Th2 cell clonal expansion at diagnosis in human type 1 diabetes.

Soon after diagnosis with type 1 diabetes (T1D), many patients experience a period of partial remission. A longer partial remission is associated with a better response to treatment, but the mechanism is not known. The frequency of CD4+CD25+CD127hi (127-hi) cells, a cell subset with an anti-inflammatory Th2 bias, correlates positively with length of partial remission. The purpose of this study was to further characterize the nature of the Th2 bias in 127-hi cells. Single cell RNA sequencing paired with TCR sequencing of sorted 127-hi memory cells identifies clonally expanded Th2 clusters in 127-hi cells from T1D, but not from healthy donors. The Th2 clusters express GATA3, GATA3-AS1, PTGDR2, IL17RB, IL4R and IL9R. The existence of 127-hi Th2 cell clonal expansion in T1D suggests that disease factors may induce clonal expansion of 127-hi Th2 cells that prolong partial remission and delay disease progression.

Synthesis and Biological Evaluation of a Library of Sulfonamide Analogs of Memantine to Target Glioblastoma.

A library of 34 lipophilic sulfonamides based upon the memantine core has been synthesized to identify potential drug candidates to cross the blood-brain barrier and target glioblastoma. The library was screened for in vitro activity against 4 mammalian cell lines, including U-87 (glioblastoma). Additional synthetic variation of the active compounds has validated the importance of specific regions of the pharmacophore, with the sulfonamide functionality and S-aryl unit displaying the most significant impact. In silico investigations suggest the active compounds might target DDR1 or RET proteins. The investigation has resulted in several compounds that warrant further development for lead optimization.

Endogenous Aß peptide promote Aß oligomerization tendency of spiked synthetic Aß in Alzheimer's disease plasma.

Alzheimer's disease (AD) is the most common form of age-associated dementia. Several studies have predicted that AD is caused by the production and deposition of the ß-amyloid peptide (Aß) in the brain, which is one of pathologic hallmarks of AD. In particular, Aß oligomers are reportedly the most toxic and pathogenic of other peptide forms. We previously developed Multimer Detection System-Oligomeric Amyloid-ß (MDS-OAß), a technique for measuring Aß oligomerization in plasma to diagnose AD. Here, we clarified the molecular sizes of oligomers that can be detected by the MDS and investigated differences in plasma spiking with a synthetic Aß peptide in the plasma of AD patients and individuals with non-AD neurological conditions. To determine Aß oligomer sizes detectable by MDS, size exclusion chromatography (SEC) was first performed on incubated samples of synthetic Aß42 peptides. As a result, no MDS signals were observed for the Aß42 monomer fractions, but strong signals were found for oligomers of 7-35-mers long. Also, an amplified luminescent proximity homogeneous assay-linked immunoassay (AlphaLISA) was used to confirm that synthetic Aß peptides not only recruited endogenous Aß in plasma but also induced significantly stronger seeding in AD plasma than in healthy control plasma. In addition, the absence of the MDS signals in Aß-depleted plasma confirmed that the increased oligomerization tendency in AD plasma is dependent on the presence of endogenous Aß in plasma. Therefore, the MDS-OAß measurement of oligomerization differences in plasma after incubation with spiked synthetic Aß peptides has significant potential in AD diagnosis.

Measurement of Exciton and Trion Energies in Multistacked hBN/WS2 Coupled Quantum Wells for Resonant Tunneling Diodes.

Quantum confinements, especially quantum in narrow wells, have been investigated because of their controllability over electrical parameters. For example, quantum dots can emit a variety of photon wavelengths even for the same material depending on their particle size. More recently, the research into two-dimensional (2D) materials has shown the availability of several quantum mechanical phenomenon confined within a sheet of materials. Starting with the gapless semimetal properties of graphene, current research has begun into the excitons and their properties within 2D materials. Even for simple 2D systems, experimental results often offer surprising results, unexpected from traditional studies. We investigated a coupled quantum well system using 2D hexagonal boron nitride (hBN) barrier as well as 2D tungsten disulfide (WS2) semiconductor arranged in stacked structures to study the various 2D to 2D interactions. We determined that for hexagonal boron nitride-tungsten disulfide (hBN/WS2) quantum well stacks, the interaction between successive wells resulted in decreasing bandgap, and the effect was pronounced even over a large distance of up to four stacks. Additionally, we observed that a single layer of isolating hBN barriers significantly reduces interlayer interaction between WS2 layers, while still preserving the interwell interactions in the alternative hBN/WS2 structure. The methods we used for the study of coupled quantum wells here show a method for determining the respective exciton energy levels and trion energy levels within 2D materials and 2D materials-based structures. Renormalization energy levels are the key in understanding conductive and photonic properties of stacked 2D materials.

