Pharmacogenomic Single Nucleotide Polymorphism (SNP) Variants As Predictors of Toxicity Phenotypes in the Treatment of Acute Childhood Leukemia

Abstract Introduction: Despite cure rates in acute lymphoblastic leukemia (ALL) exceeding 90% in clinical trials, morbidity due to drug toxicities is high. Genetic polymorphisms can influence gene expression and activity, impacting pharmacokinetics and causing inter-individual variation in drug levels, which contributes to toxicity if levels are high or relapse if levels are low. We hypothesize that pharmacogenomic testing will identify patient specific variations in genes involved in metabolism of cytotoxic agents. This knowledge will allow clinicians to optimize therapy by providing pharmacogenomics based biomarkers related to increased toxicities. Data has shown that treatment interruptions and omissions due to toxicities affect outcomes and morbidities in children with cancer. Objective : To correlate pharmacogenomic biomarkers with toxicity phenotypes in children receiving therapy for ALL. Methods: This cross-sectional study involved subjects at a tertiary academic center (Fig. 1A). Subjects aged 1 year to 26 years with ALL treated after May 2012 were eligible. A total of 75 patients treated between 2012 and 2020 were included. Pharmacogenomic testing was performed on peripheral blood. Genomic DNA was tested for 118 single-nucleotide polymorphisms (SNP) in 55 genes for transport and metabolism of cytarabine, vincristine, methotrexate, dauno/doxorubicin, and mercaptopurine/thioguanine were analyzed using the Sequenom-based genotyping that uses MALDI-TOF based chemistry. SNPs were tested using logistic regression models for association with toxicities in additive, dominant, and recessive modes of inheritance. CTCAE v4.0 was used for grading all toxicities during the first 100 days of therapy. For endocrine (endo) and neurological (neuro) toxicities, 25 patients exhibited between grade 1-3 toxicities. For gastrointestinal (GI) toxicities, 25 patients exhibited between grade 2-3 toxicities. For hematological (heme) toxicities, 11 patients exhibited between grade 2-4 toxicities. Odds ratio and 95% confidence interval were calculated for each test and SNPs with association P-value <0.05 were considered significant. To conduct multivariable SNP combinations analysis, SNPs with univariate association p-value <0.1 were selected for each toxicity, and then SNP combinations (up to 3 SNPs per model) were tested for association with each toxicity. The combination model with the 1000 permutation p-value <0.05 and lowest BIC value was selected to build a SNP score after considering the mode of inheritance and the direction of association with the toxicity for the individual genotypes. A SNP score was generated by summation of genotype scores for the individual SNPs passing the top model. Patients were further classified into either of the 3 following SNP score groups: >0, 0 or <0. Results: For a GI toxicity score derived from 3 SNPs (TYMS-rs151264360, FPGS-rs1544105, and GSTM5-rs3754446), patients with >0 score had 79% incidence of GI toxicity (N=67) as compared to 10% in patients with score of 0 and 8% in patients with score <0 (p=2.07E-05, Fig 1B). For the SNP score (AKR1C3-rs6621365, ABCB1-rs4148737, and CTPS1-rs12067645) generated for heme toxicity, higher SNP scores were associated with high toxicity (p=0.003, Figure 1C). For neurotoxicity, the 3 SNPs (DCTD-rs6829021, SCL28A3-rs17343066, and CTPS1-rs12067635) involved were all in cytarabine metabolic pathway and predicted greater neurotoxicity (56%) with a score of >0; no toxicity was observed in patients with neurotoxicity score of <0 (p=0.0005, Fig. 1D). For SNP endo toxicity score (AKR1C3-rs1937840, TYMS-rs2853539, and CTS-rs648743), we observed 91% incidence of endo toxicity in patients with toxicity score of >0 (p=4.7E-08, Fig. 1E). None of the patients with a score of <0 experienced endo toxicity. Discussion: We identified germline SNPs predictive of toxicity phenotypes in a cohort of 75 subjects with ALL. The results of our multivariable SNP combination analysis suggest susceptibility to chemotherapy-induced toxicities is likely multigenic in nature. Instead of a single SNP approach, identification of combinations of mutations in drug pathways increases the robustness of predicting a patient's response to chemotherapy. Our results provide promising SNP models that can help establish clinically relevant biomarkers allowing for individualization of cancer therapy to optimize treatment for each patient. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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The haplotypes of various TNF related genes associated with scleritis in Chinese Han

