This study assessed whether single nucleotide polymorphisms (SNPs) in the NOS2A gene increase risk for age-related macular degeneration (AMD) and interact with smoking. 998 Caucasian subjects were genotyped for 17 SNPs in NOS2A. Multivariable logistic regression identified that SNP rs8072199 was significantly associated with increased AMD risk. A significant interaction with smoking was detected for rs2248814. Stratified analysis found that the association between AMD and smoking was strongest in carriers of the AA genotype at this SNP compared to AG and GG genotypes, suggesting a possible synergistic interaction between this genotype and smoking. The results provide preliminary evidence that genetic variation in NOS2A may influence AMD risk and
International Journal of Pharmaceutical Science Invention (IJPSI) is an international journal intended for professionals and researchers in all fields of Pahrmaceutical Science. IJPSI publishes research articles and reviews within the whole field Pharmacy and Pharmaceutical Science, new teaching methods, assessment, validation and the impact of new technologies and it will continue to provide information on the latest trends and developments in this ever-expanding subject. The publications of papers are selected through double peer reviewed to ensure originality, relevance, and readability. The articles published in our journal can be accessed online.
International Journal of Pharmaceutical Science Invention (IJPSI) is an international journal intended for professionals and researchers in all fields of Pahrmaceutical Science. IJPSI publishes research articles and reviews within the whole field Pharmacy and Pharmaceutical Science, new teaching methods, assessment, validation and the impact of new technologies and it will continue to provide information on the latest trends and developments in this ever-expanding subject. The publications of papers are selected through double peer reviewed to ensure originality, relevance, and readability. The articles published in our journal can be accessed online.
Autologous Bone Marrow Mononuclear Cell Therapy for Autism: An Open Label Pro...DrAlokSharma
Autism spectrum disorders (ASD) are a group of heterogeneous neurodevelopmental disorders characterized by
deficits in verbal and nonverbal communication, social
interaction, and presence of stereotypical repetitive behavior.
Genetic and epigenetic biomarkers for therapeutic monitoring in neurological ...Pranav Sopory
Seminar held on Genetic and epigenetic biomarkers for therapeutic monitoring in neurological disorders.
Multiple Sclerosis, Alzheimer's Disease and Parkinson's Disease.
Biomarkers and epigenetic explained. New epigenetic drug targets.
Enhancing Rare Disease Literature for Researchers and PatientsErin D. Foster
Objectives: In rare disease research, structured phenotype information is crucial to document in order to draw connections between other known cases and work towards diagnosis and treatment of disease. The Human Phenotype Ontology (HPO) is a standardized vocabularly that describes phenotypic abnormalities encountered in human diseases. To enable the increased identification of traits (i.e., phenotypes) associated with rare diseases, the HPO was expanded to include layperson synonyms to make the ontology more accessible and useful to patients. Additionally, the HPO was used to annotate phenotypes in a sample of rare disease case reports to provide structured annotations of rare disease phenotypes.
Methods: The HPO was systematically reviewed and 'layperson synonyms' were added to include terms used by patients and non-medical professionals. Subsequent work annotated phenotypic descriptions in a sample of rare disease case reports with HPO terms. The literature sample was identified by filtering 'case reports' in PubMed and excluding articles that were already included in the Online Mendelian Inheritance of Man (OMIM) database. The sample set was further restricted to articles from the European Journal of Human Genetics for the pilot set, which resulted in a final sample size of 143 articles. The papers were reviewed and annotated for the following information: disease name, associated gene(s), and corresponding phenotypes.
Results: The review of the HPO resulted in approximately half of the terms including layperson synonyms. A subset of the literature sample was annotated to determine the best curation workflow. Of that subset of papers (n=20), 353 total phenotypes were identified. 12% of these phenotypes were not included in the HPO and required new term and/or synonym requests. Some challenges encountered in this work included maintaining consistency in HPO term definitions and use, as well as annotation reliability.
