Bradley E. Aouizerat

Abstract

Persistent pain after breast cancer surgery is a common clinical problem. Given the role of potassium channels in modulating neuronal excitability, coupled with recently published genetic associations with preoperative breast pain, we hypothesized that variations in potassium channel genes will be associated with persistent postsurgical breast pain. In this study, associations between 10 potassium channel genes and persistent breast pain were evaluated. Using growth mixture modeling (GMM), 4 distinct latent classes of patients, who were assessed before and monthly for 6 months after breast cancer surgery, were identified previously (ie, No Pain, Mild Pain, Moderate Pain, Severe Pain). Genotyping was done using a custom array. Using logistic regression analyses, significant differences in a number of genotype or haplotype frequencies were found between: Mild Pain vs No Pain and Severe Pain vs No Pain classes. Seven single-nucleotide polymorphisms (SNPs) across 5 genes (ie, potassium voltage-gated channel, subfamily A, member 1 [KCNA1], potassium voltage-gated channel, subfamily D, member 2 [KCND2], potassium inwardly rectifying channel, subfamily J, members 3 and 6 (KCNJ3 and KCNJ6), potassium channel, subfamily K, member 9 [KCNK9]) were associated with membership in the Mild Pain class. In addition, 3 SNPs and 1 haplotype across 4 genes (ie, KCND2, KCNJ3, KCNJ6, KCNK9) were associated with membership in the Severe Pain class. These findings suggest that variations in potassium channel genes are associated with both mild and severe persistent breast pain after breast cancer surgery. Although findings from this study warrant replication, they provide intriguing preliminary information on potential therapeutic targets.

Abstract

Subgroups of patients with breast cancer may be at greater risk for cytokine-induced changes in cognitive function after diagnosis and during treatment. The purposes of this study were to identify subgroups of patients with distinct trajectories of attentional function and evaluate for phenotypic and genotypic (i.e., cytokine gene polymorphisms) predictors of subgroup membership. Self-reported attentional function was evaluated in 397 patients with breast cancer using the Attentional Function Index before surgery and for six months after surgery (i.e., seven time points). Using growth mixture modeling, three attentional function latent classes were identified: High (41.6%), Moderate (25.4%), and Low-moderate (33.0%). Patients in the Low-moderate class were significantly younger than those in the High class, with more comorbidities and lower functional status than the other two classes. No differences were found among the classes in years of education, race/ethnicity, or other clinical characteristics. DNA was recovered from 302 patients' samples. Eighty-two single nucleotide polymorphisms among 15 candidate genes were included in the genetic association analyses. After controlling for age, comorbidities, functional status, and population stratification due to race/ethnicity, IL1R1 rs949963 remained a significant genotypic predictor of class membership in the multivariable model. Carrying the rare "A" allele (i.e., GA. +. AA) was associated with a twofold increase in the odds of belonging to a lower attentional function class (OR: 1.98; 95% CI: 1.18, 3.30; p=.009). Findings provide evidence of subgroups of women with breast cancer who report distinct trajectories of attentional function and of a genetic association between subgroup membership and an IL1R1 promoter polymorphism.

Abstract

Background: Abnormal calcium handling plays a crucial role in arrhythmias, sudden cardiac arrest (SCA), and congestive heart failure (CHF). Calsequestrin 2 (CASQ2) mutations affect calcium release and initiate malignant ventricular arrhythmias (VAs) and SCA syndromes. Common single nucleotide polymorphisms (SNPs) in CASQ2 may be associated with SCA in patients with coronary artery disease (CAD). Objective: The purpose of this study was to examine the association of common CASQ2 SNPs with the risk of SCA in patients with CAD. Methods: CASQ2 SNPs (n = 14) were genotyped and analyzed in a case control study comparing 114 patients with CAD and SCA due to VA to 311 CAD controls without VA or SCA. Results: Multivariate logistic regression adjusting for age and CHF status identified an association between rs7521023 with SCA (odds ratio [OR] 2.72, 95% confidence interval [CI] 1.44-5.13, P = .002). The substantial impact of CHF on SCA in the model (OR 26.6, 95% CI 13.40-52.70, P <.001) led us to further examine the relationship between CHF, SCA, and CASQ2 SNPs. We identified 2 CASQ2 variants (rs7521023: OR 0.4, 95% CI 0.25-0.76, P = .003; rs6684209: OR 19.8, 95% CI 3.63-108.2, P <.001) associated with CHF after adjusting for SCA, age, gender, and hypertension. Conclusion: We observed association between a CASQ2 polymorphism and SCA due to VA in patients with CAD adjusting for CHF and independent associations between CASQ2 SNPs and CHF adjusting for SCA. Further investigation in independent cohorts is needed to confirm these findings.