Social determinants of health score: does it help identify those at higher cardiovascular risk?

OBJECTIVES: Cardiovascular disease (CVD) continues to disproportionately affect disadvantaged populations, leading to calls to address social determinants of health (SDOH) as a preventive strategy. Our aim is to create a weighed SDOH score and to test the impact of each SDOH factor on the Framingham risk score (FRS) and on individual traditional CVD risk factors. STUDY DESIGN: We conducted a retrospective cohort study. METHODS: We included patients seen at a primary care clinic at UHealth/University of Miami Health System who answered a SDOH survey between September 16, 2016, and September 10, 2017. The survey included SDOH domains recommended by the American Heart Association position statement and by the National Academy of Medicine. We selected the FRS as well as all traditional CVD risk factors as our outcome metrics. RESULTS: We included 2876 patients. The mean (SD) age of our cohort was 53.8 (15.8) years, 61% were female, 9% were Black, 38% were Hispanic, and 87% reported speaking English. The statistically significant ß coefficients in the FRS model corresponded to being born outside of the United States, being a racial minority, living alone, having a high social isolation score, and having a low geocoded median household income (P < .01). Increasing quartile of SDOH score was significantly associated with higher systolic blood pressure, FRS, glycated hemoglobin, and smoking pack-years (P < .05). It was also associated with fewer minutes spent exercising weekly (P < .01). CONCLUSIONS: The addition of self-reported SDOH data has a dose effect on CVD risk factors. Future studies should address how to intervene to address social factors.

A Novel Interdisciplinary Iterative Approach for Optimizing the Electronic Health Record to Improve Perioperative Efficiency.

OBJECTIVE: We present a holistic perioperative optimization approach led by a CI team with the goal to optimize the workflow within our EHR, improve operative room metrics and user satisfaction. SUMMARY OF BACKGROUND DATA: The EHR has become integral to perioperative care. Many approaches are utilized to improve performance including systems-based approaches, process redesign, lean methodology, checklists, root cause analysis, and parallel processing. Although most reports describe strategies improving day or surgery productivity, few include perioperative interventions to improve efficiencies. METHODS: An interdisciplinary CI team consisting of clinicians, informatics specialists, and analysts spent 6 weeks assessing users and optimizing all perioperative areas (scheduling, day of surgery, postop discharge/admission). Elbow-to-elbow retraining and simultaneous content development was performed utilizing an Agile workflow process optimization with the Scrum framework. This iterative approach averaged 1 week from build to change implementation. Pre/post optimization surveys were sent. RESULTS: Two hundred forty-two perioperative enhancements were completed. While most impacted documentation, all areas were enhanced including billing, reporting, registration, device integration, scheduling, central supply, and so on. FCOTS improved from <70% to >85% and total delay was halved. These parameters were consistently sustained for over 1 year after the 6-week optimization. While only 5% of pre-optimization users agreed to proficiency in the EHR system, this improved to 70% post-optimization. Furthermore, EHR confidence and acceptance improved from 40% to 90%. CONCLUSIONS: To improve workflow efficiency, all who contribute to the perioperative process must be assessed. This IT driven initiative resulted in improved FCOTS, perioperative workflows, and user satisfaction.

Association of Plasma Oligomerized Beta Amyloid with Neurocognitive Battery Using Korean Version of Consortium to Establish a Registry for Alzheimer's Disease in Health Screening Population.