Human Genomics ◽

10.1186/s40246-020-00296-y ◽

2020 ◽

Vol 14 (1) ◽

Author(s):

Yingnan Gao ◽

Liping Du ◽

Fuzhen Li ◽

Jiadong Ding ◽

Geng Li ◽

...

Keyword(s):

Protective Factor ◽

Nucleotide Polymorphisms ◽

Chinese Han ◽

Single Nucleotide ◽

Immune Mediated ◽

Individual Snps ◽

Tnf Α ◽

Infectious Scleritis ◽

The Individual ◽

Normal Controls

Abstract Background Several studies have stated that TNF-α participates in the pathogenesis of scleritis, but also in several systemic autoimmune diseases and vasculitis, of which some are associated with scleritis. Earlier GWAS and SNP studies have confirmed that multiple SNPs of TNF related genes are associated with many immune-mediated disorders. The purpose of this study was to examine the association of TNF related gene polymorphisms with scleritis in Chinese Han. A case-control study was carried out in 556 non-infectious scleritis cases and 742 normal controls. A total of 28 single-nucleotide polymorphisms (SNPs) were genotyped by the iPLEXGold genotyping assay. Results No significant correlations were seen between the individual SNPs in the TNF related genes and scleritis. Haplotype analysis showed a significantly decreased frequency of a TNFAIP3 TGT haplotype (order of SNPs: rs9494885, rs3799491, rs2230926) (Pc = 0.021, OR = 0.717, 95% CI = 0.563–0.913) and a significantly increased frequency of a TNFSF4 GT haplotype (order of SNPs: rs3850641, rs704840) (Pc = 0.004, OR = 1.691, 95% CI = 1.205–2.372) and TNFSF15 CCC haplotype (order of SNPs: rs6478106, rs3810936, rs7865494) (Pc = 0.012, OR = 1.662, 95% CI = 1.168–2.363) in patients with scleritis as compared with healthy volunteers. Conclusions This study reveals that a TGT haplotype in TNFAIP3 may be a protective factor for the development of scleritis and that a GT haplotype in TNFSF4 and a CCC haplotype in TNFSF15 may be risk factors for scleritis in Chinese Han.

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Mitochondrial Apoptotic Priming Measured by BH3 Profiling Regulates Clinical Response to Chemotherapy in Myeloma and Acute Lymphoblastic Leukemia and Explains Therapeutic Index

Blood ◽

10.1182/blood.v118.21.1442.1442 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1442-1442

Author(s):

