Genetic implications in the pathogenesis of rheumatoid arthritis; an updated review.

Gene. 2019 Mar 20;:

Authors: Karami J, Aslani S, Jamshidi A, Garshasbi M, Mahmoudi M

Abstract
Three important factors, including genetics, environment factors and autoimmunity play a role in the pathogenesis of rheumatoid arthritis (RA). The heritability of RA has been accounted to be 50-60%, while the HLA involvement in heritability of the disease has been accounted to be 10-40%. It has been documented that shared epitope (SE) alleles, such as HLA-DRB1*01 and DRB1*04, some HLA alleles like HLA-DRB1*13 and DRB1*15 are connected to RA susceptibility. An advanced classification of SE categorizes SE alleles into four main groups namely, S1, S2, S3D, and S3P. The S2 and S3P groups have been linked to susceptibility of seropositive RA. Various genome-wide association studies (GWAS) have discovered many susceptibility loci implicated in pathogenesis of RA. Some of the important single nucleotide polymorphisms (SNPs) linked to RA are TRAF1, STAT4, CTLA4, IRF5, CCR6, PTPN22, IL23R, and PADI4. HLA and non-HLA genes may discriminate anti-cyclic citrullinated peptide (anti-CCP) antibody-positive and anti-CCP-negative RA groups. Furthermore, risk of the disease has also been linked to environmental agents, mainly cigarette smoking. Pharmacogenomics has also confirmed SNPs or genetic patterns that might be linked to drugs responses. Different aspects of genetic involvement in the pathogenesis, etiology, and RA complications are reviewed in this article.

PMID: 30904715 [PubMed - as supplied by publisher]

Population-scale genomics-Enabling precision public health.

Adv Genet. 2019;103:119-161

Authors: Sivadas A, Scaria V

Abstract
The current excitement for affordable genomics technologies and national precision medicine initiatives marks a turning point in worldwide healthcare practices. The last decade of global population sequencing efforts has defined the enormous extent of genetic variation in the human population resulting in insights into differential disease burden and response to therapy within and between populations. Population-scale pharmacogenomics helps to provide insights into the choice of optimal therapies and an opportunity to estimate, predict and minimize adverse events. Such an approach can potentially empower countries to formulate national selection and dosing policies for therapeutic agents thereby promoting public health with precision. We review the breadth and depth of worldwide population-scale sequencing efforts and its implications for the implementation of clinical pharmacogenetics toward making precision medicine a reality.

PMID: 30904093 [PubMed - in process]

Use of a Bile Salt Export Pump Knockdown Rat Susceptibility Model to Interrogate Mechanism of Drug Induced Liver Toxicity.

Toxicol Sci. 2019 Mar 23;:

Authors: Li Y, Evers R, Hafey MJ, Cheon K, Duong H, Lynch D, LaFranco-Scheuch L, Pacchione S, Tamburino A, Tanis K, Geddes K, Holder D, Rena Zhang N, Kang W, Gonzalez RJ, Galijatovic-Idrizbegovic A, Pearson K, Lebron J, Glaab WE, Sistare FD

Abstract
Inhibition of the Bile Salt Export Pump (BSEP) may be associated with clinical drug-induced liver injury, but is poorly predicted by preclinical animal models. Here we present the development of a novel rat model using siRNA knockdown (KD) of Bsep that displayed differentially enhanced hepatotoxicity to 8 Bsep inhibitors and not to 3 Bsep non-inhibitors when administered at maximally tolerated doses for 7 days. Bsep KD alone resulted in 3- and 4.5-fold increases in liver and plasma levels, respectively, of the sum of the 3 most prevalent taurine conjugated bile acids (T3-BA), approximately 90% decrease in plasma and liver glycocholic acid, and a distinct bile acid regulating gene expression pattern, without resulting in hepatotoxicity. Among the Bsep inhibitors, only asunaprevir and TAK-875 resulted in serum transaminase and total bilirubin increases associated with increases in plasma T3-BA that were enhanced by Bsep KD. Benzbromarone, lopinavir, and simeprevir caused smaller increases in plasma T3-BA, but did not result in hepatotoxicity in Bsep KD rats. Bosentan, cyclosporine A, and ritonavir, however, showed no enhancement of T3-BA in plasma in Bsep KD rats, as well as Bsep non-inhibitors acetaminophen, MK-0974, or clarithromycin. T3-BA findings were further strengthened through monitoring TCA-d4 converted from cholic acid-d4 overcoming inter-animal variability in endogenous bile acids. Bsep KD also altered liver and/or plasma levels of asunaprevir, TAK-875, TAK-875 acylglucuronide, benzbromarone, and bosentan. The Bsep KD rat model has revealed differences in the effects on bile acid homeostasis among Bsep inhibitors that can best be monitored using measures of T3-BA and TCA-d4 in plasma. However, the phenotype caused by Bsep inhibition is complex due to the involvement of several compensatory mechanisms.

