Creating and Implementing a Community-Focused, Culturally Tailored Health Marketing Campaign to Address Menthol Cigarette Use in Los Angeles County.

Introduction: Menthol tobacco products have been marketed disproportionately to communities of color for decades. Methods: In Los Angeles County, California, a health marketing campaign, which used glossy visuals and attractive people in appealing poses, reminiscent of tobacco marketing tactics, was created and implemented to educate smokers on the health risks of using menthol cigarettes. The campaign encouraged smokers to make a quit attempt by offering access to free or low-cost resources through the Kick It California quitline and the LAQuits website (laquits.com). A survey tailored for public health professionals and community members from the approximately 382,000 people in the county who smoked menthol cigarettes and were exposed to their smoke (our primary audience) was administered to generate insights about this problem. Survey data were used to finesse the campaign creative materials prior to launch. Advertisement exposures, website visits, and quitline call volume were monitored and tabulated to assess the performance of the campaign. Results: At the conclusion of its initial run (February-April 2021), the "Done with Menthol" campaign had garnered more than 66 million impressions, received approximately 56,000 clicks on its various digital media platforms, and had click-through rates that surpassed industry benchmarks. The quitline call volume for African American and Latino subgroups were 1.9 and 1.8 times higher than the average inbound call volume for corresponding months during 2018 and 2019, respectively. In its second run (May-June 2023), the campaign garnered approximately 11 million additional impressions. Conclusions: Despite having a lower budget and fewer resources than the tobacco industry, the "Done with Menthol" campaign attained excellent reach and offered free, low-cost, and accessible resources to county residents interested in tobacco use cessation.

Indiana Medical Resident's Knowledge of Surrogate Decision Making Laws.

INTRODUCTION: During the care of incapacitated patients, physicians, and medical residents discuss treatment options and gain consent to treat through healthcare surrogates. The purpose of this study is to ascertain medical residents' knowledge of healthcare consent laws, application during clinical practice, and appraise the education residents received regarding surrogate decision making laws. METHODS: Beginning in February of 2018, 35 of 113 medical residents working with patients within Indiana completed a survey. The survey explored medical residents' knowledge of health care surrogate consent laws utilized in Indiana hospitals and Veterans Affairs (VA) hospitals via clinical vignettes. RESULTS: Only 22.9% of medical residents knew the default state law in Indiana did not have a hierarchy for settling disputes among surrogates. Medical residents correctly identified which family members could participate in medical decisions 86% of the time. Under the Veterans Affairs surrogate law, medical residents correctly identified appropriate family members or friends 50% of the time and incorrectly acknowledged the chief decision makers during a dispute 30% of the time. All medical residents report only having little or some knowledge of surrogate decision making laws with only 43% having remembered receiving surrogate decision making training during their residency. CONCLUSIONS: These findings demonstrate that medical residents lack understanding of surrogate decision making laws. In order to ensure medical decisions are made by the appropriate surrogates and patient autonomy is upheld, an educational intervention is required to train medical residents about surrogate decision making laws and how they are used in clinical practice.

A high-resolution association mapping panel for the dissection of complex traits in mice.

Systems genetics relies on common genetic variants to elucidate biologic networks contributing to complex disease-related phenotypes. Mice are ideal model organisms for such approaches, but linkage analysis has been only modestly successful due to low mapping resolution. Association analysis in mice has the potential of much better resolution, but it is confounded by population structure and inadequate power to map traits that explain less than 10% of the variance, typical of mouse quantitative trait loci (QTL). We report a novel strategy for association mapping that combines classic inbred strains for mapping resolution and recombinant inbred strains for mapping power. Using a mixed model algorithm to correct for population structure, we validate the approach by mapping over 2500 cis-expression QTL with a resolution an order of magnitude narrower than traditional QTL analysis. We also report the fine mapping of metabolic traits such as plasma lipids. This resource, termed the Hybrid Mouse Diversity Panel, makes possible the integration of multiple data sets and should prove useful for systems-based approaches to complex traits and studies of gene-by-environment interactions.

Biochemical and transcriptional profiling to triage additional activities in a series of IGF-1R/IR inhibitors.

