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8 133 | Novel protein biomarker predictors of CAD in FH onset atherosclerotic CVD in participants from the Framingham Heart Study. These included many novel protein biomarkers, which when viewed as a panel of aggregate proteins, improved myocardial infarction and atherosclerotic risk prediction above and beyond established risk factors. 30 In the present study, we have highlighted six protein biomarkers as potential predictors of CAD risk in our statin-treated FH population. Since FH is already associated with an extremely elevated risk of developing CAD, 7 albeit one with significant inter-individual variation, 9-11 this represents an exciting new finding. This finding could potentially provide a tool for identifying those at high risk of developing CAD, which would then allow for personalised treatment to prevent early CAD events. This is particularly important given that intervention strategies at the preclinical stage aremore likely to confer benefit. Interestingly, while all six peptides were associatedwith disease progression (from no atherosclerotic burden, to presence of severe coronary atherosclerosis, up to symptomatic coronary event), it was the absence of these proteins that suggested the highest risk, independent of age or smoking. Of the six proteins found, the strongest association with CAD appeared to be HRG, followed by LRG1, C4B and C1BQ. ITIH3 appeared to have little association with disease progression. Our analysis suggests that the association with LRG1, C4B and C1BQ may be an artefact because of the application of risk reduction therapy but this does not appear to be the case for HRG. HRG, or histidine-rich glycoprotein, is a serum protein belonging to the cystatin superfamily, which plays a regulatory role in hemostasis and innate immunity. 31 A previous study in mice has shown that the Hrg -/- mice had higher anti-thrombin activity, shorter pro-thrombin time and reduced bleeding time, compared to their heterozygous and wild type counterparts. These findings suggest that HRG plays a role as both an anticoagulant and anti-fibrinolytic modifier, and may also regulate platelet function. As a result, the authors suggest that an absence of HRG could trigger monocyte proliferation to compensate for a decrease in phagocyte activation. Coupled with the suggestion that HRG binds several components of the coagulation and fibrinolysis cascades, 31 this implies that its absence could also play a role in the development of atherosclerosis in humans. In agreement with this is our finding of significantly reduced levels of HRG in the FH + CAD group compared to the asymptomatic FH group. Indeed, only one patient in the FH + CAD group had detectable levels of HRG, while all but one had detectable levels in the FH group. Within the FH + Ca group, 40% had detectable levels of HRG, suggesting that either a reduction in circulating HRG occurs with disease progression or there’s a possible ‘switching off” of HRG production leading to the development of atherosclerosis.