Triona Ni Chonghaile ◽

Kristopher Sarosiek ◽

Jeremy Ryan ◽

Vicki Del Gaizo Moore ◽

Yu-Tzu Tai ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Response ◽

Board Of Directors ◽

Cytotoxic Agents ◽

P Value ◽

Advisory Committees ◽

Normal Tissues ◽

Response To Chemotherapy ◽

Protein Reduction

Abstract Abstract 1442 Cytotoxic chemotherapy, still a mainstay of current cancer treatment, targets ubiquitous elements such as DNA and microtubules. Despite decades of clinical use of chemotherapy, determinants of response to such treatments are poorly understood. Here, we showed that clinical response to cytotoxic agents is largely regulated by the initial proximity of tumors' mitochondria to the apoptotic threshold. Cells that are close to the apoptotic threshold we refer to as “primed” for death. Priming is assessed by a functional assay we call BH3 profiling that measures mitochondrial response to standardized death signals in the form of peptides from the pro-apoptotic BH3-only proteins. We assessed priming across a total of 51 patient samples, 25 of which had clinical follow-up. Priming correlated to % M-protein reduction, a marker of reduced disease burden in multiple myeloma following treatment (spearman r = 0.8039, P= 0.00005 Fig 1A). Patient's with highly primed mitochondria also demonstrated a better clinical response in both multiple myeloma (P= 0.001) and in acute lymphoblastic leukemia (P= 0.0119). Pediatric ALL responds better to therapy and has a much higher long term survival rate than adult ALL (80–90% vs. 40%) (Pui et. al N Engl J Med, 2006). We found that pediatric ALL samples were more primed than adult (P = 0.007). To demonstrate the relationship between priming and chemosensitivity we perturbed priming by co-culture with stroma or by pretreatment with ABT-737 and demonstrated that altering priming changed chemosensitivity predictably. By far the most important dichotomy in sensitivity to chemotherapy is between normal tissues and cancer cells. Differences in proliferation rate, the classic explanation for this dichotomy offers only modest explanatory power with many exceptions. We therefore tested whether differential mitochondrial apoptotic priming was an important determinant of the therapeutic index from cytotoxic chemotherapy. We directly tested the mitochondrial priming of a series of normal tissues from both human (8 tissues) and mouse (8 tissues). Significantly, we found that most normal tissues along with chemoresistant (Serous borderline ovarian, Renal and Endometrial) cancers had relatively low priming (Fig 1B). Conversely chemosensitive cancers and normal hematopoietic tissues were highly primed. Differential mitochondrial priming may provide a novel explanation for the otherwise puzzling existence of a therapeutic window for cytotoxic agents. This newly appreciated determinant of response to chemotherapy could be exploited to rationally improve efficacy of cytotoxic agents or to devise better combinations of drugs.Fig 1:Mitochondrial priming regulates clinical response to chemotherapy in multiple myeloma and acute lyphoblastic leukemia (A) Loss of δΨm caused by the BMF peptide in myeloma patient samples correlates to %M-protein reduction. (B) Comparison of priming among all primary human cancers and normal tissues. The cancers with clinical follow up were classified as known chemosensitive or known chemoresistant. Cancers classified as typically chemoresistant (Serous borderline n=3, Endometrial n=3 and Renal n=3) or typically chemosensitive (childhood ALL n=17) lacked individual response data. Data shown are mean ± s.d. across all specimens tested. ANOVA was used to demonstrate statistical significance between the different categories with a Tukey's multiple comparison post test. ns - p value > 0.05 and *** p-value <0.001.Fig 1:. Mitochondrial priming regulates clinical response to chemotherapy in multiple myeloma and acute lyphoblastic leukemia (A) Loss of δΨm caused by the BMF peptide in myeloma patient samples correlates to %M-protein reduction. (B) Comparison of priming among all primary human cancers and normal tissues. The cancers with clinical follow up were classified as known chemosensitive or known chemoresistant. Cancers classified as typically chemoresistant (Serous borderline n=3, Endometrial n=3 and Renal n=3) or typically chemosensitive (childhood ALL n=17) lacked individual response data. Data shown are mean ± s.d. across all specimens tested. ANOVA was used to demonstrate statistical significance between the different categories with a Tukey's multiple comparison post test. ns - p value > 0.05 and *** p-value <0.001. Disclosures: Richardson: Millennium:; Celgene:; Johnson & Johnson:; Novartis:; Bristol Myers Squibb:. Anderson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Acetylon: Membership on an entity's Board of Directors or advisory committees. Mitsiades:Millennium: Consultancy, Honoraria. Sallan:Enzon Pharmaceuticals: Honoraria. Letai:Eutropics Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Total Hospital Costs and Readmission Rate of Patient-Specific Instrument in Total Knee Arthroplasty Patients

The Journal of Knee Surgery ◽

10.1055/s-0040-1713353 ◽

2020 ◽

Author(s):

Stephen Thomas ◽

Ankur Patel ◽

Corey Patrick ◽

Gary Delhougne

Keyword(s):

