AI-aided Precision Medicine against COVID-19: Strategic Areas of Research and Development.

J Med Internet Res. 2021 Jan 31;:

Authors: Santus E, Marino N, Cirillo D, Chersoni E, Montagud A, Santuccione Chada A, Valencia A, Hughes K, Lindvall C

Abstract
UNSTRUCTURED: Modern Artificial Intelligence (AI) technologies can play a key role in preventing and monitoring the present and the future epidemics. Here, we provide an overview of recently published literature on the COVID-19 pandemics in four strategic areas: (1) triage, diagnosis and risk prediction; (2) drug repurposing and development; (3) pharmacogenomics and vaccines; (4) mining of medical literature. In accordance to the newly proposed value-based care paradigm, we notice that AI-powered healthcare is essential to make public health systems able to efficiently handle future outbreaks and improve patient outcomes.

PMID: 33560998 [PubMed - as supplied by publisher]

Pharmacogenomics of the Efficacy and Safety of Colchicine in COLCOT.

Circ Genom Precis Med. 2021 Feb 09;:

Authors: Dubé MP, Legault MA, Lemaçon A, Lemieux Perreault LP, Fouodjio R, Waters DD, Kouz S, Pinto FJ, Maggioni AP, Diaz R, Berry C, Koenig W, Lopez-Sendon J, Gamra H, Kiwan GS, Asselin G, Provost S, Barhdadi A, Sun M, Cossette M, Blondeau L, Mongrain I, Dubois A, Rhainds D, Bouabdallaoui N, Samuel M, de Denus S, L'Allier PL, Guertin MC, Roubille F, Tardif JC

Abstract
Background - The randomized, placebo-controlled COLchicine Cardiovascular Outcomes Trial (COLCOT) has shown the benefits of colchicine 0.5 mg daily to lower the rate of ischemic cardiovascular events in patients with a recent myocardial infarction. Here, we conducted a post-hoc pharmacogenomic study of COLCOT with the aim to identify genetic predictors of the efficacy and safety of treatment with colchicine. Methods - There were 1522 participants of European descent from the COLCOT trial available for the pharmacogenomic study of COLCOT trial. The pharmacogenomic study's primary cardiovascular (CV) endpoint was defined as for the main trial, as time to first occurrence of CV death, resuscitated cardiac arrest, myocardial infarction, stroke or urgent hospitalization for angina requiring coronary revascularization. The safety endpoint was time to the first report of gastrointestinal events. Patients' DNA was genotyped using the Illumina Global Screening array followed by imputation. We performed a genome-wide association study (GWAS) in colchicine-treated patients. Results - None of the genetic variants passed the GWAS significance threshold for the primary CV endpoint conducted in 702 patients in the colchicine arm who were compliant to medication. The GWAS for gastrointestinal events was conducted in all 767 patients in the colchicine arm and found two significant association signals, one with lead variant rs6916345 (hazard ratio (HR)=1.89, 95% confidence interval (CI) 1.52-2.35, P=7.41×10-9) in a locus which colocalizes with Crohn's disease, and one with lead variant rs74795203 (HR= 2.51, 95% CI 1.82-3.47; P=2.70×10-8), an intronic variant in gene SEPHS1. The interaction terms between the genetic variants and treatment with colchicine versus placebo were significant. Conclusions - We found two genomic regions associated with gastrointestinal events in patients treated with colchicine. Those findings will benefit from replication to confirm that some patients may have genetic predispositions to lower tolerability of treatment with colchicine.

PMID: 33560138 [PubMed - as supplied by publisher]

Epigenetic Mechanisms of Resistance to Immune Checkpoint Inhibitors.