PMID: 30903168 [PubMed - as supplied by publisher]

Current Progress in Pharmacogenetics of Second-Line Antidiabetic Medications: Towards Precision Medicine for Type 2 Diabetes.

J Clin Med. 2019 Mar 21;8(3):

Authors: Heo CU, Choi CI

Abstract
Precision medicine is a scientific and medical practice for personalized therapy based on patients' individual genetic, environmental, and lifestyle characteristics. Pharmacogenetics and pharmacogenomics are also rapidly developing and expanding as a key element of precision medicine, in which the association between individual genetic variabilities and drug disposition and therapeutic responses are investigated. Type 2 diabetes (T2D) is a chronic metabolic disorder characterized by hyperglycemia mainly associated with insulin resistance, with the risk of clinically important cardiovascular, neurological, and renal complications. The latest consensus report from the American Diabetes Association and European Association for the Study of Diabetes (ADA-EASD) on the management of T2D recommends preferential use of glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and some dipeptidyl peptidase-4 (DPP-4) inhibitors after initial metformin monotherapy for diabetic patients with established atherosclerotic cardiovascular or chronic kidney disease, and with risk of hypoglycemia or body weight-related problems. In this review article, we summarized current progress on pharmacogenetics of newer second-line antidiabetic medications in clinical practices and discussed their therapeutic implications for precision medicine in T2D management. Several biomarkers associated with drug responses have been identified from extensive clinical pharmacogenetic studies, and functional variations in these genes have been shown to significantly affect drug-related glycemic control, adverse reactions, and risk of diabetic complications. More comprehensive pharmacogenetic research in various clinical settings will clarify the therapeutic implications of these genes, which may be useful tools for precision medicine in the treatment and prevention of T2D and its complications.

PMID: 30901912 [PubMed]

Limited Sensitivity of Circulating Tumor DNA Detection by Droplet Digital PCR in Non-Metastatic Operable Gastric Cancer Patients.

Cancers (Basel). 2019 Mar 21;11(3):

Authors: Cabel L, Decraene C, Bieche I, Pierga JY, Bennamoun M, Fuks D, Ferraz JM, Lefevre M, Baulande S, Bernard V, Vacher S, Mariani P, Proudhon C, Bidard FC, Louvet C

Abstract
This study was designed to monitor circulating tumor DNA (ctDNA) levels during perioperative chemotherapy in patients with non-metastatic gastric adenocarcinoma. Plasma samples were prospectively collected in patients undergoing perioperative chemotherapy for non-metastatic gastric adenocarcinoma (excluding T1N0) prior to the initiation of perioperative chemotherapy, before and after surgery (NCT02220556). In each patient, mutations retrieved by targeted next-generation sequencing (NGS) on tumor samples were then tracked in circulating cell-free DNA from 4 mL of plasma by droplet digital PCR. Thirty-two patients with a diagnosis of non-metastatic gastric adenocarcinoma were included. A trackable mutation was identified in the tumor in 20 patients, seven of whom experienced relapse during follow-up. ctDNA was detectable in four patients (N = 4/19, sensitivity: 21%; 95% confidence interval CI = 8.5⁻43%, no baseline plasma sample was available for one patient), with a median allelic frequency (MAF) of 1.6% (range: 0.8⁻2.3%). No patient with available plasma samples (N = 0/18) had detectable ctDNA levels before surgery. After surgery, one of the 13 patients with available plasma samples had a detectable ctDNA level with a low allelic frequency (0.7%); this patient experienced a very short-term distant relapse only 3 months after surgery. No ctDNA was detected after surgery in the other four patients with available plasma samples who experienced a later relapse (median = 14.4, range: 9.3⁻26 months). ctDNA monitoring during preoperative chemotherapy and after surgery does not appear to be a useful tool in clinical practice for non-metastatic gastric cancer to predict the efficacy of chemotherapy and subsequent relapse, essentially due to the poor sensitivity of ctDNA detection.