Therapeutic development of a targeted agent involves a series of decisions over additional activities that may be ignored, eliminated or pursued. This paper details the concurrent application of two methods that provide a spectrum of information about the biological activity of a compound: biochemical profiling on a large panel of kinase assays and transcriptional profiling of mRNA responses. Our mRNA profiling studies used a full dose range, identifying subsets of transcriptional responses with differing EC(50)s which may reflect distinct targets. Profiling data allowed prioritization for validation in xenograft models, generated testable hypotheses for active compounds, and informed decisions on the general utility of the series.

Abatacept does not induce direct gene expression changes in antigen-presenting cells.

BACKGROUND: It has been proposed that ligation of CD80 and CD86 induces reverse signaling into antigen-presenting cells. In this study, we tested the ability of abatacept, a soluble human fusion protein comprising the extracellular domain of cytotoxic T lymphocyte antigen 4 and a fragment of the Fc domain of IgG(1), to activate antigen-presenting cells by measuring changes in global transcriptional responses. METHODS: Affymetrix chips were used to measure gene expression levels using mRNA isolated from immature and mature human dendritic cells and a B cell line following 6 h of treatment with abatacept. RESULTS: In contrast to robust transcriptional responses induced by the control treatment phorbol-12-myristate-13-acetate, abatacept induced minimal gene changes in three different populations of antigen-presenting cells. Furthermore, no gene changes were observed in response to belatacept, a modified version of abatacept that binds with higher avidity to CD80 and CD86. CONCLUSIONS: We conclude that reverse signaling in antigen-presenting cells is unlikely to occur in response to either abatacept or belatacept, thereby supporting the modulation of CD28 signaling on T cells as the main mechanism of action for these therapeutics.

Sex differences in ethanol-induced hypothermia in ethanol-naïve and ethanol-dependent/withdrawn rats.

BACKGROUND: Human and animal findings indicate that males and females display major differences in risk for and consequences of alcohol abuse and alcoholism. These differences are in large part mediated by sex-specific hormonal environments. Gonadal and adrenal secretory products are known to modulate the neurobehavioral responses of ethanol (EtOH) dependence and withdrawal. However, the effects of these steroids on physiological adaptations, such as thermoregulation, are less well established. To study the role of sex-related hormones in mediating sex differences in the hypothermic response to acute challenge with EtOH, we compared the EtOH-induced hypothermic responses of EtOH-naïve male and female rats and EtOH-dependent (on the third day of withdrawal) male and female rats before (intact) and after depletion of all gonadal and adrenal steroids by gonadectomy (GDX) with or without adrenalectomy (ADX). METHODS: Intact and GDX male and female rats, with or without ADX, were fed an EtOH-containing liquid diet for 15 days while control (EtOH-naïve) rats were pairfed the isocaloric liquid diet without EtOH or fed normal rat chow and water. On the third day of withdrawal from the EtOH diet we tested the hypothermic response to EtOH challenge (1.5 g/kg BWt, ip). Blood alcohol content (BAC) and corticosterone (CORT) content were analyzed in a separate series of intact and GDX males and females with and without ADX in response to the EtOH challenge. RESULTS: Ethanol-induced hypothermia was significantly greater and its duration significantly longer in intact males than females when subjects were EtOH-naïve. EtOH-induced hypothermia was significantly greater in intact females than males by the third day of withdrawal from EtOH dependence. GDX in males significantly shortened the duration of the hypothermic response and tended to blunt EtOH-induced hypothermia while response duration was significantly extended by GDX in females that tended to enhance EtOH-hypothermia. EtOH-induced hypothermia was significantly enhanced and its duration significantly lengthened by combined GDX and ADX in EtOH-naïve and -withdrawn males and by combined GDX and ADX in EtOH-naïve but not EtOH-withdrawn females. These differential EtOH-induced hypothermic responses did not appear to be caused by differences in EtOH handling among the groups. The absence of adrenal activation by EtOH in the GDX-ADX males and females contributes to their enhanced EtOH-induced hypothermic responses. CONCLUSIONS: These results implicate the direct and indirect effects of removal of gonadal and adrenal secretory products as mediators of the thermoregulatory actions of EtOH.

The class II phosphoinositide 3-kinase C2beta is not essential for epidermal differentiation.