Biomolecules. 2020 07 16;10(7):

Authors: Perrier A, Didelot A, Laurent-Puig P, Blons H, Garinet S

Abstract
Immune checkpoint inhibitors (ICIs) have demonstrated to be highly efficient in treating solid tumors; however, many patients have limited benefits in terms of response and survival. This rapidly led to the investigation of combination therapies to enhance response rates. Moreover, predictive biomarkers were assessed to better select patients. Although PD-L1 expression remains the only validated marker in clinics, molecular profiling has brought valuable information, showing that the tumor mutation load and microsatellite instability (MSI) status were associated to higher response rates in nearly all cancer types. Moreover, in lung cancer, EGFR and MET mutations, oncogene fusions or STK11 inactivating mutations were associated with low response rates. Cancer progression towards invasive phenotypes that impede immune surveillance relies on complex regulatory networks and cell interactions within the tumor microenvironment. Epigenetic modifications, such as the alteration of histone patterns, chromatin structure, DNA methylation status at specific promoters and changes in microRNA levels, may alter the cell phenotype and reshape the tumor microenvironment, allowing cells to grow and escape from immune surveillance. The objective of this review is to make an update on the identified epigenetic changes that target immune surveillance and, ultimately, ICI responses, such as histone marks, DNA methylation and miR signatures. Translational studies or clinical trials, when available, and potential epigenetic biomarkers will be discussed as perspectives in the context of combination treatment strategies to enhance ICI responses in patients with solid tumors.

PMID: 32708698 [PubMed - indexed for MEDLINE]

Pharmacogenetic Testing: The Ethics of Implementing in Clinical Practice for Chronic Pain Patients.

J Pain Palliat Care Pharmacother. 2020 Jun;34(2):69-76

Authors: Fredrikson KM, Fasolino T

Abstract
Chronic pain is a common and costly healthcare problem where standard of care often involves the use of opioids and patient response varies widely. Designing a treatment plan based upon an individual's genetic signature provides an individualized patient-centered care approach that can improve functional status, quality of life, and reduce adverse drug events (ADEs). This paper will discuss the ethical implications of pharmacogenetic (PGx) testing using the principlism framework of the four moral principles: beneficence, non-maleficence, autonomy, and justice. Beneficence involves balancing the benefits and risks associated with PGx testing. Non-maleficence is the directive to do no harm to the patient in the delivery or use of PGx test results. Autonomy encompasses self-determination; the patient's right to select PGx testing. Justice is concerned with distributing benefits and burdens of PGx testing access and costs. Maximizing patient autonomy and beneficence during treatment promotes patient-centered care. Principlism supports PGx testing for patients experiencing chronic pain. Integrating PGx testing impact treatment plans and may improve the outlook for patients with chronic pain.

PMID: 31909692 [PubMed - indexed for MEDLINE]

14 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2021/02/09

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

The Future of Obsessive-Compulsive Spectrum Disorders: A Research Perspective.

Curr Top Behav Neurosci. 2021 Feb 07;:

Authors: Vats T, Fineberg NA, Hollander E

Abstract
Obsessive-compulsive disorder (OCD) sits at the epicenter of a spectrum of related conditions (often referred to as obsessive-compulsive related disorders (OCRD) or obsessive-compulsive spectrum disorders (OCSD)) that can be as disabling as they are varied in presentation. Research in the field now encompasses diverse disciplines ranging from inflammatory mechanisms to computational psychiatry, to neurocognitive endophenotypes to functional imaging to pharmacogenomics to brain stimulation approaches. As these disorders become more clearly elucidated, there is a need to continually re-evaluate the implications of research findings and to incorporate these findings into new treatment approaches that benefit both patients and clinicians. Even the Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5) is intended to be flexible and to incorporate validated and reliable biomarkers and neuroscience findings as they become available. This concluding chapter highlights just a few areas of study that promise to influence our understanding of the pathophysiology and clinical practice of OCRD. These include patient-centered outcomes research, the study of developmental brain trajectories in spectrum conditions, robot models of OCRDs, goal-directed versus habit-based behaviors, pharmacogenomics, problematic use of the Internet, and digital interventions. For example, digital medicine may become increasingly useful by identifying patients early on in the course of their illness; providing biomarkers to subtype patients; predicting treatment response; serving as a more proximal outcome measure of treatment response; or providing easily accessible and less costly forms of care. In order to address unmet clinical needs in OCRD, it is helpful to take an interdisciplinary perspective, and the work described in this collection of articles is likely to be invaluable in shaping the future of the field.

