En route to precision medicine through the integration of biological sex into pharmacogenomics

2017 ◽  
Vol 131 (4) ◽  
pp. 329-342 ◽  
Author(s):  
Lea Gaignebet ◽  
Georgios Kararigas

Frequently, pharmacomechanisms are not fully elucidated. Therefore, drug use is linked to an elevated interindividual diversity of effects, whether therapeutic or adverse, and the role of biological sex has as yet unrecognized and underestimated consequences. A pharmacogenomic approach could contribute towards the development of an adapted therapy for each male and female patient, considering also other fundamental features, such as age and ethnicity. This would represent a crucial step towards precision medicine and could be translated into clinical routine. In the present review, we consider recent results from pharmacogenomics and the role of sex in studies that are relevant to cardiovascular therapy. We focus on genome-wide analyses, because they have obvious advantages compared with targeted single-candidate gene studies. For instance, genome-wide approaches do not necessarily depend on prior knowledge of precise molecular mechanisms of drug action. Such studies can lead to findings that can be classified into three categories: first, effects occurring in the pharmacokinetic properties of the drug, e.g. through metabolic and transporter differences; second, a pharmacodynamic or drug target-related effect; and last diverse adverse effects. We conclude that the interaction of sex with genetic determinants of drug response has barely been tested in large, unbiased, pharmacogenomic studies. We put forward the theory that, to contribute towards the realization of precision medicine, it will be necessary to incorporate sex into pharmacogenomics.

Author(s):  
Carlos Sánchez-Soriano ◽  
Ewan R. Pearson ◽  
Rebecca M. Reynolds

Abstract Disturbances affecting early development have broad repercussions on the individual’s health during infancy and adulthood. Multiple observational studies throughout the years have shown that alterations of fetal growth are associated with increased cardiometabolic disease risks. However, the genetic component of this association only started to be investigated in the last 40 years, when single genes with distinct effects were investigated. Birth weight (BW), commonly reported as the outcome of developmental growth, has been estimated to be 20% to 60% heritable. Through Genome-Wide Association (GWA) meta-analyses, 190 different loci have been identified being associated with BW, and while many of these loci designate genes involved in glucose and lipid metabolism, with clear ties to fetal development, the role of others is not yet understood. In addition, due to its influence over the intrauterine environment, the maternal genotype also plays an important part in the determination of offspring BW, with the same loci having independent effects of different magnitude or even direction. There is still much to uncover regarding the genetic determinants of BW and the interactions between maternal, offspring, and even paternal genotype. To fully understand these, diverse and novel cohorts from multiple ancestries collecting extensive neonatal phenotype will be needed. This review compiles, chronologically, the main findings in the investigation of the genetics of BW.


2017 ◽  
Author(s):  
Yong Li ◽  
Yi Jin Liew ◽  
Guoxin Cui ◽  
Maha J Cziesielski ◽  
Noura Zahran ◽  
...  

The symbiotic relationship between cnidarians and dinoflagellates is the cornerstone of coral reef ecosystems. Although research is focusing on the molecular mechanisms underlying this symbiosis, the role of epigenetic mechanisms, which have been implicated in transcriptional regulation and acclimation to environmental change, is unknown. To assess the role of DNA methylation in the cnidarian-dinoflagellate symbiosis, we analyzed genome-wide CpG methylation, histone associations, and transcriptomic states of symbiotic and aposymbiotic anemones in the model systemAiptasia. We find methylated genes are marked by histone H3K36me3 and show significant reduction of spurious transcription and transcriptional noise, revealing a role of DNA methylation in the maintenance of transcriptional homeostasis. Changes in DNA methylation and expression show enrichment for symbiosis-related processes such as immunity, apoptosis, phagocytosis recognition and phagosome formation, and unveil intricate interactions between the underlying pathways. Our results demonstrate that DNA methylation provides an epigenetic mechanism of transcriptional homeostasis during symbiosis.


PPAR Research ◽  
2010 ◽  
Vol 2010 ◽  
pp. 1-12 ◽  
Author(s):  
Anne Bugge ◽  
Susanne Mandrup

The peroxisome proliferator-activated receptors (PPARs) are central regulators of fat metabolism, energy homeostasis, proliferation, and inflammation. The three PPAR subtypes, PPAR, /, and activate overlapping but also very different target gene programs. This review summarizes the insights into PPAR subtype-specific transactivation provided by genome-wide studies and discusses the recent advances in the understanding of the molecular mechanisms underlying PPAR subtype specificity with special focus on the regulatory role of AF-1.


