Ab N/Ab 1.9b N/Ab N/Ab N/Ab N/Ab 1.5b N/Ab N/Ab
N/Ac 0.52c N/Ac N/Ac 0.16c N/Ac N/Ac N/Ac N/Ac 0.21c N/Ac N/Ac
rs4986913 0.0a 0.0a 0.0a 0.0a 0.0a 0.0a 0.005a 0.0a 0.0a 0.0a 0.0a 0.0a 0.0a
N/Ab N/Ab N/Ab N/Ab N/Ab 1.6b N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab
N/Ac N/Ac N/Ac N/Ac N/Ac 0.20c N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac
rs4986910 0.0a 0.0a 0.01a 0.0a 0.0a 0.01a 0.0a 0.0a 0.0a 0.0a 0.0a 0.0a 0.0a
N/Ab 3.6b N/Ab N/Ab 3.6b N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab
N/Ac 0.06c N/Ac N/Ac 0.06c N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac
rs2740574 0.004a 0.67a 0.02a 0.0a 0.0a 0.03a 0.08a 0.0a 0.83a 0.07a 0.03a 0.76a 0.66a
N/Ab 2.4b 0.6b 0.6b 7.8b 23.2b 0.6b N/Ab 19.7b 6.4b N/Ab N/Ab
N/Ac 0.12c 0.43c 0.45c 0.005c 1.4e-6b 0.43c N/Ac 1e-5c 0.01c N/Ac N/Ac
rs4986893 0.0a 0.0a 0.0a 0.04a 0.07a 0.0a 0.0a 0.07a 0.01a 0.0a 0.0a 0.0a 0.005a
N/Ab N/Ab 14.7b 25.6b N/Ab N/Ab 30.8b 3.4b N/Ab N/Ab N/Ab 1.7b
N/Ac N/Ac 1.4e-4c 4e-7c N/Ac N/Ac 3e-8c 0.07c N/Ac N/Ac N/Ac 0.19c
rs4244285 0.09a 0.14a 0.13a 0.33a 0.26a 0.14a 0.33a 0.32a 0.21a 0.12a 0.09a 0.17a 0.15a
2.3b 2.2b N/Ab 27.6b 3.3b N/Ab N/Ab 15.7b 1.2b 0.02b 7.2b 4.5b
0.12c 0.13c N/Ac 1.5e-7c 0.07c N/Ac N/Ac 8e-5c 0.27c 0.9c 0.007c 0.03c
rs1799853 0.02a 0.04a 0.15a 0.0a 0.0a 0.08a 0.05a 0.0a 0.0a 0.10a 0.15a 0.0a 0.03a
0.9b 30.3b 5.0b 4.5b 10.7b 2.3b 5.1b 4.8b 12.7b 31.7b 5.2b 0.02b
0.34c 4e-8c 0.02c 0.03c 0.001c 0.12c 0.02c 0.02c 4e-4c 2e-8c 0.02c 0.89c
rs28399454 0.0a 0.07a
24.9b 		0.0a
N/Ab 		0.0a
N/Ab 		0.0a
N/Ab 		0.0a
N/Ab 		0.0a
N/Ab 		0.0a
N/Ab 		0.06a
18.8b 		0.0a
N/Ab 		0.0a
N/Ab 		0.13a
N/Ab 		0.15a
N/Ab
5.8e-7c N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac 1e-5c N/Ac N/Ac N/Ac N/Ac
rs1801272 0.0a 0.01a 0.04a 0.0a 0.0a 0.03a 0.01a 0.0a 0.0a 0.0a 0.05a 0.0a 0.0a
2.7b 11.8b N/Ab N/Ab 9.2b 3.2b N/Ab N/Ab N/Ab 15.8b N/Ab N/Ab
0.09c 6e-4c N/Ac N/Ac 0.002c 0.07c N/Ac N/Ac N/Ac 7e-5c N/Ac N/Ac
rs28399433 0.09a 0.06a 0.05a 0.27a 0.18a 0.04a 0.19a 0.28a 0.09a 0.10a 0.06a 0.10a 0.06a
