Journal of Personalized Medicine

Editorial

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4 pages, 189 KiB

Open AccessEditorial

Advances in Personalized Medicines along with Functional Genomics and Pharmacogenomics

by Su-Jun Lee

J. Pers. Med. 2021, 11(10), 941; https://doi.org/10.3390/jpm11100941 - 22 Sep 2021

Viewed by 1824

Abstract

State-of-the-art research on the human genome has produced remarkable research achievements in pharmacogenomics and functional genomics, and these research results are making an invaluable contribution to the advancement of personalized medicine [...] Full article

(This article belongs to the Special Issue Functional Genomics, Pharmacogenomics in Human Disease)

Research

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17 pages, 2642 KiB

Open AccessFeature PaperArticle

Functional Characterization of 21 Rare Allelic CYP1A2 Variants Identified in a Population of 4773 Japanese Individuals by Assessing Phenacetin O-Deethylation

by Masaki Kumondai, Evelyn Marie Gutiérrez Rico, Eiji Hishinuma, Yuya Nakanishi, Shuki Yamazaki, Akiko Ueda, Sakae Saito, Shu Tadaka, Kengo Kinoshita, Daisuke Saigusa, Tomoki Nakayoshi, Akifumi Oda, Noriyasu Hirasawa and Masahiro Hiratsuka

J. Pers. Med. 2021, 11(8), 690; https://doi.org/10.3390/jpm11080690 - 22 Jul 2021

Cited by 7 | Viewed by 3762

Abstract

Cytochrome P450 1A2 (CYP1A2), which accounts for approximately 13% of the total hepatic cytochrome content, catalyzes the metabolic reactions of approximately 9% of frequently used drugs, including theophylline and olanzapine. Substantial inter-individual differences in enzymatic activity have been observed among patients, which could [...] Read more.

Cytochrome P450 1A2 (CYP1A2), which accounts for approximately 13% of the total hepatic cytochrome content, catalyzes the metabolic reactions of approximately 9% of frequently used drugs, including theophylline and olanzapine. Substantial inter-individual differences in enzymatic activity have been observed among patients, which could be caused by genetic polymorphisms. Therefore, we functionally characterized 21 novel CYP1A2 variants identified in 4773 Japanese individuals by determining the kinetic parameters of phenacetin O-deethylation. Our results showed that most of the evaluated variants exhibited decreased or no enzymatic activity, which may be attributed to potential structural alterations. Notably, the Leu98Gln, Gly233Arg, Ser380del Gly454Asp, and Arg457Trp variants did not exhibit quantifiable enzymatic activity. Additionally, three-dimensional (3D) docking analyses were performed to further understand the underlying mechanisms behind variant pharmacokinetics. Our data further suggest that despite mutations occurring on the protein surface, accumulating interactions could result in the impairment of protein function through the destabilization of binding regions and changes in protein folding. Therefore, our findings provide additional information regarding rare CYP1A2 genetic variants and how their underlying effects could clarify discrepancies noted in previous phenotypical studies. This would allow the improvement of personalized therapeutics and highlight the importance of identifying and characterizing rare variants. Full article

(This article belongs to the Special Issue Functional Genomics, Pharmacogenomics in Human Disease)

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13 pages, 1116 KiB

Open AccessArticle

Effect of MACC1 Genetic Polymorphisms and Environmental Risk Factors in the Occurrence of Oral Squamous Cell Carcinoma

by Rei-Hsing Hu, Chun-Yi Chuang, Chiao-Wen Lin, Shih-Chi Su, Lun-Ching Chang, Ssu-Wei Wu, Yu-Fan Liu and Shun-Fa Yang

J. Pers. Med. 2021, 11(6), 490; https://doi.org/10.3390/jpm11060490 - 31 May 2021

Cited by 7 | Viewed by 2686

Abstract

MACC1 (Metastasis Associated in Colon Cancer 1) is found to regulate the hepatocyte growth factor (HGF)/Met signal pathway, and plays an important role in tumor proliferation, angiogenesis, and metastasis. However, the relationships between MACC1 SNPs (single nucleotide polymorphisms) and oral cancer are still [...] Read more.