The increasing prevalence of Alzheimer's disease (AD) has become a global phenomenon presenting serious social and health challenges. For detecting early molecular changes in the disease, several techniques to measure varied species of amyloid beta in the peripheral blood have been recently developed, but the efforts to associate them with cognitive assessments have yet to produce sufficient data. We prospectively collected participants from the consecutive population who visited our center for brain health screening. In total, 97 participants (F:M = 58:39) aged 69.4 ± 7.52 were assessed. Participants performed the Korean version of the Consortium to Establish a Registry for Alzheimer's disease (CERAD-K), the clinical dementia rating (CDR), plasma oligomeric amyloid-ß (OAß) level tests, routine blood tests, ApoE genotype, and brain MRI. Among total population, 55.7% had a CDR of 0, and 40.2% had a CDR of 0.5. The results showed that word memory and word recall, and the total scores of the CERAD-K were negatively correlated with the plasma OAß level. With a cut-off value of 0.78 ng/mL for the OAß level and a -1.5 standard deviation of age/sex/education adjusted norms for the CERAD-K; naming, word memory, word recall, word recognition, and total score were significantly correlated with the OAß level. No correlation between the OAß level and mini-mental status examination was found. Our results demonstrate that the level of plasma OAß was well correlated with the measure of cognitive function through the CERAD-K in the field data collected from consecutive populations. Studies on longitudinal comparisons with large cohorts will further validate the diagnostic value of plasma OAß as a useful biomarker for screening AD and predicting progression.

Superior semicircular canal dehiscence postoperative outcomes: A case series of 156 repairs.

Previous studies have looked at differences in predisposing factors, symptomology, treatment options, and outcomes in patients with SSCD experiencing audiologic and vestibular symptoms, however this study utilizes data from the largest series of SSCD patients by a single pair of neurosurgeon and head and neck surgeon to date. The objective was to determine what pre-operative factors, if any, contribute to post-operative outcomes in SSCD patients. A retrospective chart review collected patient demographics, preoperative symptoms, and postoperative symptoms. Nonparametric tests were run using IBM® SPSS® Statistics. Fisher's Exact Tests, Spearman's rho, and McNemar's test for paired comparison of binary measures were performed, with a significance level of P < 0.05. A total of 156 SSCD surgeries were performed within a cohort of 119 patients. The majority of patients were female (n = 75, 63.0%). The median age was 55 years (±12.7 years) and median follow-up length was 0.46 months (range: 0.03-59.5 months). Increased postoperative dizziness and hearing loss was significantly correlated with females (P = .048, P = .041). Additionally, males reported significantly improved postoperative hearing (P = .044) with confirmatory audiometry. Serum ionized calcium levels inversely correlated with age using spearman's coefficient (rs = -.260 P = .037). Postsurgical autophony was significantly associated with bilateral SSCD (P = .01). In conclusion, differences in outcomes between patients may have to do with bilateralism of SSCD or gender effects. Proposed theories concerning a "two hit" hypothesis and about calcium feedback regulation in SSCD may play a role in these findings. Understanding differences between symptomology will help facilitate discussions with future patients.

Sealing of superior semicircular canal dehiscence is associated with improved balance outcomes postoperatively versus plugging of the canal in middle fossa craniotomy repairs: a case series.

OBJECTIVE: The authors compared postoperative symptoms between patients with sealed and those with plugged semicircular canal dehiscence repairs. METHODS: In total, 136 ears from 118 patients who underwent surgical repair for semicircular canal dehiscence were identified via chart review. Data from postoperative MRI scans showing preservation or loss of semicircular canal fluid signal and postoperative reports of autophony, amplification, aural fullness, tinnitus, hyperacusis, hearing loss, vertigo, dizziness, disequilibrium, oscillopsia, and headache were amalgamated and analyzed. RESULTS: Patients with preservation of fluid signal were far less likely to have dizziness postoperatively (p = 0.007, OR 0.158, 95% CI 0.041-0.611). In addition, these patients were more likely to have tinnitus postoperatively (p = 0.028, OR 3.515, 95% CI 1.145-10.787). CONCLUSIONS: The authors found that superior semicircular canal dehiscence patients who undergo sealing without plugging have improved balance outcomes but show more tinnitus postoperatively than patients who undergo plugging.

Reliable Multivalued Conductance States in TaO x Memristors through Oxygen Plasma-Assisted Electrode Deposition with in Situ-Biased Conductance State Transmission Electron Microscopy Analysis.

