Inter-individual Variation In Risk Research Articles

Haptoglobin Gene Expression and Anthracycline-Related Cardiomyopathy in Childhood Cancer Survivors: A COG-ALTE03N1 Report

BackgroundAnthracycline-related cardiomyopathy is a leading cause of premature death in childhood cancer survivors. The high interindividual variability in risk suggests the need to understand the underlying pathogenesis. ObjectivesThe authors interrogated differentially expressed genes (DEGs) to identify genetic variants serving regulatory functions or genetic variants not easily identified when using genomewide array platforms. Using leads from DEGs, candidate copy number variants (CNVs) and single-nucleotide variants (SNVs) were genotyped. MethodsMessenger RNA sequencing was performed on total RNA from peripheral blood of 40 survivors with cardiomyopathy (cases) and 64 matched survivors without cardiomyopathy (control subjects). Conditional logistic regression analysis adjusting for sex, age at cancer diagnosis, anthracycline dose, and chest radiation was used to assess the associations between gene expression and cardiomyopathy and between CNVs and SNVs and cardiomyopathy. ResultsHaptoglobin (HP) was identified as the top DEG. Participants with higher HP gene expression had 6-fold greater odds of developing cardiomyopathy (OR: 6.4; 95% CI: 1.4-28.6). The HP2-specific allele among the HP genotypes (HP1-1, HP1-2, and HP2-2) had higher transcript levels, as did the G allele among SNVs previously reported to be associated with HP gene expression (rs35283911 and rs2000999). The HP1-2 and HP2-2 genotypes combined with the G/G genotype for rs35283911 and/or rs2000999 placed the survivors at 4-fold greater risk (OR: 3.9; 95% CI: 1.0-14.5) for developing cardiomyopathy. ConclusionsThese findings provide evidence of a novel association between HP2 allele and cardiomyopathy. HP binds to free hemoglobin to form an HP-hemoglobin complex, thereby preventing oxidative damage from free heme iron, thus providing biological plausibility to the mechanistic basis of the present observation.

Germline risk factors for second malignant neoplasms after treatment for pediatric hematologic malignancies.

Survivors of childhood hematologic malignancies are at a substantially higher risk of developing subsequent neoplasms (SNs) when compared with the general population. SNs commonly observed in this population include basal cell carcinoma, brain tumors, thyroid cancer, breast cancer, bone tumors, and sarcoma. Radiation is the primary therapeutic exposure associated with the development of these SNs. There is emerging evidence of an association between chemotherapeutic exposures (alkylating agents/anthracyclines) and the development of SNs. Despite a strong dose-dependent association between therapeutic exposures and SN risk, there is significant interindividual variability in the risk for SNs for any given dose of therapeutic exposure. This interindividual variability in risk suggests the role of genetic susceptibility. This article describes the clinical and molecular epidemiology of SNs commonly observed in survivors of childhood hematologic malignancies and also highlights some of the work focusing on the development of risk prediction models to facilitate targeted interventions.

Association of shorter leucocyte telomere length with risk of frailty.

BackgroundFrailty is a multidimensional syndrome of decline that affects multiple systems and predisposes to adverse health outcomes. Although chronological age is the major risk factor, inter‐individual variation in risk is not fully understood. Leucocyte telomere length (LTL), a proposed marker of biological age, has been associated with risk of many diseases. We sought to determine whether LTL is associated with risk of frailty.MethodsWe utilized cross‐sectional data from 441 781 UK Biobank participants (aged 40–69 years), with complete data on frailty indicators and LTL. Frailty was defined as the presence of at least three of five indicators: weaker grip strength, slower walking pace, weight loss in the past year, lower physical activity, and exhaustion in the past 2 weeks. LTL was measured using a validated qPCR method and reported as a ratio of the telomere repeat number (T) to a single‐copy gene (S) (T/S ratio). Association of LTL with frailty was evaluated using adjusted (chronological age, sex, deprivation, smoking, alcohol intake, body mass index, and multimorbidity) multinomial and ordinal regression models, and results are presented as relative risk (RRR) or odds ratios (OR), respectively, alongside the 95% confidence interval (CI). Mendelian randomization (MR), using 131 genetic variants associated with LTL, was used to assess if the association of LTL with frailty was causal.ResultsFrail participants (4.6%) were older (median age difference (95% CI): 3 (2.5; 3.5) years, P = 2.73 × 10−33), more likely to be female (61%, P = 1.97 × 10−129), and had shorter LTL (−0.13SD vs. 0.03SD, P = 5.43 × 10−111) than non‐frail. In adjusted analyses, both age and LTL were associated with frailty (RRR = 1.03 (95% CI: 1.02; 1.04) per year of older chronological age, P = 3.99 × 10−12; 1.10 (1.08; 1.11) per SD shorter LTL, P = 1.46 × 10−30). Within each age group (40–49, 50–59, 60–69 years), the prevalence of frailty was about 33% higher in participants with shorter (−2SD) versus longer telomeres (+2SD). MR analysis showed an association of LTL with frailty that was directionally consistent with the observational association, but not statistically significant (MR‐Median: OR (95% CI): 1.08 (0.98; 1.19) per SD shorter LTL, P = 0.13).ConclusionsInter‐individual variation in LTL is associated with the risk of frailty independently of chronological age and other risk factors. Our findings provide evidence for an additional biological determinant of frailty.

