Estrogen receptor α phosphorylated at Ser216 confers inflammatory function to mouse microglia.

Cell Commun Signal. 2020 Jul 29;18(1):117

Authors: Shindo S, Chen SH, Gotoh S, Yokobori K, Hu H, Ray M, Moore R, Nagata K, Martinez J, Hong JS, Negishi M

Abstract
BACKGROUND: Estrogen receptor α (ERα) has been suggested to regulate anti-inflammatory signaling in brain microglia, the only resident immune cells in the brain. ERα conserves the phosphorylation motif at Ser216 within the DNA binding domain. Previously, Ser216 was found to be phosphorylated in neutrophils infiltrating into the mouse uterus and to enable ERα to regulate migration. Given the implication of this phosphorylation in immune regulation, ERα was examined in mouse microglia to determine if Ser216 is phosphorylated and regulates microglia's inflammation. It was found that Ser216 was constitutively phosphorylated in microglia and demonstrated that in the absence of phosphorylated ERα in ERα KI brains microglia inflamed, confirming that phosphorylation confers ERα with anti-inflammatory capability. ERα KI mice were obese and weakened motor ability.
METHODS: Mixed glia cells were prepared from brains of 2-days-old neonates and cultured to mature and isolate microglia. An antibody against an anti-phospho-S216 peptide of ERα (αP-S216) was used to detect phosphorylated ERα in double immunofluorescence staining with ERα antibodies and a microglia maker Iba-1 antibody. A knock-in (KI) mouse line bearing the phosphorylation-blocked ERα S216A mutation (ERα KI) was generated to examine inflammation-regulating functions of phosphorylated ERα in microglia. RT-PCR, antibody array, ELISA and FACS assays were employed to measure expressions of pro- or anti-inflammatory cytokines at their mRNA and protein levels. Rotarod tests were performed to examine motor connection ability.
RESULTS: Double immune staining of mixed glia cells showed that ERα is phosphorylated at Ser216 in microglia, but not astrocytes. Immunohistochemistry with an anti-Iba-1 antibody showed that microglia cells were swollen and shortened branches in the substantial nigra (SN) of ERα KI brains, indicating the spontaneous activation of microglia as observed with those of lipopolysaccharide (LPS)-treated ERα WT brains. Pro-inflammatory cytokines were up-regulated in the brain of ERα KI brains as well as cultured microglia, whereas anti-inflammatory cytokines were down-regulated. FACS analysis showed that the number of IL-6 producing and apoptotic microglia increased in those prepared from ERα KI brains. Times of ERα KI mice on rod were shortened in Rotarod tests.
CONCLUSIONS: Blocking of Ser216 phosphorylation aggravated microglia activation and inflammation of mouse brain, thus confirming that phosphorylated ERα exerts anti-inflammatory functions. ERα KI mice enable us to further investigate the mechanism by which phosphorylated ERα regulates brain immunity and inflammation and brain diseases. Video abstract.

PMID: 32727504 [PubMed - in process]

Efficacy of Corticosteroids in Patients with SARS, MERS and COVID-19: A Systematic Review and Meta-Analysis.

J Clin Med. 2020 Jul 27;9(8):

Authors: Lee KH, Yoon S, Jeong GH, Kim JY, Han YJ, Hong SH, Ryu S, Kim JS, Lee JY, Yang JW, Lee J, Solmi M, Koyanagi A, Dragioti E, Jacob L, Radua J, Smith L, Oh H, Tizaoui K, Cargnin S, Terrazzino S, Ghayda RA, Kronbichler A, Shin JI