Transition metal oxide-based memristors have widely been proposed for applications toward artificial synapses. In general, memristors have two or more electrically switchable stable resistance states that device researchers see as an analogue to the ion channels found in biological synapses. The mechanism behind resistive switching in metal oxides has been divided into electrochemical metallization models and valence change models. The stability of the resistance states in the memristor vary widely depending on: oxide material, electrode material, deposition conditions, film thickness, and programming conditions. So far, it has been extremely challenging to obtain reliable memristors with more than two stable multivalued states along with endurances greater than ∼1000 cycles for each of those states. Using an oxygen plasma-assisted sputter deposition method of noble metal electrodes, we found that the metal-oxide interface could be deposited with substantially lower interface roughness observable at the nanometer scale. This markedly improved device reliability and function, allowing for a demonstration of memristors with four completely distinct levels from ∼6 × 10-6 to ∼4 × 10-8 S that were tested up to 104 cycles per level. Furthermore through a unique in situ transmission electron microscopy study, we were able to verify a redox reaction-type model to be dominant in our samples, leading to the higher degree of electrical state controllability. For solid-state synapse applications, the improvements to electrical properties will lead to simple device structures, with an overall power and area reduction of at least 1000 times when compared to SRAM.

Provider Perspectives on the Collection of Social Determinants of Health.

Social determinants of health (SDH) impact health outcomes. Medical centers have begun to collect SDH data, urged by government and scientific entities. Provider perspectives on collecting SDH are unknown. The aim is to understand differences in views and preferences according to provider characteristics. A cross-sectional survey of University of Miami clinical faculty was conducted in late 2016. The survey contained 11 questions: 8 demographic and departmental responsibilities questions and 3 Likert scale questions to capture collection and use of SDH perspectives. The main outcome was whether providers thought the benefit of collecting SDH outweighs the burden and risks. In all, 240 faculty members were included. The majority were men (64%), with a mean age of 51 years. Among participants, 53.5% were non-Hispanic white, 32% were Hispanic, 5% were Black/African American, and 5% were Asian. The majority agreed that SDH are important predictors of health outcomes and quality of care (83%). When comparing minority to nonminority faculty, 25% believed that SDH should only be available to PCPs, compared to 8% of nonminorities (P < 0.01). In a multivariate model, belonging to a racial ethnic minority was the only characteristic associated with believing that benefits of collecting SDH outweigh the risks (odds ratio 1.87, 95% confidence interval 1.02- 3.5) after adjusting for age, sex, minority status, health care provider type, type of responsibilities, and department. This study reveals that although most providers of a health system believe social risks impact health outcomes and quality metrics, the buy-in to collect SDH varies according to the racial/ethnic composition of the faculty.

Coronary collateralization shows sex and racial-ethnic differences in obstructive artery disease patients.

BACKGROUND: Coronary collateral circulation protects cardiac tissues from myocardial infarction damage and decreases sudden cardiac death. So far, it is unclear how coronary collateralization varies by race-ethnicity groups and by sex. METHODS: We assessed 868 patients with obstructive CAD. Patients were assessed for collateral grades based on Rentrop grading system, as well as other covariates. DNA samples were genotyped using the Affymetrix 6.0 genotyping array. To evaluate genetic contributions to collaterals, we performed admixture mapping using logistic regression with estimated local and global ancestry. RESULTS: Overall, 53% of participants had collaterals. We found difference between sex and racial-ethnic groups. Men had higher rates of collaterals than women (P-value = 0.000175). White Hispanics/Latinos showed overall higher rates of collaterals than African Americans and non-Hispanic Whites (59%, 50% and 48%, respectively, P-value = 0.017), and especially higher rates in grade 1 and grade 3 collateralization than the other two populations (P-value = 0.0257). Admixture mapping showed Native American ancestry was associated with the presence of collaterals at a region on chromosome 17 (chr17:35,243,142-41,251,931, ß = 0.55, P-value = 0.000127). African ancestry also showed association with collaterals at a different region on chromosome 17 (chr17: 32,266,966-34,463,323, ß = 0.38, P-value = 0.00072). CONCLUSIONS: In our study, collateralization showed sex and racial-ethnic differences in obstructive CAD patients. We identified two regions on chromosome 17 that were likely to harbor genetic variations that influenced collateralization.

Teratomas of the cranial vault: a systematic analysis of clinical outcomes stratified by histopathological subtypes.