MACC1 (Metastasis Associated in Colon Cancer 1) is found to regulate the hepatocyte growth factor (HGF)/Met signal pathway, and plays an important role in tumor proliferation, angiogenesis, and metastasis. However, the relationships between MACC1 SNPs (single nucleotide polymorphisms) and oral cancer are still blurred. In this study, five SNPs (rs3095007, rs1990172, rs4721888, rs975263, and rs3735615) were genotyped in 911 oral cancer patients and 1200 healthy individuals by real-time polymerase chain reaction (PCR), and the associations of oral cancer with the SNP genotypes, environmental risk factors, and clinicopathological characteristics were further analyzed. Our results showed that individuals who had GC genotype or C-allele (GC + CC) in rs4721888 would have a higher risk for oral cancer incidence than GG genotype after adjustment for betel quid chewing, cigarette smoking, and alcohol drinking. Moreover, the 715 oral cancer patients with a betel quid chewing habit, who had C-allele (TC + CC) in rs975263, would have a higher risk for lymph node metastasis. Further analyses of the sequences of rs4721888 revealed that the C-allele of rs4721888 would be a putative exonic splicing enhancer. In conclusion, MACC1 SNP rs4721888 would elevate the susceptibility for oral cancer, and SNP rs975263 would increase the metastasis risk for oral cancer patients with a betel quid chewing habit. Our data suggest that SNP rs4721888 could be a putative genetic marker for oral cancer, and SNP rs975362 may have the potential to be a prognostic marker of metastasis in an oral cancer patient. Full article

(This article belongs to the Special Issue Functional Genomics, Pharmacogenomics in Human Disease)

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10 pages, 2355 KiB

Open AccessArticle

Association of LINC00673 Genetic Variants with Progression of Oral Cancer

by Shih-Chi Su, Chiao-Wen Lin, Po-Chung Ju, Lun-Ching Chang, Chun-Yi Chuang, Yu-Fan Liu, Ming-Ju Hsieh and Shun-Fa Yang

J. Pers. Med. 2021, 11(6), 468; https://doi.org/10.3390/jpm11060468 - 25 May 2021

Cited by 18 | Viewed by 2436

Abstract

Oral squamous cell carcinoma (OSCC) is a multifactorial malignancy, and its high incidence and mortality rate remain a global public health burden. Polymorphisms in the long intergenic noncoding RNA 673 (LINC00673) have been currently connected to the predisposition to various cancer [...] Read more.

Oral squamous cell carcinoma (OSCC) is a multifactorial malignancy, and its high incidence and mortality rate remain a global public health burden. Polymorphisms in the long intergenic noncoding RNA 673 (LINC00673) have been currently connected to the predisposition to various cancer types. The present study attempted to explore the impact of LINC00673 gene polymorphisms on the risk and progression of OSCC. Three LINC00673 single-nucleotide polymorphisms (SNPs), including rs11655237, rs9914618, and rs6501551, were evaluated in 1231 OSCCC cases and 1194 cancer-free controls. We did not observe any significant association of three individual SNPs with the risk of OSCC between the case and control group. However, while assessing the clinicopathological parameters, patients carrying at least one minor allele of rs9914618 (GA and AA; OR, 1.286; 95% CI, 1.008–1.642; p = 0.043) were found to develop lymph node metastasis more often compared to those who are homozygous for the major allele. Further stratification analyses revealed that this genetic correlation with increased risk of lymphatic spread was further fortified in habitual betel quid chewers (OR, 1.534; 95% CI, 1.160–2.028; p = 0.003) or smokers (OR, 1.320; 95% CI, 1.013–1.721; p = 0.040). Moreover, through analyzing the dataset from The Cancer Genome Atlas (TCGA), we found that elevated LINC00673 levels were associated with the development of large tumors in patients with head and neck squamous cell carcinoma and the risk of lymphatic spread in smokers. These data demonstrate a joint effect of LINC00673 rs9914618 with betel nut chewing or smoking on the progression of oral cancer. Full article