PMID: 30901876 [PubMed]

Liraglutide Exerts an Anti-Inflammatory Action in Obese Patients with Type 2 Diabetes.

Rom J Intern Med. 2019 Jan 01;:

Authors: Kaidashev I, Savchenko LG, Digtiar NI, Selikhova LG, Kaidasheva EI, Shlykova OA, Vesnina LE

Abstract
INTRODUCTION: Liraglutide (L) is the analogue of human glucagon-like peptide 1 which stimulates glucose-dependent insulin secretion and can modify a level of inflammatory biomarkers. L can influence NF-kB inflammatory cascade, but the mechanisms of anti-inflammatory activities of L remain to be determined. In animal models L influenced an activity of Sirtuin 1(SIRT1). Moreover, recent evidences strongly suggest that SIRT1 up-regulation may serve as a potent therapeutic approach against development and progression of diabetic complications . The aim of this study was to investigate L effects directed on pro-inflammatory NF-kB pathway and expression of SIRT1 in obese patients with type 2 diabetes mellitus (DM).
MATERIALS AND METHODS: 15 obese patients with type 2 diabetes were studied, all using metformin (1-2 g/day) and sulfonylurea (glimiperide). All patients received L 1.2 mg daily add-on to stable therapy for 6 weeks. Blood samples were collected before, 6 weeks after start of treatment and after an overnight fast 6 weeks after stopping L, mononuclear cells (MNC) were isolated. The mRNA expression of TNF-α, TLR2, TLR4, NOD1, IL-2 and SIRT1 were measured in MNC by RT-PCR. Ceruloplasmin concentration was measured in plasma by photometric method.
RESULTS: In this add-on pilot clinical investigation we received new data that L can inhibit proinflammatory NF-kB pathway by increased SIRT1 expression in obese patients with type 2 DM improving metabolic profile. The mRNA expression in MNC of TNF-α, IkB, TLR2, TLR4, and plasma ceruloplasmin fell after 6 weeks of L. Expressions of IL-2 and NOD-1 were stable. There was a significant increase of SIRT1 mRNA expression. The mRNA expression in MNC of TNF-α, IkB, TLR2, TLR4, NOD1, SIRT1 and ceruloplasmin concentrations didn't reverse to baseline levels after 6 weeks stopping of L treatment. IL-2 expression decreased in comparison with basic level.
CONCLUSIONS: L has a potent anti-inflammatory effect as do GLP-1 agonists due to inhibition of NF-kB pathways and up-regulate SIRT1 expression, down-regulating pro-inflammatory factors including cytokines (TNF-α), extra- and intracellular receptors (TLR2, TLR4), and inflammation markers such as ceruloplasmin. Long lasting effects of L can be mediated by epigenetic regulation of NF-kB pathway by SIRT-1.

PMID: 30901315 [PubMed - as supplied by publisher]

Commercial Pharmacogenetic Tests in Psychiatry: Do they Facilitate the Implementation of Pharmacogenetic Dosing Guidelines?

Pharmacopsychiatry. 2019 Mar 21;:

Authors: Fan M, Bousman CA

Abstract
INTRODUCTION: Expert groups have created dosing guidelines to facilitate the implementation of pharmacogenetic knowledge into clinical practice and commercial pharmacogenetic tests are becoming increasingly accessible. However, the extent to which these commercial tests facilitate the implementation of dosing guidelines is not clear.
METHODS: Gene-drug pairs included on 22 commercial pharmacogenetic test panels were extracted and cross-referenced with the 74 gene-drug pairs with dosing guidelines in the Pharmacogenetics Knowledgebase, with particular attention given to the 28 gene-drug pairs relevant to psychiatry.
RESULTS: On average, 70% of the 28 gene-drug pairs most relevant to psychiatry were covered by the examined tests. Six gene-drug pairs (CYP2D6-venlafaxine, CYP2D6-paroxetine, CYP2D6-amitriptyline, CYP2C19-sertraline, CYP2C19-citalopram, CYP2C19-amitriptyline) were included by all tests. Gene-drug pairs included on less than half of the test panels included HLA-B-phenytoin (14%), HLA-A-carbamazepine (24%), HLA-B-carbamazepine (29%), and CYP2D6-zuclopenthixol (43%).
DISCUSSION: Most commercial pharmacogenetic tests we examined are well-equipped to facilitate implementation of the majority of dosing guidelines relevant to psychiatry but are limited in their ability to facilitate implementation of the full spectrum of dosing guidelines currently available.

