Medicine and Health Sciences Commons^™

Schizophrenia In Digeorge Syndrome: A Unique Case Report, Sukaina Rizvi, Ali M. Khan, Hina Saeed, Akeem M. Aribara, Alexis Carrington, Alexa Griffiths, Abdul Mohit

School of Medicine Publications

Herein we present the unique case of a 21-year-old African American woman who presented with psychotic features and the incidental finding of basal ganglia calcifications on computed tomography (CT) scan of the head. She was initially presumed to have Fahr’s syndrome in the context of idiopathic bilateral basal ganglia calcifications and psychotic features. Genetic testing performed revealed the deletion of 22q11.2, thus establishing the diagnosis of DiGeorge syndrome. This case highlights the importance of noticing subtle physical exam findings along with laboratory findings as this led to the diagnosis of DiGeorge syndrome for this patient. This case is unique in …

Adding Psychotherapy To The Naltrexone Treatment Of Alcohol Use Disorder: Metaanalytic Review, Rizwan A. Ahmed, Vijaya P. Kotapati, Ali M. Khan, Nuzhat Hussain, Mudasar Hussain, Sara Dar, Jeevan Kumar, Gulshan A. Begum, Michael Esang, Navjot Brainch, Saeed Ahmed

School of Medicine Publications

Background

It remains unclear if naltrexone combined with psychotherapy is superior to naltrexone alone in treating alcohol use disorders (AUD). The current meta-analysis examined the hypothesis that psychotherapy is a significant moderator that influences AUD-related outcomes and that naltrexone combined with psychotherapy is associated with significantly better AUD-related outcomes than naltrexone alone.

Methods

A total of 30 studies (Nnaltrexone = 2317; Nplacebo = 2056) were included. Random effects model meta-analyses were carried out for each of the studied outcomes. Subsequently, the random effects model pooled estimates from studies with and without psychotherapy were compared using a Wald test. A mixed-effect …

Deep-Coverage Whole Genome Sequences And Blood Lipids Among 16,324 Individuals, Pradeep Natarajan, Gina M. Peloso, Seyedeh M. Zekavat, May Montasser, Andrea Ganna, Mark Chaffin, Amit V. Khera, John Blangero, Joanne E. Curran, Michael C. Mahaney

School of Medicine Publications

Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits—plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among …

Transcriptomic Signatures Of Schizophrenia Revealed By Dopamine Perturbation In An Ex Vivo Model, Jubao Duan, Harald Hh Goring, Alan R. Sanders, Winton Moy, Jessica Freda, Eugene I. Drigalenko, Mark Z. Kos, Deli He, Pablo V. Gejman

School of Medicine Publications

The dopaminergic hypothesis of schizophrenia (SZ) postulates that dopaminergic over activity causes psychosis, a central feature of SZ, based on the observation that blocking dopamine (DA) improves psychotic symptoms. DA is known to have both receptor- and non-receptor-mediated effects, including oxidative mechanisms that lead to apoptosis. The role of DA-mediated oxidative processes in SZ has been little studied. Here, we have used a cell perturbation approach and measured transcriptomic profiles by RNAseq to study the effect of DA exposure on transcription in B-cell transformed lymphoblastoid cell lines (LCLs) from 514 SZ cases and 690 controls. We found that DA had …

Traf3ip2 Mediates Tweak/Tweakr-Induced Pro-Fibrotic Responses In Cultured Cardiac Fibroblasts And The Heart, Nitin A. Das, Andrea J. Carpenter, Tadashi Yoshida, Senthil A. Kumar, Sandeep Gautam, Ricardo Mostany, Reza Izadpanah, Ashok Kumar, Srinivas Mummidi, Ulrich Siebenlist, Bysani Chandrasekar

School of Medicine Publications

Persistent inflammation promotes development and progression of heart failure (HF). TWEAK (TNF-Related WEAK Inducer Of Apoptosis), a NF-κB- and/or AP-1-responsive proinflammatory cytokine that signals via TWEAK receptor (TWEAKR), is expressed at high levels in human and preclinical models of HF. Since the adapter molecule TRAF3IP2 (TRAF3 Interacting Protein 2) is an upstream regulator of various proinflammatory pathways, including those activated by NF-κB and AP-1, we hypothesized that targeting TRAF3IP2 inhibits TWEAK-induced proinflammatory and pro-fibrotic responses in vitro and in vivo. Consistent with the hypothesis, forced expression of TRAF3IP2 upregulated TWEAK and its receptor expression in cultured adult mouse cardiac fibroblasts …

