Soluble Urokinase Plasminogen Activator Receptor: Genetic Variation and Cardiovascular Disease Risk in Black Adults

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 the Black population have not been evaluated. Methods: We measured suPAR in 3492 Blacks 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.

Elevated plasma complement factor H related 5 protein is associated with venous thromboembolism

“…The same caution should be extended to findings generated using other high throughput affinity proteomics technologies vulnerable to non-specific protein binding, such as aptamer-based 77 , where missense single nucleotide polymorphisms can affect binding in a manner where a genetic difference drive associations, rather than protein levels (Supplementary information Fig. S 1f ) 78 , 79 . Studies comparing different affinity proteomics technologies have found correlations of proteins assayed with two or more platforms to range from highly concordant (Spearman´s ⍴ = 0.95) to inversely correlated ( ⍴ = −0.48) 78 , highlighting further the need for orthogonal validation of any potential biomarker identified.…”

Elevated plasma Complement Factor H Regulating Protein 5 is associated with venous thromboembolism and COVID-19 severity

“…From a technological perspective, our study demonstrates the need for orthogonal verification of any potential biomarker identified using antibody-based proteomics screening [34, 35]. The same caution should be extended to findings generated using other high throughput affinity proteomics technologies vulnerable to non-specific protein binding, such as aptamer-based [74], where missense single nucleotide polymorphisms can affect binding in a manner where a genetic difference drive associations, rather than protein levels (Figure S1 F) [75, 76]. Studies comparing different affinity proteomics technologies have found correlations of proteins assayed with two or more platforms to range from highly concordant (r = 0.95) to inversely correlated (r = −0.48) [75], highlighting further the need for orthogonal validation of any potential biomarker identified.…”

Increased soluble urokinase plasminogen activator levels modulate monocyte function to promote atherosclerosis

“…Our GWAS analysis encompasses over 24,000 individuals in whom suPAR levels were measured using the suPARnostic (ViroGates) immunoassay used in the seminal studies on suPAR, kidney disease, and CVD outcomes ( 14 , 18 , 28 , 34 , 67 ). While our analysis included participants of mostly European ethnicity, a smaller GWAS in Black individuals also identified rs4760 as a determinant of suPAR levels measured using immunoassay ( 69 ). Finally, our experimental approach relies on the use of murine models of atherosclerosis, which cannot recapitulate all the features of the human disease, with major differences in lipoprotein metabolism and bile acid absorption ( 70 ).…”