Risk Stratification in Patients with Ischemic Stroke and Residual Cardiovascular Risk with Current Secondary Prevention.

PurposeSuboptimal secondary prevention in patients with stroke causes a remaining cardiovascular risk desirable to reduce. We have validated a prognostic model for secondary preventive settings and estimated future cardiovascular risk and theoretical benefit of reaching guideline recommended risk factor targets.Patients and MethodsThe SMART-REACH (Secondary Manifestations of Arterial Disease-Reduction of Atherothrombosis for Continued Health) model for 10-year and lifetime risk of cardiovascular events was applied to 465 patients in the Norwegian Cognitive Impairment After Stroke (Nor-COAST) study, a multicenter observational study with two-year follow-up by linkage to national registries for cardiovascular disease and mortality. The residual risk when reaching recommended targets for blood pressure, low-density lipoprotein cholesterol, smoking cessation and antithrombotics was estimated.ResultsIn total, 11.2% had a new event. Calibration plots showed adequate agreement between estimated and observed 2-year prognosis (C-statistics 0.63, 95% confidence interval 0.55–0.71). Median estimated 10-year risk of recurrent cardiovascular events was 42% (Interquartile range (IQR) 32–54%) and could be reduced to 32% by optimal guideline-based therapy. The corresponding numbers for lifetime risk were 70% (IQR 63–76%) and 61%. We estimated an overall median gain of 1.4 (IQR 0.2–3.4) event-free life years if guideline targets were met.ConclusionSecondary prevention was suboptimal and residual risk remains elevated even after optimization according to current guidelines. Considerable interindividual variation in risk exists, with a corresponding variation in benefit from intensification of treatment. The SMART-REACH model can be used to identify patients with the largest benefit from more intensive treatment and follow-up.

Genome Wide Association Study (GWAS) of cognitive impairment after blood or marrow transplantation (BMT) for hematologic malignancy.

1536 Background: Cognitive impairment is prevalent in hematologic malignancy patients treated with BMT (autologous: 18.7%; allogeneic: 35.7%; Sharafeldin JCO; 2018). Given the inter-individual variability in risk of cognitive impairment in this population, we investigated the role of genetic susceptibility using a genome-wide single nucleotide polymorphism (SNP) array platform to identify novel genetic associations. Methods: Discovery: Cognitive function was assessed objectively in 239 adult BMT recipients at pre-specified timepoints: pre-BMT and at 6 mo, 1y, 2y, and 3y post-BMT. A global deficit score (GDS - a summary score of 14 standardized neuropsychological tests) was computed for each patient; a higher score indicated greater cognitive impairment. SNPs passing standard quality control filters ( > 1.4M) were used for analysis. Linear mixed effects models used GDS as the outcome, adjusted for age, sex, BMT type, baseline cognitive reserve, and the first four principal components. We used additive, codominant, and genotype models and an adjusted genome-wide significance threshold of 1.25 x 10−8. Replication: An independent cohort of 544 BMT survivors (192 cases with self-endorsed cognitive problems and 352 controls without) was used for replication. Results: Discovery: Median age at BMT was 51.3y; primary diagnoses: 47% leukemia, 32% lymphoma, 21% multiple myeloma; 57% males; 69% non-Hispanic whites: 50% allogeneic BMT, median GDS score = 0.22 (range 0-2). Forty-four SNPs were significantly associated with increased GDS (additive model: 3 SNPs; codominant model: 20 SNPs; genotype model: 21 SNPs). Estimates ranged from increase in GDS score by 0.28 points for each additional copy of risk allele, p = 1.07 x 10−8 to increase in GDS score by 1.82 points for two copies of risk allele, p = 2.3 x 10−11. Replication: Median age at BMT was 44y; primary diagnoses: 32% leukemia, 49% lymphoma, 19% multiple myeloma; 54% males; 80% non-Hispanic whites: 34% allogeneic BMT. Three SNPs were successfully replicated: rs116334183 resides within lncRNA-SEMA6D-2, which facilitates neuronal migration; rs13286152 86kb downstream of TLE-1, which promotes neuronal survival; and rs12486041 0.36Mb downstream from lncRNA-SPTSSB-1, which regulates sphingolipid production in neuronal axons and 0.36Mb upstream from TOMM22P6 linked to neural repair. Conclusions: In this first GWAS of cognitive impairment post-BMT, we identify 3 SNPs with plausible links to genes implicated in neuronal integrity. Functional studies are currently underway.

