Table 1.

List of specific gene polymorphisms and relative enzymes relevant to the human metabolism.

Polymorphism Function	Detoxification	European Allele Frequency	Effects on Enzyme Activity
Glutathione S Transferase
GST-T1 rs17856199	Detoxification of xenobiotics, carcinogenic substances, therapeutic drugs, environmental toxins, and oxidative stress products.	GST-T1 A = 0.867 C = 0.183	GST-M1 and GST-T1 homozygous deletions (pos/null) have a decreased ability to detoxify carcinogens, toxicants, and oxidative stress products. The gene deletion has been found in Caucasian and Asian populations compared to Africans [33].
GST-M1 rs366631		GST-M1 A = 0.488 G = 0.512
GST-A1 rs3957357		GST-A1 A = 0.571 G = 0.429	The distributions of GSTA1-69C > T promoter haplotypes and diplotypes were significantly different among the human populations. The frequencies of GSTA1-69C > T polymorphism were similar to those of the African American population and the populations with White ancestry, but significantly different from those reported for the populations with Asian ancestry [34].
GST-P1 rs1695		GST-P1 A = 0.669 G = 0.331	Several papers published findings associating GSTP1 Ile105Val genotypes with bronchial, childhood, or atopic asthma. Compared with the AA genotype, the GA + GG genotype decreased lung cancer susceptibility [35].
Epoxide hydrolase
EPHX1-Ex_3 rs1051740	Biotransformation enzymes converting epoxides from the degradation of aromatic compounds to trans-dihydrodiols excreted from the body. EPHX1 was shown to take part in protection against oxidative stress.	EPHX1-Ex3: T = 0.696 C = 0.304	In vitro polymorphisms in exons 3 (His113Tyr) and 4 (Arg139His) lead to reduced activity (slow allele) and increased activity (fast allele). T to C substitution (slow allele) reduces the enzyme activity. Decreased activity (histidine) A to G substitution (fast allele) increases the enzyme activity. Increased activity (arginine) [36].
EPHX1-Ex_4 rs2234922		EPHX1-Ex4: A = 0.836 G = 0.164
Cytochrome P450 family
CYP1A1_2A rs4646903	Catalysis of reactions involved in the drug metabolism and synthesis of cholesterol, steroids, and lipids, some of which are found in cigarette smoke. The enzyme’s endogenous substrate is able to metabolize some polycyclic aromatic hydrocarbons into carcinogenic intermediates.	CYP1A1-2A: A = 0.893 G = 0.107	The CYP1A1 Ile462Val polymorphism may enhance the susceptibility to cervical cancer in Caucasian females. The gene has been associated with lung cancer risk. Higher inducibility. Increased oxidation [37].
CYP1A1_2C rs1048943 Ile462Val		CYP1A1-2C: T = 0.965 C = 0.035
Cytochrome P450 2E1
CYP2E1*5B rs3813867	Cytochrome P450 2E1 (CYP2E1) is one of the major enzymes involved in the metabolism and detoxification of various drugs and xenobiotics.	CYP2E1*5B: G = 0.959 A = 0.041	The genotype distributions of CYP2E1*5B and *6 were similar to the Caucasian population but were different from East Asian populations. Wang, L.N.; Wang, F.; Liu, J.; Ying-Hui, J.; Fang, C.; Ren, X.Q. CYP1A1 Ile462Val polymorphism is associated with cervical cancer risk in Caucasians not Asians: A Meta-Analysis. Front. Physiol. 2017, 8, 1081. https://doi.org/10.3389/fphys.2017.01081. [38]
CYP2E1*6 rs6413432		CYP2E1*6: T = 0.908 A = 0.091	CYP2E1*6 polymorphism causes a reduction in CYP2E1 enzyme activity [39].
Cytochrome P450 family 2 subfamily D6 and Cytochrome P450 family 2 subfamily A6
CYP2D6 rs16947	CYP2D6 is responsible for the oxidative metabolism of 20–25% of drugs.	CYP2D6: G = 0.710 A = 0.290	Unfunctional alleles represent 26% of the variability mainly in CYP2D6*4. “Frequency of CYP2D6 Alleles Including Structural Variants in the United States” Del Tredici, A.L.; Malhotra, A.; Dedek, M.; Espin, F.; Roach, D.; dan Zhu, Guang.; Voland, J.; Moreno, T.;A. Front. Pharmacol., 2018 Pharmacogenetics and Pharmacogenomics [40]
CYP2A6 rs1801272	Nicotine metabolism is mediated primarily by cytochrome CYP2A6. The genetic variation in this gene has been linked with several smoking behavior phenotypes.	CYP2A6: A = 0.973 T = 0.026	The frequencies of this allele vary considerably among different ethnic populations, the deletion alleles being most common in Oriental people (up to 20%). Studies of Japanese populations suggest that CYP2A6 poor metabolizer genotypes result in altered nicotine kinetics and may lower cigarette smoking-elicited lung cancer risk, whereas similar studies in Caucasian populations have not revealed any clear associations between variant CYP2A6 genotypes and smoking behavior or lung cancer predisposition [41].