Phosphoinositide 3-kinases (PI3Ks) regulate an array of cellular processes and are comprised of three classes. Class I PI3Ks include the well-studied agonist-sensitive p110 isoforms; however, the functions of class II and III PI3Ks are less well characterized. Of the three class II PI3Ks, C2alpha and C2beta are widely expressed in many tissues, including the epidermis, while C2gamma is confined to the liver. In contrast to the class I PI3K p110alpha, which is expressed throughout the epidermis, C2beta was found to be localized in suprabasal cells, suggesting a potential role for C2beta in epidermal differentiation. Overexpressing C2beta in epidermal cells in vitro induced differentiation markers. To study a role for C2beta in tissue, we generated transgenic mice overexpressing C2beta in both suprabasal and basal epidermal layers. These mice lacked epidermal abnormalities. Mice deficient in C2beta were then generated by targeted gene deletion. C2beta knockout mice were viable and fertile and displayed normal epidermal growth, differentiation, barrier function, and wound healing. To exclude compensation by C2alpha, RNA interference was then used to knock down both C2alpha and C2beta in epidermal cells simultaneously. Induction of differentiation markers was unaffected in the absence of C2alpha and C2beta. These findings indicate that class II PI3Ks are not essential for epidermal differentiation.

Factors influencing physicians' screening behavior for liver cancer among high-risk patients.

BACKGROUND: Little is known about physicians' screening patterns for liver cancer despite its rising incidence. OBJECTIVE: Describe physician factors associated with liver cancer screening. DESIGN: Mailed survey. PARTICIPANTS: Physicians practicing in family practice, internal medicine, gastroenterology, or nephrology in 3 northern California counties in 2004. MEASUREMENTS: Sociodemographic and practice measures, liver cancer knowledge, attitudes, and self-reported screening behaviors. RESULTS: The response rate was 61.8% (N = 459). Gastroenterologists (100%) were more likely than Internists (88.4%), family practitioners (84.2%), or nephrologists (75.0%) to screen for liver cancer in high-risk patients (p = 0.016). In multivariate analysis, screeners were more likely than nonscreeners to think that screening for liver cancer reduced mortality (odds ratio [OR] 1.60, CI 1.09-2.34) and that not screening was a malpractice risk (OR 1.88, CI 1.29-2.75). Screeners were more likely than nonscreeners to order any screening test if it was a quality of care measure (OR 4.39, CI 1.79-10.81). CONCLUSIONS: Despite debate about screening efficacy, many physicians screen for liver cancer. Their screening behavior is influenced by malpractice and quality control concerns. More research is needed to develop better screening tests for liver cancer, to evaluate their effectiveness, and to understand how physicians behave when there is insufficient evidence.

The unfolded protein response is an important regulator of inflammatory genes in endothelial cells.

OBJECTIVE: Oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycero-phosphorylcholine (oxPAPC) accumulates in atherosclerotic lesions and in vitro studies suggest that it mediates chronic inflammatory response in endothelial cells (ECs). The goal of our studies was to identify pathways mediating the induction of inflammatory genes by oxPAPC. METHODS AND RESULTS: Using expression arrays, quantitative polymerase chain reaction (PCR), and immunoblotting we demonstrate that oxPAPC leads to endoplasmic reticulum stress and activation of the unfolded protein response (UPR) in human aortic ECs. Immunohistochemistry analysis of human atherosclerotic lesions indicated that UPR is induced in areas containing oxidized phospholipids. Using the UPR inducing agent tunicamycin and selective siRNA targeting of the ATF4 and XBP1 branches of the UPR, we demonstrate that these transcription factors are essential mediators of IL8, IL6, and MCP1 expression in human aortic ECs required for maximal inflammatory gene expression in the basal state and after oxPAPC treatment. We also identify a novel oxPAPC-induced chemokine, the CXC motif ligand 3 (CXCL3), and show that its expression requires XBP1. CONCLUSIONS: These data suggest that the UPR pathway is a general mediator of vascular inflammation and EC dysfunction in atherosclerosis, and, likely, other inflammatory disorders.

Formative Evaluation of Participant Experience With Mobile eConsent in the App-Mediated Parkinson mPower Study: A Mixed Methods Study.