Conclusion: This work contributes to knowledge of rare diseases by curating the existing literature to provide structured annotation of rare disease traits, which helps with information retrieval and data interoperability and reuse. Additionally, the expansion of the HPO to include layperson synonyms enables patients to 'self-phenotype' and contribute to the identification of rare disease traits. Following the completed annotation of the literature sample, future work will focus on incorporating the annotations into databases that collect rare disease phenotypic information. Further work is also being done to add additional layperson synonyms to the HPO through review of patient forums and medical message boards to continue to identify terminology used by actual patients.
Dna methylation signature of human fetal alcohol spectrum disorder | epigenet...BARRY STANLEY 2 fasd
Results
After correcting for the effects of genetic background, we found 658 significantly differentially methylated sites between FASD
cases and controls, with 41 displaying differences in percent methylation change >5 %. Furthermore, 101 differentially
methylated regions containing two or more CpGs were also identified, overlapping with 95 different genes. The majority of
differentially methylated genes were highly expressed at the level of mRNA in brain samples from the Allen Brain Atlas, and
independent DNA methylation data from cortical brain samples showed high correlations with BEC DNA methylation patterns.
Finally, overrepresentation analysis of genes with up-methylated CpGs revealed a significant enrichment for
neurodevelopmental processes and diseases, such as anxiety, epilepsy, and autism spectrum disorders
Dr. Ángel Carracedo - Simposio Internacional 'La enfermedad de la duda: el TOC'Fundación Ramón Areces
El 14 de noviembre de 2013, la Fundación Ramón Areces organizó y acogió en su sede un Simposio Internacional sobre 'La enfermedad de la duda: el TOC'. El Trastorno Obsesivo-Compulsivo (TOC) es un problema de salud pública, poco conocido, que afecta a un porcentaje de la población en torno a un 1-2% y que la Organización Mundial de la Salud ha situado entre las diez entidades que producen más discapacidad.
Dr. Torres gives great information on age related macular degeneration. This is a great update not only on the disease but on emerging treatments for this devastating problem.
Autologous Bone Marrow Mononuclear Cell Therapy for Autism: An Open Label Pro...DrAlokSharma
Autism spectrum disorders (ASD) are a group of heterogeneous neurodevelopmental disorders characterized by
deficits in verbal and nonverbal communication, social
interaction, and presence of stereotypical repetitive behavior.
Genetic and epigenetic biomarkers for therapeutic monitoring in neurological ...Pranav Sopory
Seminar held on Genetic and epigenetic biomarkers for therapeutic monitoring in neurological disorders.
Multiple Sclerosis, Alzheimer's Disease and Parkinson's Disease.
Biomarkers and epigenetic explained. New epigenetic drug targets.
Enhancing Rare Disease Literature for Researchers and PatientsErin D. Foster
Objectives: In rare disease research, structured phenotype information is crucial to document in order to draw connections between other known cases and work towards diagnosis and treatment of disease. The Human Phenotype Ontology (HPO) is a standardized vocabularly that describes phenotypic abnormalities encountered in human diseases. To enable the increased identification of traits (i.e., phenotypes) associated with rare diseases, the HPO was expanded to include layperson synonyms to make the ontology more accessible and useful to patients. Additionally, the HPO was used to annotate phenotypes in a sample of rare disease case reports to provide structured annotations of rare disease phenotypes.
Methods: The HPO was systematically reviewed and 'layperson synonyms' were added to include terms used by patients and non-medical professionals. Subsequent work annotated phenotypic descriptions in a sample of rare disease case reports with HPO terms. The literature sample was identified by filtering 'case reports' in PubMed and excluding articles that were already included in the Online Mendelian Inheritance of Man (OMIM) database. The sample set was further restricted to articles from the European Journal of Human Genetics for the pilot set, which resulted in a final sample size of 143 articles. The papers were reviewed and annotated for the following information: disease name, associated gene(s), and corresponding phenotypes.
Results: The review of the HPO resulted in approximately half of the terms including layperson synonyms. A subset of the literature sample was annotated to determine the best curation workflow. Of that subset of papers (n=20), 353 total phenotypes were identified. 12% of these phenotypes were not included in the HPO and required new term and/or synonym requests. Some challenges encountered in this work included maintaining consistency in HPO term definitions and use, as well as annotation reliability.