PMID: 33550566 [PubMed - as supplied by publisher]

Pharmacogenetics of Obsessive-Compulsive Disorder: An Evidence-Update.

Curr Top Behav Neurosci. 2021 Feb 07;:

Authors: Zai G

Abstract
Pharmacogenetics has become increasingly important in the treatment of psychiatric disorders because approximately 50% of individuals who take psychotropic medications do not typically respond to them. Obsessive-compulsive disorder (OCD) is one such chronic and often debilitating mental illness with significant non-response to even the first-line medication, serotonin reuptake inhibitors. Precision medicine utilizing genetic testing panels has received significant attention based on the evidence that the variability of antidepressant response and adverse effects is partly due to the variability in an individual's genome. Thus, extensive research has investigated the role of genetic factors on antidepressant response in major depressive disorder (MDD) and their utility for guiding antidepressant treatment to significantly improving outcomes in individuals with MDD. However, limited progress remains in the pharmacogenetics of OCD. This chapter will provide an overview of the recent findings in the pharmacogenetics of OCD. Promising results with limited replications have been reported for the cytochrome P450 liver metabolism genes in addition to several serotonergic and glutamatergic system genes, which may play an important role in antidepressant response in the treatment of OCD.

PMID: 33550565 [PubMed - as supplied by publisher]

Activation of bovine oocytes by protein synthesis inhibitors: New findings on the role of MPF/MAPKs†.

Biol Reprod. 2021 Feb 08;:

Authors: Valencia C, Pérez FA, Matus C, Felmer R, Arias ME

Abstract
The present study evaluated the mechanism by which protein synthesis inhibitors activate bovine oocytes. The aim was to analyze the dynamics of MPF and MAPKs. MII oocytes were activated with ionomycin (Io), ionomycin+anisomycin (ANY) and ionomycin+cycloheximide (CHX) and by in vitro fertilization (IVF). The expression of cyclin B1, p-CDK1, p-ERK1/2, p-JNK and p-P38 were evaluated by immunodetection and the kinase activity of ERK1/2 was measured by enzyme assay. Evaluations at 1, 4 and 15 hours, post-activation (hpa) showed that the expression of cyclin B1 was not modified by the treatments. ANY inactivated MPF by p-CDK1Thr14-Tyr15 at 4 hpa (p < 0.05), CHX increased pre-MPF (p-CDK1Thr161 and p-CDK1Thr14-Tyr15) at 1 hpa and IVF increased p-CDK1Thr14-Tyr15 at 17 hpf (p < 0.05). ANY and CHX reduced the levels of p-ERK1/2 at 4 hpa (p < 0.05) and its activity at 4 and 1 hpa, respectively (p < 0.05). Meanwhile, IVF increased p-ERK1/2 at 6 hpf (p < 0.05); however, its kinase activity decreased at 6 hpf (p < 0.05). p-JNK in ANY, CHX and IVF oocytes decreased at 4 hpa (p < 0.05). p-P38 was only observed at 1 hpa, with no differences between treatments. In conclusion, activation of bovine oocytes by ANY, CHX and IVF inactivates MPF by CDK1-dependent specific phosphorylation without cyclin B1 degradation. ANY or CHX promoted this inactivation, which seemed to be more delayed in the physiological activation (IVF). Both inhibitors modulated MPF activity via an ERK1/2-independent-pathway, whereas IVF activated the bovine oocytes via an ERK1/2-dependent pathway. Finally, ANY does not activate the JNK and P38 kinase pathways.

PMID: 33550378 [PubMed - as supplied by publisher]

Human tuberculosis and Mycobacterium tuberculosis complex: A review on genetic diversity, pathogenesis and omics approaches in host biomarkers discovery.