Total Knee Arthroplasty ◽

Knee Arthroplasty ◽

Hospital Cost ◽

Readmission Rate ◽

Hospital Costs ◽

Patient Specific ◽

P Value ◽

Total Hospital Cost ◽

Total Hospital ◽

Total Knee

AbstractDespite advancements in surgical technique and component design, implant loosening, stiffness, and instability remain leading causes of total knee arthroplasty (TKA) failure. Patient-specific instruments (PSI) aid in surgical precision and in implant positioning and ultimately reduce readmissions and revisions in TKA. The objective of the study was to evaluate total hospital cost and readmission rate at 30, 60, 90, and 365 days in PSI-guided TKA patients. We retrospectively reviewed patients who underwent a primary TKA for osteoarthritis from the Premier Perspective Database between 2014 and 2017 Q2. TKA with PSI patients were identified using appropriate keywords from billing records and compared against patients without PSI. Patients were excluded if they were < 21 years of age; outpatient hospital discharges; evidence of revision TKA; bilateral TKA in same discharge or different discharges. 1:1 propensity score matching was used to control patients, hospital, and clinical characteristics. Generalized Estimating Equation model with appropriate distribution and link function were used to estimate hospital related cost while logistic regression models were used to estimate 30, 60, and 90 days and 1-year readmission rate. The study matched 3,358 TKAs with PSI with TKA without PSI patients. Mean total hospital costs were statistically significantly (p < 0.0001) lower for TKA with PSI ($14,910; 95% confidence interval [CI]: $14,735–$15,087) than TKA without PSI patients ($16,018; 95% CI: $15,826–$16,212). TKA with PSI patients were 31% (odds ratio [OR]: 0.69; 95% CI: 0.51–0.95; p-value = 0.0218) less likely to be readmitted at 30 days; 35% (OR: 0.65; 95% CI: 0.50–0.86; p-value = 0.0022) less likely to be readmitted at 60 days; 32% (OR: 0.68; 95% CI: 0.53–0.88; p-value = 0.0031) less likely to be readmitted at 90 days; 28% (OR: 0.72; 95% CI: 0.60–0.86; p-value = 0.0004) less likely to be readmitted at 365 days than TKA without PSI patients. Hospitals and health care professionals can use retrospective real-world data to make informed decisions on using PSI to reduce hospital cost and readmission rate, and improve outcomes in TKA patients.

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Fully Data-Driven Pseudohealthy Synthesis for Planning Valve-Sparing Aortic Root Reconstruction using Conditional Variational Autoencoders

Current Directions in Biomedical Engineering ◽

10.1515/cdbme-2020-3072 ◽

2020 ◽

Vol 6 (3) ◽

pp. 284-287

Author(s):

Jannis Hagenah ◽

Mohamad Mehdi ◽

Floris Ernst

Keyword(s):

Aortic Root ◽

Similarity Index ◽

Ground Truth ◽

Representation Learning ◽

Patient Specific ◽

Ultrasound Images ◽

Specific Geometry ◽

The Individual ◽

Native Root ◽

Original Information

AbstractAortic root aneurysm is treated by replacing the dilated root by a grafted prosthesis which mimics the native root morphology of the individual patient. The challenge in predicting the optimal prosthesis size rises from the highly patient-specific geometry as well as the absence of the original information on the healthy root. Therefore, the estimation is only possible based on the available pathological data. In this paper, we show that representation learning with Conditional Variational Autoencoders is capable of turning the distorted geometry of the aortic root into smoother shapes while the information on the individual anatomy is preserved. We evaluated this method using ultrasound images of the porcine aortic root alongside their labels. The observed results show highly realistic resemblance in shape and size to the ground truth images. Furthermore, the similarity index has noticeably improved compared to the pathological images. This provides a promising technique in planning individual aortic root replacement.

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Age by Single Nucleotide Polymorphism Interactions on Bronchodilator Response in Asthmatics

Journal of Personalized Medicine ◽

10.3390/jpm11010059 ◽

2021 ◽

Vol 11 (1) ◽

pp. 59

Author(s):

Kirsten Voorhies ◽

Joanne E. Sordillo ◽

Michael McGeachie ◽

Elizabeth Ampleford ◽

Alberta L. Wang ◽

...