Conclusion: This work contributes to knowledge of rare diseases by curating the existing literature to provide structured annotation of rare disease traits, which helps with information retrieval and data interoperability and reuse. Additionally, the expansion of the HPO to include layperson synonyms enables patients to 'self-phenotype' and contribute to the identification of rare disease traits. Following the completed annotation of the literature sample, future work will focus on incorporating the annotations into databases that collect rare disease phenotypic information. Further work is also being done to add additional layperson synonyms to the HPO through review of patient forums and medical message boards to continue to identify terminology used by actual patients.
Dna methylation signature of human fetal alcohol spectrum disorder | epigenet...BARRY STANLEY 2 fasd
Results
After correcting for the effects of genetic background, we found 658 significantly differentially methylated sites between FASD
cases and controls, with 41 displaying differences in percent methylation change >5 %. Furthermore, 101 differentially
methylated regions containing two or more CpGs were also identified, overlapping with 95 different genes. The majority of
differentially methylated genes were highly expressed at the level of mRNA in brain samples from the Allen Brain Atlas, and
independent DNA methylation data from cortical brain samples showed high correlations with BEC DNA methylation patterns.
Finally, overrepresentation analysis of genes with up-methylated CpGs revealed a significant enrichment for
neurodevelopmental processes and diseases, such as anxiety, epilepsy, and autism spectrum disorders
Dr. Ángel Carracedo - Simposio Internacional 'La enfermedad de la duda: el TOC'Fundación Ramón Areces
El 14 de noviembre de 2013, la Fundación Ramón Areces organizó y acogió en su sede un Simposio Internacional sobre 'La enfermedad de la duda: el TOC'. El Trastorno Obsesivo-Compulsivo (TOC) es un problema de salud pública, poco conocido, que afecta a un porcentaje de la población en torno a un 1-2% y que la Organización Mundial de la Salud ha situado entre las diez entidades que producen más discapacidad.
Dr. Torres gives great information on age related macular degeneration. This is a great update not only on the disease but on emerging treatments for this devastating problem.
GENETIC BASIS OF PSYCHIATRIC DISRODERS AND THE RELEVANCE OF CLINICAL PRACTICEPRASHNATH javali
Presentation regarding the counseling of genetic disorders and the steps involved along with the process of Genetic counseling guidance,way to disclose the results,steps to be taken for the care of mentally ill persons.
International Journal of Engineering Research and Applications (IJERA) is an open access online peer reviewed international journal that publishes research and review articles in the fields of Computer Science, Neural Networks, Electrical Engineering, Software Engineering, Information Technology, Mechanical Engineering, Chemical Engineering, Plastic Engineering, Food Technology, Textile Engineering, Nano Technology & science, Power Electronics, Electronics & Communication Engineering, Computational mathematics, Image processing, Civil Engineering, Structural Engineering, Environmental Engineering, VLSI Testing & Low Power VLSI Design etc.
Prof. Dr. Vladimir Trajkovski - IMUNOGENETIC ANALYSES IN PERSONS WITH AUTISM ...Vladimir Trajkovski
This presentation Prof. Dr. Vladimir Trajkovski: IMUNOGENETIC ANALYSES IN PERSONS WITH AUTISM IN REPUBLIC OF MACEDONIA should presented in conference in Barcelona, but he wasn't there because it was cancelled.
A guideline for discontinuing antiepileptic drugs in seizure-free patients – ...Dr. Rafael Higashi
Aula apresentada por Dr. Rafael Higashi, médico neurologista sobre quando retirar droga antiepilética. A guideline for discontinuing antiepileptic drugs in seizure-free patients – Summary Statement
THE FIRST SYSTEM OF REFERENCE FOR THE MEDICAL PRACTICE OF HOMEOPATHY IN FRANCEhome
PB7 445 THE FIRST SYSTEM OF REFERENCE FOR THE MEDICAL PRACTICE
OF HOMEOPATHY IN FRANCE
J. BILLOT* (AP-HP Hôpital Corenton-Celton, Issy-les -Moulineaux, France)
Introduction At least 30% of the French population has recourse to homeopathy, with a large
proportion of elderly persons. Some 25000 practitioners prescribe homeopathic treatments.