(This article belongs to the Special Issue Functional Genomics, Pharmacogenomics in Human Disease)

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11 pages, 894 KiB

Open AccessArticle

Genetic Variants of lncRNA GAS5 Are Associated with the Clinicopathologic Development of Oral Cancer

by Ming-Hong Hsieh, Hsueh-Ju Lu, Chiao-Wen Lin, Chia-Yi Lee, Shang-Jung Yang, Pei-Hsuan Wu, Mu-Kuan Chen and Shun-Fa Yang

J. Pers. Med. 2021, 11(5), 348; https://doi.org/10.3390/jpm11050348 - 26 Apr 2021

Cited by 15 | Viewed by 2571

Abstract

The long noncoding RNA, Growth arrest-specific 5 (GAS5) plays a crucial role in the development of oral cancer. However, potential genetic variants in GAS5 that affect the susceptibility and progression of oral cancer have rarely been explored. In this study, two loci of [...] Read more.

The long noncoding RNA, Growth arrest-specific 5 (GAS5) plays a crucial role in the development of oral cancer. However, potential genetic variants in GAS5 that affect the susceptibility and progression of oral cancer have rarely been explored. In this study, two loci of GAS5 single nucleotide polymorphisms (SNPs) (rs145204276 and rs55829688) were genotyped by using the TaqMan allelic discrimination in 1125 oral cancer patients and 1195 non-oral-cancer individuals. After statistical analyses, the distribution of both the GAS5 SNP rs145204276 and GAS5 SNP rs55829688 frequencies were similar between the study and control groups. However, the patients with GAS5 SNP rs145204276 variants (Ins/Del or Del/Del) showed a higher tendency of moderate to poor cell differentiation of oral cancer (OR: 1.454, 95% CI: 1.041–2.031, p = 0.028). Moreover, the GAS5 SNP rs145204276 variants (Ins/Del or Del/Del) in the non-alcohol-drinking population were associated with significantly advanced tumor stage (OR: 1.500, 95% CI: 1.081–2.081, p = 0.015) and larger tumor size (OR: 1.494, 95% CI: 1.076–2.074, p = 0.016). Furthermore, individuals with the GAS5 SNP rs145204276 variant were associated with a higher expression of GAS5 in the GTEx database (p = 0.002), and the higher GAS5 level was associated with poor cell differentiation, advanced tumor stage and larger tumor size in head and neck squamous cell carcinoma from the TCGA database (all p < 0.05). In conclusion, the GAS5 SNP rs145204276 variant is related to poor-differentiation cell status in oral cancer. Besides, the presence of the GAS5 SNP rs145204276 variant is associated with a worse tumor stage and tumor size in oral cancer patients without alcohol drinking. Full article

(This article belongs to the Special Issue Functional Genomics, Pharmacogenomics in Human Disease)

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15 pages, 443 KiB

Open AccessArticle

The Association of IgE Levels with ADAM33 Genetic Polymorphisms among Asthmatic Patients

by Malek Zihlif, Amer Imraish, Baeth Al-Rawashdeh, Aya Qteish, Raihan Husami, Rawand Husami, Farah Tahboub, Yazun Jarrar and Su-Jun Lee

J. Pers. Med. 2021, 11(5), 329; https://doi.org/10.3390/jpm11050329 - 22 Apr 2021

Cited by 7 | Viewed by 2089

Abstract

Total serum immunoglobulin E (IgE) is elevated in multiple allergic diseases and is considered a good predictor of atopy. Several studies have been performed on the association of IgE levels with the polymorphism of the ADAM33 gene in asthmatic patients. The aim of [...] Read more.