Chelation Therapy To Prevent Diabetes-Associated Cardiovascular Events, Denisse Diaz, Vivian Fonseca, Y. Wady Aude, Gervasio A. Lamas

School of Medicine Publications

Purpose of review

For over 60 years, chelation therapy with disodium ethylene diamine tetraacetic acid (EDTA, edetate) had been used for the treatment of cardiovascular disease (CVD) despite lack of scientific evidence for efficacy and safety. The Trial to Assess Chelation Therapy (TACT) was developed and received funding from the National Institutes of Health (NIH) to ascertain the safety and efficacy of chelation therapy in patients with CVD.

Recent findings

This pivotal trial demonstrated an improvement in outcomes in postmyocardial infarction (MI) patients. Interestingly, it also showed a particularly large reduction in CVD events and all-cause mortality in the prespecified …

Feasibility Study Of A Cell Phone Intervention To Promote Mental Health Among Deported Mexican Migrants, Letza Bojorquez, Rosa María Aguilera-Guzmán, Adrián Aguilera, Silvia Mejia-Arango

School of Medicine Publications

No abstract provided.

The Chloroplast Division Protein Arc6 Acts To Inhibit Disassembly Of Gdp-Bound Ftsz2, Min Woo Sung, Rahamthulla Shaik, Allan D. Terbush, Katherine W. Osteryoung, Stanislav Vitha, Andreas Holzenburg

School of Medicine Publications

Chloroplasts host photosynthesis and fulfill other metabolic functions that are essential to plant life. They have to divide by binary fission to maintain their numbers throughout cycles of cell division. Chloroplast division is achieved by a complex ring-shaped division machinery located on both the inner (stromal) and the outer (cytosolic) side of the chloroplast envelope. The inner division ring (termed the Z ring) is formed by the assembly of tubulin-like FtsZ1 and FtsZ2 proteins. ARC6 is a key chloroplast division protein that interacts with the Z ring. ARC6 spans the inner envelope membrane, is known to stabilize or maintain the …

Visual Cycle Proteins: Structure, Function, And Roles In Human Retinal Disease, Andrew T C Tsin, Brandi Betts-Obregon, Jeffery Grigsby

School of Medicine Publications

Here, we seek to summarize the current understanding of the biochemical and molecular events mediated by visual cycle molecules in the eye. The structures and functions of selected visual cycle proteins and their roles in human retinal diseases are also highlighted. Genetic mutations and malfunctions of these proteins provide etiological evidence that many ocular diseases arise from anomalies of retinoid (vitamin A) metabolism and related visual processes. Genetic retinal disorders such as retinitis pigmentosa, Leber's congenital amaurosis, and Stargardt's disease are linked to structural changes in visual cycle proteins. Moreover, recent reports suggest that visual cycle proteins may also play …

Whole Genome Sequencing Of 91 Multiplex Schizophrenia Families Reveals Increased Burden Of Rare, Exonic Copy Number Variation In Schizophrenia Probands And Genetic Heterogeneity, Fayeza F. Khan, Phillip E. Melton, Nina S. Mccarthy, Bharti Morar, John Blangero, Eric K. Moses, Assen Jablensky

School of Medicine Publications

The importance of genomic copy number variants (CNVs) has long been recognized in the etiology of neurodevelopmental diseases. We report here the results from the CNV analysis of whole-genome sequences from 91 multiplex schizophrenia families. Employing four algorithms (CNVnator, Cn.mops, DELLY and LUMPY) to identify CNVs, we find 1231 rare deletions and 287 rare duplications in 300 individuals (77 with schizophrenia (SZ), 32 with schizoaffective disorder (SAD), 82 with another neuropsychiatric diagnosis and 109 unaffected). The size of the CNVs ranges from a few hundred base-pairs to about 1.3Mb. The total burden of CNVs does not differ significantly between affected …

American Thyroid Association Statement On Postoperative Hypoparathyroidism: Diagnosis, Prevention, And Management In Adults, Lisa A. Orloff, Sam M. Wiseman, Victor J. Bernet., Thomas J. Fahey Iii, Ashok R. Shaha, Maisie L. Shindo, Samuel K. Snyder, Brendan C. Stack Jr., John B. Sunwoo, Marilene B. Wang

School of Medicine Publications

Background: Hypoparathyroidism (hypoPT) is the most common complication following bilateral thyroid operations. Thyroid surgeons must employ strategies for minimizing and preventing post-thyroidectomy hypoPT. The objective of this American Thyroid Association Surgical Affairs Committee Statement is to provide an overview of its diagnosis, prevention, and treatment.