Abstract
(1) Background: The use of corticosteroids in critical coronavirus infections, including severe acute respiratory syndrome (SARS), Middle East Respiratory Syndrome (MERS), or Coronavirus disease 2019 (COVID-19), has been controversial. However, a meta-analysis on the efficacy of steroids in treating these coronavirus infections is lacking. (2) Purpose: We assessed a methodological criticism on the quality of previous published meta-analyses and the risk of misleading conclusions with important therapeutic consequences. We also examined the evidence of the efficacy of corticosteroids in reducing mortality in SARS, MERS and COVID-19. (3) Methods: PubMed, MEDLINE, Embase, and Web of Science were used to identify studies published until 25 April 2020, that reported associations between steroid use and mortality in treating SARS/MERS/COVID-19. Two investigators screened and extracted data independently. Searches were restricted to studies on humans, and articles that did not report the exact number of patients in each group or data on mortality were excluded. We calculated odds ratios (ORs) or hazard ratios (HRs) under the fixed- and random-effect model. (4) Results: Eight articles (4051 patients) were eligible for inclusion. Among these selected studies, 3416 patients were diagnosed with SARS, 360 patients with MERS, and 275 with COVID-19; 60.3% patients were administered steroids. The meta-analyses including all studies showed no differences overall in terms of mortality (OR 1.152, 95% CI 0.631-2.101 in the random effects model, p = 0.645). However, this conclusion might be biased, because, in some studies, the patients in the steroid group had more severe symptoms than those in the control group. In contrast, when the meta-analysis was performed restricting only to studies that used appropriate adjustment (e.g., time, disease severity), there was a significant difference between the two groups (HR 0.378, 95% CI 0.221-0.646 in the random effects model, p < 0.0001). Although there was no difference in mortality when steroids were used in severe cases, there was a difference among the group with more underlying diseases (OR 3.133, 95% CI 1.670-5.877, p < 0.001). (5) Conclusions: To our knowledge, this study is the first comprehensive systematic review and meta-analysis providing the most accurate evidence on the effect of steroids in coronavirus infections. If not contraindicated, and in the absence of side effects, the use of steroids should be considered in coronavirus infection including COVID-19.

PMID: 32726951 [PubMed]

Genetic variants that influence SARS-CoV-2 receptor TMPRSS2 expression among population cohorts from multiple continents.

Biochem Biophys Res Commun. 2020 08 20;529(2):263-269

Authors: Irham LM, Chou WH, Calkins MJ, Adikusuma W, Hsieh SL, Chang WC

Abstract
The World Health Organization recently announced that pandemic status has been achieved for coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Exponential increases in patient numbers have been reported around the world, along with proportional increases in the number of COVID-19-related deaths. The SARS-CoV-2 infection rate in a population is expected to be influenced by social practices, availability of vaccines or prophylactics, and the prevalence of susceptibility genes in the population. Previous work revealed that cellular uptake of SARS-CoV-2 requires Angiotensin Converting Enzyme 2 (ACE-2) and a cellular protease. The spike (S) protein on SARS-CoV-2 binds ACE-2, which functions as an entry receptor. Following receptor binding, transmembrane protease serine 2 (encoded by TMPRSS2) primes the S protein to allow cellular uptake. Therefore, individual expression of TMPRSS2 may be a crucial determinant of SARS-CoV-2 infection susceptibility. Here, we utilized multiple large genome databases, including the GTEx portal, SNP nexus, and Ensembl genome project, to identify gene expression profiles for TMPRSS2 and its important expression quantitative trait loci. Our results show that four variants (rs464397, rs469390, rs2070788 and rs383510) affect expression of TMPRSS2 in lung tissue. The allele frequency of each variant was then assessed in regional populations, including African, American, European, and three Asian cohorts (China, Japan and Taiwan). Interestingly, our data shows that TMPRSS2-upregulating variants are at higher frequencies in European and American populations than in the Asian populations, which implies that these populations might be relatively susceptible to SARS-CoV-2 infection.

PMID: 32703421 [PubMed - indexed for MEDLINE]

Common Genetic Variants in ABO and CLEC4M Modulate the Pharmacokinetics of Recombinant FVIII in Severe Hemophilia A Patients.

Thromb Haemost. 2020 Jul 29;:

Authors: Garcia-Martínez I, Borràs N, Martorell M, Parra R, Altisent C, Ramírez L, Álvarez-Román MT, Nuñez R, Megias-Vericat JE, Corrales I, Alonso S, Vidal F

