The purpose of this award is to provide Dr. Themistocles (Tim) Assimes, Assistant Professor of Medicine at Stanford University, the support necessary to transition him from a junior investigator to an independent physician scientist studying the genetic determinants of various human complex traits related to cardiovascular medicine. Dr. Assimes is an adult cardiologist with an advanced degree in epidemiology and biostatistics and significant experience conducting human genetic studies using existing sample sets. Career development activities focus on consolidating his expertise by 1) designing and implementing his first human subjects clinical research study involving handling of biospecimens, 2) increasing his involvement in several international genetic epidemiology collaborations, and 3) attending didactic courses to expand his knowledge base in contemporary genetics, molecular biology, advanced statistical genetics and the pathophysiology of insulin resistance (IR). An advisory committee, which includes his mentors, Drs. Thomas Quertermous and Gerald Reaven, will carefully monitor his progress towards independence. The research proposal builds on ongoing efforts in the candidate's division to identify the root causes of IR by studying South Asians, a racial/ethnic group known to be strongly predisposed to IR and its adverse consequences for unclear reasons. In this context, Specific Aim 1 proposes to quantify IR and its primary established determinants of adiposity and physical fitness in ~330 South Asians and ~100 white/Europeans using 'gold standard'measuring tools. These include an insulin suppression test to assess insulin mediated glucose uptake, DXA and abdominal MRI scans to determine total and regional body fat, pedometers to estimate current physical activity, and a symptom limited cardiopulmonary stress test to estimate maximum oxygen uptake (max VO2). A new research partnership between the non-profit South Asian Heart Center at El Camino Hospital, Mountain View, CA, and Division of Cardiovascular Medicine at Stanford University will facilitate recruitment.
This aim will test the hypothesis that a predisposition to IR in South Asians is evident even after taking into account significant differences between the two racial/ethnic groups in adiposity and physical fitness not captured by more traditional methods of assessment of these variables (e.g., BMI and physical activity questionnaires).
In Specific Aim 2, the candidate will perform genome wide genotyping in ~400 South Asians followed by gene/SNP set pathway analyses using innovative analytical techniques developed by collaborators at SAGE Bionetworks. The same analytical techniques will be applied to multiple other sample sets with GWAS and direct measures of IR representing 3 other race/ethnic groups including Europeans, East Asians, and Hispanics.
This aim will compare and contrast pathways associated with IR across all groups and test the hypothesis that South Asians are more IR because they have inherited a relatively inefficient cellular mechanism of handling glucose compared to other racial/ethnic groups.
Insulin resistance is a physiologic state where fat, muscle and liver cells lose their ability to respond to insulin. The resulting high levels of insulin predispose to the development of diabetes, heart disease, and other serious conditions. Work proposed in this grant aims to identify the reasons some populations are particularly high risk of insulin resistance and its consequences.
|Howson, Joanna M M; Zhao, Wei; Barnes, Daniel R et al. (2017) Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms. Nat Genet 49:1113-1119|
|Assimes, Themistocles L; Lee, I-T; Juang, Jyh-Ming et al. (2016) Genetics of Coronary Artery Disease in Taiwan: A Cardiometabochip Study by the Taichi Consortium. PLoS One 11:e0138014|
|Loley, Christina; Alver, Maris; Assimes, Themistocles L et al. (2016) No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis. Sci Rep 6:35278|
|Goldstein, Benjamin A; Assimes, Themistocles; Winkelmayer, Wolfgang C et al. (2015) Detecting clinically meaningful biomarkers with repeated measurements: An illustration with electronic health records. Biometrics 71:478-86|
|Salfati, Elias; Nandkeolyar, Shuktika; Fortmann, Stephen P et al. (2015) Susceptibility Loci for Clinical Coronary Artery Disease and Subclinical Coronary Atherosclerosis Throughout the Life-Course. Circ Cardiovasc Genet 8:803-11|
|Ghosh, Sujoy; Vivar, Juan; Nelson, Christopher P et al. (2015) Systems Genetics Analysis of Genome-Wide Association Study Reveals Novel Associations Between Key Biological Processes and Coronary Artery Disease. Arterioscler Thromb Vasc Biol 35:1712-22|
|Goldstein, Benjamin A; Yang, Lingyao; Salfati, Elias et al. (2015) Contemporary Considerations for Constructing a Genetic Risk Score: An Empirical Approach. Genet Epidemiol 39:439-45|
|Assimes, Themistocles L; Quertermous, Thomas (2014) Study of exonic variation identifies incremental information regarding lipid-related and coronary heart disease genes. Circ Res 115:478-80|
|Knowles, Joshua W; Assimes, Themistocles L; Tsao, Philip S et al. (2013) Measurement of insulin-mediated glucose uptake: direct comparison of the modified insulin suppression test and the euglycemic, hyperinsulinemic clamp. Metabolism 62:548-53|