Summary: HypoPT occurs when a low intact parathyroid hormone (PTH) level is accompanied by hypocalcemia. Risk factors for post-thyroidectomy hypoPT include bilateral thyroid operations, autoimmune thyroid disease, central neck dissection, substernal goiter, surgeon inexperience, and malabsorptive conditions. Medical and surgical strategies to minimize perioperative hypoPT include optimizing vitamin D levels, preserving parathyroid blood supply, and …

Epidermal-Specific Deletion Of Tc-Ptp Promotes Uvb-Induced Epidermal Cell Survival Through The Regulation Of Flk-1/Jnk Signaling, Minwoo Baek, Mihwa Kim, Jae Sung Lim, Liza D. Morales, Joselin Hernandez, Srinivas Mummidi, Sarah Williams-Blangero, Ik-Soon Jang, Andrew Tsin, Dae Joon Kim

School of Medicine Publications

UVB exposure can contribute to the development of skin cancer by modulating protein tyrosine kinase (PTK) signaling. It has been suggested that UVB radiation increases the ligand-dependent activation of PTKs and induces PTP inactivation. Our recent studies have shown that T-cell protein tyrosine phosphatase (TC-PTP) attenuates skin carcinogenesis induced by chemical regimens, which indicates its critical role in the prevention of skin cancer. In the current work, we report that TC-PTP increases keratinocyte susceptibility to UVB-induced apoptosis via the downregulation of Flk-1/JNK signaling. We showed that loss of TC-PTP led to resistance to UVB-induced apoptosis in vivo epidermis. We established …

Pegylation Of Polypropylenimine Dendrimers: Effects On Cytotoxicity, Dna Condensation, Gene Delivery And Expression In Cancer Cells, Sukrut Somani, Partha Laskar, Najla Altwaijry, Paphitchaya Kewcharoenvong, Craig Irving, Gillian Robb, Benjamin S. Pickard, Christine Dufès

School of Medicine Publications

Diaminobutyric polypropylenimine (DAB) dendrimers have been shown to be highly efficient non-viral gene delivery systems for cancer therapy. However, their cytotoxicity currently limits their applications. To overcome this issue, PEGylation of DAB dendrimer, using various PEG molecular weights and dendrimer generations, has been attempted to decrease the cytotoxicity and enhance the DNA condensation, size and zeta potential, cellular uptake and transfection efficacy of these dendriplexes. Among all the PEGylated dendrimers synthesized, generation 3- and generation 4-DAB conjugated to low molecular weight PEG (2 kDa) at a dendrimer: DNA ratio of 20:1 and 10:1 resulted in an increase in gene expression …

Genomic Dissection Of Bipolar Disorder And Schizophrenia, Including 28 Subphenotypes, Douglas M. Ruderfer, Stephan Ripke, Andrew Mcquillin, James Boocock, Ney Alliey Rodriguez

School of Medicine Publications

Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several …

Glaucomatous Optic Neuropathy Associated With Nocturnal Dip In Blood Pressure: Findings From The Maracaibo Aging Study, Jesus D. Melgarejo, Joseph H. Lee, Michele Petitto, Juan B. Yepez, Felipe A. Murati, Zhezhen Jin, Carlos A. Chavez, Rosa V. Pirela, Gustavo E. Calmon, Matthew P. Johnson, Gladys E. Maestre

School of Medicine Publications

Purpose—To determine which nocturnal blood pressure (BP) parameters (low levels or extreme dipper status) are associated with an increased risk of glaucomatous damage in Hispanics.

Design—Observational cross-sectional study.