The chemokine CCL17 is associated with protection against HIV-1 acquisition

Abstract Millions are exposed to the human immunodeficiency virus type 1 (HIV-1) every year, but not all exposed individuals become infected. This suggests a key role for host genetics in resilience or susceptibility to HIV-1 infection, but a comprehensive study of the genetic mechanisms contributing to HIV-1 acquisition risk is lacking. Here, we performed LD score regression analysis using summary statistics from the largest genome-wide association study of HIV-1 acquisition, consisting of 6,334 infected patients and 7,247 population controls. We found that HIV-1 acquisition is polygenic and highly heritable (28%). Genetic correlations performed alongside UK Biobank data revealed associations between HIV-1 acquisition and smoking, prospective memory and socioeconomic traits. Gene-level enrichment analysis identified EF-hand calcium binding domain 14 (EFCAB14) as a novel risk gene for HIV-1 acquisition. We also observed that risk variants for HIV-1 acquisition were significantly enriched for genes expressed in T-cells, but also those expressed in striatal and hippocampal neurons, which could explain the behavioral parameters genetically correlated with acquisition. Finally, we modeled how inter-individual variation in risk for HIV-1 acquisition influences the pre-exposed immune profile, by testing how individualized polygenic risk scores influence blood levels of 34 inflammatory markers in 406 HIV-1-negative individuals. We showed that higher genetic risk for HIV-1 acquisition was associated with lower levels of CCL17. Our findings corroborate a complex model for HIV-1 acquisition, whereby susceptibility is moderated by specific behavioral, cellular and immunological parameters.

Psychosocial stress and epigenetic aging.

Aging is the single most important risk factor for diseases that are currently the leading causes of morbidity and mortality. However, there is considerable inter-individual variability in risk for aging-related disease, and studies suggest that biological age can be influenced by multiple factors, including exposure to psychosocial stress. Among markers of biological age that can be affected by stress, the present article focuses on the so-called measures of epigenetic aging: DNA methylation-based age predictors that are measured in a range of tissues, including the brain, and can predict lifespan and healthspan. We review evidence linking exposure to diverse types of psychosocial stress, including early-life stress, cumulative stressful experiences, and low socioeconomic status, with accelerated epigenetic aging as a putative mediator of the effects of psychosocial environment on health and disease. The chapter also discusses methodological differences that may contribute to discordant findings across studies to date and plausible mechanisms that may underlie the effects of stress on the aging epigenome. Future studies examining the effects of adversity on epigenetic and other indicators of biological weathering may provide important insights into the pathogenesis of aging-related disease states.

Decision-Making Processes Underlying Pedestrian Behaviors at Signalized Crossing: Part 1. The First to Step off the Kerb

Pedestrians are ideal subjects for the study of decision-making, due to the inter-individual variation in risk taking. Many studies have attempted to understand which environmental factors influence the number of times pedestrians broke the rules at road-crossings, very few focused on the decision-making process of pedestrians according to the different conditions of these variables, that is to say their perception and interpretation of the information they receive. We used survival analyses and modeling to highlight the decision-making process of pedestrians crossing the road at signalized crossings in France and in Japan. For the first pedestrians to step off the kerb, we showed that the probability to cross the road follows three different processes: one at the red signal, one just before the pedestrian signal turns green, and one after the signal has turned green. Globally, the decision of the first pedestrian to cross, whether he or she does so at the green or at the red signal, is influenced by their country of residence. We identify the use of cognitive processes such as risk sensitivity and temporal discounting, and propose new concepts based on the results of this study to decrease the incidence of rule-breaking by pedestrians.

Abstract 3537: Targeted deep sequencing of driver mutations in airway epithelial cells from smokers