PMID: 30900236 [PubMed - as supplied by publisher]

TNF-α G-308A genetic variants, serum CRP-hs concentration and DNA damage in obese women.

Mol Biol Rep. 2019 Mar 21;:

Authors: Marta W, Michał C, Grażyna N

Abstract
Obesity is associated with inflammation, which can disturb genome stability. Tumor necrosis factor (TNF-α) polymorphism was found to affect TNF-α protein production and inflammation. Therefore, the present study illustrates the relationship between TNF-α polymorphism, the degree of inflammation assessed by serum high sensitivity C-reactive protein concentration (CRP-hs) and basal DNA damage in patients with obesity (BMI 30-34.9 kg/m2) and control subjects with proper body mass (BMI < 25 kg/m2). A total of 115 participants (75 obese premenopausal women; and 40 age-, and gender-matched controls) were included. Biochemical parameters (serum concentrations of total-cholesterol, HDL-cholesterol, LDL- cholesterol, triglycerides, glucose, apolipoprotein AI, CRP-hs) and endogenous DNA damage (determined by comet assay) were measured. TNF-α G-308A polymorphism (rs1800629) was analyzed by PCR-RFLP (PCR-restriction fragments length polymorphism). An effect of TNF-α genotype on serum CRP-hs concentration was noted (p = 0.031). In general, carriers of the rare A allele of the TNF-α G-308A polymorphism had significantly lower endogenous DNA damage and serum CRP-hs concentrations than GG homozygotes, however, the protective effect of the A allele was especially visible in non-obese women. Serum CRP-hs concentrations and levels of DNA damage (% DNA in tail) were significantly higher in obese than in controls (p = 0.001 and p < 0.0001, respectively). The adjusted multiple linear regression analyses revealed a significant, independent impact of obesity on DNA damage (p = 0.00000) and no effect of other covariates i.e. age, TNF-α genotype and serum CRP-hs concentration. Our study showed that obesity has a significant impact on the levels of endogenous DNA damage. Obesity abolished the protective effect of A allele of the TNF-α G-308A polymorphism on DNA damage and on inflammation development observed in non-obese A allele carriers.

PMID: 30900134 [PubMed - as supplied by publisher]

A targeted genomic alteration analysis predicts survival of melanoma patients under BRAF inhibitors.

Oncotarget. 2019 Mar 01;10(18):1669-1687

Authors: Louveau B, Delyon J, De Moura CR, Battistella M, Jouenne F, Golmard L, Sadoux A, Podgorniak MP, Chami I, Marco O, Caramel J, Dalle S, Feugeas JP, Dumaz N, Lebbe C, Mourah S

Abstract
Several mechanisms have been described to elucidate the emergence of resistance to MAPK inhibitors in melanoma and there is a crucial need for biomarkers to identify patients who are likely to achieve a better and long-lasting response to BRAF inhibitors therapy. In this study, we developed a targeted approach combining both mRNA and DNA alterations analysis focusing on relevant gene alterations involved in acquired BRAF inhibitor resistance. We collected baseline tumor samples from 64 melanoma patients at BRAF inhibitor treatment initiation and showed that the presence, prior to treatment, of mRNA over-expression of genes' subset was significantly associated with improved progression free survival and overall survival. The presence of DNA alterations was in favor of better overall survival. The genomic analysis of relapsed-matched tumor samples from 20 patients allowed us to uncover the largest landscape of resistance mechanisms reported to date as at least one resistance mechanism was identified for each patient studied. Alterations in RB1 have been most frequent and hence represent an important additional acquired resistance mechanism. Our targeted genomic analysis emerges as a relevant tool in clinical practice to identify those patients who are more likely to achieve durable response to targeted therapies and to exhaustively describe the spectrum of resistance mechanisms. Our approach can be adapted to new targeted therapies by including newly identified genetic alterations.

PMID: 30899440 [PubMed]

Vitamin D serum levels in women using contraception containing drospirenone - a preliminary study.

Arch Med Sci. 2019 Mar;15(2):554-557

Authors: Ciebiera M, Włodarczyk M, Słabuszewska-Jóźwiak A, Ciebiera M, Nowicka G, Jakiel G

PMID: 30899309 [PubMed]

Age at onset of obesity, transcription factor 7-like 2 (TCF7L2) rs7903146 polymorphism, adiponectin levels and the risk of type 2 diabetes in obese patients.