N-Acetyl Transferase
NAT1 rs4987076	N-acetyltransferase 1 detoxifies many drugs and chemicals found in the environment eliminated from the body or bioactivated to metabolites causing toxicity/cancer. NAT1 activity is regulated by genetic polymorphisms as well as environmental factors such as substrate-dependent down-regulation and oxidative stress.	NAT-1: G = 0.974 A = 0.025	NAT-1: a monomorphic form of the enzyme [42].
NAT2 rs1208	N-acetyltransferase 2 enzyme detoxifies xenobiotics (carcinogens and drugs). Variation at the NAT2 gene has been linked to the human acetylation capacity: slow, intermediate, and fast, which modifies susceptibility to cancer and adverse drug reactions.	NAT-2: G = 0.434 A = 0.565	Multiple NAT2 alleles (NAT2*5,*6, *7, and *14) have substantially decreased acetylation activity and are common in Caucasian people and populations of African descent. Link between acetylator phenotype and increased risk for bladder and colon cancer [43].
Oxidative Stress
MPO Myeloperoxidase rs2333227	Oxidoreductase catalyzing H2O2 to H2O.	MPO: C = 0.910 T = 0.089	A study of 127 Finnish patients concluded that the rs2333227 allele increased the risk of Alzheimer’s disease [44]. In a further study polymorphism of MPO was statistically associated with AD in a gender-specific manner. Myeloperoxidase polymorphism is associated with a gender-specific risk for Alzheimer’s disease [45].
Heme Oxygenase rs2071746 -413AT	Cytoprotective enzyme activated during cellular stress such as inflammation, ischemia, hypoxia, hyperoxia, and radiation.	HO1: A = 0.440 G = 0.560	In the Ala16Val, the Ala amino acid seems to be more favorable than the Val amino acid. Higher risk for Alzheimer’s disease (TT) [46].
SOD2 rs4880	Mitochondrial enzyme with a key role in protecting the cell from oxidative damage.	SOD: A = 0.502 G = 0.498	Ala16Val: The Val amino acid is less favorable. Association of smoking and homozygosity for the MnSOD Val allele contributing to an increased risk of diabetic nephropathy [47].
NRF2 rs6721961	Regulator of the cell transcriptional response to oxidative stress induced by exposure to xenobiotics.	NRF2 rs6721961 G = 0.875 (wt) T = 0.125 (mut)	The “G” and “T” alleles resulted in higher and lower expressions of NRF2 mRNA, showing that the G allele is beneficial for protection from pathologies. In contrast, the “T” allele of rs6721961 significantly increases susceptibility to the elevation of the hearing threshold at 4 kHz in the occupational setting [48]. NRF2 (rs6721961) (-617A/A) alleles in the NRF2 gene have been associated with female non-smokers with adenocarcinoma and are regarded as a prognostic biomarker for assessing the overall survival of patients with lung adenocarcinoma [49]. “C” indicates the wild allele, and “T” indicates the mutant allele [50].
NRF2 rs6706649		NRF2 rs6706649 C = 0.882 T = 0.118
NRF2 rs35652124		NRF2 rs35652124 C = 0.327 T = 0.672
NQO1 rs1800566	Enzyme involved in preventing free-redox radical generation.	NQO1 rs1800566: G = 0.809 A = 0.190	The variant enzyme, C609T, is ubiquitinated by the proteasome (greater risk for 609TT). Susceptibility risk for hepatocellular carcinoma [51].
NQO1 rs1131341	(C465T, Arg139Trp) is a polymorphism within NQO1 (NAD(P)H dehydrogenase (quinone 1)	NQO1 rs1131341 G = 0.961 A = 0.038	The variant enzyme C465T shows reduced enzyme activity. Potential risk of (ALL) Acute Lymphoblastic Leukemia (AML) Acute Myeloid Leukemia [52].