Participants—A subset (n=93) of the participants from the Maracaibo Aging Study (MAS) who met the study eligibility criteria were included. These participants — who were at least 40 years of age — had measurements for optical tomography coherence, visual field tests, 24-hour BP, office BP, and intraocular pressureHg.

Methods—Univariate and multivariate logistic regression analyses under the generalized estimating equations (GEE) framework were used to examine the relationships between …

Clinical Significance Of Muc13 In Pancreatic Ductal Adenocarcinoma, Sheema Khan, Nadeem Zafar, Shabia S. Khan, Saini Setua, Stephen Behrman, Zachary E. Stiles, Murali M. Yallapu, Prabhakar Pradhan, Meena Jaggi, Subhash C. Chauhan

School of Medicine Publications

Background—Poor prognosis of pancreatic cancer (PanCa) is associated with lack of an effective early diagnostic biomarker. This study elucidates significance of MUC13, as a diagnostic/prognostic marker of PanCa.

Methods—MUC13 was assessed in tissues using our in-house generated anti-MUC13 mouse monoclonal antibody and analyzed for clinical correlation by immunohistochemistry, immunoblotting, RT-PCR, computational and submicron scale mass-density fluctuation analyses, ROC and Kaplan Meir curve analyses.

Results—MUC13 expression was detected in 100% pancreatic intraepithelial neoplasia (PanIN) lesions (Mean composite score: MCS=5.8; AUC >0.8, P<0.0001), 94.6% of pancreatic ductal adenocarcinoma (PDAC) samples (MCS=9.7, P<0.0001) as compared to low expression in tumor adjacent tissues (MCS=4, P<0.001) along with faint or no expression in normal pancreatic tissues (MCS=0.8; AUC >0.8; P<0.0001). Nuclear MUC13 expression positively correlated with nodal metastasis (P<0.05), invasion of cancer to peripheral tissues (P<0.5) and poor patient survival (P<0.05; prognostic AUC=0.9). Submicron scale mass density and artificial intelligence based algorithm analyses also elucidated association of MUC13 with greater morphological disorder (P<0.001) and nuclear MUC13 as strong predictor for cancer aggressiveness and poor patient survival.

Conclusion—This study provides significant information regarding MUC13 expression/ subcellular localization in PanCa samples …

Intracranial Hypertension Secondary To Eosinophilic Meningitis Caused By Angiostrongylus Cantonensis, Roberto A. Cruz, Christopher Smith, Alexander B. Ramos, Brian Copeland, Paula Seal

School of Medicine Publications

Angiostrongylus Cantonensis, a nematode, is a well-known cause of eosinophilic meningitis in endemic areas such as Southeast Asia, the Pacific Islands, and Hawaii. Nevertheless, an increasing number of cases in the southeast of the U.S. have been documented recently, specifically in Louisiana, Texas, and Florida. Infection is acquired after ingesting undercooked fresh water snails, mollusks, or undercooked vegetables contaminated by the slime from infected snails or slugs. Typical signs and symptoms include fever, general malaise, meningeal signs, headaches, photophobia, nausea and vomiting. Here we present a 23 year-old woman who presented to our emergency department with signs and symptoms consistent …

Cordycepin Induces Apoptosis Of Human Ovarian Cancer Cells By Inhibiting Ccl5-Mediated Akt/Nf-Κb Signaling Pathway, Zhen Yang Cui, Soo Jung Park, Eunbi Jo, In-Hu Hwang, Kyung-Bok Lee, Sung-Woo Kim, Dae Joon Kim, Jong Chun Joo, Seok Hoon Hong, Min-Goo Lee, Ik-Soon Jang

School of Medicine Publications

The chemokine, CCL5, is a key mediator for the recruitment of immune cells into tumors and tissues. Akt/NF-κB signaling is significantly activated by CCL5. However, the role of NF-κB inactivation in apoptosis induced by negative regulation of CCL5 remains unclear. Here, we analyzed the effect of cordycepin on NF-κB activity in SKOV-3 cells and found that cordycepin-mediated inhibition of NF-κB signaling induced apoptosis in SKOV-3 cells via the serial activation of caspases. In addition, immune-blotting analysis showed that CCL5 is highly expressed in SKOV-3 cells. In addition to activating caspases, we show that, cordycepin prevents TNF-α-induced increase in CCL5, Akt, …