2019 ◽  
Vol 2 (2) ◽  
pp. 120-130 ◽  
Author(s):  
Delin Ran ◽  
Minglong Cai ◽  
Xuejun Zhang

AbstractPsoriasis is an inflammatory skin disease with a background of polygenic inheritance. Both environmental and genetic factors are involved in the etiology of the disease. In the last two decades, numerous studies have been conducted through linkage analysis, genome-wide association study (GWAS), and direct sequencing to explore the role of genetic variation in disease pathogenesis and progression. To date, >80 psoriasis susceptibility genes have been identified, including HLA-Cw6, IL12B, IL23R, and LCE3B/3C. Some genetic markers have been applied in disease prediction, clinical diagnosis, treatment, and new drug development, which could further explain the pathogenesis of psoriasis and promote the development of precision medicine. This review summarizes related research on genetic variation in psoriasis and explores implications of the findings in clinical application and the promotion of a personalized medicine project.


Author(s):  
Е.А. Трифонова ◽  
А.В. Марков ◽  
И.А. Степанов ◽  
Е.В. Ижойкина ◽  
В.А. Степанов

Многочисленными исследованиями показано, что ключевые патогенетические механизмы больших акушерских синдромов (БАС) связаны с нарушением процессов плацентации. В связи с чем, целью нашей работы являлся поиск новых генетических маркеров этих гестационных осложнений на основе интегративного анализа данных, полученных при полногеномном экспрессионном профилировании плацентарной ткани. Нами выявлено 64 гена, транскрипционная активность которых статистически значимо изменяется как минимум при двух заболеваниях группы БАС. Показана значимая роль нарушения межклеточных взаимодействий и регуляции модификации белков в плацентарной ткани при развитии изученных патологических состояний беременности, идентифицированы мастер-регуляторы, рассматриваемые в качестве потенциальных терапевтических мишеней. It is shown that the key pathogenetic mechanisms of grate obstetric syndromes (GOS) are associated with impaired placentation. The aim of the work was to search for new genetic markers of GOS on the basis of integrative analysis of genome-wide expression profiling data. We found that the transcriptional activity of 64 genes changes in at least two GOS diseases. The significant role of disturbance of intercellular interactions and regulation of protein modification in placental tissue during the development of the pregnancy complications is shown. Master regulators that are potential therapeutic targets have been identified.


2019 ◽  
Vol 16 (3) ◽  
pp. 5-25
Author(s):  
N G Astafyeva ◽  
B A Shamgunova ◽  
D Yu Kobzev ◽  
I Ae Michailova

This review presents current data on the associative relationships of genes of the major histocompatibility complex (HLA) and other genes with atopy. Despite the long history of studying the role of HLA class genes in atopy and the introduction of modern technologies and methods, many unresolved issues remain, including the difficulties caused by the heterogeneity of the human population, the complex structure and disequilibrium of linkage between different HLA genes. Although phenotypic heterogeneity is considered as the main limitation in understanding the genetic determinants of atopy, only a few studies have examined the relationships of its typical clinical manifestations induced by aeroallergens with certain HLA genes. The identified molecular mechanisms and genetic characteristics open up the possibility of using new therapeutic targets and modifying existing drugs.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 361-361 ◽  
Author(s):  
Anil Aktas Samur ◽  
Mehmet Kemal Samur ◽  
Michael A Lopez ◽  
Sanika Derebail ◽  
Kenneth C. Anderson ◽  
...  