Total serum immunoglobulin E (IgE) is elevated in multiple allergic diseases and is considered a good predictor of atopy. Several studies have been performed on the association of IgE levels with the polymorphism of the ADAM33 gene in asthmatic patients. The aim of this study was to determine whether there is an association between IgE levels and the genetic polymorphisms of the ADAM33 gene (T1, T2, T + 1, V4, S1, S2, and Q-1) in both healthy and asthmatic patients among Jordanians. The clinical data were collected for this case–control study from 267 asthmatic patients and 225 control subjects. Seven genetic polymorphisms (T1, T2, T + 1, V4, S1, S2, and Q-1) of the gene ADAM33 were analyzed using the polymerase chain reaction/restriction fragment length polymorphism method. The minor alleles (G) of T1, (A) of T2, T + 1, and (G) of V4 polymorphisms were associated with a significant increase in total serum IgE levels in adults but not children. The V4 genetic polymorphism, however, showed a significant association with IgE levels in both adults and children. The S1 polymorphism was significantly associated with the codominant module only in the adults. The S2 polymorphism showed a significant association (p-value < 0.05) in both codominant and recessive models. However, in the dominant model for both pediatric control and asthmatic patients, the association between the IgE and S2 polymorphism was insignificant (p-value = 0.7271 and 0.5259, respectively). This study found a statistically significant association between multiple ADAM33 genetic polymorphisms and IgE levels. Such findings add to the growing evidence that the ADAM33 gene has a major impact on IgE levels among asthmatic patients of Jordanian origin. Full article

(This article belongs to the Special Issue Functional Genomics, Pharmacogenomics in Human Disease)

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12 pages, 1220 KiB

Open AccessArticle

PharmaKU: A Web-Based Tool Aimed at Improving Outreach and Clinical Utility of Pharmacogenomics

by Sumi Elsa John, Arshad Mohamed Channanath, Prashantha Hebbar, Rasheeba Nizam, Thangavel Alphonse Thanaraj and Fahd Al-Mulla

J. Pers. Med. 2021, 11(3), 210; https://doi.org/10.3390/jpm11030210 - 16 Mar 2021

Cited by 6 | Viewed by 3656

Abstract

With the tremendous advancements in genome sequencing technology in the field of pharmacogenomics, data have to be made accessible to be more efficiently utilized by broader clinical disciplines. Physicians who require the drug–genome interactome information, have been challenged by the complicated pharmacogenomic star-based [...] Read more.

With the tremendous advancements in genome sequencing technology in the field of pharmacogenomics, data have to be made accessible to be more efficiently utilized by broader clinical disciplines. Physicians who require the drug–genome interactome information, have been challenged by the complicated pharmacogenomic star-based classification system. We present here an end-to-end web-based pharmacogenomics tool, PharmaKU, which has a comprehensive easy-to-use interface. PharmaKU can help to overcome several hurdles posed by previous pharmacogenomics tools, including input in hg38 format only, while hg19/GRCh37 is now the most popular reference genome assembly among clinicians and geneticists, as well as the lack of clinical recommendations and other pertinent dosage-related information. This tool extracts genetic variants from nine well-annotated pharmacogenes (for which diplotype to phenotype information is available) from whole genome variant files and uses Stargazer software to assign diplotypes and apply prescribing recommendations from pharmacogenomic resources. The tool is wrapped with a user-friendly web interface, which allows for choosing hg19 or hg38 as the reference genome version and reports results as a comprehensive PDF document. PharmaKU is anticipated to enable bench to bedside implementation of pharmacogenomics knowledge by bringing precision medicine closer to a clinical reality. Full article

(This article belongs to the Special Issue Functional Genomics, Pharmacogenomics in Human Disease)

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15 pages, 3759 KiB

Open AccessArticle

Functional Assessment of 12 Rare Allelic CYP2C9 Variants Identified in a Population of 4773 Japanese Individuals

by Masaki Kumondai, Akio Ito, Evelyn Marie Gutiérrez Rico, Eiji Hishinuma, Akiko Ueda, Sakae Saito, Tomoki Nakayoshi, Akifumi Oda, Shu Tadaka, Kengo Kinoshita, Masamitsu Maekawa, Nariyasu Mano, Noriyasu Hirasawa and Masahiro Hiratsuka

J. Pers. Med. 2021, 11(2), 94; https://doi.org/10.3390/jpm11020094 - 2 Feb 2021

Cited by 8 | Viewed by 3152

Abstract

Cytochrome P450 2C9 (CYP2C9) is an important drug-metabolizing enzyme that contributes to the metabolism of approximately 15% of clinically used drugs, including warfarin, which is known for its narrow therapeutic window. Interindividual differences in CYP2C9 enzymatic activity caused by CYP2C9 genetic polymorphisms lead [...] Read more.