A Review Of The Mechanism Of Antagonism Of N-Methyl-D-Aspartate Receptor By Ketamine In Treatment-Resistant Depression, Yasar Sattar, John Wilson, Ali M. Khan, Mahwish Adnan, Daniel Azzopardi Larios, Shristi Shrestha, Quazi Rahman, Zeeshan Mansuri, Ali Hassan, Nirav B. Patel

School of Medicine Publications

The biochemical processes involved in depression go beyond serotonin, norepinephrine, and dopamine. The N-methyl-D-aspartate (NMDA) receptor has a major role in the neurophysiology of depression. Ketamine, one of the prototypical NMDA antagonists, works rapidly in controlling depressive symptoms, including acutely suicidal behavior, by just a single injection. Ketamine may rapidly increase the glutamate levels and lead to structural neuronal changes. Increased neuronal dendritic growth may contribute to synaptogenesis and an increase in brain-derived neurotrophic factor (BDNF). Activation of the mechanistic target of rapamycin (mTOR), as well as increased levels of BDNF, may increase long-term potentiation and result in an improvement …

Mobile Personal Health Monitoring For Automated Classification Of Electrocardiogram Signals In Elderly, Luis J. Mena, Vanessa G. Felix, Alberto Ochoa, Rodolfo Ostos, Eduardo Gonzalez, Javier Aspuru, Pablo Velarde, Gladys E. Maestre

School of Medicine Publications

Mobile electrocardiogram (ECG) monitoring is an emerging area that has received increasing attention in recent years, but still real-life validation for elderly residing in low and middle-income countries is scarce. We developed a wearable ECG monitor that is integrated with a self-designed wireless sensor for ECG signal acquisition. It is used with a native purposely designed smartphone application, based on machine learning techniques, for automated classification of captured ECG beats from aged people. When tested on 100 older adults, the monitoring system discriminated normal and abnormal ECG signals with a high degree of accuracy (97%), sensitivity (100%), and specificity (96.6%). …

Choline Supplementation Prevents A Hallmark Disturbance Of Kwashiorkor In Weanling Mice Fed A Maize Vegetable Diet: Hepatic Steatosis Of Undernutrition, Thaddaeus May, Kevin C. Klatt, Jacob Smith, Eumenia Castro, Mark Manary, Marie A. Caudill, Farook Jahoor, Marta L. Fiorotto

School of Medicine Publications

Hepatic steatosis is a hallmark feature of kwashiorkor malnutrition. However, the pathogenesis of hepatic steatosis in kwashiorkor is uncertain. Our objective was to develop a mouse model of childhood undernutrition in order to test the hypothesis that feeding a maize vegetable diet (MVD), like that consumed by children at risk for kwashiorkor, will cause hepatic steatosis which is prevented by supplementation with choline. A MVD was developed with locally sourced organic ingredients, and fed to weanling mice (n = 9) for 6 or 13 days. An additional group of mice (n = 4) were fed a choline supplemented MVD. Weight, …

Insights Into The Genetic Epidemiology Of Crohn's And Rare Diseases In The Ashkenazi Jewish Population, Manuel A. Rivas, Brandon E. Avila, Jukka Koskela, Hailiang Huang, Christine Stevens, Matti Pirinen, Talin Haritunians, Benjamin M. Neale, Mitja Kurki, John Blangero, Joanne E. Curran

School of Medicine Publications

As part of a broader collaborative network of exome sequencing studies, we developed a jointly called data set of 5,685 Ashkenazi Jewish exomes. We make publicly available a resource of site and allele frequencies, which should serve as a reference for medical genetics in the Ashkenazim (hosted in part at https://ibd.broadinstitute.org, also available in gnomAD at http://gnomad.broadinstitute.org). We estimate that 34% of protein-coding alleles present in the Ashkenazi Jewish population at frequencies greater than 0.2% are significantly more frequent (mean 15-fold) than their maximum frequency observed in other reference populations. Arising via a well-described founder effect approximately 30 …

Genetic Analysis Of Deep Phenotyping Projects In Common Disorders, Elliot S. Gershon, Godfrey Pearlson, Matcheri S. Keshavan, Carol Tamminga, Ney Alliey Rodriguez