Abstract
The pharmacokinetic (PK) response of severe hemophilia A (HA) patients to infused factor VIII (FVIII) shows substantial variability. Several environmental and genetic factors are associated with changes in FVIII plasma levels and infused FVIII PK. Based on the hypothesis that factors influencing endogenous FVIII can affect FVIII PK, the contribution of single-nucleotide variants (SNVs) in candidate genes was investigated in 51 severe HA patients. The effects of blood group, F8 variant type, von Willebrand factor antigen and activity levels, age, and weight were also explored. The myPKFiT device was used to estimate individual PK parameters, and SNVs and clinically reportable F8 variants were simultaneously analyzed in an Illumina MiSeq instrument, using the microfluidics-based Fluidigm Access Array system. The contribution of SNVs to FVIII half-life and clearance was addressed by robust regression modeling, taking into account other modulators. In line with previous studies, we provide robust evidence that age, body weight, and blood group, as well as SNVs in ABO and CLEC4M, participate in the variability of FVIII PK in HA patients. Main results: each copy of the rs7853989 (ABO) allele increases FVIII half-life by 1.4 hours (p = 0.0131) and decreases clearance by 0.5 mL/h/kg (p = 5.57E-03), whereas each additional rs868875 (CLEC4M) allele reduces FVIII half-life by 1.1 hours (p = 2.90E-05) and increases clearance by 0.3 mL/h/kg (p = 1.01E-03). These results contribute to advancing efforts to improve FVIII replacement therapies by adjusting to each patient's PK profile based on pharmacogenomic data. This personalized medicine will decrease the burden of treatment and maximize the benefits obtained.

PMID: 32726853 [PubMed - as supplied by publisher]

Determination of toxic effects of Hystrix Brachyura Bezoar extracts using cancer cell lines and embryo zebrafish (Danio rerio) models and identification of active principles through GC-MS analysis.

J Ethnopharmacol. 2020 Jul 26;:113138

Authors: Firus Khan AY, Ahmed QU, Nippun TS, Hilles A, Jalal TK, Kek TL, Salleh MZ, Noor SM, Seeni A, Khatib A, Wahab RA

Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Porcupine bezoar (PB) is used as folk medicine for various medical conditions including cancer treatment in Malaysia. However, its toxicity profile has never been thoroughly ascertained to confirm its safe nature as an efficacious traditional medicine in the treatment of cancer as well as other ailments.
AIM OF THE STUDY: This study was aimed to reveal three different PBs' aqueous extracts(viz. PB-A, PB-B, PB-C) chemical constituent's profile using GC-MS analysis, anticancer property on A375, HeLa and MCF7 cancer cells, toxicity profile on zebrafish embryo morphology, EC50, LC50 and teratogenicity index.
MATERIALS AND METHODS: PBs' extracts characterization was performed through GC-MS analysis, in vitro anticancer effect was carried out on A375, HeLa and MCF7 cancer cell lines and finally and toxicity properties on three different PBs aqueous extracts (viz. PB-A, PB-B, PB-C) were determined using zebrafish embryo model.
RESULTS: The GC-MS analysis revealed 10 similar compounds in all PBs' extracts. Dilauryl thiodipropionate was found to be a major compound in all PBs' extracts followed by tetradecanoic acid. An in vitro anticancer study revealed PB extracts exerted median inhibition concentration (IC50) <50 μg/mL, on cancer cells viz. A375, HeLa and MCF7 with no significant toxicity on normal cells viz. NHDF cells. In vivo toxicity of PBs extracts found affecting tail detachment, hatching, craniofacial, brain morphology, soft tissues, edema, spinal, somites, notochord and cardiovascular system (brachycardia, disruption of blood circulation) deformities. The LC50 and EC50 demonstrated PB extracts effect as dose and time dependent with median concentration <150.0 μg/mL. Additionally, teratogenicity index (TI) viz. >1.0 revealed teratogenic property for PB extracts.
CONCLUSIONS: The findings revealed that all three PBs aqueous extracts possessed anticancer activity and exhibited significant toxicological effects on zebrafish embryos with high teratogenicity index. Hence, its use as an anticancer agent requires further investigation and medical attentions to determine its safe dose.

PMID: 32726681 [PubMed - as supplied by publisher]

Pharmacogenetic factors affecting β-blocker metabolism and response.

Expert Opin Drug Metab Toxicol. 2020 Jul 29;:

Authors: Thomas CD, Johnson JA

Abstract
INTRODUCTION: β-blockers are among the most widely prescribed of all drugs, used for treatment of a large number of cardiovascular diseases. Herein we evaluate literature pertaining to pharmacogenetics of β-blocker therapy, provide insight into the robustness of the genetic associations, and determine the appropriateness for translating these genetic associations into clinical practice.
AREAS COVERED: A literature search was conducted using PubMed to collate evidence on associations between CYP2D6, ADRB1, ADRB2, and GRK5 genetic variation and drug-response outcomes in the presence of β-blocker exposure. Pharmacokinetic, pharmacodynamic, and clinical outcomes studies were included if genotype data and β-blocker exposure were documented.
EXPERT OPINION: Substantial data suggest that specific ADRB1 and GRK5 genotypes are associated with improved β-blocker efficacy and have potential for use to guide therapy decisions in the clinical setting. While the data do not justify ordering a CYP2D6 pharmacogenetic test, if CYP2D6 genotype is available in the electronic health record, there may be clinical utility for understanding dosing of β-blockers.