Abstract Background: Inter-individual variation in risk for lung cancer is based on variation in both exposure to environmental factors and genetic predisposition. As such, it is reasonable to hypothesize that prevalence of mutations in the airway epithelium will vary based on the combined effects of these lung cancer risk factors. Genes most commonly mutated in non-small cell lung cancer were recently reported from The Cancer Genome Atlas (TCGA) project. The purpose of this study was to use targeted deep sequencing to assess the prevalence of these mutations in bronchial epithelial cells (BEC) of individuals at high demographic risk for lung cancer. Methods: We enrolled 19 individuals with varying demographic risk for lung cancer, who were undergoing standard-of-care bronchoscopy into an IRB-approved research study in which we collected 1-5 million BEC via bronchoscopic brush biopsy and extracted genomic DNA. 10 subjects were smokers with lung cancer, 6 subjects were smokers without lung cancer, and 3 subjects were non-smokers without lung cancer. For targeted deep sequencing, we prepared synthetic spike-in competitive internal standards for each of 12 gene loci commonly mutated in lung cancer based on TCGA results and combined them into an IS mixture (ISM). DNA aliquots from each patient were quantified and mixed with equivalent genome equivalents of ISM prior to library preparation to control for technical artifacts associated with library preparation and NGS platform-specific error. The DNA input varied depending on sample quantity; there were 5 samples with 50,000 genome copies loaded, 12 samples with 100,000 genome copies loaded, and 2 samples with 1 million genome copies loaded. This approach enabled reliable measurement of 95% confidence limits of variant allele frequency (VAF), controlled for technical sequencing error, and allowed confident call of variants at a VAF of 0.1% and lower. Libraries for specimens from each of the 19 subjects were first sequenced using the Illumina MiSeq platform to ensure equal coverage across targets and samples. Deeper sequencing was then obtained using the Illumina NextSeq platform. Results: Preliminary results showed that smokers harbored mutations up to 1.6% in gene loci associated with non-small cell lung cancer according to TCGA, while none were identified in non-smoking controls. Conclusion: Initial results suggest that airway epithelial cells in smokers acquire somatic mutations that gradually lead to malignant conversion. Deep sequencing replicate experiments are underway to expand these results. Citation Format: Daniel J. Craig, Thomas M. Blomquist, Erin L. Crawford, James C. Willey. Targeted deep sequencing of driver mutations in airway epithelial cells from smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3537.

Clinical and Genetic Risk Prediction of Subsequent CNS Tumors in Survivors of Childhood Cancer: A Report From the COG ALTE03N1 Study.

Purpose Survivors of childhood cancer treated with cranial radiation therapy are at risk for subsequent CNS tumors. However, significant interindividual variability in risk suggests a role for genetic susceptibility and provides an opportunity to identify survivors of childhood cancer at increased risk for these tumors. Methods We curated candidate genetic variants from previously published studies in adult-onset primary CNS tumors and replicated these in survivors of childhood cancer with and without subsequent CNS tumors (82 participants and 228 matched controls). We developed prediction models to identify survivors at high or low risk for subsequent CNS tumors and validated these models in an independent matched case-control sample (25 participants and 54 controls). Results We demonstrated an association between six previously published single nucleotide polymorphisms (rs15869 [ BRCA2], rs1805389 [ LIG4], rs8079544 [ TP53], rs25489 [ XRCC1], rs1673041 [ POLD1], and rs11615 [ ERCC1]) and subsequent CNS tumors in survivors of childhood cancer. Including genetic variants in a Final Model containing age at primary cancer, sex, and cranial radiation therapy dose yielded an area under the curve of 0.81 (95% CI, 0.76 to 0.86), which was superior ( P = .002) to the Clinical Model (area under the curve, 0.73; 95% CI, 0.66 to 0.80). The prediction model was successfully validated. The sensitivity and specificity of predicting survivors of childhood cancer at highest or lowest risk of subsequent CNS tumors was 87.5% and 83.5%, respectively. Conclusion It is possible to identify survivors of childhood cancer at high or low risk for subsequent CNS tumors on the basis of genetic and clinical information. This information can be used to inform surveillance for early detection of subsequent CNS tumors.

Abstract 4595: The impact of CYP2A6 genetic polymorphisms on nicotine metabolism and lung cancer risk in two prospective cohorts of smokers