Arch Med Sci. 2019 Mar;15(2):321-329

Authors: Wrzosek M, Sawicka A, Wrzosek M, Piątkiewicz P, Tałałaj M, Nowicka G

Abstract
Introduction: Interaction between obesity and genetic factors involved in the regulatory pathways of glucose homeostasis may play a significant role in diabetes development in the obese. The aim of this study was to investigate the associations between the TCF7L2 rs7903146 polymorphism, adiponectin levels, age at onset of obesity and the occurrence of type 2 diabetes (T2D) in a sample of obese Polish adults.
Material and methods: A total of 474 unrelated obese subjects were included in this study. Real-time PCR was used to detect the TCF7L2 rs7903146 polymorphism. Serum level of adiponectin was determined by the ELISA method. Standard assays were used to measure total cholesterol, HDL cholesterol, triglycerides, glucose and HbA1c concentrations. We used multiple logistic regression to identify factors associated with type 2 diabetes.
Results: We found that the T allele of rs7903146 was significantly associated with T2D risk (odds ratio of 1.59 for T allele, p = 0.005). This association persisted after adjusting for confounders in the recessive model (odds ratio of 3.54 for TT genotype, p = 0.011). Serum adiponectin levels were significantly lower in diabetic subjects than in nondiabetic individuals (3.6 vs. 5.6 µg/ml, p < 0.001). Participants who were obese at age ≥ 20 years had significantly higher odds of having T2D (OR = 4.94) than those with the onset of obesity before 20 years (p < 0.001).
Conclusions: Our study highlights the significance of the relationship between the TCF7L2 polymorphism, a person's age at onset of obesity and the prevalence of T2D, and confirms lower adiponectin levels in obese diabetics in comparison to obese nondiabetics.

PMID: 30899283 [PubMed]

A Bibliometric Analysis of Scientific Production on Second-Generation Anti-Psychotic Drugs in Malaysia.

Malays J Med Sci. 2018 May;25(3):40-55

Authors: López-Muñoz F, Povedano-Montero FJ, Chee KY, Shen WW, Fernández-Martín P, García-Pacios J, Rubio G, Álamo C

Abstract
Objective: We carried out a bibliometric study on the scientific papers related to second-generation antipsychotic drugs (SGAs) in Malaysia.
Methods: With the SCOPUS database, we selected those documents made in Malaysia whose title included descriptors related to SGAs. We applied bibliometric indicators of production and dispersion, as Price's law and Bradford's law, respectively. We also calculated the participation index of the different countries. The bibliometric data were also been correlated with some social and health data from Malaysia (total per capita expenditure on health and gross domestic expenditure on R&D).
Results: We found 105 original documents published between 2004 and 2016. Our results fulfilled Price's law, with scientific production on SGAs showing exponential growth (r = 0.401, vs. r = 0.260 after linear adjustment). The drugs most studied are olanzapine (9 documents), clozapine (7), and risperidone (7). Division into Bradford zones yields a nucleus occupied by the Medical Journal of Malaysia, Singapore Medical Journal, Australian and New Zealand Journal of Psychiatry, and Pharmacogenomics. Totally, 63 different journals were used, but only one in the top four journals had an impact factor being greater than 3.
Conclusion: The publications on SGAs in Malaysia have undergone exponential growth, without evidence a saturation point.

PMID: 30899186 [PubMed]

Clioquinol: To harm or heal.

Pharmacol Ther. 2019 Mar 18;:

Authors: Perez DR, Sklar LA, Chigaev A

Abstract
Clioquinol, one of the first mass-produced drugs, was considered safe and efficacious for many years. It was used as an antifungal and an antiprotozoal drug until it was linked to an outbreak of subacute myelo-optic neuropathy (SMON), a debilitating disease almost exclusively confined to Japan. Today, new information regarding clioquinol targets and its mechanism of action, as well as genetic variation (SNPs) in efflux transporters in the Japanese population, provide a unique interpretation of the existing phenomena. Further understanding of clioquinol's role in the inhibition of cAMP efflux and promoting apoptosis might offer promise for the treatment of cancer and/or neurodegenerative diseases. Here, we highlight recent developments in the field and discuss possible connections, hypotheses and perspectives in clioquinol-related research.