Object: Development of a system of reference for the medical practice of homeopathy in
order to meet with the legal obligations of evaluation and training of homeopaths. Method :
1- Creation by the Société Française d’Homéopathie of a working group of expert specialists
representative of the medical practice of homeopathy to determine: - a basic methodology:
self-evaluation according to the method of practice groups; - the subject: « the homeopathic
medical file»; - the aims and requirements of quality; - the standards of evaluation; - the
number and content of items or inquiries 2- Verification of the text’s form by a reader’s
group; 3- Verification of acceptability and feasibility by a group test; 4- New meeting of the
working group to register the modifications shown necessary by the feasibility study; 5-
Presentation of the text to the methodologists approved by the Haute Autorité de la Santé
(Health Department); 6- Finalization of the project and transmission to the Haute Autorité de
la Santé for validation. Results: Elaboration of a system of analysis with reference to the
«homeopathic medical file», according to the method of practice groups. This system of
reference includes a questionnaire concerning the symptoms noted in the patient’s file: in
order to be of homeopathic value, the symptoms must be precisely characterized and
organized according to their relative importance. Conclusion This system of reference was
validated by the Haute Autorité de la Santé in February 2007. Several practice groups have
already used this system of reference to validate the legal obligations of their profesional
practice. The complete text of this system of reference can be downloaded on web-site:
WWW. homeopathie- francaise. fr
Blood-based biological ageing and red cell distribution width are associated ...LearningSpaceTutors
Aging clocks tag the actual underlying age of an organism and its discrepancy with chronological age and have been reported to predict incident disease risk in the general population. However, the relationship with neurodegenerative risk and in particular with Parkinson’s Disease (PD) remains unclear, with few discordant findings reporting associations with both incident and prevalent PD risk.
Similar to Smocking can cause macular degeneration (20)
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
5. • Nitric oxide synthase, inducible is
an that in humans is
encoded by the NOS2 gene
6. is the central area of the retina, which
provides the most detailed
It is a medical condition which usually affects
and results in of
the visual field (the macula) because of damage to the
retina.
It occurs in “dry” and “wet” forms.
It is a major cause of blindness and visual impairment
in older adults (>50 years).
Macular degeneration can make it difficult or impossible
to read or recognize faces, although enough peripheral
vision remains to allow other activities of daily life.
7.
8.
9. Picture of the fundus showing intermediate age-related macular degeneration
10. NIH Public Access
Author Manuscript
Ann Hum Genet. Author manuscript;
available in PMC 2011 May 1.
Published in final edited form as:
Ann Hum Genet. 2010 May ; 74(3):
195–201. doi:10.1111/j.1469-
1809.2010.00570.x.
11. Analysis of single nucleotide polymorphisms in the NOS2A
gene
and interaction with smoking in age-related macular
degeneration
JUAN A. AYALA-HAEDO1, PAUL J. GALLINS1, PATRICE L. WHITEHEAD1, STEPHEN G.
SCHWARTZ2, JACLYN L. KOVACH2, ERIC A. POSTEL3, ANITA AGARWAL4, GAOFENG
WANG1, JONATHAN L. HAINES5, MARGARET A. PERICAK-VANCE1, and WILLIAM K.
SCOTT1
1John P. Hussman Institute for Human Genomics and the Dr. John T. Macdonald Foundation
Department of Human Genetics, University of Miami Miller School of Medicine, 1501 NW 10th
Avenue, Miami, FL 33136
2Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, 311 9th Street N.,
Suite #100, Naples, FL 34102
3Duke University Eye Center, Duke University, Box 3802 DUMC, Durham, NC 27710-3802
4Vanderbilt Eye Institute, Vanderbilt University, 2311 Pierce Avenue, Nashville, TN 37232-8808
5Center for Human Genetics Research, Vanderbilt University Medical Center, 519 Light Hall,
Nashville, TN 37232-0700
12. SUMMARY
Age-related macular degeneration (AMD)
is a complex degenerative
disease influenced by both genetic and
environmental risk factors.