Abstract

Purpose of the research: To attempt to replicate the associations found in our previous study of patients and family caregivers between interleukin 6 (IL6) and nuclear factor kappa beta 2 (NFKB2) and sleep disturbance and to identify additional genetic associations in a larger sample of patients with breast cancer. Methods and sample: Patients with breast cancer (n=398) were recruited prior to surgery and followed for six months. Patients completed a self-report measure of sleep disturbance and provided a blood sample for genomic analyses. Growth mixture modeling was used to identify distinct latent classes of patients with higher and lower levels of sleep disturbance. Key results: Patients who were younger and who had higher comorbidity and lower functional status were more likely to be in the high sustained sleep disturbance class. Variations in three cytokine genes (i.e., IL1 receptor 2 (IL1R2), IL13, NFKB2) predicted latent class membership. Conclusions: Polymorphisms in cytokine genes may partially explain inter-individual variability in sleep disturbance. Determination of high risk phenotypes and associated molecular markers may allow for earlier identification of patients at higher risk for developing sleep disturbance and lead to the development of more targeted clinical interventions.

Abstract

Persistent pain following breast cancer surgery is a significant clinical problem. Although immune mechanisms may play a role in the development and maintenance of persistent pain, few studies have evaluated for associations between persistent breast pain following breast cancer surgery and variations in cytokine genes. In this study, associations between previously identified extreme persistent breast pain phenotypes (ie, no pain vs severe pain) and single nucleotide polymorphisms (SNPs) spanning 15 cytokine genes were evaluated. In unadjusted analyses, the frequency of 13 SNPs and 3 haplotypes in 7 genes differed significantly between the no pain and severe pain classes. After adjustment for preoperative breast pain and the severity of average postoperative pain, 1 SNP (ie, interleukin [IL] 1 receptor 2 rs11674595) and 1 haplotype (ie, IL10 haplotype A8) were associated with pain group membership. These findings suggest a role for cytokine gene polymorphisms in the development of persistent breast pain following breast cancer surgery. Perspective This study evaluated for associations between cytokine gene variations and the severity of persistent breast pain in women following breast cancer surgery. Variations in 2 cytokine genes were associated with severe breast pain. The results suggest that cytokines play a role in the development of persistent postsurgical pain.

Abstract

Oncology patients are at high risk for developing sleep disturbance and fatigue due a number of physiological and psychological factors associated with cancer, its treatment, and the burden of living with a chronic condition. Progress in our understanding of sleep disturbance and fatigue in oncology patients has been stymied by varying definitions for each symptom, as well as different instruments to measure each symptom. In addition, the co-occurrence of these and other common symptoms suggests that analytic methodologies that are currently available should be considered to model the relationships between these and among other common symptoms. The purpose of the chapter is to describe the prevalence, risk factors, measurement considerations, proposed mechanisms for and novel approaches to the study of these two common symptoms in oncology patients. Interventions to improve sleep and reduce fatigue are also described.

Abstract

Background: Lymphedema (LE) is a frequent complication following breast cancer treatment. While progress is being made in the identification of phenotypic risk factors for the development of LE, little information is available on the molecular characterization of LE. The purpose of this study was to determine if variations in pro-and anti-inflammatory cytokine genes were associated with LE following breast cancer treatment. Methods and Results: Breast cancer patients completed a number of self-report questionnaires. LE was evaluated using bioimpedance spectroscopy. Genotyping was done using a custom genotyping array. No differences were found between patients with (n=155) and without LE (n=387) for the majority of the demographic and clinical characteristics. Patients with LE had a significantly higher body mass index, more advanced disease, and a higher number of lymph nodes removed. Genetic associations were identified for three genes (i.e., interleukin (IL4) 4 (rs2227284), IL 10 (rs1518111), and nuclear kappa factor beta 2 (NFKB2 (rs1056890)) associated with inflammatory responses. Conclusions: These genetic associations suggest a role for a number of pro-and anti-inflammatory genes in the development of LE following breast cancer treatment.

