Identification of genetic markers associated with ibrutinib-related cardiovascular toxicity.

7526 Background: Cardiovascular side effects (CVSEs: atrial fibrillation, hypertension, etc.) are common in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib and often lead to dose reductions or discontinuation. However, the etiology of ibrutinib related CVSEs has not been elucidated. This study sought to interrogate the association between ibrutinib related CVSEs and polymorphisms in genes of the Bruton Tyrosine Kinase (BTK) signaling pathway (identified through Ingenuity Pathway Analysis) Methods: Newly diagnosed and relapsed patients with CLL who underwent treatment with ibrutinib between December 2019 and November 2020 at Levine Cancer Institute were identified. Buccal swabs were collected through an IRB approved specimen collection protocol. Data extraction included: demographics, CLL stage, cytogenetics, previous treatments, ibrutinib start dates and dose, drug related SEs, and other medications. DNA isolated from buccal swabs was genotyped for 40 single nucleotide polymorphisms (SNPs) in GATA4, SGK1, KCNQ1, KCNA4, NPPA and SCN5A genes using a custom NGS panel. Logistic regression analysis evaluated the association between SNPs and CVSEs. Results: In 50 evaluable patients, the median age was 71 years (range:48-90) and 50% received frontline ibrutinib monotherapy. CVSEs occurred in 20% of patients (n=10). In univariate analysis, 4 SNPs in 3 genes were significantly associated with CVSEs (Table). Because the genes were in the same pathway, a genetic risk score was developed which indicated that patients with at least 2 SNPs had a 12-fold increase in risk of CVSEs (Table). Conclusions: Our findings provide insights into the genetic determinants of ibrutinib related CVSEs. If replicated in a larger study, this will facilitate utility of pharmacogenetic testing (for GATA4, KCNQ1 and KCNA5 polymorphisms ) as a clinical tool to individualize ibrutinib treatment.[Table: see text]

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PSV-13 Genetic parameters and quantitative trait loci for heat stress related traits in sheep

Journal of Animal Science ◽

10.1093/jas/skaa054.289 ◽

2020 ◽

Vol 98 (Supplement_3) ◽

pp. 163-164

Author(s):

Devin R Jacobs ◽

Claudia E Silvera-Rojas ◽

Jennifer M Bormann ◽

Terry A Gipson ◽

Arthur L Goetsch ◽

...

Keyword(s):

Heat Stress ◽

Quantitative Trait Loci ◽

Rectal Temperature ◽

Quantitative Trait ◽

Fixed Effects ◽

Univariate Analysis ◽

Average Daily Gain ◽

The United States ◽

Nucleotide Polymorphisms ◽

Trait Loci

Abstract Greater selection emphasis has been placed on efficiency than on fitness in livestock populations over the last several decades. Heat stress is a concern in production systems due to the negative effects on production, reproduction, and immunity. The objective of the study was to estimate variance components and identify quantitative trait loci (QTL) for heat stress related traits in sheep. A total of 125 Dorper, Katahdin, and St. Croix ewes originating from four regions of the United States were selected for the experiment. Animals were separated into four trials due to facility limitations. Data were collected for each trial over four consecutive two-week periods in an environmentally controlled facility with targeted heat load index (HLI) for daytime/nighttime of 70/70, 85/77, 90/77, and 95/81. Body weight was collected three times per week and rectal temperature was collected weekly. Black globe temperature and humidity were measured every 15 minutes. Animals were genotyped using the Illumina OvineSNP50 BeadChip. After quality control, 49,396 effective single nucleotide polymorphisms were included in the univariate analysis performed with the BLUPF90 suite of programs. Fixed effects in the models included region of origin, breed, trial, and age as a covariate. Traits analyzed included rectal temperature at 95 HLI (RT95), feed intake at 95 HLI (FI95), and average daily gain for the period for HLI between 90 and 95 (ADG). Heritabilities for RT95, FI95, and ADG were 0.35, 0.10, and 0.10, respectively. Largest effect QTL were identified on chromosomes 23, 9, and 6 for RT95, chromosomes 9, 2, and 20 for FI95, and chromosomes 6, 1, and 5 for ADG. Many of the regions identified have also been associated with weight and carcass traits in other studies, but few had obvious connections to the heat stress related response. In conclusion, results suggest selection could improve heat tolerance in sheep.