Microbiol Res. 2021 Jan 29;246:126674

Authors: Kanabalan RD, Lee LJ, Lee TY, Chong PP, Hassan L, Ismail R, Chin VK

Abstract
Mycobacterium tuberculosis complex (MTBC) refers to a group of mycobacteria encompassing nine members of closely related species that causes tuberculosis in animals and humans. Among the nine members, Mycobacterium tuberculosis (M. tuberculosis) remains the main causative agent for human tuberculosis that results in high mortality and morbidity globally. In general, MTBC species are low in diversity but exhibit distinctive biological differences and phenotypes among different MTBC lineages. MTBC species are likely to have evolved from a common ancestor through insertions/deletions processes resulting in species speciation with different degrees of pathogenicity. The pathogenesis of human tuberculosis is complex and remains poorly understood. It involves multi-interactions or evolutionary co-options between host factors and bacterial determinants for survival of the MTBC. Granuloma formation as a protection or survival mechanism in hosts by MTBC remains controversial. Additionally, MTBC species are capable of modulating host immune response and have adopted several mechanisms to evade from host immune attack in order to survive in humans. On the other hand, current diagnostic tools for human tuberculosis are inadequate and have several shortcomings. Numerous studies have suggested the potential of host biomarkers in early diagnosis of tuberculosis, in disease differentiation and in treatment monitoring. "Multi-omics" approaches provide holistic views to dissect the association of MTBC species with humans and offer great advantages in host biomarkers discovery. Thus, in this review, we seek to understand how the genetic variations in MTBC lead to species speciation with different pathogenicity. Furthermore, we also discuss how the host and bacterial players contribute to the pathogenesis of human tuberculosis. Lastly, we provide an overview of the journey of "omics" approaches in host biomarkers discovery in human tuberculosis and provide some interesting insights on the challenges and directions of "omics" approaches in host biomarkers innovation and clinical implementation.

PMID: 33549960 [PubMed - as supplied by publisher]

Understanding the effect of increased cell specific productivity on galactosylation of monoclonal antibodies produced using Chinese hamster ovary cells.

J Biotechnol. 2021 Feb 04;:

Authors: Madabhushi SR, Podtelezhnikov AA, Murgolo N, Xu S, Lin H

Abstract
Achieving optimal productivity and desired product quality of the therapeutic monoclonal antibody (mAb) is one of the primary goals of process development. Across the various mAb programs at our company, we observed that increasing the specific productivity (qp) results in a decrease in the % galactosylation (%Gal) level on the protein. In order to gain further insight into this correlation, cells were cultured under different process conditions such as pH or media osmolality or in the presence of supplements such as sodium butyrate. A range of qp and N-glycan profiles were obtained with the greatest changes observed under high pH (lower qp, higher %Gal), higher osmolality (higher qp, lower %Gal) or sodium butyrate (moderately higher qp, moderately lower %Gal) conditions. Abundance of individual glycan species highlighted different bottlenecks in the N-glycosylation pathway depending on the treatment condition. Transcriptomics analysis was performed to identify changes in gene expression profiles that correlate with the inverse relationship between qp and %Gal. Results showed downregulation of Beta-1,4-galactosyltransferase 1 (B4GalT1), UDP-GlcNAc and Mn2+ transporter (slc35a3 and slc39a8 respectively) for the high osmolality conditions. Significant downregulation of slc39a8 (Mn2+ transporter) was observed for the sodium butyrate condition. No significant differences were observed for any of the genes in the N-glycosylation pathway under the high pH condition even though this condition showed highest %Gal. Together, data suggests that different treatments have distinct complex mechanisms by which the overall glycan levels of a mAb are influenced. Further studies based on these results will help build the knowledge necessary to design strategies to obtain the desired productivity and product quality of mAbs.

PMID: 33549674 [PubMed - as supplied by publisher]

Clinical significance of HRAS and KRAS genes expression in patients with non-small-cell lung cancer - preliminary findings.

