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1.
Int J Mol Sci ; 24(17)2023 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-37685967

RESUMEN

Familial dysbetalipoproteinemia (FD) is a highly atherogenic genetically based lipid disorder with an underestimated actual prevalence. In recent years, several biochemical algorithms have been developed to diagnose FD using available laboratory tests. The practical applicability of FD diagnostic criteria and the prevalence of FD in Russia have not been previously assessed. We demonstrated that the diagnostic algorithms of FD, including the diagnostic apoB levels, require correction, taking into account the distribution of apoB levels in the population. At the same time, a triglycerides cutoff ≥ 1.5 mmol/L may be a useful tool in identifying subjects with FD. In this study, a high prevalence of FD was detected: 0.67% (one in 150) based on the ε2ε2 haplotype and triglycerides levels ≥ 1.5 mmol/L. We also analyzed the presence and pathogenicity of APOE variants associated with autosomal dominant FD in a large research sample.


Asunto(s)
Hiperlipoproteinemia Tipo III , Humanos , Proyectos Piloto , Prevalencia , Apolipoproteínas B , Federación de Rusia/epidemiología , Triglicéridos
2.
Front Cardiovasc Med ; 10: 1205787, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37342443

RESUMEN

Background: Left ventricular noncompaction (LVNC) cardiomyopathy is a disorder that can be complicated by heart failure, arrhythmias, thromboembolism, and sudden cardiac death. The aim of this study is to clarify the genetic landscape of LVNC in a large cohort of well-phenotyped Russian patients with LVNC, including 48 families (n=214). Methods: All index patients underwent clinical examination and genetic analysis, as well as family members who agreed to participate in the clinical study and/or in the genetic testing. The genetic testing included next generation sequencing and genetic classification according to ACMG guidelines. Results: A total of 55 alleles of 54 pathogenic and likely pathogenic variants in 24 genes were identified, with the largest number in the MYH7 and TTN genes. A significant proportion of variants -8 of 54 (14.8%) -have not been described earlier in other populations and may be specific to LVNC patients in Russia. In LVNC patients, the presence of each subsequent variant is associated with increased odds of having more severe LVNC subtypes than isolated LVNC with preserved ejection fraction. The corresponding odds ratio is 2.77 (1.37 -7.37; p <0.001) per variant after adjustment for sex, age, and family. Conclusion: Overall, the genetic analysis of LVNC patients, accompanied by cardiomyopathy-related family history analysis, resulted in a high diagnostic yield of 89.6%. These results suggest that genetic screening should be applied to the diagnosis and prognosis of LVNC patients.

3.
Genes (Basel) ; 13(10)2022 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-36292635

RESUMEN

Variants of the MYH7 gene have been associated with a number of primary cardiac conditions, including left ventricular noncompaction cardiomyopathy (LVNC). Most cases of MYH7-related diseases are associated with such variant types as missense substitutions and in-frame indels. Thus, truncating variants in MYH7 (MYH7tv) and associated mechanism of haploinsufficiency are usually considered not pathogenic in these disorders. However, recent large-scale studies demonstrated evidence of the significance of MYH7tv for LVNC and gave rise to an assumption that haploinsufficiency may be the causal mechanism for LVNC. In this article, we present a family with isolated LVNC and a heterozygous splice variant of the MYH7 gene, analyze possible consequences of this variant and conclude that not all variants that are predicted truncating really act through haploinsufficiency. This study can highlight the importance of a precise assessment of MYH7 splicing variants and their participation in the development of LVNC.


Asunto(s)
Cardiomiopatías , No Compactación Aislada del Miocardio Ventricular , Humanos , No Compactación Aislada del Miocardio Ventricular/genética , Mutación , Corazón , Mutación Missense , Cadenas Pesadas de Miosina/genética , Miosinas Cardíacas/genética
4.
Front Cardiovasc Med ; 9: 982607, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36093134

RESUMEN

One of the most common autosomal dominant disorders is familial hypercholesterolemia (FH), causing premature atherosclerotic cardiovascular diseases and a high risk of death due to lifelong exposure to elevated low-density lipoprotein cholesterol (LDL-C) levels. FH has a proven arsenal of treatments and the opportunity for genetic diagnosis. Despite this, FH remains largely underdiagnosed worldwide. Cascade screening is a cost-effective method for the identification of new patients with FH and the prevention of cardiovascular diseases. It is usually based only on clinical data. We describe a 48-year-old index patient with a very high LDL-C level without controlled guidelines-based medication, premature atherosclerosis, and a rare variant in the low-density lipoprotein receptor (LDLR) gene. Phenotypic cascade screening identified three additional FH relatives, namely the proband's daughter, and two young grandsons. The genetic screening made it possible to rule out FH in the proband's younger grandson. This clinical case demonstrates that genetic cascade screening is the most effective way of identifying new FH cases. We also first described in detail the phenotype of patients with a likely pathogenic variant LDLR-p.K223_D227dup.

