The impact of the Low Density Lipoprotein Receptor gene mutation type on carotid intima media thickness in families with familial hypercholesterolemia.

Vasiliki Metaxa, Ioannis Skoumas, Christos Pitsavos, Evaggelos Oikonomou, Constantina Masoura, Christodoulos Stefanadis



Background: Familial hypercholesterolemia (FH) is a highly atherogenic condition that leads to progressive atherosclerosis and premature cardiovascular disease(pCVD). FH is caused by mutations of the Low Density Lipoprotein Receptor(LDLR) gene.
Aim: To evaluate the impact of the LDLR gene mutation type, on carotid intima media thickness(c-IMT), in patients with FH.
Methods: We enrolled 56 families(119 patients, 56 hypercholesterolemic parents aged 44 ± 10 years and 63 hypercholesterolemic offsprings aged 17 ± 4 years), clinically diagnosed as FH patients, according to the Dutch Lipid Clinic Score. Their lipid profile was assessed before any treatment was provided and molecular analysis of the LDLR gene was performed. The offsprings’ population underwent ultrasound imaging of the carotid arterial wall, c-IMT was evaluated and atherosclerotic plaques were also assessed. We finally recorded the offsprings’ individual and family history, of the 1st and 2nd degree relatives, including all major events and deaths from premature CVD.
Results: An LDLR gene mutation was found in 34 out of the 56 families(57% of the total population). Offsprings carrying a receptor-negative mutation had statistically significantly increased c-IMT compared to receptor-defective carriers(p<0.001). No differences were found among risk factors such as age, sex or total cholesterol. Multi-linear regression analysis revealed that each LDLR gene mutation type affects differently c-IMT(patients with receptor-negative mutations present 0,2 mm greater c-IMT compared to receptor-defective) after adjustment for age, sex, TC, LDL, HDL, APOA1, APOB, Lpa, BMI, arterial hypertension, smoking habits and fasting glucose(beta=554, p=0.001).
Conclusions: According to our findings, receptor-negative mutations seem to have greater impact on c-IMT, compared to receptor-defective.

Keywords: Familial hypercholesterolemia, carotid intima-media thickness, LDLR gene mutations, premature cardiovascular disease