DNA damage Repair
hOGG1 rs1052133	The human 8-oxoG DNA glycosylase 1 plays a central role in repairing 8-oxoGs via the base excision repair pathway. Evidence suggests that hOGG1 affects the activity as a genetic marker for the prediction of personal susceptibility to several cancers.	hOGG1 C = 0.778 G = 0.221	In solid tumors, the genotypes CG and/or GG at hOGG1 rs1052133 have been reported to be associated with an increased risk of various types of cancer. The polymorphic site of hOGG1, i.e., rs1052133 (Ser326Cys), C to G showed that the glycosylase activity of the “G” variant is more sensitive to inactivation by oxidizing agents than that of the “C” wild-type, and cells carrying the “G” allele may accumulate mutations more readily under oxidative stress [53].
XRCC1 rs25487 Arg399Gln	The protein encoded by XRCC1 is involved in the repair of DNA single-strand breaks formed by exposure to ionizing radiation and alkylating agents.	XRCC1 C = 0.642 T = 0.357	XRCC1 has protective gene polymorphisms due to the enhanced repair activity even though the Arg399Gln polymorphism (rs25487 and rs1799782 Arg194Trp) have been reported to be related to prostate cancer [54].
rs1799782 Arg194Trp		G = 0.937 A = 0.062
XRCC3 rs861539	The gene is involved in the homologous recombination repair pathway (HRR) of double-stranded DNA, deputed to repair chromosomal fragmentation, translocations, and deletions.	XRCC3 G = 0.617 A = 0.382	XRCC3 promotes the homology-directed repair of DNA damage in mammalian cells. Three amino acid substitution variants of DNA repair genes (XRCC1 Arg194Trp, XRCC1 Arg399Gln, and XRCC3 Thr241Met) showed an association with breast cancer susceptibility. Polymorphisms of XRCC1 and XRCC3 genes and susceptibility to breast cancer [55].
XPD/ERCC2 rs13181	The ERCC2 contributes to the synthesis of XPD protein. This is an essential subunit of a group of proteins known as the TFIIH complex with two major functions: the activation of gene transcription and the repair of damaged DNA.	XPD/ERCC2 T = 0.626 G = 0.373	XPD protein is involved in transcription initiation and in the control of the cell cycle and apoptosis. The ERCC2-rs13181 C allele was associated with a significantly increased risk of colorectal cancer risk [56].
Alcohol dehydrogenase
ADH1B rs1229984 Arg 48 His	Enzymes involved in alcohol metabolism. The functional variant, Arg48His (rs1229984), is located in the ADH1B gene and protects against alcohol dependence.	ADH1B G = 0.951 A = 0.048	ADH1B has been reported to associate with reduced rates of alcohol and drug dependence. The allele with increased activity, meaning the more rapid oxidation of ethanol to acetaldehyde, is His48, encoded by rs1229984. Carriers with one or two ADH alleles, such as (G/A) or (A/A) have a reduced risk for alcoholism. These findings support that the His allele can greatly lower the risk of AD and alcohol abuse and provide strong evidence for the involvement of the ADH1B gene in the pathogenesis of AD and alcohol-induced diseases in particular in multiple populations such as Asian populations [57].
ADH1B rs2066702 Arg370Cys		ADH1B G = 0.997 A = 0.002	ADH1B Arg370Cys is monomorphic in European populations, but it has been shown to have a small effect on the rate of alcohol elimination in African Americans [58].
ADH1C rs698 Ile350Val	The rs698(A) allele is the most common, encoding isoleucine; the rare (T) allele encodes the variant phenylalanine	ADH1C A = 0.609 T = 0.391	An increasing number of studies have investigated the association between ADH polymorphisms and cancer risk in humans. AA normal enzyme activity AT-TT reduction in the enzyme activity and intolerance to ethanol. Among them, studies of the ADH1C Ile350Val (rs698) variant accounted for more than others. The results indicate that ADH1C Ile350Val polymorphism may contribute to cancer risk among African populations and Asian populations [59].
ADH4 rs3805322	The alcohol dehydrogenase (ADH) family represents one of the key sets of enzymes responsible for the oxidation of alcohol. This enzyme is an important member of this family, it is a functional candidate for alcohol dependence in human consumption of alcohol.	ADH4 A = 0.998 G = 0.003	A significantly increased risk of developing esophageal squamous-cell carcinoma was revealed in subjects with the AA genotype for rs3805322 (ADH4) compared with those with the AG or GG genotype [60].
Aldehyde dehydrogenase
ALDH2 rs671 Glu504Lys	Aldehyde dehydrogenases efficiently oxidize and, in most instances, detoxifies a significant number of chemical aldehydes which otherwise would be harmful to the organism.	ALDH G = 1.000	Individuals with the ALDH2 504Lys variant were less associated with alcoholic liver disease compared to those with ALDH2 504Glu by genotypic and allelic analyses [61].