0.2b 3.0b 28.7b 8.0b 3.9b 10.5b 32.2b 0.002b 0.1b 1.2b 0.1b 1.4b
0.64c 0.08c 8e-8c 0.01c 0.04c 0.001c 1e-8c 0.96c 0.75c 0.27c 0.70c 0.23c
rs3745274 0.31a 0.35a 0.28a 0.27a 0.33a 0.23a 0.23a 0.22a 0.36a 0.31a 0.30a 0.40a 0.38a
0.05b 0.6b 15.5b 0.1b 3.8b 4.6b 5.3b 1.2b N/Ab 0.04b 4.7b 2.5b
0.82c 0.40c 8.4e-5c 0.71c 0.05c 0.03c 0.02c 0.27c N/Ac 0.83c 0.03c 0.11c
rs28399499 0.0a 0.1a 0.0a 0.0a 0.0a 0.0a 0.0a 0.0a 0.06a 0.08a 0.0a 0.12a 0.05a
33.5b N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab 20.6b 2.5b N/Ab N/Ab 32.2b
1e-8c N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac 6e-6c 0.11c N/Ac N/Ac 1e-8c
rs59421388 0.0a 0.04a 0.0a 0.0a 0.0a 0.0a 0.0a 0.0a 0.09a 0.0a 0.0a 0.11a 0.08a
13.7b N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab
2e-4c N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac
rs28371725 0.14a 0.02a 0.12a 0.03a 0.08a 0.07a 0.15a 0.01a 0.03a 0.02a 0.14a 0.01a 0.05a
14.8b 0.5b 16.8b 4.4b 5.9b 0.002b 30.1b 17.6b 15.8b N/Ab 28.7b 11.8b
1e-4c 0.46c 4e-5c 0.03c 0.01c 0.96c 4e-8c 3e-5c 7e-5c N/Ac 8e-8c 6e-4c
rs61736512 0.0a 0.04a 0.0a 0.0a 0.0a 0.0a 0.0a 0.0a 0.17a 0.0a 0.0a 0.11a 0.09a
13.7b N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab 32.2b
2e-4c N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac 1e-8c
rs28371706 0.0a 0.15a 0.0a 0.0a 0.0a 0.0a 0.0a 0.0a 0.19a 0.0a 0.0a 0.25a 0.20a
N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab
N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac
rs5030656 0.0a 0.01a 0.02a 0.0a 0.0a 0.04a 0.0a 0.0a 0.0a 0.01a 0.01a 0.0a 0.0a
2.7b 6.8b N/Ab N/Ab 13.0b N/Ab N/Ab N/Ab 2.6b 11.0b N/Ab N/Ab
0.99c 0.01c N/Ac N/Ac 3e-4c N/Ac N/Ac N/Ac 0.11c 0.001c N/Ac N/Ac
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Notes: aMinor allele frequency, bChi-square value, cp-value, when p-value < 0.05 is considered a significant difference. 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, ACB; African Caribbeans in Barbados.