PMID: 30898518 [PubMed - as supplied by publisher]

A Disinhibitory Microcircuit Mediates Conditioned Social Fear in the Prefrontal Cortex.

Neuron. 2019 Mar 08;:

Authors: Xu H, Liu L, Tian Y, Wang J, Li J, Zheng J, Zhao H, He M, Xu TL, Duan S, Xu H

Abstract
Fear behavior is under tight control of the prefrontal cortex, but the underlying microcircuit mechanism remains elusive. In particular, it is unclear how distinct subtypes of inhibitory interneurons (INs) within prefrontal cortex interact and contribute to fear expression. We employed a social fear conditioning paradigm and induced robust social fear in mice. We found that social fear is characterized by activation of dorsal medial prefrontal cortex (dmPFC) and is largely diminished by dmPFC inactivation. With a combination of in vivo electrophysiological recordings and fiber photometry together with cell-type-specific pharmacogenetics, we further demonstrated that somatostatin (SST) INs suppressed parvalbumin (PV) INs and disinhibited pyramidal cells and consequently enhanced dmPFC output to mediate social fear responses. These results reveal a previously unknown disinhibitory microcircuit in prefrontal cortex through interactions between IN subtypes and suggest that SST INs-mediated disinhibition represents an important circuit mechanism in gating social fear behavior.

PMID: 30898376 [PubMed - as supplied by publisher]

Targeting gap junction in epilepsy: Perspectives and challenges.

Biomed Pharmacother. 2019 Jan;109:57-65

Authors: Li Q, Li QQ, Jia JN, Liu ZQ, Zhou HH, Mao XY

Abstract
Gap junctions (GJs) are multiple cellular intercellular connections that allow ions to pass directly into the cytoplasm of neighboring cells. Electrical coupling mediated by GJs plays a role in the generation of highly synchronous electrical activity. Accumulative investigations show that GJs in the brain are involved in the generation, synchronization and maintenance of seizure events. At the same time, GJ blockers exert potent curative potential on epilepsy in vivo or in vitro. This review aims to shed light on the role of GJs in epileptogenesis. Targeting GJs is likely to be served as a novel therapeutic approach on epileptic patients.

PMID: 30396092 [PubMed - indexed for MEDLINE]

Association of Chromosome 9p21 with Subsequent Coronary Heart Disease Events: A GENIUS-CHD Study of Individual Participant Data.

Circ Genom Precis Med. 2019 Mar 21;:

Authors: Patel RS, Schmidt AF, Tragante V, McCubrey RO, Holmes MV, Howe LJ, Direk K, Åkerblom A, Leander K, Virani SS, Kaminski KA, Muehlschlegel JD, Dubé MP, Allayee H, Almgren P, Alver M, Baranova EV, Behlouli H, Boeckx B, Braund PS, Breitling LP, Delgado G, Duarte NE, Dufresne L, Eriksson N, Foco L, Gijsberts CM, Gong Y, Hartiala J, Heydarpour M, Hubacek JA, Kleber M, Kofink D, Kuukasjärvi P, Lee VV, Leiherer A, Lenzini PA, Levin D, Lyytikäinen LP, Martinelli N, Mons U, Nelson CP, Nikus K, Pilbrow AP, Ploski R, Sun YV, Tanck MWT, Tang WHW, Trompet S, van der Laan SW, Van Setten J, Vilmundarson RO, Viviani Anselmi C, Vlachopoulou E, Boerwinkle E, Briguori C, Carlquist JF, Carruthers KF, Casu G, Deanfield J, Deloukas P, Dudbridge F, Fitzpatrick N, Gigante B, James S, Lokki ML, Lotufo PA, Marziliano N, Mordi IR, Muhlestein JB, Newton-Cheh C, Pitha J, Saely CH, Samman-Tahhan A, Sandesara PB, Teren A, Timmis A, Van de Werf F, Wauters E, Wilde AAM, Ford I, Stott DJ, Algra A, Andreassi MG, Ardissino D, Arsenault BJ, Ballantyne CM, Bergmeijer TO, Bezzina CR, Body SC, Bogaty P, de Borst GJ, Brenner H, Burkhardt R, Carpeggiani C, Condorelli G, Cooper-DeHoff RM, Cresci S, de Faire U, Doughty RN, Drexel H, Engert JC, Fox KAA, Girelli D, Hagström E, Hazen SL, Held C, Hemingway H, Hoefer IE, Hovingh GK, Johnson JA, de Jong PA, Jukema JW, Kaczor MP, Kähönen M, Kettner J, Kiliszek M, Klungel OH, Lagerqvist B, Lambrechts D, Laurikka JO, Lehtimäki T, Lindholm D, Mahmoodi BK, Maitland-van der Zee AH, McPherson R, Melander O, Metspalu A, Pepinski W, Olivieri O, Opolski G, Palmer CN, Pasterkamp G, Pepine CJ, Pereira AC, Pilote L, Quyyumi AA, Richards AM, Sanak M, Scholz M, Siegbahn A, Sinisalo J, Smith JG, Spertus JA, Stewart AFR, Szczeklik W, Szpakowicz A, Ten Berg JM, Thanassoulis G, Thiery J, van der Graaf Y, Visseren FLJ, Waltenberger J, Van der Harst P, Tardif JC, Sattar N, Lang CC, Paré G, Brophy JM, Anderson JL, März W, Wallentin L, Cameron VA, Horne BD, Samani NJ, Hingorani AD, Asselbergs FW