Abstract Background. Cytochrome P450 2A6 (CYP2A6) is polymorphic and catalyzes the metabolism of nicotine and certain tobacco-specific carcinogens, including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), thus may affect smoking behavior and contribute to substantial inter-individual variation in risk of smoking-related lung cancer. CYP2A6 genetic profiling coupled with biomarkers of tobacco constituents may enhance our understanding of the gene-environmental interaction on lung cancer risk and identify high-risk smokers for targeted preventive interventions. Methods. A nested case-control study including 513 incident lung cancers and an equal number of individually matched controls, all current smokers, was conducted within two population-based prospective cohorts with >80,000 Chinese men and women aged 45-74 years in Shanghai and Singapore. Quantified were 4 common allelic variants of CYP2A6 (*4, *7, *9 and rs1137115), urinary total nicotine, total cotinine (COT), total 3-hydroxy cotinine (3HC), and total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, a NNK metabolite). Calculated were total nicotine equivalent (TNE = the sum of total nicotine, COT and 3HC), and the 3HC:COT ratio as a measure of CYP2A6 activity. Logistic regression method was used to calculate odd ratios and 95% confidence intervals for lung cancer associated CYP2A6 genotypes and urinary biomarkers. Results. The smoking-adjusted ORs (95% CIs) of lung cancer comparing the highest to lowest quartile of total nicotine, total COT, total 3HC, TNE, and total NNAL were 2.49 (1.72-3.62), 3.03 (2.35-5.41), 3.56 (2.35-5.41), 3.35 (2.25-5.00), and 2.43 (1.65-3.57), respectively (all Ps for trend < 0.001). All 4 individual mutant variants of CYP2A6 were associated with reduced 3HC:COT ratio (all Ps for trend < 0.05). When all 4 genotypes were combined to create a CYP2A6 index with 5 groups: G1 (most efficient) to G5 (least efficient), the 3HC:COT ratio for G1 was 4 times that of G5 with a strong dose-dependent genotype-phenotype relation (P trend < 0.001). Smokers with CYP2A6 G5 consumed significantly fewer cigarettes and excreted lower urinary TNE (P trend < 0.001). Compared with CYP2A6 G1, the multivariate-adjusted ORs (95% CIs) of lung cancer for G2, G3, G4 and G5 were 0.95 (0.64-1.42), 1.04 (0.67-1.63), 0.54 (0.34-0.86) and 0.69 (0.43-1.13), respectively, (P trend = 0.005). Furthermore, there was a suggestive interaction between CYP2A6 index and total NNAL on lung cancer risk (P interaction = 0.087). Conclusion. CYP2A6 genetic polymorphisms have a strong influence on cigarette consumption, nicotine uptake and metabolism. In addition to reduced carcinogen exposure, altered metabolism of the tobacco-specific carcinogen NNK may contribute to the reduced risk of lung cancer in smokers with low functional CYP2A6 genotypes. Grants: R01 CA129534, R01 CA144034, UM1 CA182876. Citation Format: Jian-Min Yuan, Heather H. Nelson, Lesley M. Butler, Steven G. Carmella, Renwei Wang, Jennifer Adams-Haduch, Stephen S. Hecht, Woon-Puay Koh, Yu-Tang Gao, Sharon E. Murphy. The impact of CYP2A6 genetic polymorphisms on nicotine metabolism and lung cancer risk in two prospective cohorts of smokers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4595. doi:10.1158/1538-7445.AM2015-4595

SLCO1B1 transporter polymorphism is not associated with risk of myopathy in Czech population

Objectives: Statins are the most common drugs used in both primary and secondary cardiovascular disease prevention. SLCO1B1 codes for solute carrier organic anion transporter, which has been shown to regulate the hepatic uptake of statins and some other drugs. In patient using statins is elevated risk of undesirable side effects (USE) - developing of myalgia or myopathy. A significant inter-individual variability in risk of USE is likely to have a strong genetic background.

Fine Mapping Reveals That Promotion Susceptibility Locus 1 (Psl1) Is a Compound Locus With Multiple Genes That Modify Susceptibility to Skin Tumor Development

Although it is well known that the majority of human cancers occur as the result of exposure to environmental carcinogens, it is clear that not all individuals exposed to a specific environmental carcinogen have the same risk of developing cancer. Considerable evidence indicates that common allelic variants of low-penetrance, tumor susceptibility genes are responsible for this interindividual variation in risk. We previously reported a skin tumor promotion susceptibility locus, Psl1, which maps to the distal portion of chromosome 9, that modified skin tumor promotion susceptibility in the mouse. Furthermore, Psl1 was shown to consist of at least two subloci (i.e., Psl1.1 and Psl1.2) and that glutathione S-transferase alpha 4 (Gsta4), which maps to Psl1.2, is a skin tumor promotion susceptibility gene. Finally, variants of human GSTA4 were found to be associated with risk of nonmelanoma skin cancer. In the current study, a combination of nested and contiguous C57BL/6 congenic mouse strains, each inheriting a different portion of the Psl1 locus from DBA/2, were tested for susceptibility to skin tumor promotion with 12-O-tetradecanoylphorbol-13-acetate. These analyses indicate that Psl1 is a compound locus with at least six genes, including Gsta4, that modify skin tumor promotion susceptibility. More than 550 protein-coding genes map within the Psl1 locus. Fine mapping of the Psl1 locus, along with two-strain haplotype analysis, gene expression analysis, and the identification of genes with amino acid variants, has produced a list of fewer than 25 candidate skin tumor promotion susceptibility genes.

