Nels C Olson1, Laura M Raffield2, Anne H Moxley2, Tyne W Miller-Fleming3, Paul L Auer4, Nora Franceschini5, Debby Ngo6, Timothy A Thornton7, Ethan M Lange8, Yun Li2,9,10, Deborah A Nickerson11, Neil A Zakai1,12, Robert E Gerszten6, Nancy J Cox3, Adolfo Correa13, Karen L Mohlke2, Alexander P Reiner14. 1. Departments of Pathology and Laboratory Medicine (N.C.O., N.A.Z.), University of Vermont, Burlington. 2. Departments of Genetics (L.M.R., A.H.M., Y.L., K.L.M.), University of North Carolina, Chapel Hill. 3. Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (T.W.M.-F., N.J.C.). 4. Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee (P.L.A.). 5. Epidemiology (N.F.), University of North Carolina, Chapel Hill. 6. Beth Israel Deaconess Medical Center, Boston, MA (D.N., R.E.G.). 7. Departments of Biostatistics (T.A.T.), University of Washington, Seattle. 8. Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora (E.M.L.). 9. Biostatistics (Y.L.), University of North Carolina, Chapel Hill. 10. Computer Science (Y.L.), University of North Carolina, Chapel Hill. 11. Genome Sciences (D.A.N.), University of Washington, Seattle. 12. Medicine (N.A.Z.), Larner College of Medicine, University of Vermont, Burlington. 13. Department of Medicine, University of Mississippi Medical Center, Jackson (A.C.). 14. Epidemiology (A.P.R.), University of Washington, Seattle.
Abstract
BACKGROUND: suPAR (Soluble urokinase plasminogen activator receptor) has emerged as an important biomarker of coagulation, inflammation, and cardiovascular disease (CVD) risk. The contribution of suPAR to CVD risk and its genetic influence in Black populations have not been evaluated. METHODS: We measured suPAR in 3492 Black adults from the prospective, community-based JHS (Jackson Heart Study). Cross-sectional associations of suPAR with lifestyle and CVD risk factors were assessed, whole-genome sequence data were used to evaluate genetic associations of suPAR, and relationships of suPAR with incident CVD outcomes and overall mortality were estimated over follow-up. RESULTS: In Cox models adjusted for traditional CVD risk factors, estimated glomerular filtration rate, and CRP (C-reactive protein), each 1-SD higher suPAR was associated with a 21% to 31% increased risk of incident coronary heart disease, heart failure, stroke, and mortality. In the genome-wide association study, 2 missense (rs399145 encoding p.Thr86Ala, rs4760 encoding p.Phe272Leu) and 2 noncoding regulatory variants (rs73935023 within an enhancer element and rs4251805 within the promoter) of PLAUR on chromosome 19 were each independently associated with suPAR and together explained 14% of suPAR phenotypic variation. The allele frequencies of each of the four suPAR-associated genetic variants differ considerably across African and European populations. We further show that PLAUR rs73935023 can alter transcriptional activity in vitro. We did not find any association between genetically determined suPAR and CVD in JHS or a larger electronic medical record-based analyses of Blacks or Whites. CONCLUSIONS: Our results demonstrate the importance of ancestry-differentiated genetic variation on suPAR levels and indicate suPAR is a CVD biomarker in Black adults.
BACKGROUND: suPAR (Soluble urokinase plasminogen activator receptor) has emerged as an important biomarker of coagulation, inflammation, and cardiovascular disease (CVD) risk. The contribution of suPAR to CVD risk and its genetic influence in Black populations have not been evaluated. METHODS: We measured suPAR in 3492 Black adults from the prospective, community-based JHS (Jackson Heart Study). Cross-sectional associations of suPAR with lifestyle and CVD risk factors were assessed, whole-genome sequence data were used to evaluate genetic associations of suPAR, and relationships of suPAR with incident CVD outcomes and overall mortality were estimated over follow-up. RESULTS: In Cox models adjusted for traditional CVD risk factors, estimated glomerular filtration rate, and CRP (C-reactive protein), each 1-SD higher suPAR was associated with a 21% to 31% increased risk of incident coronary heart disease, heart failure, stroke, and mortality. In the genome-wide association study, 2 missense (rs399145 encoding p.Thr86Ala, rs4760 encoding p.Phe272Leu) and 2 noncoding regulatory variants (rs73935023 within an enhancer element and rs4251805 within the promoter) of PLAUR on chromosome 19 were each independently associated with suPAR and together explained 14% of suPAR phenotypic variation. The allele frequencies of each of the four suPAR-associated genetic variants differ considerably across African and European populations. We further show that PLAUR rs73935023 can alter transcriptional activity in vitro. We did not find any association between genetically determined suPAR and CVD in JHS or a larger electronic medical record-based analyses of Blacks or Whites. CONCLUSIONS: Our results demonstrate the importance of ancestry-differentiated genetic variation on suPAR levels and indicate suPAR is a CVD biomarker in Black adults.
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