Abbreviation: N/A, not applicable.

It is also clear from Table 3 that the similarity of the studied polymorphisms within the Chechens population with other compared population varied from one to another. The CEU Utah (USA residents with Northern and Western European ancestry from the CEPH collection) and TSI (Toscani in Italy) had the highest similarity among the studied population with around 25% differences; ie, around 75% of the studied variants had the same frequency and distribution in Chechens and other compared populations. This similarity in the distribution of the compared SNPs decreased to reach around 30% when compared to LWK (Luhya in Webeye).

Furthermore, the significant variants within the selected genes within Chechen were compared to the available variants within six populations listed in the Exome Aggregation Consortium (ExAC) database as shown in Table 4.

Table 4.

VIP Variants Within the Pharmacogenes in Chechen Compared to Six ExAC Populations Worldwide

SNP\Population Chechen African East Asian Latino European (Non-Finnish) South Asian European (Finnish)
rs3918290 0.003a 0.001a 0.00a 0.001a 0.006a 0.005a 0.022a
2.4b 26.1b 2.2b 0.45b 0.20b 5.6b
0.12c 3.3e-7c 0.13c 0.50c 0.65c 0.02c
rs1065776 0.01a 0.18a 0.04a 0.05a 0.04a 0.11a 0.07a
N/Ab 9.4b 12.5b 8.6b N/Ab 17.7b
N/Ac 0.002c 4e-4c 0.003c N/Ac 3e-5c
rs701265 0.17a 0.69a 0.29a 0.22a 0.14a 0.19a 0.15a
N/Ab 22.8b 6.4b 1.3b 1.4b 0.71b
N/Ac 2e-6c 0.01c 0.26c 0.24c 0.40c
rs2066702 0.01a 0.19a 0.0001a 0.01a 0.002a 0.002a 0.00a
N/Ab N/Ab 0.46b 17.9b 21b N/Ab
N/Ac N/Ac 0.50c 2e-5c 5e-6c N/Ac
rs1229984 0.12a 0.99a 0.27a 0.94a 0.95a 0.95a 0.99a
N/Ab 34.0b N/Ab N/Ab N/Ab N/Ab
N/Ac 1e-8c N/Ac N/Ac N/Ac N/Ac
rs698 0.27a 0.15a 0.08a 0.33a 0.40a 0.32a 0.51a
33.8b N/Ab 6.2b 23.4b 5.1b N/Ab
1e-8c N/Ac 0.01c 1e-6c 0.02c N/Ac
rs3846662 0.43a 0.88a 0.53a 0.47a 0.44a 0.59a 0.47a
N/Ab 1.4b 12.2b 19.7b 0.50b 11.5b
N/Ac 0.24c 5e-4c 1e-5c 0.47c 0.001c
rs1042713 0.37a 0.49a 0.55a 0.42a 0.38a 0.46a 0.45a
18.4b N/Ab 2.9b 0.1b 8.9b 6.7b
2e-5c N/Ac 0.09c 0.78c 0.003c 0.01c
rs1042714 0.31a 0.82a 0.91a 0.83a 0.58a 0.79a 0.63a
N/Ab N/Ab N/Ab N/Ab N/Ab N/Ab
N/Ac N/Ac N/Ac N/Ac N/Ac N/Ac
rs1800888 0.003a 0.002a 0.00a 0.006a 0.01a 0.004a 0.004a
0.05b 26.1b 0.45b 3.0b 0.05b 0.1b
0.82c 3.3e-7c 0.49c 0.08c 0.82c 0.76c
rs2066853 0.13a 0.45a 0.37a 0.12a 0.10a 0.14a 0.11a
N/Ab N/Ab 0.1b 2.8b 0.3b 0.49b
N/Ac N/Ac 0.77c 0.09c 0.59c 0.482c
rs3815459 0.27a 0.37a 0.72a 0.38a 0.33a 0.39a 0.44a
1.6b 33.4b 0.59b 6.9b 0.50b 0.03b
0.21c 1e-8c 0.44c 0.01c 0.48c 0.86c
rs5219 0.46a 0.94a 0.64a 0.61a 0.63a 0.63a 0.53a
N/Ab N/Ab 29.3b N/Ab N/Ab 4.9b
N/Ac N/Ac 6e-8c N/Ac N/Ac 0.03c
rs4149056 0.04a 0.03a 0.13a 0.11a 0.16a 0.05a 0.21a
1.3b 22.4b 15.6b N/Ab 0.84b N/Ab
0.24c 2e-6c 1e-4c N/Ac 0.35c N/Ac
rs12659 0.49a 0.55a 0.49a 0.56a 0.58a 0.64a 0.56a
4.0b 0.007b 7.3b 11.2b 31.7b 5.6b
0.05c 0.93c 0.006c 0.001c 2e-8c 0.02c
rs1051266 0.48a 0.42a 0.52a 0.59a 0.60a 0.61a 0.60a