Genetic Susceptibility to Anthracycline-Related Congestive Heart Failure (CHF) in Survivors of Hematopoietic Cell Transplantation (HCT)

AbstractAbstract ▪589▪This icon denotes a clinically relevant abstract Background:HCT survivors are at increased risk for developing cardiovascular disease, including CHF. We have demonstrated that the risk of post-HCT CHF is primarily ascribed to pre-HCT exposure to anthracyclines. The anthracycline-related cardiotoxicity is dose-dependent, with well-established factors that modify this association, such as young age at exposure to anthracyclines, female gender, chest irradiation, and presence of conventional cardiovascular risk factors (CVRFs: hypertension, diabetes mellitus, and dyslipidemia). However, these modifiers fail to explain the wide inter-individual variability in the risk of anthracycline-related CHF. Proposed pathogenesis of anthracycline-related CHF includes oxidative stress and intracardiac metabolic derangements induced by anthracycline toxic metabolites. Inherent susceptibility in these pathways could explain the inter-individual variability in risk – an area that is unstudied in this population. Methods:A nested case-control approach was used to evaluate the impact of functional SNPs in candidate genes hypothesized to be associated with anthracycline-related CHF. Cases were defined per the American Heart Association criteria for clinical CHF. Individuals with CHF and with pre-HCT germline DNA were identified from 2950 patients transplanted at City of Hope between 1988 and 2007. This cohort formed the sampling frame for selecting controls (without CHF) matched on: age at HCT, type of HCT (allo, auto), race/ethnicity confirmed by genetic ancestry, anthracycline dose, and length of follow-up. We studied genes involved in free radical metabolism (NAD[P]H oxidase: subunits NCF4, RAC2, CYBA; Hemochromatosis: HFE; Superoxide dismutase: SOD; Apolipoprotein E: ApoE), genes involved in regulation of the renin-angiotensin and beta-adrenergic systems (AGT, AGTR1, ACE, ADRB1, ADRB2) as well as those impacting the pharmacodynamics of anthracyclines (carbonyl reductase: CBR1 and CBR3; Multidrug resistant protein: MRP1 and MRP2). Results:The cumulative incidence of CHF was 6% at 15 years after transplantation; Pre-HCT germline DNA was available for 77 patients with CHF; median age at HCT was 47.5 yrs (16.0–68.6); 82% underwent autologous HCT; 60% were non-Hispanic white; median anthracycline dose was 300 mg/m2 (60–650); median time to CHF: 2.8 yrs (0.1–12.7). One-hundred and seventy eight matched controls with available germline DNA were identified. There was no difference in underlying diagnosis, conditioning regimen, and body mass index (BMI) at HCT between cases and controls. Cases were more likely to be female (55.8% vs. 34%, p<0.01), to have received chest radiation prior to HCT (14.3% vs. 5.1%, p=0.01), and have hypertension following HCT (28.6% vs. 14.6%, p<0.01) when compared to controls. Multivariate conditional logistic regression revealed an increased risk of CHF in individuals with variants of genes coding for the NAD(P)H oxidase subunit RAC2 (rs13058338, 7508T→A; Odds Ratio [OR]: 2.8, p<0.01), HFE (rs17999945, 63C→G; OR: 2.5, p=0.01) or the doxorubicin efflux transporter MRP2 (rs8187710, Cys1515Tyr; OR: 4.3, p<0.01). Compared to males with one or no at-risk alleles, female HCT survivors with ≥2 at-risk alleles were at highest risk of CHF (Table; OR=17.1, p<0.01). Conclusion:Our findings support the “unifying hypothesis” that the risk of anthracycline-related cardiotoxicity is significantly modified by high-risk variants of RAC2 (free radical generation), HFE (dysregulation of iron homeostasis and free radical generation), and MRP2 (intracellular accumulation of cardiotoxic anthracyclines). These data could facilitate the development of novel approaches for targeted surveillance as well as early intervention strategies in HCT survivors at highest risk for CHF.OR95% CIP-ValueMale, <2 SNPs1.0____Male, ≥2 SNPs5.01.10–22.530.04Female, <2 SNPs2.41.11–5.160.03Female, ≥2 SNPs17.14.63–63.36<0.01Model adjusted for: chest radiation exposure, BMI, underlying diagnosis, post-HCT CVRFs (hypertension, diabetes, dyslipidemia).Case-Control matching criteria: age at HCT, race/ethnicity, lifetime anthracycline dose, type of HCT, length of follow-up. Disclosures:No relevant conflicts of interest to declare.