PMID: 32726152 [PubMed - as supplied by publisher]

Psychiatric Side Effects of Chloroquine.

J Clin Psychiatry. 2020 Jul 28;81(5):

Authors: Gressier F, Verstuyft C, Becquemont L, Falissard B, Corruble E

PMID: 32726000 [PubMed - as supplied by publisher]

Pathogenic mosaic variants in congenital hypogonadotropic hypogonadism.

Genet Med. 2020 Jul 29;:

Authors: Acierno JS, Xu C, Papadakis GE, Niederländer NJ, Rademaker JD, Meylan J, Messina A, Kolesinska Z, Quinton R, Lang-Muritano M, Bartholdi D, Halperin I, De Geyter C, Bouligand J, Bartoloni L, Young J, Santoni FA, Pitteloud N

Abstract
PURPOSE: Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder resulting in absent puberty and infertility. The genetic architecture is complex with multiple loci involved, variable expressivity, and incomplete penetrance. The majority of cases are sporadic, consistent with a disease affecting fertility. The current study aims to investigate mosaicism as a genetic mechanism for CHH, focusing on de novo rare variants in CHH genes.
METHODS: We evaluated 60 trios for de novo rare sequencing variants (RSV) in known CHH genes using exome sequencing. Potential mosaicism was suspected among RSVs with altered allelic ratios and confirmed using customized ultradeep sequencing (UDS) in multiple tissues.
RESULTS: Among the 60 trios, 10 probands harbored de novo pathogenic variants in CHH genes. Custom UDS demonstrated that three of these de novo variants were in fact postzygotic mosaicism-two in FGFR1 (p.Leu630Pro and p.Gly348Arg), and one in CHD7 (p.Arg2428*). Statistically significant variation across multiple tissues (DNA from blood, buccal, hair follicle, urine) confirmed their mosaic nature.
CONCLUSIONS: We identified a significant number of de novo pathogenic variants in CHH of which a notable number (3/10) exhibited mosaicism. This report of postzygotic mosaicism in CHH patients provides valuable information for accurate genetic counseling.

PMID: 32724172 [PubMed - as supplied by publisher]

In vitro and ex vivo gene expression profiling reveals differential kinetic response of HSPs and UPR genes is associated with PI resistance in multiple myeloma.

Blood Cancer J. 2020 Jul 28;10(7):78

Authors: Mitra AK, Kumar H, Ramakrishnan V, Chen L, Baughn L, Kumar S, Rajkumar SV, Van Ness BG

Abstract
Extensive inter-individual variation in response to chemotherapy (sensitive vs resistant tumors) is a serious cause of concern in the treatment of multiple myeloma (MM). In this study, we used human myeloma cell lines (HMCLs), and patient-derived CD138+ cells to compare kinetic changes in gene expression patterns between innate proteasome inhibitor (PI)-sensitive and PI-resistant HMCLs following test dosing with the second-generation PI Ixazomib. We found 1553 genes that changed significantly post treatment in PI-sensitive HMCLs compared with only seven in PI-resistant HMCLs (p < 0.05). Genes that were uniquely regulated in PI-resistant lines were RICTOR (activated), HNF4A, miR-16-5p (activated), MYCN (inhibited), and MYC (inhibited). Ingenuity pathway analysis (IPA) using top kinetic response genes identified the proteasome ubiquitination pathway (PUP), and nuclear factor erythroid 2-related factor 2 (NRF2)-mediated oxidative stress response as top canonical pathways in Ix-sensitive cell lines and patient-derived cells, whereas EIF2 signaling and mTOR signaling pathways were unique to PI resistance. Further, 10 genes were common between our in vitro and ex vivo post-treatment kinetic PI response profiles and Shaughnessy's GEP80-postBz gene expression signature, including the high-risk PUP gene PSMD4. Notably, we found that heat shock proteins and PUP pathway genes showed significant higher upregulation in Ix-sensitive lines compared with the fold-change in Ix-resistant myelomas.