13.5b 0.01b 6.6b 8.1b 10.3b 8.8b
2e-4c 0.93c 0.01c 0.004c 0.001c 0.003c
rs1131596 0.47a 0.36a 0.51a 0.56a 0.59a 0.58a 0.61a
16.6b 1.4b 8.1b 20.3b N/Ab 12.8b
4e-5c 0.23c 0.004c 1e-5c N/Ac 3e-4c
rs4148323 0.0a 0.0009a 0.15a 0.03a 0.004a 0.02a 0.05a
0.2b 5.9b 8.9b 1.1b 6.4b 15.9b
0.59c 0.01c 0.003c 0.27c 0.01c 7.7e-5c
rs4680 0.50a 0.32a 0.28a 0.41a 0.53a 0.45a 0.57a
N/Ab N/Ab 11.3b 1.1b 3.5b 6.6b
N/Ac N/Ac 7.6e-4c 0.30c 0.06c 0.009c
rs1695 0.30a 0.44a 0.18a 0.53a 0.31a 0.29a 0.27a
27.7b 29.3b N/Ab 0.7b 0.1b 0.8b
1.4e-7c 6e-8c N/Ac 0.41c 0.71c 0.35c
rs1138272 0.10a 0.02a 0.0003a 0.03a 0.08a 0.07a 0.08a
N/Ab N/Ab N/Ab 1.5b 3.6b 0.7b
N/Ac N/Ac N/Ac 0.22c 0.05c 0.41c
rs10264272 0.0a 0.12a 0.0a 0.01a 0.001a 0.0002a 0.0a
N/Ab N/Ab 2.67b 0.27b 0.08b N/Ab
N/Ac N/Ac 0.10c 0.60c 0.78c N/Ac
rs4986913 0.0a 0.0a 0.0a 0.0a 0.0a 0.001a 0.0a
N/Ab N/Ab N/Ab N/Ab 0.26b N/Ab
N/Ac N/Ac N/Ac N/Ac 0.61c N/Ac
rs4986910 0.0a 0.001a 0.0a 0.002a 0.007a 0.0a 0.02a
0.41b N/Ab 0.60b 2.5b N/Ab 7.0b
0.52c N/Ac 0.43c 0.11c N/Ac 0.008c
rs4986909 0.0a 0.0a 0.0a 0.002a 5.994e-05 0.0a 0.0a
N/Ab N/Ab 0.05b 0.02b N/Ab N/Ab
N/Ac N/Ac 0.81c 0.88c N/Ac N/Ac
rs4986893 0.0a 0.0005a 0.07a 0.0004a 0.0002a 0.004a 0.0002a
0.16b 23.9b 0.08b 0.06b 1.2b 0.05b
0.68c 1e-6c 0.76c 0.80c 0.27c 0.82c
rs4244285 0.09a 0.18a 0.31a 0.10a 0.15a 0.34a 0.18a
18.0b N/Ab 0.39b 8.6b N/Ab 18.3b
2.2e-5c N/Ac 0.53c 0.003c N/Ac 1.8e-5c
rs1799853 0.02a 0.02a 0.0003a 0.07a 0.13a 0.05a 0.12a
0.004b N/Ab 9.3b 31.5b 3.5b 27.3b
0.94c N/Ac 0.002c 2e-8c 0.05c 1.7e-7c
rs28399454 0.0a 0.11a 0.0a 0.006a 0.0004a 0.0a 0.0a
N/Ab N/Ab 1.9b 0.1b N/Ab N/Ab
N/Ac N/Ac 0.15c 0.73c N/Ac N/Ac
rs1801272 0.0a 0.005a 0.0a 0.012a 0.025a 0.011a 0.023a
1.5b N/Ab 4.0b 8.7b 3.8b 7.9b
0.20c N/Ac 0.04c 0.003c 0.04c 0.004c
rs28399433 0.09a 0.083a 0.23a 0.138a 0.068a 0.144a 0.11a
0.3b 0.30b 5.6b 2.8b 7.1b 1.1b
0.57c 0.57c 0.01c 0.09c 0.007c 0.28c
rs3745274 0.31a 0.37a 0.19a 0.32a 0.24a 0.19a 0.19a
4.1b 31.6b 0.08b 8.9b 8.2b 29.4b
0.04c 2e-8c 0.76c 0.003c 0.004c 6e-8c
rs28399499 0.0a 0.07a 0.0a 0.003a 0.0001a 0.0001a 0.0a
25.2b N/Ab 1.1b 0.04b 0.04b N/Ab
5.1e-7c N/Ac 0.30c 0.83c 0.83c N/Ac
rs59421388 0.0a 0.092a
33.6b
1e-8c 		0.0001a
0.04b
0.84c 		0.004a
1.2b
0.26c 		0.0003a
0.09b
0.76c 		0.0001a
0.04b
0.84c 		0.0a
N/Ab
N/Ac
rs28371725 0.14a 0.03a 0.03a 0.03a 0.09a 0.15a 0.03a
N/Ab N/Ab 9.3b 9.3b 0.2b N/Ab
N/Ac N/Ac 0.002c 0.002c 0.64c N/Ac
rs61736512 0.0a 0.10a 0.0005a 0.004a 0.0003a 0.0002a 0.0a
N/Ab 0.15a 1.3a 0.08a 0.08a N/Ab
N/Ac 0.69c 0.25c 0.76c 0.77c N/Ac
rs28371706 0.0a 0.197a 0.0a 0.007a 0.002a 0.001a 0.0002a
N/Ab N/Ab 2.4b 0.71b 0.1b 0.05b
N/Ac N/Ac 0.12c 0.39c 0.75c 0.81c
rs5030656 0.0a 0.004a 0.0a 0.012a 0.03a 0.002a 0.015a
1.4b N/Ab 4.3b 10.4b 0.6b 5.2b
0.22c N/Ac 0.04c 0.001c 0.41c 0.02c
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Notes: aMinor allele frequency, bChi-square value, cp-value, when p-value < 0.05 is considered a significant difference.