We assessed whether single nucleotidepolymorphisms
(SNPs) in the NOS2A gene increase risk and
modulate the effect of smoking in AMD.
998 Caucasian subjects (712 AMD cases and 286
controls) were genotyped for 17 SNPs in NOS2A.
13. Summary –cont.
Multivariable logistic regression models containing SNP
genotypes, age, sex, smoking status and genotype/smoking interaction
were constructed.
SNP rs8072199 was significantly associated with AMD (OR = 1.3; 95% CI :
1.02, 1.65; P = 0.035).
A significant interaction with smoking was detected at rs2248814 (P =
0.037). Stratified data by genotypes demonstrated that the association
between AMD and smoking was stronger in carriers of AA genotypes (OR
=35.98; 95% CI: 3.19, 405.98) than in carriers of the AG genotype
(OR=3.05; 95% CI: 1.36, 6.74)or GG genotype (OR=2.1; 95% CI:
0.91, 4.84). The results suggest a possible synergistic interaction of AA
genotype with smoking, although the result bears replication in larger
samples.
Our data suggests that SNPs in the NOS2A gene are associated
with increased risk for AMD and might modulate the effect
of smoking on AMD.
14. INTRODUCTION
Definition:
Age-related macular degeneration (AMD) is a
degenerative disorder that is characterized by
loss of central vision due to the loss of the
photoreceptors and retinal pigment
epithelium (RPE) in the macula, an area in
the central retina responsible for visual
acuity.
15. INTRODUCTION
Epidemiology:
It is the main cause of irreversible visual loss in
the elderly in developed countries.
AMD affects over 8 million Americans and its
prevalence increases with age.
The overall disease prevalence is also expected to
increase to at least 50% by 2020, due to the
increasing age of the American population .
AMD affects Caucasians more than other races.
16. Introduction cont.
Risk Factors:
Linkage and association studies have reported
genes that are risk factors for developing the
disease; the most well-replicated of these are:
1. complement factor H (CFH),
2. complement factor B (CFB) and
3. complement component 2 (C2),
4. ARMS2 (LOC387715)/HTRA1
5. complement component 3 (C3), and
6. apolipoprotein E.
17. Introduction- risk factors cont.
Non-modifiable risk factors such as age, female
gender, and race;
such as antioxidant
intake, smoking, hypertension and obesity .
is the strongest, most well-
established risk factor for AMD.
Most recently, it has been demonstrated in an
animal model that exposed to smoking
developed signs of degeneration in the and
, structures that are intimately
involved in the AMD disease pathogenesis.
18. Introduction- risk factors
In addition, in vitro studies of glial cell cultures and murine
lung epithelium cells demonstrated a direct interaction
between smoking and the NOS2A gene that codes for the
inducible form of nitric oxide synthase (iNOS). Cells exposed
to smoke condensates demonstrated a reduction in iNOS
protein expression and enzymatic activity decreasing
therefore the oxidative stress pathway activation.
The NOS2A gene is an attractive AMD candidate gene given
its interaction with smoking and its role in host
defense, inflammation and neovascularization.
The purpose of our study was to assess the main effect of
single nucleotide polymorphisms (SNPs) in the NOS2A gene
in AMD as well as a possible interaction with smoking.
19. MATERIALS AND METHODS
Subjects
Individuals were recruited from:
1. the Duke University Eye Center
(DUEC),
2. the VanderbiltEye Institute (VEI)
and
3. the Bascom Palmer Eye Institute
(BPEI) at the University of Miami,
20. MATERIALS AND METHODS
Medicine under research protocols approved by the
Institutional Review Boards at each institution.
Written informed consent was obtained from all
participants.
All study subjects were examined by a retinal
specialist.
