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SUMMARY Background: Severe hypercholesterolemia and family history of early vascular diseases are important determinants of the development of the endothelium dependent vasodilation in familial hypercholesterolemia. Mutations of the LDL-R-gene (low-density lipoprotein receptor gene) are characterized by a high genetic heterogenicity. Nearly 80% of the population specific heterogenicity are due to point mutations along the LDL-R gene. The different expression of the defect gene in LDL-R mutation carriers as well as the presence of elevated LDL levels in non-mutation carriers makes diagnosis difficult. So far, there is no optimal diagnostic algorithm in familial hypercholesterolemia. Objective To study the endothelium-dependent vasodilation (flow-mediated vasodilation) in carriers and noncarriers of LDL-R defective gene and utilize them to screen for defects in the LDL receptor (spot mutations and polymorphisms) in severe hypercholesterolemia (HC) in molecular biological analysis. Study was conducted in patients with diagnosed and presumed familial hypercholesterolemia according to Simon-Broome criteria. Ìaterials and methods: 464 first relatives of families with familial hypercholesterolemia were tested, of them 120 meet Simon-Broome inclusion criteria. Total cholesterol, triglycerides, cholesterol of high density lipoproteins, cholesterol of low density lipoproteins are determined, using the enzyme- colorimetric method. Molecular analysis included: DNA isolation, amplification of a target DNA fragment by polymerase chain reaction, Single Strand Conformation Polymorphysm (SSCP) and direct DNA sequencing. The Hewlett Packard SONOS 5500 with a 7.5 MHz triplex transducer and the MedicaSoft.IMT lab software packet were used to determine the flow-mediated vaso- dilation. Results: According to the presence or absence of genetic mutations, patients were assigned into two groups - carriers of LDL-R gene point mutations - 22 (18.33%) patients - of them 16 (13.33%) were carriers of an unknown mutation (not registered in the available data bases-1073G>A) and non- carriers - 98 patients - 81.67%. All 18 exons of the LDL-R gene were tested. Median age of non-carriers is 43.41±0.43 years, that of carriers -45.40±0.27 years (ð<0.001). There is no statistically significant difference in the patients' distribution according to sex (χ 2 =0.06; ð>0.05). There is not statistical significant difference on all biomarkers of the atherogenic risk between two group (p>0.05), as for flow- mediated vasodilation (p>0.05). Conclusion: Endothelium- dependent vasodilation (flow-mediated vasodilation) are not an indicator of the presence of point mutations and polymorphisms of the LDL-R gene.

journal of imab

ENDOTHELIUM-DEPENDENT VASODILATION AND SCREENING FOR MOLECULAR DEFECTS OF THE LDL-R GENE IN BULGARIANS WITH UNTREATED AYMPTOMATIC SEVERE HYPERCHOLESTEROLEMIA