Cytochrome P450 2C9 (CYP2C9) is an important drug-metabolizing enzyme that contributes to the metabolism of approximately 15% of clinically used drugs, including warfarin, which is known for its narrow therapeutic window. Interindividual differences in CYP2C9 enzymatic activity caused by CYP2C9 genetic polymorphisms lead to inconsistent treatment responses in patients. Thus, in this study, we characterized the functional differences in CYP2C9 wild-type (CYP2C9.1), CYP2C9.2, CYP2C9.3, and 12 rare novel variants identified in 4773 Japanese individuals. These CYP2C9 variants were heterologously expressed in 293FT cells, and the kinetic parameters (K_m, k_cat, V_max, catalytic efficiency, and CL_int) of (S)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation were estimated. From this analysis, almost all novel CYP2C9 variants showed significantly reduced or null enzymatic activity compared with that of the CYP2C9 wild-type. A strong correlation was found in catalytic efficiencies between (S)-warfarin 7-hydroxylation and tolbutamide 4-hydroxylation among all studied CYP2C9 variants. The causes of the observed perturbation in enzyme activity were evaluated by three-dimensional structural modeling. Our findings could clarify a part of discrepancies among genotype–phenotype associations based on the novel CYP2C9 rare allelic variants and could, therefore, improve personalized medicine, including the selection of the appropriate warfarin dose. Full article

(This article belongs to the Special Issue Functional Genomics, Pharmacogenomics in Human Disease)

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9 pages, 1263 KiB

Open AccessArticle

rs6837671A>G in FAM13A Is a Trans-Ethnic Genetic Variant Interacting with Vitamin D Levels to Affect Chronic Obstructive Pulmonary Disease

by Said El Shamieh, Ali Salami, Mirna Fawaz, Rania Jounblat, Mirna Waked and Rajaa Fakhoury

J. Pers. Med. 2021, 11(2), 84; https://doi.org/10.3390/jpm11020084 - 30 Jan 2021

Cited by 1 | Viewed by 2119

Abstract

(1) Background and objectives: Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality throughout the world. In addition to genetics, increasing evidence suggests that Vitamin D (VitD) might be involved in different pathogenic mechanisms in COPD. Furthermore, the prevalence of VitD [...] Read more.

(1) Background and objectives: Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality throughout the world. In addition to genetics, increasing evidence suggests that Vitamin D (VitD) might be involved in different pathogenic mechanisms in COPD. Furthermore, the prevalence of VitD insufficiency is exceptionally high in COPD patients and increases with the severity. Based on the above, we first tested the relation between the top 10 single nucleotide polymorphisms from genome-wide association studies and the risk of COPD. Then, we investigated whether VitD levels might also have a role in COPD. A meta-analysis followed, combining our participants with previously published European and non-European populations (15,716 cases and 48,107 controls). (2) Methods: 631 Lebanese participants were recruited, of which ~28% were affected with COPD. Demographic and clinical data were collected, and DNA was genotyped using Kompetitive allele-specific PCR (KASPT^M). Adjusted multiple logistic regression models were used. Bonferroni corrections were also applied. The statistical power was also assessed. (3) Results: Both rs6837671A>G in FAM13A and VitD levels were significantly associated with increased risk of COPD (OR = 1.75, p = 0.01, and OR = 3.10, p < 0.001 respectively). An interaction between rs6837671A>G in FAM13A and VitD levels, which increased COPD risk, was found (OR = 3.35 and p < 0.001). The meta-analysis showed that rs6837671G increases COPD risk in populations from different origins; Europeans, Asians, and now in Middle-Eastern. (4) Conclusions: Our results suggest that rs6837671A>G in FAM13A is a trans-ethnic genetic variant that interact with VitD to affect COPD. Full article