BACKGROUND: To fully capitalize on the promise of mobile technology to enable scalable, participant-centered research, we must develop companion self-administered electronic informed consent (eConsent) processes. As we do so, we have an ethical obligation to ensure that core tenants of informed consent-informedness, comprehension, and voluntariness-are upheld. Furthermore, we should be wary of recapitulating the pitfalls of "traditional" informed consent processes. OBJECTIVE: Our objective was to describe the essential qualities of participant experience, including delineation of common and novel themes relating to informed consent, with a self-administered, smartphone-based eConsent process. We sought to identify participant responses related to informedness, comprehension, and voluntariness as well as to capture any emergent themes relating to the informed consent process in an app-mediated research study. METHODS: We performed qualitative thematic analysis of participant responses to a daily general prompt collected over a 6-month period within the Parkinson mPower app. We employed a combination of a priori and emergent codes for our analysis. A priori codes focused on the core concepts of informed consent; emergent codes were derived to capture additional themes relating to self-administered consent processes. We used self-reported demographic information from the study's baseline survey to characterize study participants and respondents. RESULTS: During the study period, 9846 people completed the eConsent process and enrolled in the Parkinson mPower study. In total, 2758 participants submitted 7483 comments; initial categorization identified a subset of 3875 germane responses submitted by 1678 distinct participants. Respondents were more likely to self-report a Parkinson disease diagnosis (30.21% vs 11.10%), be female (28.26% vs 20.18%), be older (42.89 years vs 34.47 years), and have completed more formal education (66.23% with a 4-year college degree or more education vs 55.77%) than all the mPower participants (P<.001 for all values). Within our qualitative analysis, 3 conceptual domains emerged. First, consistent with fully facilitated in-person informed consent settings, we observed a broad spectrum of comprehension of core research concepts following eConsent. Second, we identified new consent themes born out of the remote mobile research setting, for example the impact of the study design on the engagement of controls and the misconstruction of the open response field as a method for responsive communication with researchers, that bear consideration for inclusion within self-administered eConsent. Finally, our findings highlighted participants' desire to be empowered as partners. CONCLUSIONS: Our study serves as a formative evaluation of participant experience with a self-administered informed consent process via a mobile app. Areas for future investigation include direct comparison of the efficacy of self-administered eConsent with facilitated informed consent processes, exploring the potential benefits and pitfalls of smartphone user behavioral habits on participant engagement in research, and developing best practices to increase informedness, comprehension, and voluntariness via participant coengagement in the research endeavor.

Lasting neuroendocrine-immune effects of traumatic brain injury in rats.

Traumatic brain injury (TBI) is a principal cause of long-term physical, cognitive, behavioral, and social deficits in young adults, which frequently coexist with a high incidence of substance abuse disorders. However, few studies have examined the long-term effects of TBI on the neuroendocrine-immune system. TBI was induced in adult male rats under isoflurane anesthesia by cortical contusion injury with a pneumatic piston positioned stereotaxically over the left parietal cortex. Controls underwent sham surgery without injury. At 4 weeks post-injury, the plasma corticosterone response to 30-min restraint stress was significantly blunted in TBI rats compared to the sham controls. One week later, transmitters were implanted for continuous biotelemetric recording of body temperature and spontaneous locomotor activity. At 6 weeks post-injury, the febrile response to i.p. injection of the bacterial endotoxin, lipopolysaccharide (LPS; 50 microg/kg), was significantly lower in TBI than in sham rats. At 8 weeks, swimming in the forced swim test was significantly less in TBI than sham rats. At 9 weeks, rats were rendered ethanol (EtOH) dependent by feeding an EtOH-containing liquid diet for 14 days. Cosine rhythmometry analysis of circadian body temperature Midline Estimating Statistic of Rhythm (MESOR), amplitudes, and acrophases indicated differential effects of EtOH and withdrawal in the two groups. Light- and dark-phase activity analysis indicated that TBI rats were significantly more active than the sham group, and that EtOH and withdrawal differentially affected their activity. Given the extensive interactions of the neuroendocrine-immune systems, these results demonstrate that TBI produces lasting dysregulation amidst the central substrates for allostasis and circadian rhythmicity.

Role of the 14-3-3 C-terminal loop in ligand interaction.

14-3-3 proteins are a family of conserved dimeric molecules that interact with a broad range of target proteins, most of which contain phosphoserine/threonine. The amphipathic groove of 14-3-3 is the main structural feature involved in mediating its associations. We have studied another domain of 14-3-3, the C-terminal loop, to determine what role it plays in ligand interaction. A truncated form of 14-3-3zeta lacking this C-terminal loop was generated and found to bind with higher affinity than the wild-type 14-3-3zeta protein to the ligands Raf-1 and Bad. Interestingly, the truncated 14-3-3zeta also showed increased association with the 14-3-3 binding-deficient Bad/S136A mutant. Taken together, these data support a role for the C-terminal loop as a general inhibitor of 14-3-3/ligand interactions. This may provide a mechanism by which inappropriate associations with 14-3-3 are prevented.