Keyword(s):

Candidate Genes ◽

P Value ◽

Genome Wide Association Studies ◽

Genetic Associations ◽

Single Nucleotide ◽

Significance Level ◽

Bronchodilator Response ◽

Genome Wide ◽

A Genome ◽

Β2 Agonists

An unaddressed and important issue is the role age plays in modulating response to short acting β2-agonists in individuals with asthma. The objective of this study was to identify whether age modifies genetic associations of single nucleotide polymorphisms (SNPs) with bronchodilator response (BDR) to β2-agonists. Using three cohorts with a total of 892 subjects, we ran a genome wide interaction study (GWIS) for each cohort to examine SNP by age interactions with BDR. A fixed effect meta-analysis was used to combine the results. In order to determine if previously identified BDR SNPs had an age interaction, we also examined 16 polymorphisms in candidate genes from two published genome wide association studies (GWAS) of BDR. There were no significant SNP by age interactions on BDR using the genome wide significance level of 5 × 10−8. Using a suggestive significance level of 5 × 10−6, three interactions, including one for a SNP within PRAG1 (rs4840337), were significant and replicated at the significance level of 0.05. Considering candidate genes from two previous GWAS of BDR, three SNPs (rs10476900 (near ADRB2) [p-value = 0.009], rs10827492 (CREM) [p-value = 0.02], and rs72646209 (NCOA3) [p-value = 0.02]) had a marginally significant interaction with age on BDR (p < 0.05). Our results suggest age may be an important modifier of genetic associations for BDR in asthma.

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Use of Thromboelastography Platelet Mapping for Assessment of Individual Platelet Response Secondary to Oral Antiplatelet Therapy after Percutaneous Coronary Intervention: An Attempt to Start Personalized Antiplatelet Therapy in India

Journal of Cardiac Critical Care TSS ◽

10.1055/s-0041-1724225 ◽

2021 ◽

Author(s):

Suvro Sankha Datta ◽

Dibyendu De ◽

Nadeem Afroz Muslim

Keyword(s):

Percutaneous Coronary Intervention ◽

Antiplatelet Therapy ◽

Platelet Reactivity ◽

Coronary Intervention ◽

Platelet Inhibition ◽

P Value ◽

Platelet Response ◽

Percutaneous Coronary ◽

The Individual ◽

Platelet Functions

AbstractHigh on-treatment platelet reactivity (HPR) with P2Y12 receptor antagonists in patients treated with dual antiplatelet therapy (DAPT) is strongly associated with adverse ischemic events after percutaneous coronary intervention (PCI). This prospective study was conducted to assess individual platelet response and HPR to antiplatelet medications in post-PCI cases by thromboelastography platelet mapping (TEG-PM). Total 82 patients who were on aspirin and on either clopidogrel, prasugrel, or ticagrelor were evaluated. The percentage of platelet inhibition to arachidonic acid (AA) and adenosine disdiphosphate (ADP) was calculated by [100-{(MA ADP/AA–MA Fibrin) / (MA Thrombin–MA Fibrin) × 100}], taking 50% response as cut-off for HPR. HPR to clopidogrel and prasugrel was 14.29 and 12.5%, respectively. No HPR was detected to aspirin and ticagrelor. The mean percentage of platelet inhibition was significantly higher in patients with ticagrelor 82.99, 95% confidence interval (CI) of [77.3, 88.7] as compared with clopidogrel 72.21, 95% CI of [65.3, 79.1] and prasugrel 64.2, 95% CI of [52.5, 75.9] (p-value of 0.041 and 0.003, respectively). Aspirin along with ticagrelor is associated with a higher mean percentage of platelet inhibition, and lower HPR as compared with the usage of aspirin combined with clopidogrel or prasugrel. Additionally, it might also be concluded that TEG-PM could be used effectively to measure the individual platelet functions which would make oral antiplatelet therapy more personalized for cardiac patients.