The patients were examined by slitlamp biomicroscopy
and dilated fundus examination, including indirect
ophthalmoscopy.
In addition, fundus imaging was obtained in all
patients.
21. MATERIALS AND METHODS
The pictures were graded using amodified grading
system based on the Age-Related Eye Disease
Study (AREDS) which has been previously
described in detail . Briefly, the grading system
was scored from 1 to 5. The 1 and 2 categories
corresponded to controls. The rest corresponded
to mild (grade 3) and advanced (grades 4 and 5)
stages of AMD .
22. MATERIALS AND METHODS
A detailed smoking history was obtained by self-
administered questionnaire.
Participants were asked if they had smoked
more than 100 cigarettes in their life time; an
affirmative answer lead to the description of the
amount of cigarettes per day, age they had
started smoking, if they had quit, and when.
From these measures, a binary measure of
‘ever’ smoking and pack-years of exposure were
calculated.
23. MATERIALS AND METHODS
We included in the study a total of 998 non-Hispanic
Caucasian participants, (712 AMDcases [grades 3, 4 and
5] and 286 unrelated controls [grades 1 and 2]. The total
population was assessed for a main SNP effect.
A subset of the population with environmental risk
information, including smoking history, (705 non-Hispanic
Caucasian participants) was included in the analysis of
SNP/smoking interaction (466 AMD cases [grades 3, 4 and
5] and 239 unrelated controls [grades 1 and 2]). A full
description of the participants by clinical findings and
smoking status is presented in Table 1.
24.
25. MATERIALS AND METHODS
DNA Analysis and Genotyping
The whole blood obtained was processed for DNA
extraction using a standard protocol.
The Tagger function of the Haploviewprogram was
employed to select ‘tagSNPs’ that capture the Common
variation among the phase II Hapmap SNPs. TagSNPs
that tagged other variants with an r2 ≥ of 0.67 were
selected for the study. In addition, two previously
validated coding sequence SNPs (rs1060826
andrs16966563) were obtained form the NCBI data base
and were also included in the analysis.
26. DNA Analysis and Genotyping
• We genotyped 17 SNPs in the 998 subjects included in the
study using TaqMan assays. Pairwise linkage disequilibrium
(LD) (r2) was assessed to evaluate for residual correlations
in both cases and controls for all pairwise marker
combinations using theHaploview program. For quality
control purposes, 2 different samples from the Fondation
Jean Dausset-Centre d’etude de Polymorphisme Humain
(CEPH) were plated in quadruplicate on each 384-well
plate. Additionally, internal controls were replicated
throughout the sample list to ensure efficiency. Laboratory
personnel were blinded to sample phenotypes and
replicate sample locations. Additionally, each plate met a
quality control efficiency of 100% and a genotyping
efficiency of ≥95%.
27. MATERIALS AND METHODS
Statistical Analysis
Deviations from Hardy-Weinberg equilibrium were
evaluated using the Genetic Data Analysis program.
The association analysis was conducted using logistic
regression as implemented in theStatistical Analysis
Software version 9.1.. First, each was examined for
association controlling for confounding by age and sex.
Then, in the subset for which smoking data were
available, we fit models including
genotype, age, sex, smoking status and a two-way
interaction term between genotype and smoking.
28. MATERIALS AND METHODS
Statistical Analysis:
A model was constructed coding for additive genotypic
effects, and each term was tested for significant
association with AMD using a Wald chi-square test
and a nominal significance level of p<0.05. The
strength of the association was evaluated by the odds
ratio and 95% confidence intervals. For models with
significant interaction terms (p<0.05), differential
association of smoking by risk allele carrier status was
assessed using a stratified analysis.
No correction for multiple comparisons was utilized for
the data analysis.
29. RESULTS
A multivariable logistic regression analysis adjusting
for age and sex was performed on all 998 subjects
[286 controls (grades 1, 2) and 712 AMD cases
(grades 3, 4, 5)]. SNP rs8072199 was significantly
associated with AMD under the additive model (p=
0.035). Models containing SNP/smoking interaction
terms were created for all markers under the
additive genetic model, for all 705 subjects with
available smoking data [466 cases(grades 3, 4 and
5) and 239 controls (grades 1 and 2)].