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Independent and combined associations between fast-food outlet exposure and genetic risk for obesity: a population-based, cross-sectional study in the UK

BMC Medicine ◽

10.1186/s12916-021-01902-z ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Thomas Burgoine ◽

Pablo Monsivais ◽

Stephen J. Sharp ◽

Nita G. Forouhi ◽

Nicholas J. Wareham

Keyword(s):

Genetic Risk ◽

Fast Food ◽

Genetic Risk Score ◽

Population Based ◽

Overweight And Obesity ◽

Nucleotide Polymorphisms ◽

Food Outlet ◽

Cross Sectional ◽

Fast Food Outlet ◽

Common Genetic Variants

Abstract Background Characteristics of the built environment, such as neighbourhood fast-food outlet exposure, are increasingly recognised as risk factors for unhealthy diet and obesity. Obesity also has a genetic component, with common genetic variants explaining a substantial proportion of population-level obesity susceptibility. However, it is not known whether and to what extent associations between fast-food outlet exposure and body weight are modified by genetic predisposition to obesity. Methods We used data from the Fenland Study, a population-based sample of 12,435 UK adults (mean age 48.6 years). We derived a genetic risk score associated with BMI (BMI-GRS) from 96 BMI-associated single nucleotide polymorphisms. Neighbourhood fast-food exposure was defined as quartiles of counts of outlets around the home address. We used multivariable regression models to estimate the associations of each exposure, independently and in combination, with measured BMI, overweight and obesity, and investigated interactions. Results We found independent associations between BMI-GRS and risk of overweight (RR = 1.34, 95% CI 1.23–1.47) and obesity (RR = 1.73, 95% CI 1.55–1.93), and between fast-food outlet exposure and risk of obesity (highest vs lowest quartile RR = 1.58, 95% CI 1.21–2.05). There was no evidence of an interaction of fast-food outlet exposure and genetic risk on BMI (P = 0.09), risk of overweight (P = 0.51), or risk of obesity (P = 0.27). The combination of higher BMI-GRS and highest fast-food outlet exposure was associated with 2.70 (95% CI 1.99–3.66) times greater risk of obesity. Conclusions Our study demonstrated independent associations of both genetic obesity risk and neighbourhood fast-food outlet exposure with adiposity. These important drivers of the obesity epidemic have to date been studied in isolation. Neighbourhood fast-food outlet exposure remains a potential target of policy intervention to prevent obesity and promote the public’s health.

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Ex Vivo Mitochondrial Respiration Parallels Biochemical Response to Ibrutinib in CLL Cells

Cancers ◽

10.3390/cancers13020354 ◽

2021 ◽

Vol 13 (2) ◽

pp. 354

Author(s):

Subir Roy Chowdhury ◽

Cheryl Peltier ◽

Sen Hou ◽

Amandeep Singh ◽

James B. Johnston ◽

...

Keyword(s):

Mitochondrial Respiration ◽

Ex Vivo ◽

Standard Dose ◽

Cell Receptor ◽

Lymphocytic Leukemia ◽

Clinical Tool ◽

Potential Biomarker ◽

Apoptotic Pathways ◽

The Impact

Mitochondrial respiration is becoming more commonly used as a preclinical tool and potential biomarker for chronic lymphocytic leukemia (CLL) and activated B-cell receptor (BCR) signaling. However, respiration parameters have not been evaluated with respect to dose of ibrutinib given in clinical practice or the effect of progression on ibrutinib treatment on respiration of CLL cells. We evaluated the impact of low and standard dose ibrutinib on CLL cells from patients treated in vivo on mitochondrial respiration using Oroboros oxygraph. Cytokines CCL3 and CCL4 were evaluated using the Mesoscale. Western blot analysis was used to evaluate the BCR and apoptotic pathways. We observed no difference in the mitochondrial respiration rates or levels of plasma chemokine (C-C motif) ligands 3 and 4 (CCL3/CCL4), β-2 microglobulin (β-2 M) and lactate dehydrogenase (LDH) between low and standard doses of ibrutinib. This may confirm why clinical observations of the safety and efficacy of low dose ibrutinib are observed in practice. Of interest, we also observed that the mitochondrial respiration of CLL cells paralleled the increase in β-2 M and LDH at progression. Our study further supports mitochondrial respiration as a biomarker for response and progression on ibrutinib in CLL cells and a valuable pre-clinical tool.