(This article belongs to the Special Issue Functional Genomics, Pharmacogenomics in Human Disease)

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12 pages, 1936 KiB

Open AccessArticle

Association of UBE3C Variants with Reduced Kidney Function in Patients with Diabetic Kidney Disease

by Ying-Chun Chen, Mei-Yi Wu, Zhi-Lei Yu, Wan-Hsuan Chou, Yi-Ting Lai, Chih-Chin Kao, Imaniar Noor Faridah, Mai-Szu Wu and Wei-Chiao Chang

J. Pers. Med. 2020, 10(4), 210; https://doi.org/10.3390/jpm10040210 - 6 Nov 2020

Cited by 3 | Viewed by 2461

Abstract

Diabetic kidney disease (DKD) is the leading cause of morbidity and mortality in patients with diabetes mellitus (DM) and the most common variant of end-stage renal disease (ESRD) globally. The economic burden of ESRD treatment with dialysis is substantial. The incidence and prevalence [...] Read more.

Diabetic kidney disease (DKD) is the leading cause of morbidity and mortality in patients with diabetes mellitus (DM) and the most common variant of end-stage renal disease (ESRD) globally. The economic burden of ESRD treatment with dialysis is substantial. The incidence and prevalence of ESRD in Taiwan remain the highest worldwide. Therefore, identifying genetic factors affecting kidney function would have valuable clinical implications. We performed microarray experiments and identified that ubiquitin protein ligase E3C (UBE3C) is differentially expressed in two DKD patient groups with extreme (low and high) urine protein-to-creatinine ratios. A follow-up genotyping study was performed in a larger group to investigate any specific variants of UBE3C associated with DKD. A total of 263 patients were included in the study, comprising 172 patients with DKD and 91 control subjects (patients with DM without chronic kidney disease (CKD)). Two UBE3C variants (rs3802129(AA) and rs7807(CC)) were determined to be associated with reduced kidney function. The haplotype analysis revealed that rs3802129/rs3815217 (block 1) with A/G haplotype and rs8101/rs7807 (block 2) with T/C haplotype were associated with higher risks of CKD phenotypes. These findings suggest a clinical role of UBE3C variants in DKD risk. Full article

(This article belongs to the Special Issue Functional Genomics, Pharmacogenomics in Human Disease)

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Review

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20 pages, 5790 KiB

Open AccessReview

Pharmacogenomics Variability of Lipid-Lowering Therapies in Familial Hypercholesterolemia

by Nagham N. Hindi, Jamil Alenbawi and Georges Nemer

J. Pers. Med. 2021, 11(9), 877; https://doi.org/10.3390/jpm11090877 - 31 Aug 2021

Cited by 12 | Viewed by 4321

Abstract

The exponential expansion of genomic data coupled with the lack of appropriate clinical categorization of the variants is posing a major challenge to conventional medications for many common and rare diseases. To narrow this gap and achieve the goals of personalized medicine, a [...] Read more.

The exponential expansion of genomic data coupled with the lack of appropriate clinical categorization of the variants is posing a major challenge to conventional medications for many common and rare diseases. To narrow this gap and achieve the goals of personalized medicine, a collaborative effort should be made to characterize the genomic variants functionally and clinically with a massive global genomic sequencing of “healthy” subjects from several ethnicities. Familial-based clustered diseases with homogenous genetic backgrounds are amongst the most beneficial tools to help address this challenge. This review will discuss the diagnosis, management, and clinical monitoring of familial hypercholesterolemia patients from a wide angle to cover both the genetic mutations underlying the phenotype, and the pharmacogenomic traits unveiled by the conventional and novel therapeutic approaches. Achieving a drug-related interactive genomic map will potentially benefit populations at risk across the globe who suffer from dyslipidemia. Full article

(This article belongs to the Special Issue Functional Genomics, Pharmacogenomics in Human Disease)

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10 pages, 507 KiB

Open AccessReview

Importance of NUDT15 Polymorphisms in Thiopurine Treatments

by Yoichi Tanaka and Yoshiro Saito

J. Pers. Med. 2021, 11(8), 778; https://doi.org/10.3390/jpm11080778 - 10 Aug 2021

Cited by 8 | Viewed by 3418

Abstract

Thiopurines, mercaptopurine, and azathioprine are used as immunosuppressants in the treatments of inflammatory bowel disease, rheumatoid arthritis, and organ transplantation and as chemotherapeutic drugs for the treatment of acute leukemia and chronic myeloid leukemia. This drug class sometimes causes severe adverse reactions, including [...] Read more.