Alternative splicing (AS) is a critical post-transcriptional event, which affects the number of cellular processes. Aberrant splicing of some genes has been reported in multiple myeloma (MM). However, to date, whole-transcriptome-wide AS study has not been performed. We used deep RNA-sequencing data from 16 normal plasma cells (NPC) and 360 newly-diagnosed MM patients to describe the landscape of the alternative splicing events and the molecular mechanisms driving aberrant AS in MM. Global splicing analysis showed that mutually exclusive exon (MXE) (n=510) and Skipped Exon (SE) (n=417) are the most frequent splicing events in MM compared to NPC. Among these events, ~54% were observed in genes which are not differentially expressed between MM and NPC and 46% of the AS events (SE, MXE, retained intron, alternative 3'/5' sites) were observed in differentially expressed genes targeting 203 unique genes. AS affected RNA transcription regulation genes such as IKZF1, IKZF3, and key regulatory elements in MM including, IRF3, IRF4, or key transcription factors such as MEF2C, XPB1, STAT2, and ILF3. In general, AS targetted DNA replication, cell cycle, and apoptosis pathways. MM subgroups showed a heterogeneity for AS events. Monosomy 14, t(4;14), del1p and del17p had the highest number of unique (not observed in other subgroups) AS events compared to NPC.To understanding the molecular mechanisms driving aberrant alternate splicing we next investigated115 splicing factors (SF) in MM and associated them with AS events. We observed that ~40% of SF were dysregulated (dysregulated expression and/or copy number alteration) in MM compared to NPC, including SRSF, PCBP and RBM families. To understand the key binding regions, we have performed SF binding motif enrichment analysis around AS events and found that SRFS1, SRSF9, and PCB1 motifs to be enriched among the splicing events. Importantly, SRSF1 expression was linked with survival in two independent MM datasets.We therefore explored functional role of SRSF1 in MM with perturbation studies. While upregulation of SRSF1 expression significantly increased the cell growth and survival, conversely downregulation of SRSF1 inhibited the both. To dissect the mechanisms of SRSF1-mediated MM growth induction, we utilized SRSF1 mutants lacking either of the 2 RNA-recognition motifs or the serine/argine-rich C-terminal domain involved in protein-protein interactions, and recruitment of spliceosome components. We also utilized a C-terminal fusion of SRSF1 with the nuclear-retention signal of SRSF2 (NRS1 mutant), to force SRSF1 retention in the nucleus and assess the role of its nuclear versus cytoplasmic functions. These studies suggested that SRSF1-regulated AS effects MM cell proliferation. We surprisingly also found that even NRS1 mutant failed to promote MM growth, suggesting an important role of cytoplasmic SRSF1 in promoting MM cells proliferation.We next investigated alternative splicing pattern changes induced by SRSF1 knock down.When analyzing cellular functions of SRSF1-regulated splicing events, we found that SRSF1 knock down affect's genes in the RNA processing pathway as well as genes involved in cancer-related functions such as mTOR, E2F and MYC-related pathways. Splicing analysis was corroborated with immunoprecipitation (IP) followed by mass spectrometry (MS) analysis of T7-tagged SRSF1 MM cells.Finally, using genome wide chromatin and transcription landscape mapping techniques, we have found SRSF1 to be under the transcriptional control of oncogenic E2F1 in MM cells. Consistent with these findings, we observed greater in vitro loss of viability in a large panel of MM cell lines compared with PBMCs from healthy volunteers, following exposure to the splicing modulator pladeniolide. In summary, this study for the first time reports a detailed splicing landscape in myeloma and highlights the biological and clinical importance of alternative splicing events. Moreover, these results indicate a functional role and clinical significance of a gene involved in regulation of alternate splicing in MM, highlighting the need to further understand the splicing pattern in myeloma initiation and progression. Disclosures Anderson: Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Oncopep: Other: Scientific Founder; Sanofi-Aventis: Other: Advisory Board; Bristol-Myers Squibb: Other: Scientific Founder. Avet-Loiseau:takeda: Consultancy, Other: travel fees, lecture fees, Research Funding; celgene: Consultancy, Other: travel fees, lecture fees, Research Funding. Munshi:Adaptive: Consultancy; Abbvie: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Oncopep: Consultancy; Amgen: Consultancy; Celgene: Consultancy.


Acta Naturae ◽  
2014 ◽  
Vol 6 (2) ◽  
pp. 71-83 ◽  
Author(s):  
E. A. Trifonova ◽  
T. V. Gabidulina ◽  
N. I. Ershov ◽  
V. N. Serebrova ◽  
A. Yu. Vorozhishcheva ◽  
...  