5.
J Pers Med ; 12(7)2022 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-35887629

RESUMEN

Cystic fibrosis, phenylketonuria, alpha-1 antitrypsin deficiency, and sensorineural hearing loss are among the most common autosomal recessive diseases, which require carrier screening. The evaluation of population allele frequencies (AF) of pathogenic variants in genes associated with these conditions and the choice of the best genotyping method are the necessary steps toward development and practical implementation of carrier-screening programs. We performed custom panel genotyping of 3821 unrelated participants from two Russian population representative samples and three patient groups using real-time polymerase chain reaction (PCR) and next generation sequencing (NGS). The custom panel included 115 known pathogenic variants in the CFTR, PAH, SERPINA1, and GJB2 genes. Overall, 38 variants were detected. The comparison of genotyping platforms revealed the following advantages of real-time PCR: relatively low cost, simple genotyping data analysis, and easier detection of large indels, while NGS showed better accuracy of variants identification and capability for detection of additional pathogenic variants in adjacent regions. A total of 23 variants had significant differences in estimated AF comparing with non-Finnish Europeans from gnomAD. This study provides new AF data for variants associated with the studied disorders and the comparison of genotyping methods for carrier screening.

6.
Front Genet ; 12: 709419, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34691145

RESUMEN

We performed a targeted sequencing of 242 clinically important genes mostly associated with cardiovascular diseases in a representative population sample of 1,658 individuals from the Ivanovo region northeast of Moscow. Approximately 11% of 11,876 detected variants were not found in the Single Nucleotide Polymorphism Database (dbSNP) or reported earlier in the Russian population. Most novel variants were singletons and doubletons in our sample, and virtually no novel alleles presumably specific for the Russian population were able to reach the frequencies above 0.1-0.2%. The overwhelming majority (99.3%) of variants detected in this study in three or more copies were shared with other populations. We found two dominant and seven recessive known pathogenic variants with allele frequencies significantly increased compared to those in the gnomAD non-Finnish Europeans. Of the 242 targeted genes, 28 were in the list of 59 genes for which the American College of Medical Genetics and Genomics (ACMG) recommended the reporting of incidental findings. Based on the number of variants detected in the sequenced subset of ACMG59 genes, we approximated the prevalence of known pathogenic and novel or rare protein-truncating variants in the complete set of ACMG59 genes in the Ivanovo population at 1.4 and 2.8%, respectively. We analyzed the available clinical data and observed the incomplete penetrance of known pathogenic variants in the 28 ACMG59 genes: only 1 individual out of 12 with such variants had the phenotype most likely related to the variant. When known pathogenic and novel or rare protein-truncating variants were considered together, the overall rate of confirmed phenotypes was about 19%, with maximum in the subset of novel protein-truncating variants. We report three novel protein truncating variants in APOB and one in MYH7 observed in individuals with hypobetalipoproteinemia and hypertrophic cardiomyopathy, respectively. Our results provide a valuable reference for the clinical interpretation of gene sequencing in Russian and other populations.

7.
J Pers Med ; 11(6)2021 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-34074024

RESUMEN

Heterozygous familial hypercholesterolemia (HeFH) is one of the most common genetic conditions but remains substantially underdiagnosed. The aim of our study was to investigate the prevalence of HeFH in the population of 11 different regions of Russia. Individuals were selected from the Epidemiology of Cardiovascular Risk Factors and Diseases in Regions of the Russian Federation Study. All participants who had low-density lipoprotein cholesterol (LDL-C) higher than 4.9 mmol/L, or LDL-C lower than 4.9 mmol/L, but had statin therapy, were additionally examined by FH experts. FH was diagnosed using the Dutch Lipid Clinic Network criteria, incorporating genetic testing. HeFH prevalence was assessed for 18,142 participants. The prevalence of patients with definite or probable HeFH combined was 0.58% (1 in 173). A total of 16.1% of patients with definite or probable HeFH had tendon xanthomas; 36.2% had mutations in one of the three genes; 45.6% of FH patients had coronary artery disease; 63% of HeFH patients received statins; one patient received an additional PCSK9 inhibitor; no patients received ezetimibe. Only 3% of patients reached the LDL-C goal based on 2019 ESC/EAS guidelines. Underdiagnosis and undertreatment of FH in Russia underline the need for the intensification of FH detection with early and aggressive cholesterol-lowering treatment.