Abbreviation: N/A, not applicable.

Discussion

This study was conducted on Chechens group living in Jordan. This subpopulation has a distinct genetic makeup as a genetically isolated population.19 Our findings demonstrate that the Chechen living in Jordan may have widely varying genetic allele distribution for clinically relevant SNPs compared to other populations. Assessment of the VIP genetic polymorphism frequencies within such a minority group can attribute to studies of the theoretical basis of drug toxicity and efficacy.

Several single nucleotide variants within the CYP450 genes have been reported as clinically significant. For example; within the CYP2J2 gene, the variant rs890293 genotypes AA + AC have been shown to be correlated to an increased risk of nausea and vomiting when treated with tacrolimus in individuals with Kidney Transplantation as compared to genotype CC.20

rs4244285 (GG) genotype of CYP2C19 is associated with increased risk of toxicity when treated with cyclophosphamide in women with Lupus Erythematosus, as compared to genotypes AA + AG.21 Besides, patients with the genotype GG of rs4986893 and treated with phenytoin may have a decreased likelihood of drug reaction with eosinophilia and systemic symptoms (DRESS) as compared to patients with the AG and AA genotypes.22 It also was found that allele A is associated with an increased risk of cardiovascular events when treated with clopidogrel in patients with coronary disease as compared to genotype GG.23 Moreover, allele A of rs4986893 is associated with decreased clopidogrel inhibition of ADP-induced platelet aggregation when treated with clopidogrel in healthy individuals as compared to genotype GG.24,25

Furthermore, our findings reveal that the alternative allele (T) frequency of rs1229984 in ADH1B gene among Chechen was much less than in Latino (94%), African (99%), European non-Finnish (95%), South Asian (95%) and European Finnish (99%) according to ExAC database. rs1229984 was reported as a clinically significant variant, whereas TT genotype was associated with increased Vmax of ethanol in healthy individuals as compared to genotypes CC and CT among mixed population.26

Furthermore, within ADRB2 gene, the frequency of the minor allele (G) of rs1042714 among Chechen was significantly lower than it among others Latino (83%), African 82%, European non-Finnish (58%), South Asian 79 and European Finnish (63%) and East Asian (91%). It was suggested that allele G of rs1042714 was associated with an increased reduction in resting blood pressure when treated with carvedilol in healthy individuals as compared to allele G in a study conducted in a mixed population.27 While Genotype CC was reported to be associated with decreased improvement in heart failure patients when treated with carvedilol compared to genotypes GG and CG.28

In this study, we found that rs5219 of KCNJ11 gene among Chechen was distributed differently from other populations. It was proposed that the Genotype (TT) is associated with an increased likelihood of Diabetes II Mellitus.29

One significant limitation for this study is the sample size, large study cohort is recommended to compare the variants frequencies with other population. In addition, better designed statistical analyses should be provided for accurate results. In conclusion, rare variants detected in isolated populations can significantly guide to understanding a potential biological process and identifying genetic loci involved in the development of clinically relevant treatment for different diseases.

Funding Statement

This study was funded by the Deanship of Research (RN: 126/2017), Jordan University of Science and Technology.

Ethics Committee Approval and Patient Consent

This study was conducted in agreement with the Human ethics committee at National Center for Diabetes, Endocrinology and Genetics (NCDEG) and Jordan University of Science and Technology (JUST), policy number (GM7601). Written informed consent was obtained from all volunteers in the study.

Disclosure

The authors declare that they have no competing interests.

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