School of Medicine Publications

Several studies of complex psychotic disorders with large numbers of neurobiological phenotypes are currently under way, in living patients and controls, and on assemblies of brain specimens. Genetic analyses of such data typically present challenges, because of the choice of underlying hypotheses on genetic architecture of the studied disorders and phenotypes, large numbers of phenotypes, the appropriate multiple testing corrections, limited numbers of subjects, imputations required on missing phenotypes and genotypes, and the cross-disciplinary nature of the phenotype measures. Advances in genotype and phenotype imputation, and in genome-wide association (GWAS) methods, are useful in dealing with these challenges. As compared …

Interphotoreceptor Retinoid-Binding Protein Implications In Diabetic Retinopathy, Kevin Bermea

School of Medicine Publications

The interphotoreceptor retinoid-binding protein (IRBP) is the most abundant protein in the interphotoreceptor matrix (IPM) and its levels decrease beginning in the early stages of diabetes. IRBP participates in the delivery of retinoids between retinal cells to carry out the visual cycle and also protects those retinoids against degradation in the IPM. IRBP deficiency is related to several conditions such as retinitis pigmentosa, cone-rod dystrophy, increased oxidative stress in the photoreceptors, and myopia. Decreased IRBP levels in diabetes could be due to the secretion of inflammatory cytokines and a direct effect of hyperglycemia on the photoreceptors. It is known that …

Meeting Report: ‘How Do I Incorporate Research Into My Family Practice?’: Reflections On Experiences Of And Solutions For Young Family Doctors, Kenneth Yakubu, Maria C. Colon-Gonzalez, Kyle Hoedebecke, Vasiliki Gkarmiri, Nagwa N. Hegazy, Olugbemi O. Popoola

School of Medicine Publications

Background: Family doctors (FDs) focus on biopsychosocial components of health during consultations. However, much of the evidence employed by these doctors is produced by researchers who are not routinely involved in family practice. Family doctors competent in both clinical practice and research are essential to addressing this gap. With the growing recognition of family medicine as the specialty of choice for many young doctors, there is a scarcity of literature that describes their experiences in combining research and daily family practice.

Aim: Members from Young Doctor Movements (YDMs) under the auspices of the World Organisation of Family Doctors (WONCA) …

Antibody-Drug Conjugates For Cancer Therapy: Chemistry To Clinical Implications, Nirnoy Dan, Saini Setua, Vivek K. Kashyap, Sheema Khan, Meena Jaggi, Murali M. Yallapu, Subhash C. Chauhan

School of Medicine Publications

Chemotherapy is one of themajor therapeutic options for cancer treatment. Chemotherapy is often associated with a low therapeutic window due to its poor specificity towards tumor cells/tissues. Antibody-drug conjugate (ADC) technology may provide a potentially new therapeutic solution for cancer treatment. ADC technology uses an antibody-mediated delivery of cytotoxic drugs to the tumors in a targeted manner, while sparing normal cells. Such a targeted approach can improve the tumor-to-normal tissue selectivity and specificity in chemotherapy. Considering its importance in cancer treatment, we aim to review recent efforts for the design and development of ADCs. ADCs are mainly composed of an …

Exome Sequencing Identifies Genetic Variants Associated With Circulating Lipid Levels In Mexican Americans: The Insulin Resistance Atherosclerosis Family Study (Irasfs), Chuan Gao, Keri L. Tabb, Latchezar Dimitrov, Kent D. Taylor, Nan Wang, Xiuqing Guo, Jirong Long, Jerome I. Rotter, Richard M. Watanabe, Joanne E. Curran, John Blangero

School of Medicine Publications

Genome-wide association studies have identified numerous variants associated with lipid levels; yet, the majority are located in non-coding regions with unclear mechanisms. In the Insulin Resistance Atherosclerosis Family Study (IRASFS), heritability estimates suggest a strong genetic basis: low-density lipoprotein (LDL, h2 = 0.50), high-density lipoprotein (HDL, h2 = 0.57), total cholesterol (TC, h2 = 0.53), and triglyceride (TG, h2 = 0.42) levels. Exome sequencing of 1,205 Mexican Americans (90 pedigrees) from the IRASFS identified 548,889 variants and association and linkage analyses with lipid levels were performed. One genome-wide significant signal was detected in APOA5 with TG (rs651821, PTG = 3.67 …