PMID: 32724061 [PubMed - as supplied by publisher]

DNA derived from archival tumor specimens can be used for germline pharmacogenetic analyses.

Pharmacogenomics. 2020 Jul 29;:

Authors: Hertz DL, Kidwell KM, Douglas JA, Viale G, Leyland-Jones B, Regan M, Rae JM

PMID: 32723153 [PubMed - as supplied by publisher]

CYP2C19 genotype-guided antiplatelet therapy: promises and pitfalls.

Pharmacogenomics. 2020 Jul 29;:

Authors: Ellithi M, Baye J, Wilke RA

Abstract
Pharmacogenetic variants can alter the mechanism of action (pharmacodynamic gene variants) or kinetic processes such as absorption, distribution, metabolism and elimination (pharmacokinetic gene variants). Many initial successes in precision medicine occurred in the context of genes encoding the cytochromes P450 (CYP enzymes). CYP2C19 activates the antiplatelet drug clopidogrel, and polymorphisms in the CYP2C19 gene are known to alter the outcome for patients taking clopidogrel in the context of cardiovascular disease. CYP2C19 loss-of-function alleles are specifically associated with increased risk for coronary stent thrombosis and major adverse cardiovascular events in patients taking clopidogrel following percutaneous coronary intervention. We explore successes and challenges encountered as the clinical and scientific communities advance CYP2C19 genotyping in the context of routine patient care.

PMID: 32723143 [PubMed - as supplied by publisher]

Pharmacogenetics and statin-related myopathy: what do we know?

Pharmacogenomics. 2020 Jul 29;:

Authors: Turner RM, Radman I, Bozina N, Alfirevic A

PMID: 32723135 [PubMed - as supplied by publisher]

Predictors of tacrolimus pharmacokinetic variability: current evidences and future perspectives.

Expert Opin Drug Metab Toxicol. 2020 Jul 28;:

Authors: Degraeve A, Moudio S, Haufroid V, Chaib Eddour D, Mourad M, Bindels LB, Elens L

Abstract
INTRODUCTION: In kidney transplantation, tacrolimus (TAC) is at the cornerstone of current immunosuppressive strategies. Though because of its narrow therapeutic index, it is critical to ensure that TAC levels are maintained within this sharp window through reactive adjustments. This would allow maximizing efficiency while limiting drug-associated toxicity. However, TAC high intra- and inter-patient pharmacokinetic (PK) variability makes it more laborious to accurately predict the appropriate dosage required for a given patient.
AREAS COVERED: This review summarizes the state-of-the-art knowledge regarding drug interactions, demographic and pharmacogenetics factors as predictors of TAC PK. We provide a scoring index for each association to grade its relevance and we present practical recommendations, when possible for clinical practice.
EXPERT OPINION: The management of TAC concentration in transplanted kidney patients is as critical as it is challenging. Recommendations based on rigorous scientific evidences are lacking as knowledge of potential predictors remains limited outside of DDIs. Awareness of these limitations should pave the way for studies looking at demographic and pharmacogenetic factors as well as gut microbiota composition in order to promote tailored treatment plans. Therapeutic approaches considering patients' clinical singularities may help allowing to maintain appropriate concentration of TAC.

PMID: 32721175 [PubMed - as supplied by publisher]

Correction: Developing a common framework for evaluating the implementation of genomic medicine interventions in clinical care: the IGNITE Network's Common Measures Working Group.

Genet Med. 2020 Jul 27;:

Authors: Orlando LA, Sperber NR, Voils C, Nichols M, Myers RA, Wu RR, Rakhra-Burris T, Levy KD, Levy M, Pollin TI, Guan Y, Horowitz CR, Ramos M, Kimmel SE, McDonough CW, Madden EB, Damschroder LJ, IGNITE Network

Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PMID: 32719392 [PubMed - as supplied by publisher]

CACNA1S haploinsufficiency confers resistance to New World arenavirus infection.

Proc Natl Acad Sci U S A. 2020 Jul 27;:

Authors: Sarute N, Ross SR

Abstract
Understanding the genetics of susceptibility to infectious agents is of great importance to our ability to combat disease. Here, we show that voltage-gated calcium channels (VGCCs) are critical for cellular binding and entry of the New World arenaviruses Junín and Tacaribe virus, suggesting that zoonosis via these receptors could occur. Moreover, we demonstrate that α1s haploinsufficiency renders cells and mice more resistant to infection by these viruses. In addition to being more resistant to infection, haploinsufficient cells and mice required a lower dosage of VGCC antagonists to block infection. These studies underscore the importance of genetic variation in susceptibility to both viruses and pharmaceutics.