Genetic polymorphisms of the dopamine and serotonin systems modulate the neurophysiological response to feedback and risk taking in healthy humans

Genetic differences in the dopamine and serotonin systems have been suggested as potential factors underlying interindividual variability in risk taking and in brain activation during the processing of feedback. Here, we studied the effects of dopaminergic (dopamine transporter [DAT1], catecholamine-O-methyltransferase val158met [COMT]) and serotonergic (serotonin transporter [5HTTLPR]) polymorphisms on risk taking and brain responses following feedback in 60 healthy female subjects. The subjects completed a well-established experimental gambling paradigm while an electroencephalogram was recorded. During the task, risk-taking behavior and prefrontal brain responses (feedback-related negativity [FRN]) following monetary gains and losses were assessed. FRN amplitudes were enhanced for nine-repeat-allele carriers of the DAT1 and short-allele carriers of 5HTTLPR, which are both presumably linked to less transporter activity and higher neurotransmitter levels. Moreover, nine-repeat DAT1 carriers displayed a trend toward increased risk taking in general, whereas 5HTTLPR short-allele carriers showed decreased risk taking following gains. COMT val158met genotype was unrelated to FRN amplitude and average risk taking. However, COMT met/met carriers showed a pronounced feedback P3 amplitude independent of valence, and a gradual increase in risk taking during the gambling task. In sum, the present findings underline the importance of genetic variability in the dopamine and serotonin systems regarding the neurophysiology of feedback processing.

5-HTTLPR status predictive of neocortical 5-HT4 binding assessed with [11C]SB207145 PET in humans

Serotonin (5-HT) is a neuromodulator affecting myriad aspects of personality and behavior and has been implicated in the pathophysiology of affective disorders including depression and anxiety. The 5-HTTLPR is a common genetic polymorphism within the promoter region of the gene coding for the serotonin transporter such that the S allele is associated with reduced transcriptional efficacy compared to the L allele, potentially contributing to increased serotonin levels. In humans, this genetic variant has been linked to inter-individual variability in risk for affective disorders, related aspects of personality and brain function including response to threat. However, its effects on aspects of serotonin signaling in humans are not fully understood. Studies in animals suggest that the 5-HT 4 receptor (5-HT(4)) shows a monotonic inverse association with long-term changes in serotonin levels indicating that it may be a useful measure for identifying differences in serotonergic neurotransmission. In 47 healthy adults we evaluated the association between 5-HTTLPR status and in vivo 5-HT(4) receptor binding assessed with [(11)C]SB207145 positron emission tomography (PET). We observed a significant association within the neocortex where [(11)C]SB207145 binding was 9% lower in S carriers compared to LL homozygotes. We did not find evidence for an effect of season or a season-by-5-HTTLPR interaction effect on regional [(11)C]SB207145 binding. Our findings are consistent with a model wherein the 5-HTTLPR S allele is associated with relatively increased serotonin levels. These findings provide novel evidence supporting an effect of 5-HTTLPR status on serotonergic neurotransmission in adult humans. There were no indications of seasonal effects on serotonergic neurotransmission.

Anthracycline-related cardiomyopathy in childhood cancer survivors and association with polymorphisms in the carbonyl reductase genes: A Children's Oncology Group study.

9512 Background: Anthracycline-related cardiomyopathy is a well-recognized dose-limiting complication. Inter-individual variability in risk exists, potentially due to genetic susceptibility. Carbonyl reductases (CBR) catalyze reduction of anthracyclines to cardiotoxic alcohol metabolites. Polymorphisms in CBR3 V244M and CBR1 G1096A impact CBR activity. We examined the role of functional polymorphisms in CBR3 and CBR1 on risk of cardiomyopathy. Methods: Using a case-control design, 165 cases with documented cardiomyopathy and 323 controls (cancer survivors with no cardiomyopathy; matched on primary diagnosis, follow-up, race/ethnicity) provided germline DNA. Therapeutic exposures were summarized. Results: Primary diagnoses included acute leukemia (164), lymphoma (111), sarcoma (120) and others (93); 51% were females; 77% whites; median age at cancer diagnosis: 7.5 years; time to cardiomyopathy: 7.1 years; median anthracycline dose – cases: 300mg/m2; controls: 140mg/m2. Multivariate analysis revealed anthracycline dose (per 100mg/m2: OR=1.8, p<0.001), and chest radiation (OR=3.13, p=0.05) to be associated with cardiomyopathy. The role of polymorphisms in CBR3/CBR1 was then examined, adjusting for chest radiation. There was a borderline association between CBR3 V244M and cardiomyopathy (OR=1.5, p=0.08 for GG vs. GA/A); and no association for CBR1 G1096A (OR=1.0, p=0.9). However, upon stratification by anthracycline does, the association with CBR3 V244M became stronger among subjects exposed to ≤250mg/m2 (OR=6.4, p=0.006), but disappeared for those exposed to >250mg/m2 (OR=0.9, p=0.8). Similar but non-significant associations were observed for CBR1 (OR=3.3, p=0.10; OR=0.8, p=0.7, respectively). Conclusions: Using the largest cohort of documented cardiomyopathy, this report demonstrates a clear dose-response relation between anthracyclines and cardiomyopathy, and selectively greater impact of CBR3 on risk of cardiomyopathy after low-dose anthracycline exposure. These data identify a definable subset of patients that may benefit from cardioprotection, surveillance or pharmacologic interventions. No significant financial relationships to disclose.