8.
Front Cardiovasc Med ; 8: 778961, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-35096999

RESUMEN

We reported a case of sitosterolemia, which is a rare genetic disease, characterized by increased plant sterol absorption and great heterogeneity of clinical manifestations. Our patient was initially referred to the lipid clinic due to high cholesterol levels and premature cardiovascular disease. Diagnosis of familial hypercholesterolemia was established in accordance with the Dutch Lipid Clinic Network criteria. Next-generation sequencing was later performed, which revealed a nonsense mutation in the ABCG8 gene, which led to the diagnosis of sitosterolemia. The aim of our report is to demonstrate, how genetic testing helped to make the correct diagnosis and to explain many of the patient's health problems, which etiology remained unclear for many years.

9.
Biopreserv Biobank ; 19(1): 73-82, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33058731

RESUMEN

The research biobanking field is developing rapidly in Russia. Over the course of the last decade, numerous biobanks were created or formed from existing collections of human and environmental biospecimens. The Russian National Association of Biobanks and Biobanking Specialists (NASBIO) was established in December 2018, aiming to: (1) unite professionals and research centers to create and develop a network of biobanks in Russia; (2) provide services and expertise in the field of biobanking; (3) execute various research projects utilizing biobanks' infrastructure; and (4) facilitate integration of Russian biomedical research centers into global research activities. The organizational structure, aims, and plans of this newly formed national association are reviewed in this article. The founders of NASBIO hope that the association will promote further development of biobanks and their networking in Russia, which is critically important for the success of national biomedical, pharmaceutical, and biotechnological research, and can facilitate international biobanking projects on a global scale.


Asunto(s)
Bancos de Muestras Biológicas , Investigación Biomédica , Humanos , Federación de Rusia , Especialización
10.
J Pers Med ; 10(3)2020 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-32971794

RESUMEN

Genetic screening is an advanced tool for reducing recessive disease burden. Nowadays, it is still unclear as to the number of genes or their variants that are necessary for effective screening. This paper describes the development of a carrier screening custom panel for cystic fibrosis, phenylketonuria, alpha-1 antitrypsin deficiency, and sensorineural hearing loss consisting of 116 variants in the CFTR, PAH, SERPINA1, and GJB2 genes. The approach is based on the cheapest and fastest method, on using a small number of genes, and on the estimation of the effectiveness of carriers' detection. The custom panel was tested on a population-based cohort that included 1244 participants. Genotypes were determined by the TaqMan OpenArray Genotyping platform on the QuantStudio 12K Flex Real-Time PCR System. The frequency of heterozygotes in the Russian population was 16.87% or 1:6 (CI95%: 14.76-19.00% by Clopper-Pearson exact method): in CFTR-2.81% (1:36), PAH-2.33% (1:43), SERPINA1-4.90% (1:20), and GJB2-6.83% (1:15). The data on allele frequencies were obtained for the first time on a Russian population. The panel allows us to identify the vast majority of carriers of recessive diseases in the population. It is an effective approach to carrier screening for common recessive diseases.

11.
Front Cardiovasc Med ; 7: 585779, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33537346

RESUMEN

We present a case of a 40-year-old male with premature atherosclerosis, with evidence of both eruptive and tendinous xanthomas, which could imply an increase in both low-density lipoprotein (LDL) and triglyceride (TG) levels. However, his LDL was 2.08 mmol/l, TG -11.8 mmol/l on rosuvastatin 20 mg. Genetic evaluation was performed using a custom panel consisting of 25 genes and 280 variants responsible for lipid metabolism. A rare ε2ε1 genotype of apolipoprotein E was detected. The combination of clinical manifestations and genetic factors in this patient leads to the diagnosis of familial dysbetalipoproteinemia. Implementation of genetic testing into routine clinical practice could not only improve disease diagnostics and management, but also help prevent their development.

12.
Biomed Rep ; 11(4): 154-164, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31565221

RESUMEN

Adiponectin, endothelin and nitric oxide (NO) are major regulators of vascular function. An imbalance of vasoactive factors contributes to the onset and progression of atherosclerosis. Various single nucleotide polymorphisms (SNPs) are considered to be risk factors for coronary heart disease. However, the molecular mechanisms of their associations with the components of endothelial dysfunction are poorly understood. In the present study, rs17366743, rs17300539, rs266729, rs182052 and rs2241766 SNPs of the adiponectin (ADIPOQ) gene and rs2070699, rs1800542 and rs1800543 SNPs of the endothelin-1 (EDN1) gene were genotyped in 477 patients with coronary heart disease who were subjected to coronary angiography, in order to determine the presence or absence of coronary atherosclerosis. The serum levels of adiponectin, endothelin and stable metabolites of NO, (nitrate and nitrite NOx), were assayed and their associations with the SNP genotypes and coronary lesions were calculated. The results indicated that rs17366743 of the ADIPOQ gene and rs2070699 and rs1800543 of the EDN1 gene were associated with the levels of NOx in women, which in turn was associated with cardiovascular mortality. In men, rs182052 and rs266729 of the ADIPOQ gene were associated with adiponectin levels, whereas rs17366743 of the ADIPOQ gene was associated with endothelin levels. Additionally, these SNPs were indirectly associated with the prevalence of coronary lesions in men. Therefore, the tested SNPs can be considered potential risk factors that lead to imbalance of vasoactive mediators in a gender-specific manner and contribute to the development of clinical manifestations of atherosclerosis.

