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120 | Chapter 8 Abstract Background Familial hypercholesterolaemia (FH) is the most common and serious monogenic disorder of lipid metabolism. The incidence of CAD varies among both treated and untreated FH patients. Objective: The aim of the study was to utilise proteomics to identify novel protein biomarkers that differentiate genetically confirmed FH patients at high CAD risk from low CAD risk. Methods Sixty genetically confirmed FH patients were recruited and stratified into; (i) asymptomatic FH with low atherosclerotic burden (FH, n=20); (ii) asymptomatic FH with high atherosclerotic burden (FH + Ca, n=20); and (iii) FH with previously confirmed symptomatic CAD (FH + CAD, n=20). Results Six new potential proteins were identified; leucine-rich alpha-2-glycoprotein (LRG1), inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3), complement C4-B (C4B), complement C1q subcomponent subunit B (C1QB), monocyte differentiation antigen (CD14) and histidine-rich glycoprotein (HRG). There were significant associations between gender and C4B (Z=2.31, p=0.021), C1QB (Z=2.49, p=0.013), CD14 (Z=2.17, p=0.03) and HRG (Z=2.14, p=0.033). There were significant associations between smoking and LRG1 (χ 2 2 =6.59, p=0.037), CB4 (χ 2 2 =7.85, p=0.02) and HRG (χ 2 2 =6.11, p=0.047). All the peptides were significantly associated with progression of CAD, independently of age and smoking. However, the absence of the proteins was the strongest marker. The most accurate predictor of CAD was HRG (AUROC=0.922), while LRG1, C4B and C1QB were excellent predictors of CAD (AUROC>0.9). For prediction of either coronary atherosclerosis or CAD; LRG1, C4B, C1QB and HRG were relatively good predictors. Conclusions The present study has identified six novel protein biomarkers that are associated with atherosclerotic disease progression and subsequent coronary events in patients with FH.