Tau overexpression impacts a neuroinflammation gene expression network perturbed in Alzheimer's disease.

Filamentous inclusions of the microtubule-associated protein, tau, define a variety of neurodegenerative diseases known as tauopathies, including Alzheimer's disease (AD). To better understand the role of tau-mediated effects on pathophysiology and global central nervous system function, we extensively characterized gene expression, pathology and behavior of the rTg4510 mouse model, which overexpresses a mutant form of human tau that causes Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We found that the most predominantly altered gene expression pathways in rTg4510 mice were in inflammatory processes. These results closely matched the causal immune function and microglial gene-regulatory network recently identified in AD. We identified additional gene expression changes by laser microdissecting specific regions of the hippocampus, which highlighted alterations in neuronal network activity. Expression of inflammatory genes and markers of neuronal activity changed as a function of age in rTg4510 mice and coincided with behavioral deficits. Inflammatory changes were tau-dependent, as they were reversed by suppression of the tau transgene. Our results suggest that the alterations in microglial phenotypes that appear to contribute to the pathogenesis of Alzheimer's disease may be driven by tau dysfunction, in addition to the direct effects of beta-amyloid.

11ß-hydroxysteroid dehydrogenase type 1 gene knockout attenuates atherosclerosis and in vivo foam cell formation in hyperlipidemic apoE⁻/⁻ mice.

BACKGROUND: Chronic glucocorticoid excess has been linked to increased atherosclerosis and general cardiovascular risk in humans. The enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD1) increases active glucocorticoid levels within tissues by catalyzing the conversion of cortisone to cortisol. Pharmacological inhibition of 11ßHSD1 has been shown to reduce atherosclerosis in murine models. However, the cellular and molecular details for this effect have not been elucidated. METHODOLOGY/PRINCIPAL FINDINGS: To examine the role of 11ßHSD1 in atherogenesis, 11ßHSD1 knockout mice were created on the pro-atherogenic apoE⁻/⁻ background. Following 14 weeks of Western diet, aortic cholesterol levels were reduced 50% in 11ßHSD1⁻/⁻/apoE⁻/⁻ mice vs. 11ßHSD1⁺/⁺/apoE⁻/⁻ mice without changes in plasma cholesterol. Aortic 7-ketocholesterol content was reduced 40% in 11ßHSD1⁻/⁻/apoE⁻/⁻ mice vs. control. In the aortic root, plaque size, necrotic core area and macrophage content were reduced ∼30% in 11ßHSD1⁻/⁻/apoE⁻/⁻mice. Bone marrow transplantation from 11ßHSD1⁻/⁻/apoE⁻/⁻ mice into apoE⁻/⁻ recipients reduced plaque area 39-46% in the thoracic aorta. In vivo foam cell formation was evaluated in thioglycollate-elicited peritoneal macrophages from 11ßHSD1⁺/⁺/apoE⁻/⁻ and 11ßHSD1⁻/⁻/apoE⁻/⁻ mice fed a Western diet for ∼5 weeks. Foam cell cholesterol levels were reduced 48% in 11ßHSD1⁻/⁻/apoE⁻/⁻ mice vs. control. Microarray profiling of peritoneal macrophages revealed differential expression of genes involved in inflammation, stress response and energy metabolism. Several toll-like receptors (TLRs) were downregulated in 11ßHSD1⁻/⁻/apoE⁻/⁻ mice including TLR 1, 3 and 4. Cytokine release from 11ßHSD1⁻/⁻/apoE⁻/⁻-derived peritoneal foam cells was attenuated following challenge with oxidized LDL. CONCLUSIONS: These findings suggest that 11ßHSD1 inhibition may have the potential to limit plaque development at the vessel wall and regulate foam cell formation independent of changes in plasma lipids. The diminished cytokine response to oxidized LDL stimulation is consistent with the reduction in TLR expression and suggests involvement of 11ßHSD1 in modulating binding of pro-atherogenic TLR ligands.

Control of keratinocyte proliferation and differentiation by p63.

