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Genetic epidemiology study and methodology development
 

Research focuses:

One of our researches is primarily focused on longitudinal genetic study of cardiovascular aging and diseases. Vascular aging (VA) is the progressive alteration of vascular structure over time, and the aging-associated vascular remodeling is mainly characterized by increased artery stiffness, which can be quantified by "biomarkers" including pulse wave velocity (PWV), augmentation index (AIx), pulse pressure (PP), carotid intima-media thickness (IMT), and blood flow velocity (BFV). The progress of these "biomarkers", known as vascular aging phenotypes, in early age strongly predicts the occurrence of cardiovascular disease (CVD), the leading cause of death in the old age, which account for over 85% of the mortality of individuals older than 65 years in the USA.

 


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The second area of our research is the development of powerful and computationally efficient statistical genetic methods, including rare variant test, pathway association test, and test of high-order gene-gene, gene-environment interaction, cumulative multiple variant and pleiotropic effects.  1) Rare variant test: Because of very low frequency of rare genetic variants in population, traditional single-marker and multivariate methods have exceptionally low power for testing effects of rare variants. Our research objective is to develop a computationally fast and powerful method that are applicable for any known or unknown phenotype distribution, mixed protective or risk rare variant effects and different sequencing strategies (random sequencing or extreme phenotype sequencing).  2) Pathway association test: A large number of genome-wide association studies have been completed up to date. The objective is to develop a computationally fast and powerful method that can test for pathway associations by post-GWAS analysis with adjustment for linkage disequilibrium among different genetic variants.  3) Test of high-order gene-gene, gene-environment interaction, cumulative multiple variant and pleiotropic effects. As a complement to GWAS, The objective is to develop powerful method for testing effects of multiple genetic variants over genome.

The third area of our research is the epidemiology study of Chinese children's development. Collaborating with Shanghai Jiao-Tong University Medical School, by studying Chinese children at early age and puberty, our research objective is to identify the specific life styles, environment and genetic factors that can influence children's development, primarily focused on sleeping problem and development of obesity. The long-term objective is to help devising strategies for promotion of healthy development and prevention of obesity at young age.

 

Personnel:

  • Hao Mei, Ph.D., PI, Tulane University 
     
  • Michal Jazwinski, PhD (PI) and Aging Study group, Tulane University 
     
  • Gerald Berenson, PhD (PI) and Bogalusa Heart Study group, Tulane University
     
  • Fan Jiang, MD, PhD (PI) and Shanghai Children's Sleep Project. Shanghai Jiao-Tong University Medical School.
     
  • Eden R. Martin, Ph.D (Consultant), Professor of Human Genetics, Director, Center for Genetic epidemiology and Statistical Genetics, University of Miami.
     
  • Bruce Weir, PhD(Consultant),  Chair and Professor of Biostatistics, Adjunct Professor of Genome Sciences, University of Washington

 

Studies:


 

Genome-wide gene expression study of osteogenic cells for osteoporosis

Osteoporosis is a major public health problem, especially in women. It is mainly characterized by low bone mineral density (BMD). Women have much lower BMD than men. Some BMD genes/genomic regions are sex-specific. Menopause is associated with rapid bone loss. 


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Bone marrow mesenchymal stem cells (BMMSCs) and peripheral blood monocytes (PBMs), are precursors for osteoblasts (bone formation cells) and osteoclasts (bone resorption cells), respectively.

The GOAL of this project is to identify genes that are differentially expressed (at mRNA levels) in BMMSCs and PBMs in females with low vs. high BMD and with menopausal status changes. Such genes are expected to be important for variation of female BMD and women health in general.

We are recruiting otherwise healthy females aged 50-55, stratified by discordant BMD values and menopausal status. Bone marrow aspiration and phlebotomy will be performed on the recruited subjects to isolate BMMSCs and PBMs. Total RNA will be extracted from the isolated cells. Using the total RNA extracted, microarray profiling experiments and analyses will be performed for >40,000 known human genes and ESTs to identify differentially expressed genes/ESTs in low vs. high BMD subjects, which will be further verified with real-time RT-PCR.

As preliminary studies for this project, we have published several papers on microarray profiling of PBMs in high vs. low BMD subjects (J Biol Chem. 2005 12;280(32):29011-6; J Bone Miner Res. 2010 25(2):339-55; Bone. 2009 44(5):1010-4). These studies have identified several interesting genes/proteins important to osteoporosis.


 

Genome-wide association study of periodontitis

Periodontitis, characterized by progressive loss of periodontal attachment and alveolar bone, is one of the most prevalent chronic diseases and a major cause for loss of permanent teeth in the US. Periodontitis affects ~35% of the US adults over the age of 30 years.

Pathogenesis of periodontitis is complex, with multiple contributing factors, such as life styles, nutrition, systemic diseases, and medications etc. Among these factors, genetic determination is most important as evidenced by a high heritability of ~50% for periodontitis. However, specific genes underlying periodontitis are currently unknown.

With recent significant advances in densely spaced SNP identification, high-throughput genotyping technologies, improved knowledge of linkage disequilibrium (LD) patterns and haplotype structure across the human genome, genome-wide association studies (GWAS) have now become a feasible and powerful strategy for genetic dissection of human common diseases.

 

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Our general hypothesis is that risk genes for periodontitis can be detected with a powerful GWAS. To make preparation for such a GWAS, under the support of an NIH RC2 grant, we are performing a pilot study to extract and quantitate genomic DNA from buffy coat samples from periodontitis subjects and normal controls, which are provided by our collaborators, Dr. Robert Genco's group at University of Buffalo.

 

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Department of Biostatistics, 1440 Canal Street, Suite 2001, New Orleans, LA 70112, 504-988-5164 kbranley@tulane.edu