RESUMEN
Familial hypercholesterolemia (FH) is a common autosomal codominant disorder, characterized by elevated low-density lipoprotein cholesterol levels causing premature atherosclerotic cardiovascular disease. About 2900 variants of LDLR, APOB, and PCSK9 genes potentially associated with FH have been described earlier. Nevertheless, the genetics of FH in a Russian population is poorly understood. The aim of this study is to present data on the spectrum of LDLR, APOB, and PCSK9 gene variants in a cohort of 595 index Russian patients with FH, as well as an additional systematic analysis of the literature for the period of 1995-2020 on LDLR, APOB and PCSK9 gene variants described in Russian patients with FH. We used targeted and whole genome sequencing to search for variants. Accordingly, when combining our novel data and the data of a systematic literature review, we described 224 variants: 187 variants in LDLR, 14 variants in APOB, and 23 variants in PCSK9. A significant proportion of variants, 81 of 224 (36.1%), were not described earlier in FH patients in other populations and may be specific for Russia. Thus, this study significantly supplements knowledge about the spectrum of variants causing FH in Russia and may contribute to a wider implementation of genetic diagnostics in FH patients in Russia.
Asunto(s)
Apolipoproteína B-100/genética , Predisposición Genética a la Enfermedad , Hiperlipoproteinemia Tipo II/genética , Proproteína Convertasa 9/genética , Receptores de LDL/genética , Estudios de Cohortes , Análisis Mutacional de ADN , Variación Genética , Humanos , Hiperlipoproteinemia Tipo II/epidemiología , Mutación , Federación de Rusia/epidemiología , Secuenciación Completa del GenomaRESUMEN
BACKGROUND: The role of plasma cholesterol in impairing arterial function and elasticity remains unclear. We evaluated arterial stiffness, measured locally in the common carotid artery by high-resolution echo-tracking, and aortic stiffness, using carotid-femoral pulse wave velocity (PWV) (the "gold-standard" measurement of arterial stiffness), in treatment-naive patients with heterozygous familial hypercholesterolemia (FH). METHODS: The study included 66 patients with FH (10-66 years old) and 57 first-degree relatives without FH (11-61 years old). Carotid-femoral PWV was determined by SphygmoCor (AtCor, Australia). The parameters of carotid stiffness ß-index, Peterson elastic modulus and local PWV were assessed with regard to the common carotid artery at a distance of 1cm from the bifurcation (AlokaProsound Alpha7, Japan). RESULTS: FH patients showed significantly higher ß-index (6.3(4.8-8.2) vs. 5.2(4.2-6.4), p = 0.005), Ep (78(53-111) kPa vs. 62(48-79) kPa, p = 0.006), local PWV (5.4(4.5-6.4) m/c vs. 4.7(4.2-5.4) m/c, p = 0.005), but comparable values of carotid-femoral PWV (6.76(7.0-7.92) m/c vs. 6.48(6.16-7.12) m/c, p = 0.138). Carotid arteries and the aorta stiffened with age in patients with FH, but after 30 years, carotid arteries stiffened more significantly than the aorta. CONCLUSIONS: Our study demonstrated that treatment-naive patients with FH had stiffer carotid arteries than their relatives, but showed no difference in aortic stiffness. We also found out that the rate of reduction of elasticity of the aorta and carotid arteries in FH patients varies: it is observed earlier in carotid arteries than in the aorta.
Asunto(s)
Arterias Carótidas/fisiopatología , Hiperlipoproteinemia Tipo II/fisiopatología , Análisis de la Onda del Pulso/métodos , Rigidez Vascular , Adolescente , Adulto , Anciano , Aorta/diagnóstico por imagen , Aorta/fisiopatología , Arterias Carótidas/diagnóstico por imagen , Niño , Elasticidad/fisiología , Femenino , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico por imagen , Masculino , Persona de Mediana EdadRESUMEN
A widely adopted ultrasound surrogate marker for predicting cardiovascular risk is mean intima-medial thickness (mean-IMT). There are, however, certain limitations to this methodology. We compared the severity of carotid atherosclerosis in adult patients with high cardiovascular risk (patients with familial hypercholesterolemia [FH] and without previous statin treatment) and in their adult FH-free first-degree relatives using not only mean-IMT, but also maximum-IMT, plaque number, plaque score and percent area stenosis. Mean-IMT has not differed in both groups (0.64 ± 0.18 mm vs. 0.58 ± 0.13 mm in the control group, p = 0.349). Maximum-IMT (0.99 ± 0.35 vs. 0.76 ± 0.19, p = 0.0057), plaque number (3 ± 3 vs. 1 ± 2, p = 0.0009), plaque score (5.14 ± 4.97 mm vs. 1.58 ± 3.09 mm, p = 0.0009) and percent area stenosis (38% ± 22% vs. 12% ± 20%, p = 0.0004) were significantly higher for FH patients than for their relatives. We have demonstrated that plaque number, plaque score and percent area stenosis markers were more sensitive than mean-IMT for cardiovascular risk estimation in patients with familial hypercholesterolemia.