PMID: 32719120 [PubMed - as supplied by publisher]

Tomatine Displays Antitumor Potential in In Vitro Models of Metastatic Melanoma.

Int J Mol Sci. 2020 Jul 23;21(15):

Authors: Serratì S, Porcelli L, Guida S, Ferretta A, Iacobazzi RM, Cocco T, Maida I, Tamasi G, Rossi C, Manganelli M, Tommasi S, Azzariti A, Guida G

Abstract
There is a growing interest in the cytotoxic effects of bioactive glycoalkaloids, such as α-tomatine on tumor cells. Here, for the first time, we determine the antitumor potential of tomatine, a mixture of α-tomatine and dehydrotomatine, in metastatic melanoma (MM) cell lines harboring different BRAF and MC1R variants. We performed cytotoxicity experiments and annexin-V/propidium iodide staining to assess the apoptotic/necrotic status of the cells. ER stress and autophagy markers were revealed by Western Blot, whereas antiangiogenic and vascular-disrupting effects were evaluated through a capillary tube formation assay on matrigel and by ELISA kit for VEGF release determination. Cell invasion was determined by a Boyden chamber matrigel assay. Tomatine reduced 50% of cell viability and induced a concentration-dependent increase of apoptotic cells in the range of 0.5-1 μM in terms of α-tomatine. The extent of apoptosis was more than two-fold higher in V600BRAF-D184H/D184H MC1R cells than in BRAF wild-type cells and V600BRAF-MC1R wild-type cell lines. Additionally, tomatine increased the LC3I/II autophagy marker, p-eIF2α, and p-Erk1/2 levels in BRAF wild-type cells. Notably, tomatine strongly reduced cell invasion and melanoma-dependent angiogenesis by reducing VEGF release and tumor-stimulating effects on capillary tube formation. Collectively, our findings support tomatine as a potential antitumor agent in MM.

PMID: 32718103 [PubMed - in process]

PharmVar and the Landscape of Pharmacogenetic Resources.

Clin Pharmacol Ther. 2020 01;107(1):43-46

Authors: Gaedigk A, Whirl-Carrillo M, Pratt VM, Miller NA, Klein TE

PMID: 31758698 [PubMed - indexed for MEDLINE]

Genetic polymorphisms in genes of class switch recombination and multiple myeloma risk and survival: an IMMEnSE study.

Leuk Lymphoma. 2019 07;60(7):1803-1811

Authors: Campa D, Martino A, Macauda A, Dudziński M, Suska A, Druzd-Sitek A, Raab MS, Moreno V, Huhn S, Butrym A, Sainz J, Szombath G, Rymko M, Marques H, Lesueur F, Vangsted AJ, Vogel U, Kruszewski M, Subocz E, Buda G, Iskierka-Jażdżewska E, Ríos R, Merz M, Schöttker B, Mazur G, Perrial E, Martinez-Lopez J, Butterbach K, García Sanz R, Goldschmidt H, Brenner H, Jamroziak K, Reis RM, Kadar K, Dumontet C, Wątek M, Haastrup EK, Helbig G, Jurczyszyn A, Jerez A, Varkonyi J, Barington T, Grzasko N, Zaucha JM, Andersen V, Zawirska D, Canzian F

Abstract
Genetic variants in genes acting during the maturation process of immature B-cell to differentiated plasma cell could influence the risk of developing multiple myeloma (MM). During B-cell maturation, several programmed genetic rearrangements occur to increase the variation of the immunoglobulin chains. Class switch recombination (CSR) is one of the most important among these mechanisms. Germline polymorphisms altering even subtly this process could play a role in the etiology and outcome of MM. We performed an association study of 30 genetic variants in the key CSR genes, using 2632 MM patients and 2848 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the Heidelberg MM Group and the ESTHER cohort. We found an association between LIG4-rs1555902 and decreased MM risk, which approached statistical significance, as well as significant associations between AICDA-rs3794318 and better outcome. Our results add to our knowledge on the genetic component of MM risk and survival.

PMID: 30633655 [PubMed - indexed for MEDLINE]

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pharmacogenomics

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

pharmacogenomics

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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.