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Sex Differences in Circadian Clock Genes and Myocardial Infarction Susceptibility

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd8050053 ◽

2021 ◽

Vol 8 (5) ◽

pp. 53

Author(s):

Ivana Škrlec ◽

Jasminka Talapko ◽

Martina Juzbašić ◽

Robert Steiner

Keyword(s):

Myocardial Infarction ◽

Cardiovascular Disease ◽

Circadian Rhythm ◽

Single Nucleotide Polymorphisms ◽

Clock Genes ◽

P Value ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Biological Sex ◽

Significant Difference

The growing body of evidence shows a significant difference in the circadian rhythm of cardiovascular disease based on biological sex. The incidence of cardiovascular disease varies between women and men. Additionally, biological sex is vital for the timely application of therapy—chronotherapy, which benefits both sexes. This study aimed to examine the potential difference of single nucleotide polymorphisms (SNPs) of the circadian rhythm genes ARNTL, CLOCK, CRY2 and PER2 in women and men with myocardial infarction. A cross-sectional study was conducted, including 200 patients with myocardial infarction. Altogether, ten single nucleotide polymorphisms in the ARNTL, CLOCK, CRY2 and PER2 genes were analyzed. The Chi-square test yielded statistically significant differences in CLOCK gene rs11932595 polymorphism in a recessive genotype model between women and men with a p-value of 0.03 and an odds ratio 2.66, and a corresponding 95% confidence interval of 1.07 to 6.66. Other analyzed polymorphisms of the circadian rhythm genes ARNTL, CRY2, and PER2 did not significantly differ between the sexes. According to the study’s current results, the CLOCK gene’s genetic variability might affect myocardial infarction concerning biological sex.

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Safety climate and related factors in rehabilitation nurses of hospitals in Iran

Work ◽

10.3233/wor-203368 ◽

2021 ◽

pp. 1-8

Author(s):

Javad vatani ◽

Zahra Khanikosarkhizi ◽

Mohammad Ali Shahabi Rabori ◽

mohammad khandan ◽

Mohsen aminizadeh ◽

...

Keyword(s):

Safety Climate ◽

Cross Sectional Study ◽

P Value ◽

Related Factors ◽

Cross Sectional ◽

Climate Assessment ◽

Safety Work ◽

Significant Difference ◽

Training Courses ◽

The Individual

BACKGROUND: Safety climate is a common insight of staff that indicates individuals’ attitudes toward safety and priority of safety at work. OBJECTIVES: Nursing is a risky job where paying attention to safety is crucial. The assessment of the safety climate is one of the methods to measure the safety conditions in this occupation. The aim of this study was to assess the safety climate of rehabilitation nurses working in hospitals in Tehran. METHODS: This is a cross-sectional study which was carried out on 140 rehabilitation nurses selected from all hospitals and clinics in Tehran in 2019. To collect the required data, a two-section questionnaire was used. The first section was related to demographic factors and the second part (22 statements) was to measure the safety climate using nurses’ safety climate assessment questionnaire. The collected data were analyzed by SPSS V16 using independent t-test, ANOVA, Kruskal-Wallis and Mann-Whitney U test at the 5% level. RESULTS: Findings showed that the total mean of safety climate was 3.06±0.56. According to the results, a significant difference was found between the positive and negative satisfaction of nurses with safety climates (P-value = 0.03), communication with nurses (P-value = 0.01) and supervisors’ attitude (P-value = 0.02). Furthermore, a significant difference in safety climate between the individual with the second job and the individual without second could be observed (P-value = 0.01). CONCLUSIONS: The results indicated that the safety climate was not at an acceptable level. Thus, it is essential to introduce safety training courses (e.g. safety, work-rest balance, and so on) and to improve the safety performance at work.

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Factors associated with successful return to work in young heart failure and ischaemic heart disease patients following index hospital admission

European Journal of Preventive Cardiology ◽

10.1093/eurjpc/zwab061.312 ◽

2021 ◽

Vol 28 (Supplement_1) ◽

Author(s):

HV Thakkar ◽

L Hollingsworth ◽

JA Enright ◽

S Sanderson ◽

RJ Macfadyen ◽

...