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Collagen I triggers directional migration, invasion and matrix remodeling of stroma cells in a 3D spheroid model of endometriosis

Scientific Reports ◽

10.1038/s41598-021-83645-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Anna Stejskalová ◽

Victoria Fincke ◽

Melissa Nowak ◽

Yvonne Schmidt ◽

Katrin Borrmann ◽

...

Keyword(s):

Single Cells ◽

Fold Increase ◽

Experimental Models ◽

Collagen I ◽

Matrix Remodeling ◽

Clinical Tool ◽

Directional Migration ◽

Endometrial Cells ◽

Small Molecule Drugs ◽

Actomyosin Contraction

AbstractEndometriosis is a painful gynecological condition characterized by ectopic growth of endometrial cells. Little is known about its pathogenesis, which is partially due to a lack of suitable experimental models. Here, we use endometrial stromal (St-T1b), primary endometriotic stromal, epithelial endometriotic (12Z) and co-culture (1:1 St-T1b:12Z) spheroids to mimic the architecture of endometrium, and either collagen I or Matrigel to model ectopic locations. Stromal spheroids, but not single cells, assumed coordinated directional migration followed by matrix remodeling of collagen I on day 5 or 7, resembling ectopic lesions. While generally a higher area fold increase of spheroids occurred on collagen I compared to Matrigel, directional migration was not observed in co-culture or in 12Z cells. The fold increase in area on collagen I was significantly reduced by MMP inhibition in stromal but not 12Z cells. Inhibiting ROCK signalling responsible for actomyosin contraction increased the fold increase of area and metabolic activity compared to untreated controls on Matrigel. The number of protrusions emanating from 12Z spheroids on Matrigel was decreased by microRNA miR-200b and increased by miR-145. This study demonstrates that spheroid assay is a promising pre-clinical tool that can be used to evaluate small molecule drugs and microRNA-based therapeutics for endometriosis.

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Abstract 15318: Association of Single-Nucleotide Polymorphisms with Left Atrial Scar in Patients with Atrial Fibrillation

Circulation ◽

10.1161/circ.130.suppl_2.15318 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Sanghamitra Mohanty ◽

Amelia W Hall ◽

Prasant Mohanty ◽

Chintan Trivedi ◽

Luigi Di Biase ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Left Atrial ◽

Transforming Growth Factor ◽

Univariate Analysis ◽

Scar Formation ◽

Taqman Assay ◽

Inverse Association ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Caveolin 1

Introduction: Earlier studies have demonstrated that some AF patients develop spontaneous atrial scarring that leads to genesis and perpetuation of the arrhythmia. However, it is still unclear why it happens in some and not in others. Therefore, we hypothesized that the atrial scar phenotype is associated with certain specific genetic variants and examined the relationship between AF-related single-nucleotide polymorphisms (SNP) and left atrial scar. Methods: Four hundred AF patients (67% male, 62±12 year, left atrial size 45.3±7 mm, 64% non-paroxysmal) undergoing catheter ablation were prospectively enrolled at our center. DNA extraction and genotyping for 16 AF-associated SNPS identified by GWAS study were performed from the collected blood samples using Qiagen QiaAMP 96 well blood kit and TaqMan assay respectively. Three hundred seventy-two DNA samples were available for genotyping. The Hardy-Weinberg equilibrium was assessed using Chi-square analyses. Multivariable logistic model was utilized to identify predictors of LA scar after adjusting for age, gender, LA size, hypertension and diabetes mellitus and odds ratio (OR) and 95% confidence intervals were computed. Results: Of all 16 SNPs, rs3807989 showed a strong inverse association with LA scar at univariate analysis (0.54 [0.348-0.89] p= 0.014) in the overall population. After adjustment for covariates, the association became highly significant indicating a 50% reduction in scar risk (OR 0.50 (0.30-0.83) p=0.007). When stratified by type of AF, rs3807989 genotype predicted a substantially stronger 69% risk-reduction in the non-PAF population (OR 0.31 (0.15-0.62) p=0.0009). Conclusion: The SNP, rs3807989 on chromosome 7p31, was demonstrated to be associated with reduced risk of left atrial scar formation in AF patients. This genetic variant is located in close proximity to the caveolin-1 gene which is known to have an anti-fibrotic role by inhibiting transforming growth factor-β1, a key mediator in the fibrosis process. Therefore, it can be postulated that by some unknown mechanism the candidate chromosomal variant potentially upregulates caveolin-1 function resulting in attenuation of fibrosis and scar formation.