Abstract
BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.
METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103,357 Europeans with established CHD at baseline from the GENIUS-CHD Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/MI), occurred in 13,040 of the 93,115 participants with available outcome data. Effect estimates were compared to case/control risk obtained from CARDIoGRAMPlusC4D including 47,222 CHD cases and 122,264 controls free of CHD.
RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/MI among those with established CHD at baseline (GENIUS-CHD OR 1.02; 95% CI 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D OR 1.20; 95% CI 1.18-1.22; p for interaction Conclusions: In contrast to studies comparing individuals with CHD to disease free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

PMID: 30897348 [PubMed - as supplied by publisher]

Hyperprogression-Immunotherapy-Related Phenomenon vs Intrinsic Natural History of Cancer.

JAMA Oncol. 2019 Mar 21;:

Authors: Pearson AT, Sweis RF

PMID: 30896751 [PubMed - as supplied by publisher]

Subsequent Event Risk in Individuals with Established Coronary Heart Disease: Design and Rationale of the GENIUS-CHD Consortium.

Circ Genom Precis Med. 2019 Mar 21;:

Authors: Patel R, Tragante V, Schmidt AF, McCubrey RO, Holmes MV, Howe LJ, Direk K, Åkerblom A, Leander K, Virani SS, Kaminski KA, Muehlschlegel JD, Allayee H, Almgren P, Alver M, Baranova EV, Behlouli H, Boeckx B, Braund PS, Breitling LP, Delgado G, Duarte NE, Dubé MP, Dufresne L, Eriksson N, Foco L, Scholz M, Gijsberts CM, Glinge C, Gong Y, Hartiala J, Heydarpour M, Hubacek JA, Kleber M, Kofink D, Kotti S, Kuukasjärvi P, Lee VV, Leiherer A, Lenzini PA, Levin D, Lyytikäinen LP, Martinelli N, Mons U, Nelson CP, Nikus K, Pilbrow AP, Ploski R, Sun YV, Tanck MWT, Tang WHW, Trompet S, van der Laan SW, Van Setten J, Vilmundarson RO, Viviani Anselmi C, Vlachopoulou E, Al Ali L, Boerwinkle E, Briguori C, Carlquist JF, Carruthers KF, Casu G, Deanfield J, Deloukas P, Dudbridge F, Engström T, Fitzpatrick N, Fox K, Gigante B, James S, Lokki ML, Lotufo PA, Marziliano N, Mordi IR, Muhlestein JB, Newton-Cheh C, Pitha J, Saely CH, Samman-Tahhan A, Sandesara PB, Teren A, Timmis A, Van de Werf F, Wauters E, Wilde AAM, Ford I, Stott DJ, Algra A, Andreassi MG, Ardissino D, Arsenault BJ, Ballantyne CM, Bergmeijer TO, Bezzina CR, Body SC, Boersma EH, Bogaty P, Bots M, Brenner H, Brugts JJ, Burkhardt R, Carpeggiani C, Condorelli G, Cooper-DeHoff RM, Cresci S, Danchin N, de Faire U, Doughty RN, Drexel H, Engert JC, Fox KAA, Girelli D, Grobbee DE, Hagström E, Hazen SL, Held C, Hemingway H, Hoefer IE, Hovingh GK, Jabbari R, Johnson JA, Jukema JW, Kaczor MP, Kähönen M, Kettner J, Kiliszek M, Klungel OH, Lagerqvist B, Lambrechts D, Laurikka JO, Lehtimäki T, Lindholm D, Mahmoodi BK, Maitland-van der Zee AH, McPherson R, Melander O, Metspalu A, Niemcunowicz-Janica A, Olivieri O, Opolski G, Palmer CN, Pasterkamp G, Pepine CJ, Pereira AC, Pilote L, Quyyumi AA, Richards AM, Sanak M, Siegbahn A, Simon T, Sinisalo J, Smith JG, Spertus JA, Stender S, Stewart AFR, Szczeklik W, Szpakowicz A, Tardif JC, Ten Berg JM, Tfelt-Hansen J, Thanassoulis G, Thiery J, Torp-Pedersen C, van der Graaf Y, Visseren FLJ, Waltenberger J, Weeke PE, Van der Harst P, Lang CC, Sattar N, Cameron VA, Anderson JL, Brophy JM, Paré G, Horne BD, März W, Wallentin L, Samani NJ, Hingorani AD, Asselbergs FW