Keyword(s):

Heart Failure ◽

Return To Work ◽

Decompensated Heart Failure ◽

Individual Factors ◽

P Value ◽

Complex Interplay ◽

Coronary Syndrome ◽

Funding Sources ◽

Financial Benefits ◽

The Individual

Abstract Funding Acknowledgements Type of funding sources: None. Background Factors influencing return to remunerated work following an acute cardiac illness are poorly defined. We wished to compare the factors in our cohorts following first presentation of acute coronary syndrome(ACS) and decompensated heart failure(HF). Methods Prospectively identified subjects, aged 18-65years, from a rehabilitation population for ACS and HF during 2018-2019 underwent a survey. Results Of 133cases meeting inclusion criteria, 84 completed the survey(41 HF, 80% male, mean age 55years; 43 ACS, 86% male, mean age 57years). Socio-economic indexes for Areas(SIEFA) index were similar for HF(900) & ACS(909) groups, which represents 11th and 14th percentile for Australia respectively. Cardiovascular risk factors were similar except hypercholesterolemia(37% v 60%; p = 0.029) was more common in ACS. Many subjects did not continue beyond Yr12, (54% HF v 30% ACS; p = 0.029). A majority of ACS cases returned to work as compared with HF(70% v 44%; p = 0.017)(Figure). On multivariate analysis, male gender[p = 0.031;OR 13.71 (1.28-147.36)]; access to financial benefits[p < 0.001;OR 22.75 (4.31-119.99)] and a desire to return to work [p = 0.014;OR 12.1 (1.67-87.82)] were associated with successful return to work (Table). Limitations Our study has small numbers so will be difficult to generalise to a wider population. We do show a signal towards the complex interplay of the social and individual factors in determining return to work. Further larger studies are required to tease out the differences between the individual factors to help predict return to work in the Australian context. Conclusion Successful return to work for patients with first presentation of ACS or HF could not be reliably predicted. Patients with ACS returned to work more often than HF. In HF patients who do n to return to work, recurrent symptoms, individual motivation, social support and access to financial benefits have a complex interplay. Predictors of return to work Predictor P value OR (95% CI) Diagnosis (heart failure) 0.095 0.29 (0.07, 1.24) Gender (male) 0.031 13.71 (1.28, 147.36) Access to benefit (none) <0.001 22.75 (4.31, 119.99) Desire to RTW (yes) 0.014 12.1 (1.67, 87.82) Abstract Figure. Rates of return to work in the 2 groups

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Synergistic effect of genetic polymorphisms in TLR6 and TLR10 genes on the risk of pulmonary tuberculosis in a Moldavian population

Innate Immunity ◽

10.1177/17534259211029996 ◽

2021 ◽

pp. 175342592110299

Author(s):

Alexander Varzari ◽

Igor V. Deyneko ◽

Elena Tudor ◽

Harald Grallert ◽

Thomas Illig

Keyword(s):

Pulmonary Tuberculosis ◽

Interaction Analysis ◽

P Value ◽

Fisher Exact Test ◽

Snp Analysis ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Exact Test ◽

Pulmonary Tb ◽

The Republic

Polymorphisms in genes that control immune function and regulation may influence susceptibility to pulmonary tuberculosis (TB). In this study, 14 polymorphisms in 12 key genes involved in the immune response ( VDR, MR1, TLR1, TLR2, TLR10, SLC11A1, IL1B, IL10, IFNG, TNF, IRAK1, and FOXP3) were tested for their association with pulmonary TB in 271 patients with TB and 251 community-matched controls from the Republic of Moldova. In addition, gene–gene interactions involved in TB susceptibility were analyzed for a total of 43 genetic loci. Single nucleotide polymorphism (SNP) analysis revealed a nominal association between TNF rs1800629 and pulmonary TB (Fisher exact test P = 0.01843). In the pairwise interaction analysis, the combination of the genotypes TLR6 rs5743810 GA and TLR10 rs11096957 GT was significantly associated with an increased genetic risk of pulmonary TB (OR = 2.48, 95% CI = 1.62–3.85; Fisher exact test P value = 1.5 × 10−5, significant after Bonferroni correction). In conclusion, the TLR6 rs5743810 and TLR10 rs11096957 two-locus interaction confers a significantly higher risk for pulmonary TB; due to its high frequency in the population, this SNP combination may serve as a novel biomarker for predicting TB susceptibility.

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