Thiopurines, mercaptopurine, and azathioprine are used as immunosuppressants in the treatments of inflammatory bowel disease, rheumatoid arthritis, and organ transplantation and as chemotherapeutic drugs for the treatment of acute leukemia and chronic myeloid leukemia. This drug class sometimes causes severe adverse reactions, including bone marrow suppression and hair loss. Genetic polymorphisms of the metabolizing enzyme thiopurine S-methyltransferase have been used for predicting these reactions in Caucasians, but these allele frequencies are less frequently observed in Asian populations. Recently, nudix hydrolase 15 (NUDT15) polymorphisms have been shown to play an important role in thiopurine-induced adverse reactions in Asians. In this review, we summarize the NUDT15 studies, mainly in Asian countries, and their implementation in several countries. Full article

(This article belongs to the Special Issue Functional Genomics, Pharmacogenomics in Human Disease)

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13 pages, 697 KiB

Open AccessFeature PaperReview

The Functionality of UDP-Glucuronosyltransferase Genetic Variants and their Association with Drug Responses and Human Diseases

by Yazun Jarrar and Su-Jun Lee

J. Pers. Med. 2021, 11(6), 554; https://doi.org/10.3390/jpm11060554 - 14 Jun 2021

Cited by 18 | Viewed by 6632

Abstract

UDP-glucuronosyltransferases (UGTs) are phase II drug-metabolizing enzymes that metabolize endogenous fatty acids such as arachidonic acid metabolites, as well as many prescription drugs, such as opioids, antiepileptics, and antiviral drugs. The UGT1A and 2B genes are highly polymorphic, and their genetic variants may [...] Read more.

UDP-glucuronosyltransferases (UGTs) are phase II drug-metabolizing enzymes that metabolize endogenous fatty acids such as arachidonic acid metabolites, as well as many prescription drugs, such as opioids, antiepileptics, and antiviral drugs. The UGT1A and 2B genes are highly polymorphic, and their genetic variants may affect the pharmacokinetics and hence the responses of many drugs and fatty acids. This study collected data and updated the current view of the molecular functionality of genetic variants on UGT genes that impact drug responses and the susceptibility to human diseases. The functional information of UGT genetic variants with clinical associations are essential to understand the inter-individual variation in drug responses and susceptibility to toxicity. Full article

(This article belongs to the Special Issue Functional Genomics, Pharmacogenomics in Human Disease)

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18 pages, 2136 KiB

Open AccessReview

A Novel Precision Approach to Overcome the “Addiction Pandemic” by Incorporating Genetic Addiction Risk Severity (GARS) and Dopamine Homeostasis Restoration

by Kenneth Blum, Shan Kazmi, Edward J. Modestino, Bill William Downs, Debasis Bagchi, David Baron, Thomas McLaughlin, Richard Green, Rehan Jalali, Panayotis K. Thanos, Igor Elman, Rajendra D. Badgaiyan, Abdalla Bowirrat and Mark S. Gold

J. Pers. Med. 2021, 11(3), 212; https://doi.org/10.3390/jpm11030212 - 16 Mar 2021

Cited by 16 | Viewed by 5365

Abstract

This article describes a unique therapeutic precision intervention, a formulation of enkephalinase inhibitors, enkephalin, and dopamine-releasing neuronutrients, to induce dopamine homeostasis for detoxification and treatment of individuals genetically predisposed to developing reward deficiency syndrome (RDS). The formulations are based on the results of [...] Read more.