Abstract
BACKGROUND: The "GENetIcs of sUbSequent Coronary Heart Disease" (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.
METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185,614 participants with either acute coronary syndrome, stable CHD or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.
RESULTS: Enrollment into the individual studies took place between 1985 to present day with duration of follow up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (HR 1.15 95% CI 1.14-1.16) per 5-year increase, male sex (HR 1.17, 95% CI 1.13-1.21) and smoking (HR 1.43, 95% CI 1.35-1.51) with risk of subsequent CHD death or myocardial infarction, and differing associations with other individual and composite cardiovascular endpoints.
CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and non-genetic determinants of subsequent event risk in individuals with established CHD, in order to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.

PMID: 30896328 [PubMed - as supplied by publisher]

IGNITE network: Response of patients to genomic medicine interventions.

Mol Genet Genomic Med. 2019 Mar 20;:e636

Authors: Orlando LA, Voils C, Horowitz CR, Myers RA, Arwood MJ, Cicali EJ, McDonough CW, Pollin TI, Guan Y, Levy KD, Ramirez A, Quittner A, Madden EB

Abstract
BACKGROUND: The IGNITE network funds six genomic medicine projects. Though interventions varied, we hypothesized that synergies across projects could be leveraged to better understand the participant experiences with genomic medicine interventions. Therefore, we performed cross-network analyses to identify associations between participant demographics and attitudes toward the intervention (attitude), plan to share results (share), and quality of life (QOL).
METHODS: Data collection for demographics, attitude, share, and QOL surveys were standardized across projects. Recruitment and survey administration varied by each project's protocol.
RESULTS: Participants (N = 6,817) were 67.2% (N = 4,584) female, and 37.4% (N = 3,544) were minority. Mean age = 54.0 (sd 14.a). Younger participants were as follows: (1) more positive in attitude pre-intervention (1.15-fold decrease/10-year age increase (OR)) and more negative after (1.14-fold increase OR); (2) higher in QOL pre-intervention (1.07-fold increase OR) and postintervention; (3) more likely to share results (1.12-fold increase OR). Race was significant when sharing results (white participants increased OR = 1.88), but not for change in QOL pre-postintervention or attitude.
CONCLUSION: Our findings demonstrate the feasibility of this approach and identified a few key themes which are as follows: age was consistently significant across the three outcomes, whereas race had less of an impact than expected. However, these are only associations and thus warrant further study.

PMID: 30895746 [PubMed - as supplied by publisher]

Multi-site investigation of strategies for the clinical implementation of CYP2D6 genotyping to guide drug prescribing.

Genet Med. 2019 Mar 21;:

Authors: Cavallari LH, Van Driest SL, Prows CA, Bishop JR, Limdi NA, Pratt VM, Ramsey LB, Smith DM, Tuteja S, Duong BQ, Hicks JK, Lee JC, Obeng AO, Beitelshees AL, Bell GC, Blake K, Crona DJ, Dressler L, Gregg RA, Hines LJ, Scott SA, Shelton RC, Weitzel KW, Johnson JA, Peterson JF, Empey PE, Skaar TC, IGNITE Network

Abstract
PURPOSE: A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers.
METHODS: We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned.
RESULTS: Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy-number variation and nine common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability.
CONCLUSION: There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs.

PMID: 30894703 [PubMed - as supplied by publisher]