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DBS: Section on Statistical Genetics & Bioinformatics
Age-Related Inflammatory Changes: The Role of Genes and Body Composition Changes – funded by the National Institute on Aging
Lead Principal Investigator at Wake Forest University Health Sciences – Y. Liu
Study Staff – Kurt Lohman
This proposal aims to quantify the effects of inflammatory genes and body composition changes on age-related changes in inflammatory markers
Claude D. Pepper: Older Americans Independence Center
Lead Principal Investigator at Wake Forest University Health Sciences – M.E. Miller
Study Staff – June Pierce
The major goals of this project are the testing and dissemination of effective therapies for the treatment and prevention of physical disability from chronic diseases in later life.
Gene Mapping in Systemic Lupus Erythematosus – funded by the National Institute of Arthritis and Musculosketal and Skin Diseases (NIAMS) and Oklahoma Medical Research Foundation.
Lead Principal Investigator at Wake Forest University Health Sciences – Carl Langefeld
Study Staff –Adrienne Williams, Paula Ramos
Systemic Lupus Erythematosus (SLE) is characterized by widespread immune activation and autoantibody production, leading to vasculitis and systemic end-organ damage. The available data indicate that genes such as HLA Class II alleles and the lymphoid phosphatase PTPN22 are important risk factors for SLE, however it is likely that there are many additional alleles contributing to the SLE phenotype. In recent years, the current application has bridged a transition into association-based studies to identify the genetic factors contributing to human lupus. Here further studies are proposed on three promising candidate genes that show evidence for association with SLE: estrogen receptor related gamma (ESRRG), PTPN22, and interferon regulatory factor 5 (IRF-5). The genetic evidence for IRF-5 is particularly strong, with the recent demonstration of an association signal in SLE that exceeds genome-wide significance (P=2.4 x 10~15). Furthermore, the SNP in IRF-5 that shows the strongest evidence for association introduces a splice donor site for an alternative first exon of the gene, leading to the production of a unique mRNA isoform and perhaps altered interferon signaling. In addition, follow-up studies are proposed for the first genome-wide association screen in SLE, which is currently underway as part of the International SLE Genetics Network (SLEGEN). The Gene Mapping in Systemic Lupus Erythematosus is a collaboration between Dr. Tim Behrens, who has a long track-record of contributions to understanding the genetics and pathophysiology of SLE at the University of Minnesota, Dr. Carl Langefeld at Wake Forest University who has provided longstanding analytic support for the project, and Dr. David Altshuler at the Broad Institute of Harvard and MIT who has significant expertise in population and medical genetics. This study leverages the large, well-phenotyped Minnesota SLE family and case collection, the infrastructure for high-throughput genotyping at Broad, and significant capabilities in statistical and population genetic analysis. It is anticipated that these experiments will lead rapidly to the identification of novel alleles that contribute to SLE, and ultimately to improvements in our understanding and treatment of autoimmunity.
Lay summary: The current proposal aims to identify genetic factors that contribute to the autoimmune disease systemic lupus erythematosus. We expect that the information learned will lead to better ways to diagnose and treat lupus and other autoimmune diseases.
Genetics of African American Type 2 Diabetes – Funded by the National Institutes of Health and the National Institute of Diabetes and Digestive and Kidney Diseases
Principal Investigator at Wake Forest University Health Sciences – Don Bowden
Study Staff – Carl Langefeld, Lingyi Lu, Matt Stiegert
The goal of this study is to identify type 2 diabetes genes of importance in African American populations.
Genetic Analysis of African American Hypertensive End-Stage Renal Disease – funded by the National Institute of Diabetes and Digestive and Kidney Diseases
Lead Principal Investigator at Wake Forest University Health Sciences – Barry Freedman
Study Staff – Carl Langefeld, Jasmin Divers, Lingyi Lu, Mary Cunningham, Matt Stiegert
The focus for this application is to locate and identify one or more genes that cause hypertension-associated end-stage renal (H-ESRD) disease in the African American population.