This article describes a unique therapeutic precision intervention, a formulation of enkephalinase inhibitors, enkephalin, and dopamine-releasing neuronutrients, to induce dopamine homeostasis for detoxification and treatment of individuals genetically predisposed to developing reward deficiency syndrome (RDS). The formulations are based on the results of the addiction risk severity (GARS) test. Based on both neurogenetic and epigenetic evidence, the test evaluates the presence of reward genes and risk alleles. Existing evidence demonstrates that the novel genetic risk testing system can successfully stratify the potential for developing opioid use disorder (OUD) related risks or before initiating opioid analgesic therapy and RDS risk for people in recovery. In the case of opioid use disorders, long-term maintenance agonist treatments like methadone and buprenorphine may create RDS, or RDS may have been in existence, but not recognized. The test will also assess the potential for benefit from medication-assisted treatment with dopamine augmentation. RDS methodology holds a strong promise for reducing the burden of addictive disorders for individuals, their families, and society as a whole by guiding the restoration of dopamine homeostasisthrough anti-reward allostatic neuroadaptations. WC 175. Full article

(This article belongs to the Special Issue Functional Genomics, Pharmacogenomics in Human Disease)

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14 pages, 1512 KiB

Open AccessReview

Estrogen Sulfotransferase (SULT1E1): Its Molecular Regulation, Polymorphisms, and Clinical Perspectives

by MyeongJin Yi, Masahiko Negishi and Su-Jun Lee

J. Pers. Med. 2021, 11(3), 194; https://doi.org/10.3390/jpm11030194 - 11 Mar 2021

Cited by 21 | Viewed by 4625

Abstract

Estrogen sulfotransferase (SULT1E1) is a phase II enzyme that sulfates estrogens to inactivate them and regulate their homeostasis. This enzyme is also involved in the sulfation of thyroid hormones and several marketed medicines. Though the profound action of SULT1E1 in molecular/pathological biology has [...] Read more.

Estrogen sulfotransferase (SULT1E1) is a phase II enzyme that sulfates estrogens to inactivate them and regulate their homeostasis. This enzyme is also involved in the sulfation of thyroid hormones and several marketed medicines. Though the profound action of SULT1E1 in molecular/pathological biology has been extensively studied, its genetic variants and functional studies have been comparatively rarely studied. Genetic variants of this gene are associated with some diseases, especially sex-hormone-related cancers. Comprehending the role and polymorphisms of SULT1E1 is crucial to developing and integrating its clinical relevance; therefore, this study gathered and reviewed various literature studies to outline several aspects of the function, molecular regulation, and polymorphisms of SULT1E1. Full article

(This article belongs to the Special Issue Functional Genomics, Pharmacogenomics in Human Disease)

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Other

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9 pages, 7244 KiB

Open AccessCase Report

Pharmacogenomics of Allopurinol and Sulfamethoxazole/Trimethoprim: Case Series and Review of the Literature

by Ogechi Ikediobi and Jeremy A. Schneider

J. Pers. Med. 2021, 11(2), 71; https://doi.org/10.3390/jpm11020071 - 26 Jan 2021

Cited by 6 | Viewed by 5101

Abstract

Severe cutaneous adverse drug reactions (SCAR) such as the Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DIHS) can be induced by a plethora of medications. The field of pharmacogenomics aims to prevent severe adverse drug [...] Read more.

Severe cutaneous adverse drug reactions (SCAR) such as the Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DIHS) can be induced by a plethora of medications. The field of pharmacogenomics aims to prevent severe adverse drug reactions by using our knowledge of the inherited or acquired genetic risk of drug metabolizing enzymes, drug targets, or the human leukocyte antigen (HLA) genotype. Dermatologists are experts in the diagnosis and management of severe cutaneous adverse drug reactions (SCAR) in both the inpatient and outpatient setting. However, most dermatologists in the US have not focused on the prevention of SCAR. Therefore, this paper presents a case series and review of the literature highlighting salient examples of how dermatologists can apply pharmacogenomics in the diagnosis and especially in the prevention of SCAR induced by allopurinol and sulfamethoxazole/trimethoprim, two commonly prescribed medications. Full article

(This article belongs to the Special Issue Functional Genomics, Pharmacogenomics in Human Disease)

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