BMC Cancer. 2021 Feb 06;21(1):130

Authors: Pązik M, Michalska K, Żebrowska-Nawrocka M, Zawadzka I, Łochowski M, Balcerczak E

Abstract
BACKGROUND: The RAS family protooncogenes, including KRAS, NRAS and HRAS, encode proteins responsible for the regulation of growth, differentiation and survival of many cell types. The HRAS and KRAS oncogene mutations are well defined, however, the clinical significance of RAS expressions in non-small-cell lung cancer (NSCLC) is still uncertain.
METHODS: A total of 39 whole blood samples of NSCLC (the investigated group), collected at three points of time: at the time of diagnosis, 100 days and 1 year after the surgery as well as 35 tissue samples obtained during the surgery were included in this study. HRAS and KRAS genes mRNA expression were assessed using quantitative real-time polymerase chain reaction techniques.
RESULTS: Increased relative HRAS mRNA level in blood was found significantly more frequently in the group of smokers (p = 0.008). Patients with squamous cell carcinoma subtypes of NSCLC were more likely to show an overexpression of HRAS gene in blood, but not statistically significant (p = 0.065). In tumor tissue overexpression of HRAS gene was associated with adenocarcinoma subtype (p = 0.049). No statistically significant associations were found for the expression of KRAS with any clinicopathological parameters, except the age of patients, within the study. There were no differences between the relative HRAS and KRAS genes expression levels in blood samples taken from the same patients during the 3 observation points, as well as between blood collected from patients before surgery and tissue samples obtained during operation.
CONCLUSION: The potential associations between high HRAS expression levels, age, smoking status and histological type of cancer were observed, which emphasizes the need for further study of the RAS family. Therefore, subsequent research involving larger numbers of patients and a longer follow-up, as well as multicenter study are necessary to confirm our findings.

PMID: 33549031 [PubMed - in process]

Genetic ancestry plays a central role in population pharmacogenomics.

Commun Biol. 2021 Feb 05;4(1):171

Authors: Yang HC, Chen CW, Lin YT, Chu SK

Abstract
Recent studies have pointed out the essential role of genetic ancestry in population pharmacogenetics. In this study, we analyzed the whole-genome sequencing data from The 1000 Genomes Project (Phase 3) and the pharmacogenetic information from Drug Bank, PharmGKB, PharmaADME, and Biotransformation. Here we show that ancestry-informative markers are enriched in pharmacogenetic loci, suggesting that trans-ancestry differentiation must be carefully considered in population pharmacogenetics studies. Ancestry-informative pharmacogenetic loci are located in both protein-coding and non-protein-coding regions, illustrating that a whole-genome analysis is necessary for an unbiased examination over pharmacogenetic loci. Finally, those ancestry-informative pharmacogenetic loci that target multiple drugs are often a functional variant, which reflects their importance in biological functions and pathways. In summary, we develop an efficient algorithm for an ultrahigh-dimensional principal component analysis. We create genetic catalogs of ancestry-informative markers and genes. We explore pharmacogenetic patterns and establish a high-accuracy prediction panel of genetic ancestry. Moreover, we construct a genetic ancestry pharmacogenomic database Genetic Ancestry PhD ( http://hcyang.stat.sinica.edu.tw/databases/genetic_ancestry_phd/ ).

PMID: 33547344 [PubMed - as supplied by publisher]

Translation of pharmacogenomic drug labels into the clinic. Current problems.

Pharmacol Res. 2020 03;153:104620

Authors: Ingelman-Sundberg M

PMID: 31899313 [PubMed - indexed for MEDLINE]

16 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2021/02/06

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Druggable targets meet oncogenic drivers: opportunities and limitations of target-based classification of tumors and the role of Molecular Tumor Boards.

ESMO Open. 2021 Feb 01;6(2):100040

Authors: Danesi R, Fogli S, Indraccolo S, Del Re M, Dei Tos AP, Leoncini L, Antonuzzo L, Bonanno L, Guarneri V, Pierini A, Amunni G, Conte P

Abstract
The therapeutic landscape of cancer is changing rapidly due to the growing number of approved drugs capable of targeting specific genetic alterations. This aspect, together with the development of noninvasive methods for the assessment of somatic mutations in the peripheral blood of patients, generated a growing interest toward a new tumor-agnostic classification system based on 'predictive' biomarkers. The current review article discusses this emerging alternative approach to the classification of cancer and its implications for the selection of treatments. It is suggested that different types of cancers sharing the same molecular profiles could benefit from the same targeted drugs. Although recent clinical trials have demonstrated that this approach cannot be generalized, there are also specific examples that demonstrate the clinical utility of this alternative vision. In this rapidly evolving scenario, a multidisciplinary approach managed by institutional Molecular Tumor Boards is fundamental to interpret the biological and clinical relevance of genetic alterations and the complexity of their relationship with treatment response.