Impact of matrix metalloproteinase-1 gene variations on risk of acute coronary syndrome

This case-control study was conducted to investigate whether genetic variations in the matrix metalloproteinase-1 gene promoter were related to risk of acute coronary syndrome (ACS). 222 patients with ACS and 191 normal controls were examined by means of polymerase chain reaction (PCR) and restriction fragment length polymorphism. A significantly higher frequency of AA genotype of -519A/G polymorphism was observed in ACS patients than in the controls (P<0.001). The relative risk of ACS in patients carrying A allele of -519A/G polymorphism was 1.33 [P<0.001, 95% confidence interval (CI)=1.12-1.57]. Linkage disequilibrium test and haplotype analysis indicated that the AT haplotype significantly increased the risk of ACS (P=0.004, 95% CI=1.14-2.04, odds ratio=1.53). Compared with the AT haplotype, the GT haplotype was associated with a reduced occurrence of ACS (P<0.001, 95% CI=0.36-0.70, odds ratio=0.51). Our findings suggested that genetic variations in the matrix metalloproteinase-1 gene promoter may contribute to interindividual variability in risk of ACS, and help predict susceptible individuals.

Perceiving Others’ Perceptions of Risk

The recent literature providing insights from neuroscience and evolutionary biology into how individuals perceive risky choice situations represents a "second wave" of findings that recapitulates as well as challenges the risk perception research begun in the 1980s, which relied on psychometric survey research. Gleaning insights from the first wave of research that could improve the communication and control of environmental risks has yielded disappointing results. This is a result, in part, of the eagerness of scholars and pundits to posit a chasm between the "rational" and "objective" perceptions of experts, on the one hand, and a lay public that is seen as lurching between "paranoia and neglect" and as insensitive to the magnitude of risks. Interpretations of the psychometric research have suffered from inattention to uncertainty and interindividual variability in risk, to expert biases, and to important aspects of risky choice that were not explored in the first wave of research. Initial signs indicate that neuroscience and evolutionary biology research may fall prey to similar misinterpretations. This article summarizes some of the most intriguing findings of the "second wave" of risk perception research and advances four themes that may help make the new findings less divisive and more useful for improving risk communication and risk management. Continued research into risk perception should perhaps be embedded in a more general theory of public choice in the face of uncertain and variable costs and benefits and with a respect for distributive justice as an important goal in risk management.

CEBPG transcription factor correlates with antioxidant and DNA repair genes in normal bronchial epithelial cells but not in individuals with bronchogenic carcinoma

BackgroundCigarette smoking is the primary cause of bronchogenic carcinoma (BC), yet only 10–15% of heavy smokers develop BC and it is likely that this variation in risk is, in part, genetically determined. We previously reported a set of antioxidant genes for which transcript abundance was lower in normal bronchial epithelial cells (NBEC) of BC individuals compared to non-BC individuals. In unpublished studies of the same NBEC samples, transcript abundance values for several DNA repair genes were correlated with these antioxidant genes. From these data, we hypothesized that antioxidant and DNA repair genes are co-regulated by one or more transcription factors and that inter-individual variation in expression and/or function of one or more of these transcription factors is responsible for inter-individual variation in risk for BC.MethodsThe putative transcription factor recognition sites common to six of the antioxidant genes were identified through in silico DNA sequence analysis. The transcript abundance values of these transcription factors (n = 6) and an expanded group of antioxidant and DNA repair genes (n = 16) were measured simultaneously by quantitative PCR in NBEC of 24 non-BC and 25 BC individuals.ResultsCEBPG transcription factor was significantly (p < 0.01) correlated with eight of the antioxidant or DNA repair genes in non-BC individuals but not in BC individuals. In BC individuals the correlation with CEBPG was significantly (p < 0.01) lower than that of non-BC individuals for four of the genes (XRCC1, ERCC5, GSTP1, and SOD1) and the difference was nearly significant for GPX1. The only other transcription factor correlated with any of these five target genes in non-BC individuals was E2F1. E2F1 was correlated with GSTP1 among non-BC individuals, but in contrast to CEBPG, there was no significant difference in this correlation in non-BC individuals compared to BC individuals.ConclusionWe conclude that CEBPG is the transcription factor primarily responsible for regulating transcription of key antioxidant and DNA repair genes in non-BC individuals. Further, we conclude that the heavy smokers selected for development of BC are those who have sub-optimal regulation of antioxidant and DNA repair genes by CEBPG.