Daniel H Katz1, Usman A Tahir1, Alexander G Bick2, Akhil Pampana2, Debby Ngo1, Mark D Benson1, Zhi Yu3, Jeremy M Robbins1, Zsu-Zsu Chen1, Daniel E Cruz1, Shuliang Deng1, Laurie Farrell1, Sumita Sinha1, Alec A Schmaier1, Dongxiao Shen1, Yan Gao3, Michael E Hall3, Adolfo Correa3, Russell P Tracy4, Peter Durda4, Kent D Taylor5, Yongmei Liu6, W Craig Johnson7, Xiuqing Guo5, Jie Yao5, Yii-Der Ida Chen5, Ani W Manichaikul8,9, Deepti Jain10, Claude Bouchard11, Mark A Sarzynski12, Stephen S Rich8, Jerome I Rotter5, Thomas J Wang13, James G Wilson1, Pradeep Natarajan2,14,15, Robert E Gerszten1,2. 1. Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA (D.H.K., U.A.T., D.N., M.D.B., J.M.R., Z.-Z.C., D.E.C., S.D., L.F., S.S., A.A.S., D.S., J.G.W., R.E.G.). 2. Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge (A.G.B., A.P., Z.Y., P.N., R.E.G.). 3. University of Mississippi Medical Center, Jackson (Y.G., M.E.H., A.C.). 4. Department of Pathology Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington (R.P.T., P.D.). 5. Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-University of California, Los Angeles, Medical Center, Torrance (K.D.T., X.G., J.Y., Y.-D.I.C., J.I.R.). 6. Department of Medicine, Division of Cardiology, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC (Y.L.). 7. Department of Biostatistics (W.C.J.), University of Washington, Seattle. 8. Center for Public Health Genomics (A.W.M., S.S.R.), University of Virginia, Charlottesville. 9. Division of Biostatistics and Epidemiology, Department of Public Health Sciences (A.W.M.), University of Virginia, Charlottesville. 10. University of Washington, Seattle (D.J.). 11. Human Genomic Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA (C.B.). 12. Department of Exercise Science, University of South Carolina, Columbia (M.A.S.). 13. Department of Medicine, University of Texas Southwestern Medical Center, Dallas (T.J.W.). 14. Cardiovascular Research Center, Massachusetts General Hospital, Boston (P.N.). 15. Department of Medicine, Harvard Medical School, Boston, MA (P.N.). National Heart, Lung, and Blood Institute TOPMed (Trans-Omics for Precision Medicine) Consortium.
Abstract
BACKGROUND: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. METHODS: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). RESULTS: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10-11. These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P=3.27×10-30) and MMP-3 (β=-0.60±0.05, P=1.67×10-32), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P=1.34×10-17) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. CONCLUSIONS: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.
BACKGROUND: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. METHODS: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). RESULTS: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10-11. These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P=3.27×10-30) and MMP-3 (β=-0.60±0.05, P=1.67×10-32), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P=1.34×10-17) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. CONCLUSIONS: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.
Entities:
Keywords:
cardiovascular disease; genetics; proteomics; race and ethnicity
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