Genetics of Adiposity and Glucose Homeostasis: The IRAS Family Study – funded by the National Heart, Lung and Blood Institute
Lead Principal Investigator at Wake Forest University Health Sciences – Lynne Wagenknecht
Study Staff – Carl Langefeld, Mark Brown, Leora Henkin, Adrienne Williams, Julie Ziegler, Wei Wang
The IRAS Family Study is a multi-center investigation to identify genes and risk factors for adiposity and glucose homeostasis phenotypes. Wake Forest University (Department of Public Health Sciences) serves as the Data Coordinating Center. The ascertainment, recruitment and baseline phenotypic assessment of this minority-only cohort (African American and Hispanic) has been successfully completed by the three clinical centers during the first five-year funding period. A total of 132 pedigrees (2019 individuals) generated 2675 sibling pairs and 5175 avuncular pairs. Genetic and epidemiological analyses of the phenotypic data have been conducted and results disseminated. These investigations have identified substantial genetic contribution within these direct measures of adiposity and glucose homeostasis phenotypes, and they have revealed important genetic and environmental relationships between these phenotypes. Linkage analyses have identified genomic regions related to adiposity and glucose homeostasis phenotypes. The linkage results have motivated follow-up by molecular genetic approaches.
The continuation of this project was funded by NHLBI in January 2005. It targets the further exploration of genomic regions and positional cloning of genes contributing to variation in adiposity and glucose homeostasis. Furthermore, it will expand the phenotypic domains of adiposity and glucose homeostasis by re-examining the original cohort and measuring new phenotypes (adipocytokines, total body fat and lean mass by DXA, behaviors) and obtaining repeated measurements of selected original phenotypes (CT-measured abdominal fat and fasting insulin) for use in epidemiologic and genetic analyses.
Identification of Diabetes Genes on Human Chromosome 20q12-q13/1 –funded by the National Institute of Diabetes and Digestive and Kidney Diseases
Principal Investigator at Wake Forest University Health Sciences – Don Bowden
Study Staff – Carl Langefeld, Jasmin Divers, Lingyi Lu
The goal of this study is to map, clone, sequence, and determine the function of human genes which cause Type 2 diabetes mellitus (non-insulin dependent diabetes, NIDDM, maturity onset diabetes).
Interaction Effects of Genes in the inflammation pathway and dietary, supplement, and medication exposures on general cancer risk – funded by the National Institutes of Health
Principal Investigator at Wake Forest University Health Sciences – J. Xu
Study Staff – Carl Langefeld
The goals of this study is to 1) test for main effect of genetic variants in ~1,000 genes involved in innate immunity and inflammatory responses on overall cancer risk, and 2) test for interaction effects of genetic variants with dietary, supplement, and NSAID exposures on overall cancer risk.
Interaction of PTEN and CDKN1B in PCa susceptibility – funded by the National Cancer Institute
Principal Investigator at Wake Forest University Health Sciences – J. Xu
Study Staff – Matt Stiegert
This study proposes to systematically identify and evaluate mutations and sequence variants in PTEN and CDKN1B using high throughput sequencing and genotyping methods in a well-established collection of 188 HPC families, each of which have at least 3 men affected with prostate cancer.
The International Consortium on the Genetics of Systemic Lupus Erythematosus (SLEGEN) Comprehensive SNP-based Genome Screen of SLE families (SLEGEN 2) (https://www.SLEGEN.org) – funded by the Alliance for Lupus Research (www.lupusresearch.org) and the Oklahoma Medical Research Foundation.
Principal Investigator at Wake Forest University Health Sciences – Carl Langefeld
Study Staff – Jasmin Divers, Miranda Marion, Adrienne Williams, Julie Ziegler, Wei Wang, Laurie Russell
The genetic makeup of an individual strongly influences the risk of developing systemic lupus erythematosus (SLE). The identification of genes that predispose an individual to SLE will lead to earlier and better diagnosis, better treatments, and possibly prevention.
To this end, the International Consortium on the Genetics of Systemic Lupus Erythematosus (SLEGEN) was formed in 2004 and is composed of lupus researchers who have agreed to pool their knowledge and resources to search for genes that predispose to lupus. Currently, eight laboratories have contributed DNA samples for genotyping at the Broad Institute that will be analyzed for association with SLE by Dr. Carl Langefeld and his team, as part of a four stage study design. Stages one and two of this design have been graciously funded by the Alliance for Lupus Research (www.lupusresearch.org). The first stage is among the first applications of the 317,000 Illumina single nucleotide polymorphism (SNP) chip technologies (Thomas et al. 2005; Am J Hum Genet 77:337-345). In this stage of the study, approximately 767 SLE patients (cases) will be compared to approximately 383 non-SLE patients (controls) for differences among the 317,000 SNPs.