PMID: 33540286 [PubMed - as supplied by publisher]

Geography, generalisability, and susceptibility in clinical trials.

Lancet Respir Med. 2021 Feb 01;:

Authors: Clougherty JE, Kinnee EJ, Cardet JC, Mauger D, Bacharier L, Beigelman A, Blake KV, Cabana MD, Castro M, Chmiel JF, Covar R, Fitzpatrick A, Gaffin JM, Gentile D, Israel E, Jackson DJ, Kraft M, Krishnan JA, Kumar HV, Lang JE, Lazarus SC, Lemanske RF, Lima J, Martinez FD, Morgan W, Moy J, Myers R, Naureckas ET, Ortega VE, Peters SP, Phipatanakul W, Pongracic JA, Ross K, Sheehan WJ, Smith LJ, Solway J, Sorkness CA, Wechsler ME, Wenzel S, White SR, Holguin F

PMID: 33539731 [PubMed - as supplied by publisher]

Pharmacogenomics education and perceptions: is there a gap between internal medicine resident and attending physicians?

Pharmacogenomics. 2021 Feb 04;:

Authors: Rohrer Vitek CR, Giri J, Caraballo PJ, Curry TB, Nicholson WT

Abstract
Aim: To determine if differences in self-reported pharmacogenomics knowledge, skills and perceptions exist between internal medicine residents and attending physicians. Materials & methods: Forty-six internal medicine residents and 54 attending physicians completed surveys. Thirteen participated in focus groups to explore themes emerging from the surveys. Results: Resident physicians reported a greater amount of pharmacogenomics training compared with attending physicians (48 vs 13%, p < 0.00012). No differences were found in self-reported knowledge, skills and perceptions. Conclusion: Both groups expressed pharmacogenomics was relevant to their current clinical practice; they should be able to provide information to patients and use to guide prescribing, but lacked sufficient education to be able to do so effectively. Practical approaches are needed to teach pharmacogenomics concepts and address point-of-care gaps.

PMID: 33538610 [PubMed - as supplied by publisher]

Current Trends in Genetics and Neonatal Care.

Adv Neonatal Care. 2021 Feb 02;:

Authors: Uveges MK, Holm IA

Abstract
BACKGROUND: Genetic and genomic health applications are rapidly changing. A clear and updated description of these applications for the neonatal population is needed to guide current nursing practice.
PURPOSE: To provide scientific evidence and guidance on the current genetic and genomic applications pertinent to neonatal care.
METHODS: A search of CINAHL and PubMed was conducted using the search terms "newborn/neonatal" and "genetics," "genomics," "newborn screening," "pharmacogenomics," "ethical," and "legal." Google searches were also conducted to synthesize professional guidelines, position statements, and current genetic practices.
FINDINGS/RESULTS: Components of the newborn genetic assessment, including details on the newborn physical examination, family history, and laboratory tests pertinent to the newborn, are reported. The history and process of newborn screening are described, in addition to the impact of advancements, such as whole exome and genome sequencing, on newborn screening. Pharmacogenomics, a genomic application that is currently utilized primarily in the research context for neonates, is described and future implications stated. Finally, the specific ethical and legal implications for these genetic and genomic applications are detailed, along with genetic/genomic resources for nurses.
IMPLICATIONS FOR PRACTICE: Providing nurses with the most up-to-date evidence on genetic and genomic applications ensures their involvement and contributions to quality neonatal care.
IMPLICATIONS FOR RESEARCH: Ongoing genetic/genomic research is needed to understand the implications of genetic/genomic applications on the neonatal population and how these new applications will change neonatal care.

PMID: 33538495 [PubMed - as supplied by publisher]

Relationship Between Interleukin-6 -174G/C Genetic Variant and Efficacy of Methotrexate Treatment in Psoriatic Arthritis Patients.