30. Results
No significant interactions were detected. However, when
considering just grade 5 (273 cases) and grade 1 (169
controls), a SNP/smoking interaction was detected for
rs2248814 (p=0.039); rs1060826 presented a
borderline significant value (p=0.061).
Due to high LD (r2 = 0.95 in cases and 0.96 in controls)
between these two SNPs and based on the exonic
location of rs1060826 we chose both SNP genotypes to
stratify the data and examine the modification of the
effect of smoking by allele carrier status.
31. Results
Individuals with AMD were 35 times as likely to have smoked as controls with the AA
genotype.
Individuals carrying one or no copies of the A allele were only 3 or 2 times as
likely to have smoked as controls, respectively..
Additionally, a similar trend was observed when the smoking effect was evaluated using
pack-years of exposure, comparing ‘heaviersmokers’ (above the median pack-years) or
‘lighter smokers’ (below the median) versus ‘never smoked’. The smoking effect seemed
to be stronger in the heavy smokers than in light smokers.
The pattern observed suggests a synergy between the effectof smoking and the AA
genotype at rs2248814 and rs1060826. The fact that the SNP/smoking interaction was
detected when comparing the grade 1 (controls) and grade 5 subjects (neovascular
cases) is in agreement with previous work indicating that both smoking and iNOS
induction are individually associated with the neovascularization processthat occurs in
advanced neovascular AMD.
32. RESULTS
While these results are intriguing, they should be interpreted cautiously.
SNPs rs8072199
and rs2248814, significant for SNP main effect and SNP/smoking
interaction, respectively,
are in low linkage disequilibrium (r2=0.07) and neither has a known
functional effect on
iNOS, so that the effect seen in this sample might be due to a third, untyped
SNP located in
the gene that is in moderate LD with both of these SNPs. The results
presented here are from
a single sample and do not withstand conservative corrections for multiple
comparisons. In
addition, while the point estimates of the OR for smoking are very different
across genotype
strata, the small samples sizes produce large 95% confidence intervals that
overlap,
indicating that the true value for the OR may not be different across
genotypes.
33. Results
This
indicates that futher examination in larger data sets is warranted.
However, the results
generate interesting hypotheses about a possible role of iNOS in AMD and a
gene-smoking
interaction in the disease which bear examination in other data sets.
Because we had previously reported an interaction between smoking and
ARMS2 (Schmidt
et al., 2006), we also performed a two way and a three way interaction
analysis in our subset
of individuals with smoking history data. The two way analysis that included
SNPs in
NOS2A and ARMS2 and the three way analysis including SNPs in the two
genes and
smoking did not detect any significant interactions (data not shown
34. RESULTS
We also tested the previously reported interaction between the ARMS2 SNP rs10490924 and
smoking, previously reported in a subset the data set used in this paper (Schmidt et al.,
2006). The ARMS2-smoking interaction was not statistically significant in the current data
set (p=0.10), and the OR for the interaction term was weaker (ORi=1.7) than observed for
NOS2A and smoking (ORi=2.36).
Consistent with a recessive model, the stratified analysis demonstrated that the strength of
the association between smoking and AMD increased in homozygous carriers of the
rs2248814 and rs1060826 risk allele A (OR=35.98, 95% CI [3.19, 405.98], p=0.0038 and
OR=35.63, 95% CI [3.12, 406.67], p=0.004, respectively) than in carriers of the AG
genotype (OR=3.05, 95% CI [1.38, 6.74] p=0.0058 and OR=2.83, 95% CI [1.27, 6.31]
p=0.011, respectively) or GG genotype (OR=2.1, 95% CI [0.911, 4.84] p=0.082 and
OR=2.13, 95% CI [0.94, 4.85] p=0.072, respectively) (Table 3).