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Causal associations of obesity with chronic kidney disease and arterial stiffness: a Mendelian randomization study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab633 ◽

2021 ◽

Author(s):

Chaojie Ye ◽

Lijie Kong ◽

Zhiyun Zhao ◽

Mian Li ◽

Shuangyuan Wang ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Standard Deviation ◽

Kidney Disease ◽

Single Nucleotide Polymorphisms ◽

Arterial Stiffness ◽

Genetic Risk ◽

Mendelian Randomization ◽

Genetic Risk Score ◽

Nucleotide Polymorphisms ◽

Single Nucleotide

Abstract Purpose Observational studies have associated obesity with chronic kidney disease (CKD) and arterial stiffness, but the causality remains unclear. We aimed to investigate the causality of obesity with CKD and arterial stiffness using Mendelian randomization (MR) analysis. Methods We genotyped 14 body mass index (BMI)-associated variants validated in East Asians in 11384 Chinese adults. A genetic risk score based on the 14 variants and the 14 individual single nucleotide polymorphisms were respectively used as instrumental variables (IVs). CKD was defined as estimated glomerular filtration rate <60 mL/min/1.73 m 2. Arterial stiffness was defined as brachial-ankle pulse wave velocity >1550 cm/s. Results Using the genetic risk score as the IV, we demonstrated causal relations of each 1-standard deviation increment in BMI with CKD (odds ratio [OR]: 2.36; 95% confidence interval [CI]: 1.11-5.00) and arterial stiffness (OR: 1.71; 95% CI: 1.22-2.39). Using the 14 single nucleotide polymorphisms individually as IVs, each 1-standard deviation increment in BMI casually associated with CKD (OR: 2.58; 95% CI: 1.39-4.79) and arterial stiffness (OR: 1.87; 95% CI: 1.24-2.81) in the inverse-variance weighted analysis, and MR-Egger regression revealed no evidence of horizontal pleiotropy (Both P for intercept≥0.34). The causality between obesity and CKD was validated in two-sample MR analysis among Europeans (681275 of Genetic Investigation of ANthropometric Traits and 133413 of CKD Genetics). Conclusions This study provided novel insights into causality of obesity with CKD and arterial stiffness, highlighting the importance of weight management for primary prevention and control of subclinical vascular diseases.

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SNPs in genes encoding for IL-10, TNF-α, and NFκB p105/p50 are associated with clinical prognostic factors for patients with Hodgkin lymphoma

PLoS ONE ◽

10.1371/journal.pone.0248259 ◽

2021 ◽

Vol 16 (3) ◽

pp. e0248259

Author(s):

Rafael Dezen Gaiolla ◽

Marcelo Padovani de Toledo Moraes ◽

Deilson Elgui de Oliveira

Keyword(s):