Preeclampsia is one of the most severe gestational complications which is one of the leading causes of maternal and perinatal morbidity and mortality. A growth in the incidence of severe and combined forms of the pathology has been observed in recent years. According to modern concepts, inadequate cytotrophoblast invasion into the spiral arteries of the uterus and development of the ischemia-reperfusion syndrome in the placental tissue play the leading role in the development of preeclampsia, which is characterized by multipleorgan failure. In this regard, our work was aimed at studying the patterns of placental tissue transcriptome that are specific to females with PE and with physiological pregnancy, as well as identifying the potential promising biomarkers and molecular mechanisms of this pathology. We have identified 63 genes whose expression proved to differ significantly in the placental tissue of females with PE and with physiological pregnancy. A cluster of differentially expressed genes (DEG) whose expression level is increased in patients with preeclampsia includes not only the known candidate genes that have been identified in many other genome-wide studies (e.g., LEP, BHLHB2, SIGLEC6, RDH13, BCL6), but also new genes (ANKRD37, SYDE1, CYBA, ITGB2, etc.), which can be considered as new biological markers of preeclampsia and are of further interest. The results of a functional annotation of DEG show that the development of preeclampsia may be related to a stress response, immune processes, the regulation of cell-cell interactions, intracellular signaling cascades, etc. In addition, the features of the differential gene expression depending on preeclampsia severity were revealed. We have found evidence of the important role of the molecular mechanisms responsible for the failure of immunological tolerance and initiation of the pro-inflammatory cascade in the development of severe preeclampsia. The results obtained elaborate the concept of the pathophysiology of preeclampsia and contain the information necessary to work out measures for targeted therapy of this disease.


2018 ◽  
Vol 114 (8) ◽  
pp. 1073-1081 ◽  
Author(s):  
Liam R Brunham ◽  
Steven Baker ◽  
Andrew Mammen ◽  
G B John Mancini ◽  
Robert S Rosenson

AbstractStatin therapy reduces cardiovascular events in patients with, or at risk of, atherosclerotic cardiovascular disease. However, statins are underutilized in patients for whom they are indicated and are frequently discontinued. Discontinuation may be the result of statin-associated muscle symptoms (SAMS), which encompass a broad spectrum of clinical phenotypes from myalgia to severe myopathy. As with many adverse drug reactions (ADRs), inter-individual variability in susceptibility to SAMS is due, at least in part, to differences in host genetics. The genetic basis for SAMS has been investigated in candidate gene studies, genome-wide association studies, and, more recently, studies of multi-omic networks, including at the transcriptome level. In this article, we provide a systematic review of the pharmacogenetic basis of SAMS, focusing on how an understanding of the genetic and molecular determinants of SAMS can be considered in a personalized approach to reduce the incidence of this ADR, optimize statin adherence, and reduce the risk for cardiovascular events.


Author(s):  
Kimberley W J van der Sloot ◽  
Michiel D Voskuil ◽  
Tjasso Blokzijl ◽  
Annemieke Dinkla ◽  
Lars Ravesloot ◽  
...  

Abstract Background The role of Mycobacterium avium subspecies paratuberculosis (MAP) in inflammatory bowel disease (IBD), especially Crohn’s disease (CD) is controversial due conflicting results, lack of reproducibility and standardized tests. The current study focuses on the role of MAP in disease progression and genetic susceptibility as MAP is likely one of many factors involved in the complex pathogenesis of IBD, potentially affecting a subgroup depending on genetic susceptibility. Methods Serum from 812 patients was evaluated with seven immunoglobulin (Ig) isotype-specific serology tests assessing humoral response to three different MAP antigens. For each of these in total 21 tests, the intra-assay and inter-assay coefficients were used to evaluate test accuracy. Reliable assays were subsequently analyzed in relation to disease characteristics and need for biological therapy/surgery. Genome wide genotyping was available for all participants. Genetic determinants of humoral response to MAP antigens were evaluated using genome-wide association analysis and polygenic risk scores (PRS). Results High IgA or IgM response to MAP2609 was associated with increased use of biological therapy in CD and UC (odds ratio 2.69; 95% confidence interval 1.44-5.01; 2.60, 1.46-4.64, respectively). No associations were seen for risk of surgery (p-values>0.29). We could not identify genetic determinants nor polygenic risk scores for MAP response with genome-wide significance. Conclusions Extensive assays for serological response to MAP were evaluated using stringent criteria for reliability. Increased IgA and IgM response to MAP antigens was seen in patients exposed to biological therapy, while no genetic determinants underlying this humoral response were found.


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