35. DISCUSSION
In our study, we demonstrated that a SNP present in the NOS2A
gene, rs8072199, conferred an increased risk for AMD when
controlling for age and sex. Prior studies of in vitro glialcell cultures
and murine lung epithelium cells exposed to smoke condensates
demonstrated
AMD several mechanisms are thought to be responsible for disease
pathogenesis including oxidative stress related processes and
abnormal inflammatory pathway activation.The nitric oxide synthase
(NOS) enzyme system is known to participate in both phenomena.
.
36. Discussion
The expression of NOS2A gene that codes for inducible nitric oxide synthase (iNOS)
has
been demonstrated in activated inflammatory cells in AMD as well as in RPE and
Müller
cells (Ando et al., 2002b) and in choroidal neovascularization membranes of AMD
patients
(Hattenbach et al., 2002): its blockade has demonstrated to improve the formation of
aberrant choroidal vessel in late stage AMD (Ando et al., 2002). Prior work on RPE
and
photoreceptor cells exposed to NO have shown a decrease in proliferation (Goureau
et al.,
1993) and increase in apoptosis (Ju et al., 2001; Osborne & Wood, 2004)
respectively, that
could also play a role in the disease pathogenesis. Therefore, the fact that we found a
main
effect in a SNP in the NOS2A gene in our data set further implicates the gene in the
disease
37. Discussion
Smoking has been traditionally identified as one of the strongest disease risk factors,
increasing risk in a dose dependent fashion in smokers as compared to non smokers
(Clemons et al., 2005; Khan et al., 2006; Tomany et al., 2004). Strong evidence exits for a
possible causative role resulting in RPE dysfunction and death in an animal model of AMD
(Fujihara et al., 2008). Smoking has been shown to decrease blood antioxidants levels and to
favor an oxidative state (Moriarty et al., 2003), which then results in increased
mitochondrial mediated apoptosis that could partially explain the cell death that ensues in
AMD (Jiang et al., 2005). However, the fact that the known attributed risk conferred by
AYALA-HAEDO et al. Page 5
Ann Hum Genet. Author manuscript; available in PMC 2011 May 1. smoking can be so dramatically
influenced by homozygous carriage of the risk allele
constitutes a fascinating finding, with significant future implications not only in the research
area but also in the public health arena
38. Discussion
Interestingly, the rs2248814 and rs1060826 AA genotypes are the same genotypes that have
been previously reported to modify the smoking effect and confer an increased risk for
Parkinson Disease (PD) (Hancock et al., 2006; Hancock et al., 2008). The main difference
with the current study is that in PD smoking has a protective effect (Hague et al., 2004;
Hancock et al., 2006; Levecque et al., 2003), partially attributed to the possible protective
effect that nicotine may exert against neurotoxic insults (Fratiglioni & Wang, 2000; Preux et
al., 2000) and a decreased iNOS induction and activity (Hoyt et al., 2003; Mazzio et al.,
2005). Therefore, the presence of either rs2248814 or rs1060826 AA genotype in the
NOS2A gene should remove or at least reduce the possible negative regulation of smoking
on iNOS production and activity. In AMD, however, rs2248814/ rs1060826 AA genotype
and smoking have a synergistic effect. These somewhat conflicting results may reflect
varying degrees of linkage disequilibrium with one or more true functional variants, which
remain to be identified. As previously stated, relatively few cases and controls carry the AA
genotypes, and the wide confidence intervals on the estimated OR suggest that the true OR
may not be significantly different. Therefore, these results should be regarded as hypothesis
generating and further studies are necessary to determine if the presence of the AA genotype
in either rs2248814 or rs1060826 is correlated with a modified protein expression or activity
when cells are exposed to smoking that could account for the effects observed both in PD
and AMD.
40. Acknowledgments
• This research was supported by National
Institutes of Health grant EY12118 (to MP-V
and JLH). A subset of the
• participants was ascertained while Margaret
A. Pericak-Vance was a faculty member at
Duke University.
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• This research was supported by National Institutes of Health grant EY12118 (to MP-V and JLH). A subset of the
• participants was ascertained while Margaret A. Pericak-Vance was a faculty member at Duke University.
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