Hippocampal Protein Kinase D1 Is Necessary For Dhpg-Induced Learning And Memory Impairments In Rats, Wei Wang, Florian Duclot, Bradley R. Groveman, Nicole Carrier, Haifa Qiao, Xiao-Qian Fang, Hui Wang, Wenkuan Xin, Michael W. Salter, Xin-Sheng Ding

School of Medicine Publications

Background

Understanding molecular mechanisms underlying the induction of learning and memory impairments remains a challenge. Recent investigations have shown that the activation of group I mGluRs (mGluR1 and mGluR5) in cultured hippocampal neurons by application of (S)-3,5-Dihydroxyphenylglycine (DHPG) causes the regulated internalization of N-methyl-D-aspartate receptors (NMDARs), which subsequently activates protein kinase D1 (PKD1). Through phosphorylating the C-terminals of the NMDAR GluN2 subunits, PKD1 down-regulates the activity of remaining (non-internalized) surface NMDARs. The knockdown of PKD1 does not affect the DHPG-induced inhibition of AMPA receptor-mediated miniature excitatory post-synaptic currents (mEPSCs) but prevents the DHPG-induced inhibition of NMDAR-mediated mEPSCs in …

Obesity And Obesogenic Growth Are Both Highly Heritable And Modified By Diet In A Nonhuman Primate Model, The African Green Monkey (Chlorocebus Aethiops Sabaeus), C. A. Schmitt, S. K. Service, A. J. Jasinska, Thomas D. Dyer, M. J. Jorgensen, R. M. Cantor, G. M. Weinstock, John Blangero, J. R. Kaplan, N. B. Freimer

School of Medicine Publications

OBJECTIVE: In humans, the ontogeny of obesity throughout the life course and the genetics underlying it has been historically difficult to study. We compared, in a non-human primate model, the lifelong growth trajectories of obese and non-obese adults to assess the heritability of and map potential genomic regions implicated in growth and obesity.

STUDY POPULATION: A total of 905 African green monkeys, or vervets (Chlorocebus aethiops sabaeus) (472 females, 433 males) from a pedigreed captive colony. METHODS: We measured fasted body weight (BW), crown-to-rump length (CRL), body-mass index (BMI) and waist circumference (WC) from 2000 to 2015. We used a …

A Genetic Association Study Of Carotid Intima-Media Thickness (Cimt) And Plaque In Mexican Americans And European Americans With Rheumatoid Arthritis, Rector Arya, Agustin Escalante, Vidya S. Farook, Jose F. Restrepo, Daniel F. Battafarano, Marcio Almeida, Mark Kos, Marcel Fourcaudot, Srinivas Mummidi, Satish Kumar, Joanne E. Curran, Christopher Jenkinson, John Blangero, Ravi Duggirala, Inmaculada Del Rincon

School of Medicine Publications

Background and aims: Little is known about specific genetic determinants of carotid-intima-media thickness (CIMT) and carotid plaque in subjects with rheumatoid arthritis (RA). We have used the Metabochip array to fine map and replicate loci that influence variation in these phenotypes in Mexican Americans (MAs) and European Americans (EAs).

Methods: CIMT and plaque were measured using ultrasound from 700 MA and 415 EA patients with RA and we conducted association analyses with the Metabochip single nucleotide polymorphism (SNP) data using PLINK.

Results: In MAs, 12 SNPs from 11 chromosomes and 6 SNPs from 6 chromosomes showed suggestive associations (p < 1 × 10-4) with CIMT and plaque, respectively. The strongest association was observed between CIMT and rs17526722 (SLC17A2 gene) (β ± SE = -0.84 ± 0.18, p = 3.80 × 10-6). In EAs, 9 SNPs from 7 chromosomes and 7 SNPs from 7 chromosomes showed suggestive associations with CIMT and plaque, respectively. The top association for CIMT was observed with rs1867148 (PPCDC gene, β ± SE = -0.28 ± 0.06, p = 5.11 × 10-6). We also observed strong association between plaque and two novel loci: rs496916 from COL4A1 gene (OR = 0.51, p = 3.15 × 10-6) in MAs and rs515291 from SLCA13 gene (OR = 0.50, p = 3.09 × 10-5) in EAs.

Conclusions: …