BACKGROUND: Teratomas of the cranial vault are divided into histopathological subtypes and grouped by prognoses: mature (good prognosis), mixed/malignant and immature teratomas (intermediate prognosis). This schema also includes non-teratomatous tumors. The authors of this study sought to elucidate histologically dependent predictors of survival and further clarify the classification system of intracranial teratomas. METHODS: We performed a systematic analysis of the published literature to identify studies describing patients with intracranial teratomas diagnosed with magnetic resonance imaging (MRI) and presenting definite information on histologies, therapies, and outcomes at a minimum follow-up of 2 years. Disease-free (DFS) and overall survival (OS) were evaluated. RESULTS: A total of 18 articles comprised of 134 patients were included. On univariate analysis, male sex and gross-total resection (GTR) were associated with high mean DFS (p = 0.0362 and p < 0.0001, respectively). On multivariate analysis, mature teratomas located in the pineal, and those having undergone subtotal resection (STR) demonstrated high mean OS (p = 0.0023 and p = 0.0044, respectively). Mature and mixed/malignant suprasellar teratomas had equally higher mean OS versus immature suprasellar teratomas (p < 0.0001). Mature and immature teratomas treated with adjuvant therapy had significantly higher mean OS compared to those managed with surgery alone (p = 0.0421 and p = 0.0423, respectively). Males with immature teratomas had the highest mean OS (p < 0.0001). Immature teratomas managed with surgery alone had higher mean DFS, but lower mean OS, compared to those treated with adjuvant therapy (p = 0.0176 and p = 0.0423, respectively). CONCLUSIONS: Our data highlight the divergent nature of the different histopathological subtypes of teratomas, and suggest that survival outcomes are multifactorial. Specifically, male sex, pineal, suprasellar, GTR, and STR were dependent predictors of OS, while histopathology was an independent predictor of OS.

Central Neurocytoma: A Review of Clinical Management and Histopathologic Features.

Central neurocytoma (CN) is a rare, benign brain tumor often located in the lateral ventricles. CN may cause obstructive hydrocephalus and manifest as signs of increased intracranial pressure. The goal of treatment for CN is a gross total resection (GTR), which often yields excellent prognosis with a very high rate of tumor control and survival. Adjuvant radiosurgery and radiotherapy may be considered to improve tumor control when GTR cannot be achieved. Chemotherapy is also not considered a primary treatment, but has been used as a salvage therapy. The radiological features of CN are indistinguishable from those of other brain tumors; therefore, many histological markers, such as synaptophysin, can be very useful for diagnosing CNs. Furthermore, the MIB-1 Labeling Index seems to be correlated with the prognosis of CN. We also discuss oncogenes associated with these elusive tumors. Further studies may improve our ability to accurately diagnose CNs and to design the optimal treatment regimens for patients with CNs.

Enhancement of resistive switching under confined current path distribution enabled by insertion of atomically thin defective monolayer graphene.

Resistive random access memory (ReRAM) devices have been extensively investigated resulting in significant enhancement of switching properties. However fluctuations in switching parameters are still critical weak points which cause serious failures during 'reading' and 'writing' operations of ReRAM devices. It is believed that such fluctuations may be originated by random creation and rupture of conducting filaments inside ReRAM oxides. Here, we introduce defective monolayer graphene between an oxide film and an electrode to induce confined current path distribution inside the oxide film, and thus control the creation and rupture of conducting filaments. The ReRAM device with an atomically thin interlayer of defective monolayer graphene reveals much reduced fluctuations in switching parameters compared to a conventional one. Our results demonstrate that defective monolayer graphene paves the way to reliable ReRAM devices operating under confined current path distribution.

Cardiac performance, biomarkers and gene expression studies in previously sedentary men participating in half-marathon training.

BACKGROUND: The mechanisms through which exercise reduces cardiovascular disease are not fully understood. We used echocardiograms, cardiac biomarkers and gene expression to investigate cardiovascular effects associated with exercise training. METHODS: Nineteen sedentary men (22-37 years) completed a 17-week half-marathon training program. Serial measurements of resting heart rate, blood pressure, maximum oxygen consumption, lipids, C-reactive protein, cardiac troponin T, echocardiograms and blood for gene expression were obtained from baseline to peak training. Controls included 22 sedentary men who did not exercise. RESULTS: Among the training group, VO2 max increased from 37.1 to 42.0 ml/kg/min (p < 0.001). Significant changes were seen in left ventricular wall thickness and mass, stroke volume, resting heart rate and blood pressure (p < 0.001). The control group demonstrated no significant changes. Expression profiling in the training group identified 10 significantly over-expressed and 53 significantly under-expressed loci involved in inflammatory pathways. Dividing the training group into high and low responders based on percent change in VO2 max identified loci that differentiated these two groups at baseline and after training. CONCLUSION: Intensive exercise training leads to significant increase in cardiac and hemodynamic performance, and significant changes in expression of genes involved in immune and inflammatory response.