Juvenile Rheumatoid Arthritis (JRA) as a Complex Genetic Trait – funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and Children’s Hospital Medical Center – Cincinnati
Principal Investigator at Wake Forest University Health Sciences – Carl Langefeld
Study Staff – Miranda Marion, Adrienne Williams, Matt Stiegert, Wei Wang, Mark Brown, Mary Cunningham
The risk of JRA in siblings of JRA cases is much greater than that in the general population, suggesting a genetic (familial) basis for the disease. At the same time, the clinical appearance of the disease (single joint/multiple joint involvement, severity, age at onset) suggests that there may be heterogeneity at ht genetic level. Thus, collection of families with multiple affected children with JRA and performance of a genome-wide screen will allow detection of regions of the genome that could harbor JRA susceptibility genes.
Machine Learning to Identify Complex Interactions in Genome-Wide Association Data – funded by the National Institutes of Health
Principal Investigator at Wake Forest University Health Sciences – D. Herrington
Study Staff – Carl Langefeld
This project aims to develop new approaches to identify the relationship between genetic and environmental factors which could then be used to identify people at high risk for a disease. Determining specific genetic and/or environmental factors that influence a person’s risk of disease may help doctors reduce risk for disease and reveal new treatments for disease.
Mapping Genes for NIDDM Nephropathy in African Americans – funded by the National Institute of Diabetes and Digestive and Kidney Disease
Principal Investigator at Wake Forest University Health Sciences – Don Bowden
Study Staff – Carl Langefeld, Jasmin Divers, Lingyi Lu
The focus of this project renewal is to locate and identify one or more genes using modern molecular genetic methods.
MESA Family – sponsored by the National Heart, Lung and Blood Institute (NHBLI)
Principal Investigator at Wake Forest University Health Sciences – Don Bowden
Study Staff – Mark Brown
This unique study will examine the range of noninvasive measures of subclinical CVD, including assessment of coronary calcium by computerized tomography (EBCT or helical CT), carotid ultrasound, and magnetic resonance imaging (MRI). MESA will include 6500 subjects drawn from four ethnic groups: whites, African Americans, Hispanics and Chinese Americans.
Pericardial fat and subclinical and clinical measures of coronary heart disease – funded by the National Heart, Lung and Blood Institute
Principal Investigator at Wake Forest University Health Sciences – J. Ding
Study Staff – Kurt Lohman
The proposed study, an ancillary study to the Multi-Ethnic Study of Atherosclerosis, will examine the association of pericardial fat with subclinical coronary heart disease measured by CT, the association of baseline and changes in pericardial fat with changes in calcified coronary plaque over three years, and the risk of clinical coronary heart disease associated with pericardial fat.
SNPs and Extend of Atherosclerosis (SEA) U01 – funded by the National Heart, Lung and Blood Institute
Lead Principal Investigator at Wake Forest University Health Sciences – David Herrington
Study Staff – Carl Langefeld
Subclinical CVD in African American Type 2 Diabetes – funded by the National Institutes of Health
Lead Principal Investigator at Wake Forest University Health Sciences – B.I. Freedman
Study Staff – Carl Langefeld, Mary Cunningham
The long term objective of the African American-Diabetes Heart Study is to identify the causes of the markedly lower amounts of calcified atherosclerotic plaque in African American (AA) subjects with type 2 diabetes mellitus (T2DM), relative to European American (EA).
Type 1 Diabetes Genetics Consortium – funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the University of Virginia
Lead Principal Investigator at Wake Forest University Health Sciences – Joan Hilner
Study Staff – Mark Brown, June Pierce, Lingyi Lu, Kurt Lohman, Hoa Teuschler
The goal of the consortium is to organize international efforts to identify genes that determine an individual’s risk for Type 1 diabetes.
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