Hodgkin Lymphoma ◽

Univariate Analysis ◽

Stage Iv ◽

Inflammatory Cells ◽

Cytokine Gene Expression ◽

Nucleotide Polymorphisms ◽

Promoter Regions ◽

Tnf Α ◽

Mediastinal Disease ◽

Genes Encoding

Classical Hodgkin lymphoma (cHL) is a B-cell-derived malignant neoplasia that has a unique histological distribution, in which the scarce malignant Hodgkin and Reed-Sternberg cells are surrounded by nonmalignant inflammatory cells. The interactions between the malignant and inflammatory cells are mediated by aberrantly produced cytokines, which play an important role in tumor immunopathogenesis. Single nucleotide polymorphisms (SNPs) in genes encoding cytokines and their regulatory proteins may influence the peripheral levels of these molecules and affect disease’s pathobiology. In this study, we evaluate SNPs in the promoter regions of the genes encoding for two key cytokines in Hodgkin lymphoma: IL-10 (SNP/pIL10–592, rs1800872; and SNP/pIL10–1082, rs1800896) and TNF-α (SNP/pTNF -238, rs361525; and SNP/pTNF -862, rs1800630), as well as an SNP in the intronic region of the NFκB1 gene (SNP/iNFKB1, rs1585215), an important regulator of cytokine gene expression. We then look to their possible association with clinical and laboratory features in cHL patients. Seventy-three patients with cHL are genotyped by qPCR-high resolution melting. The SNPs’ genotypes are analyzed individually for each SNP, and when more than two allelic combinations are identified, the genotypes are also divided into two groups according to proposed biological relevance. By univariate analysis, patients harboring SNP/pTNF -238 AG genotype more frequently have EBV-associated cHL compared to homozygous GG, whereas the presence of mediastinal disease (bulky and nonbulky) is more common in the pIL10–592 AC/CC group compared to the AA homozygous group. Patients with SNP/iNFKB1 AA genotype more frequently have stage IV and extranodal disease at diagnosis. These results indicate that some SNPs’ genotypes for IL-10 and TNF-α genes are associated with prognostic parameters in cHL. For the first time, the SNP/iNFKB1 is described in association with clinical features of the disease.

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Association of RETN and TNFRSF1B polymorphisms with TNF-α inhibitor response in rheumatoid arthritis patients

10.21203/rs.2.24442/v1 ◽

2020 ◽

Author(s):

Nga Thi Trinh ◽

Hyun Jeong Kim ◽

Woorim Kim ◽

Sang Oh Kang ◽

Kyung Hyun Min ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Statistical Significance ◽

Univariate Analysis ◽

Multivariable Logistic Regression Analysis ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Final Model ◽

Asian Populations ◽

Tnf Α

Abstract Background: Despite the improvement from the introduction of tumor necrosis factor inhibitors (TNFi) in the rheumatoid arthritis (RA), TNFi therapy fails for more than 30% or results in a partial response. Thus, we aimed to explore treatment marker by examining the association of single nucleotide polymorphisms (SNPs) with response to TNFi therapy.Method: Genes associated with RA or RA treatment were reviewed and fourteen SNPs with minor allele frequency ≥ 20% in the East Asian populations were selected and analyzed. Data were collected from 105 RA patients. Our primary endpoint was the disease activity score using 28-joint count after six months of treatment (DAS28-6month). The secondary outcomes were the subcomponents of DAS28.Results: A total of 88 patients were included in the final analyses. Among the 14 SNPs analyzed, one SNP showed statistical significance in DAS28-6month: patients with the GG allele of RETN rs1862513 had a 4.7 times higher chance of low disease activity at 6-months than GC or CC-carriers (p = 0.033), as indicated by multivariable logistic regression analysis. Rs3397 was marginally significant in univariate analysis (p=0.059), but was significant in the multivariable model (p=0.041). The final model explained 24.5% (Nagelkerke R2) of the variance in DAS28-6month.Conclusion: Our results demonstrated that, among the genes related to RA, SNPs in RETN and TNFRSF1B were associated with the response of TNFi treatment.

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Two Novel Polymorphisms in 5' Flanking Region of the Mesothelin Gene are Associated with Soluble Mesothelin-Related Peptide (SMRP) Levels

The International Journal of Biological Markers ◽

10.5301/jbm.2011.8332 ◽

2011 ◽

Vol 26 (2) ◽

pp. 117-123 ◽

Cited By ~ 8

Author(s):

Alfonso Cristaudo ◽

Rudy Foddis ◽

Alessandra Bonotti ◽

Silvia Simonini ◽

Agnese Vivaldi ◽

...

