Kim, Charles X.

Objectives: We investigated the association of 47 candidate proteomic markers in pathways of inflammation, thrombosis, lipoprotein metabolism, vascular remodeling, and vasoregulation, with the ankle-brachial index (ABI) and peripheral arterial disease (PAD) in a bi-ethnic cohort of African Americans (AA) and non-Hispanic Whites (NHW). Methods: Multiple assay platforms were used to measure 47 candidate proteomic markers in 1324 AA and 1237 NHW participants belonging to hypertensive sibships. ABI was measured using a standard protocol, with values >1.4 excluded and PAD defined as ABI <0.9. Multivariable regression analyses (with generalized estimating equations) were employed to identify markers independently associated with ABI and PAD after adjusting for age, BMI, smoking, hypertension, diabetes, history of heart attack and stroke, medication use, total and HDL cholesterol, and estimated GFR as well as physical activity, alcohol consumption and education level. Results: Higher circulating levels of CRP, myeloperoxidase, NT-proBNP, osteoprotegerin, D-Dimer and fibrinogen were each associated with lower ABI in both AA and NHW. Additional markers significantly associated with lower ABI were; in AA - serum amyloid A, ICAM, IL-6, TNFR-I, TNFR-II, MCP-1, Lp(a), pro-atrial natriuretic peptide, pro-arginine vasopressin, pro-adrenomedullin, pro-endothelin, osteonectin, Factor VIII; and in NHW- Hsp27, ox-LDL and resistin. Markers associated with presence of PAD were: in AA - CRP, NT-proBNP, Lp(a), pro-arginine vasopressin and osteoprotegerin; in NHW -CRP, NT-proBNP, Hsp27, myeloperoxidase, oxidized-LDL, Factor VIII, and D-Dimer. When the significant markers were included in a final model, the R 2 for ABI increased from 15.9 to 19.4 for AA and from 18.1 to 22.1 for NHW; the c-statistic for PAD increased from 0.791 to 0.833 inAA and from 0.841 to 0.866 in NHW. Conclusions: Novel protein markers significantly add to prediction of ABI and PAD in both AA and NHW and may have clinical utility in diagnosis and prognosis of PAD as well as in identifying new therapies for atherosclerotic vascular disease.