Impact of CMS coverage decision on access to transcatheter aortic valve replacement.

OBJECTIVES: To assess the impact of the Centers for Medicare and Medicaid Services (CMS) national coverage determination (NCD) on access for patients with aortic stenosis (AS) with transcatheter aortic valve replacement (TAVR) in a tertiary care center. BACKGROUND: TAVR has given hope to patients with AS who are deemed inoperable. The effects of the NCD on access to patients with AS has not been evaluated. MATERIALS AND METHODS: A total of 94 inoperable AS patients were evaluated and treated from December 2011 through June of 2012 with TAVR. Patients who underwent transfemoral (TF) vs. non-TF access were compared. The CMS NCD was released on May 1, 2012 and on July 1, 2012, the nontransfemoral access program was put on hold due to lack of reimbursement. RESULTS: Patients in the TF (n = 33) and non-TF access (n = 61) groups were similar in age (85.2 ± 6.3 vs. 84.8 ± 6.6 P = 0.74) and STS mortality (9.38 ± 5.33 vs. 7.91 ± 3.69, P = 0.074). The iliofemoral arteries were larger diameter in the TF group (7.72 ± 1.49 vs. 6.21 ± 1.78, P < 0.001) and males (7.39 ± 1.81 vs. 6.1 ± 1.61 P < 0.001). More women underwent valve implantation via non-TF access (73 vs. 23%, P = 0.03). After the NCD, 21 patients who previously qualified for non-TF TAVR would not be reimbursed by CMS. Four died soon after. CONCLUSIONS: After the NCD, the proportion of inoperable patients with severe AS that can be treated with TAVR was greatly reduced due the lack of reimbursement for TAVR via non-TF access. This effect is particularly pronounced in women. © 2014 Wiley Periodicals, Inc.

A plasma-treated chalcogenide switch device for stackable scalable 3D nanoscale memory.

Stackable select devices such as the oxide p-n junction diode and the Schottky diode (one-way switch) have been proposed for non-volatile unipolar resistive switching devices; however, bidirectional select devices (or two-way switch) need to be developed for bipolar resistive switching devices. Here we report on a fully stackable switching device that solves several problems including current density, temperature stability, cycling endurance and cycle distribution. We demonstrate that the threshold switching device based on As-Ge-Te-Si material significantly improves cycling endurance performance by reactive nitrogen deposition and nitrogen plasma hardening. Formation of the thin Si3N4 glass layer by the plasma treatment retards tellurium diffusion during cycling. Scalability of threshold switching devices is measured down to 30 nm scale with extremely fast switching speed of ~2 ns.

Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis.

Smooth muscle cell (SMC) proliferation is a hallmark of vascular injury and disease. Global hypomethylation occurs during SMC proliferation in culture and in vivo during neointimal formation. Regardless of the programmed or stochastic nature of hypomethylation, identifying these changes is important in understanding vascular disease, as maintenance of a cells' epigenetic profile is essential for maintaining cellular phenotype. Global hypomethylation of proliferating aortic SMCs and concomitant decrease of DNMT1 expression were identified in culture during passage. An epigenome screen identified regions of the genome that were hypomethylated during proliferation and a region containing Collagen, type XV, alpha 1 (COL15A1) was selected by 'genomic convergence' for characterization. COL15A1 transcript and protein levels increased with passage-dependent decreases in DNA methylation and the transcript was sensitive to treatment with 5-Aza-2'-deoxycytidine, suggesting DNA methylation-mediated gene expression. Phenotypically, knockdown of COL15A1 increased SMC migration and decreased proliferation and Col15a1 expression was induced in an atherosclerotic lesion and localized to the atherosclerotic cap. A sequence variant in COL15A1 that is significantly associated with atherosclerosis (rs4142986, P = 0.017, OR = 1.434) was methylated and methylation of the risk allele correlated with decreased gene expression and increased atherosclerosis in human aorta. In summary, hypomethylation of COL15A1 occurs during SMC proliferation and the consequent increased gene expression may impact SMC phenotype and atherosclerosis formation. Hypomethylated genes, such as COL15A1, provide evidence for concomitant epigenetic regulation and genetic susceptibility, and define a class of causal targets that sit at the intersection of genetic and epigenetic predisposition in the etiology of complex disease.