Keyword(s):

Healthy Subjects ◽

Fold Increase ◽

High Rate ◽

Pleural Mesothelioma ◽

Clinical Use ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Elisa Kit ◽

Surveillance Programs ◽

Flanking Region

Background and aims Increased concentrations of soluble mesothelin-related peptides (SMRP) have been found in sera of patients with malignant pleural mesothelioma (MPM) even if a relatively high rate of false positives has hampered their clinical use as a tumor marker. Individual SMRP levels could be affected by polymorphic elements. The aim of this study was to investigate the association between single nucleotide polymorphisms within the promoter-5'UTR regions and SMRP levels in healthy asbestos-exposed individuals and patients suffering from MPM. Methods The promoter-5'UTR regions of the mesothelin gene were genotyped in 59 healthy asbestos-exposed subjects and 27 MPM patients. SMRP levels were measured using a commercially available ELISA kit. Results Two novel polymorphisms, an A>C variant (called New1) and a C>T variant (called New2), were identified. In healthy subjects, high SMRP levels were associated with the C-variant of New1, with an average 1.62-fold increase compared with AA homozygotes (p<0.0001). Most of the C-allele carriers had SMRP levels above the threshold of 1.00 nM. We set two different SMRP cutoffs on the basis of the combined New1+New2 genotypes. Conclusions New1-New2 genotypes could be employed as markers for setting individualized and appropriate thresholds of “normality” when SMRP is used in surveillance programs of asbestos-exposed people.

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ANGPT2 and NOS3 Polymorphisms and Clinical Outcome in Advanced Hepatocellular Carcinoma Patients Receiving Sorafenib

Cancers ◽

10.3390/cancers11071023 ◽

2019 ◽

Vol 11 (7) ◽

pp. 1023 ◽

Cited By ~ 13

Author(s):

Giorgia Marisi ◽

Elisabetta Petracci ◽

Francesco Raimondi ◽

Luca Faloppi ◽

Francesco Giuseppe Foschi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Direct Sequencing ◽

Univariate Analysis ◽

Progression Free Survival ◽

Standard Of Care ◽

Advanced Hepatocellular Carcinoma ◽

Nucleotide Polymorphisms ◽

Number Of Patients ◽

Angiopoietin 2 ◽

Oxide Synthase

Sorafenib represents the standard of care for advanced hepatocellular carcinoma (HCC), even though a large number of patients have reported limited efficacy. The aim of the present study was to evaluate the prognostic value of single-nucleotide polymorphisms on angiopoietin-2 (ANGPT2) and endothelial-derived nitric oxide synthase (NOS3) genes in 135 patients with advanced HCC receiving sorafenib. Eight ANGPT2 polymorphisms were analyzed by direct sequencing in relation to overall survival (OS) and progression-free survival (PFS). In univariate analysis, ANGPT2rs55633437 and NOS3 rs2070744 were associated with OS and PFS. In particular, patients with ANGPT2rs55633437 TT/GT genotypes had significantly lower median OS (4.66 vs. 15.5 months, hazard ratio (HR) 4.86, 95% CI 2.73–8.67, p < 0.001) and PFS (1.58 vs. 6.27 months, HR 4.79, 95% CI 2.73–8.35, p < 0.001) than those homozygous for the G allele. Moreover, patients with NOS3 rs2070744 TC/CC genotypes had significantly higher median OS (15.6 vs. 9.1 months, HR 0.65, 95% CI 0.44–0.97; p = 0.036) and PFS (7.03 vs. 3.5 months, HR 0.43, 95% CI 0.30–0.63; p < 0.001) than patients homozygous for the T allele. Multivariate analysis confirmed these polymorphisms as independent prognostic factors. Our results suggest that ANGPT2rs55633437 and NOS3 rs2070744 polymorphisms could identify a subset of HCC patients more resistant to sorafenib.

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