The NHLBI CPS team has been heavily invested in research related to SHARe (SNP Health Association Resource), and in initiating and piloting multiple phases of the SABRe CVD Initiative (Systems Approach to Biomarker Research in Cardiovascular Disease). I. Dr. Levy Much of Dr. Levy'd personal scientific effort in 2009 has been devoted to two efforts: a) genetic research and b) biomarker research. A) Dr. Levy is leading Framingham efforts in the area of hypertension genetics. This effort comprises 3 elements: i) Leader of the SHARe Blood Pressure Working Group, ii) Leader of the CARe Blood Pressure Working Group, and iii) Resequencing projects directed at hypertension candidate genes. In conjunction with SHARe, Dr. Levy has established a CHARGE Consortium Blood Pressure Genetics Working Group consisting of investigators from Framingham, ARIC, Rotterdam, CHS, and AGES. The CHARGE blood pressure genome-wide association study (GWAS) findings were published in Nature Genetics. Briefly, our GWAS of systolic (SBP), diastolic BP (DBP), and hypertension in the CHARGE Consortium (n=29,136) identified 13 SNPs for SBP, 20 for DBP, and 10 for hypertension at p <4x10-7. We identified four loci that attained genome-wide significance (p<5x10-8) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK/ULK3, SH2B3, TBX3/TBX5, ULK4), and one for hypertension (ATP2B1). Dr. Levy now co-leads a yet larger international blood pressure genetics consortium known as ICBP, which includes GWAS data on nearly 70,000 people and de novo replication genotyping on another 70,000 people. This is the largest blood pressure consortium in the world and results from this effort indicate that about 25 blood pressure loci have been identified. Similarly, as co-leader of the CARe Blood Pressure Working Group, Dr. Levy will help in analyzing 2500 cardiovascular candidate genes in relation to blood pressure. Third, Dr. Levy is co-PI (with Chris Newton-Cheh) of a resequencing study that will characterize rare variants in 23 BP candidate genes. We are in the process of genotyping about 250 variants (mostly missense) in these genes that are differentially present at the low or high extremes of blood pressure. We completed genotyping these variants in 7000 Framingham participants in the third quarter of 2009 and should have results completed in the beginning of FY '10. Dr. Levy and Dr. Newton-Cheh will expand the number of blood pressure candidate genes to be resequenced in individuals at the extremes of the population blood pressure extremes and will genotype variants of interest in 7000 people from Framingham. Replication of findings will be sought across other NHLBI funded studies, either via in silico lookup within GWAS results, or via de novo genotyping. In this way the CPS is at the cutting edge of identifying both common and rare variants associated interindividual variation in blood pressure with the belief that identifying novel BP genes advances our understanding of BP regulation and highlights potential drug targets for the prevention or treatment of hypertension. B) The second major focus of Dr. Levy's effort in FY '09 has been the SABRe CVD Initiative. For SABRe Project 1, we finalized of a CRADA to conduct state-of-the-art discovery metabolomics and proteomics of atherosclerotic cardiovascular disease and metabolic syndrome risk factors. Feasibility testing of plasma samples on multiple metabolomic and proteomic platforms was carried out and indicated a high level of success in identifying hundreds of metabolites and proteins with high reproducibility. For SABRe Project 2, we are nearing the completion of a contract to conduct immunoassays on 7000 Framingham participants for 180 most promising protein biomarkers. For SABRe Project 3, we completed a feasibility study of gene expression profiling in 3 sources of WBC-derived RNA from 50 Framingham participants;all lab work was successfully completed by the NHLBI Core Microarray Lab (Dr. Raghavachari) and analyses were completed by Dr. Peter Munson's lab (CIT). We plan to move forward with a large-scale study of gene expression in 6000 Framingham individuals. When this resource is combined with the SHARe database, we will be able to catalog genetic contributions to gene expression and the relations of common genetic variation and gene expression to disease phenotypes. I have met with David Lipman and Jim Ostell to plan for NCBI to create a resource of gene expression data and to make this accessible to the outside scientific community in a manner similar to the SHARe resource. Last, for SABRe Project 4, we are profiling microRNA expression in 6000 Framingham participants (extramural contract with Dr. Jane Freedman at Boston University). A feasibility study of microRNA levels in 50 Framingham participants was completed in FY '09. II. Dr. Fox Dr. Fox's scientific focus is in the areas of metabolic risk factors for cardiovascular disease, including obesity, diabetes, and chronic kidney disease. The Fox lab remains highly productive, with 39 articles published from Oct 2008 to Sept 2009, and several additional articles at various stages of preparation. A) In the area of obesity, Dr. Fox continues to successfully mentor several post-doctoral fellows and junior faculty members in the creation and use of several CT fat datasets related to subcutaneous and visceral abdominal fat, pericardial fat, fatty liver, peri-aortic fat, and fatty kidney. This work has resulted in 14 published manuscripts in 2008, with several additional manuscripts in variation stages of preparation. In addition, Dr. Fox continues to lead the CHARGe adiposity working group, an international consortium. This work resulted in the identification of NRXN3 in relation to adiposity traits and was published in 2009. This group is now actively collaborating with the GIANT consortium, working on large-scale GWAS projects in the area of anthropometric traits. B) In the area of diabetes, Dr. Fox has mentored Sarah Rosner Preis (NHLBI fellow) in studies of diabetes and cardiovascular disease. This work resulted in two publications in Circulation in 2009-2009. Dr. Fox also participated in several glycemic traits related projects in terms of candidate gene studies and genome-wide association, resulting in several high-profile publications C) Kidney disease research efforts included mentoring of Meredith Foster (doctoral student) in the area of fatty kidney, as well as Conall OSheaghdha, an NHBLI post-doctoral fellow. Dr. Fox has expanded initial collaborations in the area of CKD genetics. She currently leads the CHARGE renal working group, which has lead to the discovery of 8 new genes for uric acid, 5 genes for chronic kidney disease, and 11 genes for serum electrolytes, resulting in senior-author publications this past year in the Lancet and Nature Genetics. The discovery of the UMOD gene in association with CKD has lead to novel biomarker discovery work. Dr. Fox is also the founder and convener of CKDGen, an international consortium dedicated to uncovering genes for renal disease. CKDGen includes more than 20 participating studies with over 70,000 individual participants and 100 investigators. This group has recently identified 13 new genes for kidney disease.
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