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Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights Into Cardiovascular Disease.
Katz, Daniel H; Tahir, Usman A; Bick, Alexander G; Pampana, Akhil; Ngo, Debby; Benson, Mark D; Yu, Zhi; Robbins, Jeremy M; Chen, Zsu-Zsu; Cruz, Daniel E; Deng, Shuliang; Farrell, Laurie; Sinha, Sumita; Schmaier, Alec A; Shen, Dongxiao; Gao, Yan; Hall, Michael E; Correa, Adolfo; Tracy, Russell P; Durda, Peter; Taylor, Kent D; Liu, Yongmei; Johnson, W Craig; Guo, Xiuqing; Yao, Jie; Ida Chen, Yii-Der; Manichaikul, Ani W; Jain, Deepti; Bouchard, Claude; Sarzynski, Mark A; Rich, Stephen S; Rotter, Jerome I; Wang, Thomas J; Wilson, James G; Natarajan, Pradeep; Gerszten, Robert E.
  • Katz DH; 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.).
  • Tahir UA; 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.).
  • Bick AG; Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge (A.G.B., A.P., Z.Y., P.N., R.E.G.).
  • Pampana A; Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge (A.G.B., A.P., Z.Y., P.N., R.E.G.).
  • Ngo D; 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.).
  • Benson MD; 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.).
  • Yu Z; University of Mississippi Medical Center, Jackson (Y.G., M.E.H., A.C.).
  • Robbins JM; 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.).
  • Chen ZZ; 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.).
  • Cruz DE; 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.).
  • Deng S; 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.).
  • Farrell L; 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.).
  • Sinha S; 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.).
  • Schmaier AA; 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.).
  • Shen D; 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.).
  • Gao Y; University of Mississippi Medical Center, Jackson (Y.G., M.E.H., A.C.).
  • Hall ME; University of Mississippi Medical Center, Jackson (Y.G., M.E.H., A.C.).
  • Correa A; University of Mississippi Medical Center, Jackson (Y.G., M.E.H., A.C.).
  • Tracy RP; Department of Pathology Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington (R.P.T., P.D.).
  • Durda P; Department of Pathology Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington (R.P.T., P.D.).
  • Taylor KD; 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.).
  • Liu Y; Department of Medicine, Division of Cardiology, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC (Y.L.).
  • Johnson WC; Department of Biostatistics (W.C.J.), University of Washington, Seattle.
  • Guo X; 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.).
  • Yao J; 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.).
  • Ida Chen YD; 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.).
  • Manichaikul AW; Center for Public Health Genomics (A.W.M., S.S.R.), University of Virginia, Charlottesville.
  • Jain D; Division of Biostatistics and Epidemiology, Department of Public Health Sciences (A.W.M.), University of Virginia, Charlottesville.
  • Bouchard C; University of Washington, Seattle (D.J.).
  • Sarzynski MA; Human Genomic Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA (C.B.).
  • Rich SS; Department of Exercise Science, University of South Carolina, Columbia (M.A.S.).
  • Rotter JI; Center for Public Health Genomics (A.W.M., S.S.R.), University of Virginia, Charlottesville.
  • Wang TJ; 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.).
  • Wilson JG; Department of Medicine, University of Texas Southwestern Medical Center, Dallas (T.J.W.).
  • Natarajan P; 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.).
  • Gerszten RE; Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge (A.G.B., A.P., Z.Y., P.N., R.E.G.).
Circulation ; 145(5): 357-370, 2022 02.
Article en En | MEDLINE | ID: mdl-34814699
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, ß=0.61±0.05, P=3.27×10-30) and MMP-3 (ß=-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, ß=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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Enfermedades Cardiovasculares / Proteoma / Estudio de Asociación del Genoma Completo Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Adult / Female / Humans / Male Idioma: En Año: 2022 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Enfermedades Cardiovasculares / Proteoma / Estudio de Asociación del Genoma Completo Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Adult / Female / Humans / Male Idioma: En Año: 2022 Tipo del documento: Article