Pharmgenomics Pers Med. 2021;14:157-166

Authors: Sokolik R, Iwaszko M, Świerkot J, Wysoczańska B, Korman L, Wiland P, Bogunia-Kubik K

Abstract
Introduction: The purpose of the study was to investigate whether single-nucleotide polymorphisms (SNPs) IL-6 -174 G/C and IL-6R Asp358Ala are associated with susceptibility to psoriatic arthritis (PsA) or affect response to treatment with methotrexate (MTX).
Patients and Methods: Seventy-four patients diagnosed with PsA and qualified for MTX treatment were enrolled to the study. The control group consisted of 120 healthy individuals. Polymorphisms IL-6 -174 G/C and IL-6R Asp358Ala were genotyped using a polymerase chain reaction (PCR) amplification employing LightSNiP assays.
Results: A significant association between the IL-6 -174 CC genotype and an improved clinical outcome of MTX therapy was observed. A good response was more frequently observed among PsA patients bearing the IL-6 -174 CC genotype than patients with the GC or GG genotypes (P = 0.007). On the other hand, patients carrying the IL-6 -174 GC genotype less frequently responded to MTX treatment as compared to patients with other genotypes (P = 0.006). With respect to the IL-6R Asp358Ala SNP, there were no significant differences in genotype and allelic frequencies in relation to clinical outcome of MTX treatment. No association was found between the IL-6 -174 G/C or IL-6R Asp358Ala SNPs and PsA susceptibility.
Conclusion: Results from this study provide evidence that the IL-6 -174 G/C polymorphism might influence efficacy of MTX treatment.

PMID: 33536774 [PubMed]

CYP2C9 Variations and Their Pharmacogenetic Implications Among Diverse South Asian Populations.

Pharmgenomics Pers Med. 2021;14:135-147

Authors: Nizamuddin S, Dubey S, Singh S, Sharma S, Machha P, Thangaraj K

Abstract
Introduction: Allelic frequency distribution of drug metabolizing enzyme genes among populations is important to identify risk groups for adverse drug reaction and to select representative populations for clinical trials. Although India emerged as an important hub for clinical trials, information about the pharmacogenetic diversity for this region is still lacking. Here, we investigated genetic diversity of cytochrome-P450-2C9 (CYP2C9) gene which metabolizes wide range of drugs and is highly expressed in the human liver.
Methods: In total, 1278 individuals from 36 diverse Indian populations, 210 individuals from in-house data-repository and 489 other South Asian samples from the 1000 Genomes Project were selected. Variants observed in CYP2C9 gene were subjected to various statistical analyses.
Results: High frequency of CYP2C9*3 (~13%) and CYP2C9*3/*3 (~1%) was observed among South Asians, compared to 21 populations living outside the Indian subcontinent. The allelic/genotypic frequency does not correlate with geographical location or linguistic affiliation, except populations speaking Tibeto-Burmans language, who have lower frequency of CYP2C9*3 and CYP2C9*3/*3. Since, South Asians practice strict endogamy, presence of unique mutation and high frequency of homozygous genotypes not surprising. CYP2C9*3 has been associated with therapeutic response.The effect of CYP2C9*3/*3 is more pronounced compared to heterozygous and wild type homozygous genotypes as evident in many in vitro studies. As South Asians have high frequency, it would be interesting to explore potential of CYP2C9*3 as a marker for personalized therapy. Our study revealed several rare functional variants, which form eight novel and rare haplotypes of CYP2C9 (CYP2C9*63-*70). Of which, CYP2C9*64, *65, *66, *68, *69 and *70 haplotypes are South Asian-specific.
Conclusion: Overall, we find high genetic heterogeneity within South Asians and identified South Asian-specific putative functional CYP2C9 haplotypes. High frequency of CYP2C9*3 and CYP2C9*3/*3 was observed in South Asian populations. Taken together, current study greatly enriches the knowledge of naturally occurring CYP2C9 variants and its diversity in South Asia, which are relevant to further CYP2C9-related functional research and for personalized medicine.

PMID: 33536773 [PubMed]