The p53 family member p63 has been implicated in both the development and maintenance of stratified epithelial tissues, including the epidermis. Increasing data support p63 function in the regenerative capacity of basal keratinocytes by maintaining cell proliferation. Recent studies further suggest this regulation relies on inhibition of p53 activity. In addition, p63 appears to exert separate control over epidermal differentiation, which may involve control of such key signaling molecules as IKKalpha and Notch. While studies over the past decade have greatly expanded our knowledge of p63 function, much remains to be understood regarding how p63 regulates epidermal homeostasis. Future efforts to identify and validate direct p63 target genes as well as to understand the expression and function of individual p63 isoforms will be important to further define how p63 functions in the control of keratinocyte proliferation and differentiation.

A retrospective analysis of toxicogenomics in the safety assessment of drug candidates.

Toxicogenomics is considered a valuable tool for reducing pharmaceutical candidate attrition by facilitating earlier identification, prediction and understanding of toxicities. A retrospective evaluation of 3 years of routine transcriptional profiling in non-clinical safety studies was undertaken to assess the utility of toxicogenomics in drug safety assessment. Based on the analysis of studies with 33 compounds, marked global transcriptional changes (> 4% transcripts at p < 0.01) were shown to be a robust biomarker for dosages considered to be toxic . In general, there was an inconsistent correlation between transcription and histopathology, most likely due to differences in sensitivity to focal microscopic lesions, to secondary effects, and to events that precede structural tissue changes. For 60% of toxicities investigated with multiple time-point data, transcriptional changes were observed prior to changes in traditional study endpoints. Candidate transcriptional markers of pharmacologic effects were detected in 40% of targets profiled. Mechanistic classification of toxicity was obtained for 30% of targets. Furthermore, data comparison to compendia of transcriptional changes provided assessments of the specificity of transcriptional responses. Overall, our experience suggests that toxicogenomics has contributed to a greater understanding of mechanisms of toxicity and to reducing drug attrition by empiric analysis where safety assessment combines toxicogenomic and traditional evaluations.

p63 regulates proliferation and differentiation of developmentally mature keratinocytes.

p63 is a multi-isoform p53 family member required for epidermal development. Contrasting roles for p63 in either the initial commitment to the stratified epithelial cell fate or in stem cell-based self-renewal have been proposed. To investigate p63 function in a post-developmental context, we used siRNAs directed against p63 to down-regulate p63 expression in regenerating human epidermis. Loss of p63 resulted in severe tissue hypoplasia and inhibited both stratification and differentiation in a cell-autonomous manner. Although p63-deficient cells exhibited hypoproliferation, differentiation defects were not due to tissue hypoplasia. Simultaneous p63 and p53 knockdown rescued the cell proliferation defect of p63 knockdown alone but failed to restore differentiation, suggesting that defects in epidermal proliferation and differentiation are mediated via p53-dependent and -independent mechanisms, respectively. Furthermore, DeltaNp63 isoforms are the main mediators of p63 effects, although TAp63 isoforms may contribute to late differentiation. These data indicate that p63 is required for both the proliferative and differentiation potential of developmentally mature keratinocytes.

Identification of inflammatory gene modules based on variations of human endothelial cell responses to oxidized lipids.

Oxidized phospholipids are thought to promote atherogenesis by stimulating endothelial cells (ECs) to produce inflammatory cytokines, such as IL-8. In studies with mouse models, we previously demonstrated that genetic variation in inflammatory responses of endothelial cells to oxidized lipids contributes importantly to atherosclerosis susceptibility. We now show that similar variations occur in cultured aortic ECs derived from multiple heart transplant donors. These variations were stably maintained between passages and, thus, reflect either genetic or epigenetic regulatory differences. Expression array analysis of aortic EC cultures derived from 12 individuals revealed that >1,000 genes were regulated by oxidized phospholipids. We have used the observed variations in the sampled population to construct a gene coexpression network comprised of 15 modules of highly connected genes. We show that several identified modules are significantly enriched in genes for known pathways and confirm a module enriched for unfolded protein response (UPR) genes using siRNA and the UPR inducer tunicamycin. On the basis of the constructed network, we predicted that a gene of unknown function (MGC4504) present in the UPR module is a target for UPR transcriptional activator ATF4. Our data also indicate that IL-8 is present in the UPR module and is regulated, in part, by the UPR. We validate these by using siRNA. In conclusion, we show that interindividual variability can be used to group genes into pathways and predict gene-gene regulatory relationships, thus identifying targets potentially involved in susceptibility to common diseases such as atherosclerosis.