Abstract

Purpose: This study explored the relationships between variations in cytokines genes and depressive symptoms in a sample of patients who were assessed prior to and for six months following breast cancer surgery. Phenotypic differences between Resilient (n = 155) and Subsyndromal (n = 180) depressive symptom classes, as well as variations in cytokine genes were evaluated. Method: Patients were recruited prior to surgery and followed for six months. Growth mixture modeling was used to identify distinct latent classes based on Center for Epidemiological Studies Depression (CES-D) Scale scores. Eighty-two single nucleotide polymorphisms and 35 haplotypes among 15 candidate cytokine genes were evaluated. Results: Patients in the Subsyndromal class were significantly younger, more likely to be married or partnered, and reported a significantly lower functional status. Variation in three cytokine genes (i.e., interferon gamma receptor 1 (IFNGR1 rs9376268), interleukin 6 (IL6 rs2069840), tumor necrosis factor alpha (TNFA rs1799964)), as well as age and functional status predicted membership in the Subsyndromal versus the Resilient class. Conclusions: A variation in TNFA that was associated with Subsyndromal depressive symptoms in a sample of patients and their family caregivers was confirmed in this sample. Variations in cytokine genes may place these patients at higher risk for the development of Subsyndromal levels of depressive symptoms.

Abstract

Fatigue has been associated with inflammation and cytokine activity among adults, but this relationship has not been evaluated among adults living with HIV. Diurnal patterns of fatigue have been previously identified in adults with HIV/AIDS. Thus, the purpose of this study was to describe these fatigue patterns in relation to cytokine plasma concentrations and gene polymorphisms. A convenience sample of 317 adults living with HIV/AIDS completed a measure of fatigue in the morning and evening for three consecutive days; participants reporting low levels of both morning and evening fatigue (n= 110) or high levels of fatigue in the morning and evening (n= 114) were included in the analysis, resulting in a final sample of 224 adults (151 men, 55 women, and 18 transgender). Plasma cytokines were analyzed, and genotyping was conducted for 15 candidate genes involved in cytokine signaling: interferon-gamma (IFNG), IFNG receptor 1 (IFNGR1), interleukins (IL), nuclear factor of kappa light polypeptide gene enhancer in B cells (NFKB-1 and -2), and tumor necrosis factor alpha (TNFA). Demographic and clinical variables were evaluated as potential covariates. Controlling for genomic estimates of ancestry and self-reported race/ethnicity and gender, the high fatigue pattern was associated with five single nucleotide polymorphisms (SNPs): IL1B rs1071676 and rs1143627, IL4 rs2243274, and TNFA rs1800683 and rs1041981. The IL1B and TNFA polymorphisms were not associated with plasma levels of IL-1β or TNFα, respectively. This study strengthens the evidence for an association between inflammation and fatigue. In this chronic illness population, the cytokine polymorphisms associated with high levels of morning and evening fatigue provide direction for future personalized medicine intervention research.

Abstract

Study Objectives: Cytokine activity and polymorphisms have been associated with sleep outcomes in prior animal and human research. The purpose of this study was to determine whether circulating plasma cytokines and cytokine polymorphisms are associated with the poor sleep maintenance commonly experienced by adults living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Design: Cross-sectional descriptive study. Setting: HIV clinics and community sites in the San Francisco Bay area. Participants: A convenience sample of 289 adults (193 men, 73 women, and 23 transgender) living with HIV/AIDS. Interventions: None. Measurements and Results: A wrist actigraph was worn for 72 h to estimate the percentage of wake after sleep onset (WASO%) and total sleep time (TST), plasma cytokines were analyzed, and genotyping was conducted for 15 candidate genes involved in cytokine signaling: interferongamma (IFNG), IFNG receptor 1 (IFNGR1), interleukins (IL1B, IL1R2, IL1R2, IL2, IL4, IL6, IL8, IL10, IL13, IL17A), nuclear factor of kappa light polypeptide gene enhancer in B cells (NFKB1 and NFKB2), and tumor necrosis factor-alpha (TNFA). Controlling for demographic variables such as race and sex, and clinical variables such as CD4+ count and medications, higher WASO% was associated with single nucleotide polymorphisms (SNPs) of IL1R2 rs11674595 and TNFA rs1041981 and less WASO% was associated with IL2 rs2069776. IL1R2 rs11674595 and TNFA rs1041981 were also associated with short sleep duration. Conclusions: This study strengthens the evidence for an association between inflammation and sleep maintenance problems. In this chronic illness population, cytokine polymorphisms associated with wake after sleep onset provide direction for intervention research aimed at comparing anti-inflammatory mechanisms with hypnotic agents for improving sleep maintenance and total sleep time.