13.
Hum Mutat ; 40(6): 734-741, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30908796

RESUMEN

Mutations in DES, encoding desmin protein, are associated with different kinds of skeletal and/or cardiac myopathies. However, it is unknown, whether DES mutations are associated with left ventricular hypertrabeculation (LVHT). Here, we performed a clinical examination and subsequent genetic analysis in a family, with two individuals presenting LVHT with conduction disease and skeletal myopathy. The genetic analysis revealed a novel small in-frame deletion within the DES gene, p.Q113_L115del, affecting the α-helical rod domain. Immunohistochemistry analysis of explanted myocardial tissue from the index patient revealed an abnormal cytoplasmic accumulation of desmin and a degraded sarcomeric structure. Cell transfection experiments with wild-type and mutant desmin verified the cytoplasmic aggregation and accumulation of mutant desmin. Cotransfection experiments were performed to model the heterozygous state of the patients and revealed a dominant negative effect of the mutant desmin on filament assembly. DES:p.Q113_L115del is classified as a pathogenic mutation associated with dilated cardiomyopathy with prominent LVHT.


Asunto(s)
Cardiomiopatía Dilatada/genética , Desmina/química , Desmina/genética , Eliminación de Secuencia , Adulto , Cardiomiopatía Dilatada/metabolismo , Citoplasma/metabolismo , Desmina/metabolismo , Femenino , Cardiopatías Congénitas , Humanos , Masculino , Modelos Moleculares , Linaje , Dominios Proteicos , Proteolisis , Sarcómeros/metabolismo
14.
PLoS One ; 12(7): e0181148, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28719663

RESUMEN

BACKGROUND: The prevalence of familial hypercholesterolemia (FH) in Russia has not previously been evaluated. The aim of our study was to investigate the prevalence of FH in the population of the West Siberian region of Russia, and then estimate the frequency of coronary artery disease (CAD) and treatment with cholesterol-lowering medication in FH patients. METHODS: The sample of our study consisted of participants from the population-based cohort of The Epidemiology of Cardiovascular Risk Factors and Diseases in Regions of the Russian Federation Study (ESSE-RF), conducted in the Tyumen and Kemerovo regions (1,630 and 1,622 people, respectively, aged 25-64). All participants who had LDL-cholesterol higher than 4.9 mmol/l and who had LDL-cholesterol less than or equal to 4.9 mmol/l but had statin therapy were examined and interviewed by experts in FH. RESULTS: The prevalence of patients with definite FH was 0.24% (one in 407) (95% confidence interval [CI]: 0.06%-0.42%), with probable FH was 0.68% (one in 148) (95% CI: 0.38%-0.98%), and with definite or probable FH combined was 0.92% (one in 108) (95% CI: 0.58%-1.26%). 40% (95% CI: 20.8%-59.2%) of patients with definite or probable FH had CAD. However, only 23% (95% CI: 6.3%-39.7%) of patients with definite or probable FH were on statins. The odds ratios for CAD and myocardial infarction (MI), adjusted for age, gender, region, smoking, hypertension, and diabetes mellitus, were 3.71 (95% CI: 1.58-8.72) (p = 0.003) and 4.06 (95% CI: 0.89-18.55) (р = 0.070) respectively for individuals with definite or probable FH relative to those who were unlikely to have FH. CONCLUSIONS: The prevalence of FH in Russia may be significantly higher than previously estimated. There is underdiagnosis and undertreatment of FH in Russia.


Asunto(s)
Hiperlipoproteinemia Tipo II/epidemiología , Adulto , Anticolesterolemiantes/uso terapéutico , Femenino , Humanos , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Prevalencia , Factores de Riesgo , Federación de Rusia/epidemiología
15.
PLoS One ; 11(7): e0158964, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27434535

RESUMEN

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 Edad
16.
Ultrasound Med Biol ; 38(3): 417-22, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22261515

RESUMEN

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.


Asunto(s)
Grosor Intima-Media Carotídeo , Estenosis Carotídea/diagnóstico por imagen , Estenosis Carotídea/etiología , Hiperlipoproteinemia Tipo II/complicaciones , Hiperlipoproteinemia Tipo II/diagnóstico por imagen , Túnica Íntima/diagnóstico por imagen , Ultrasonografía/métodos , Adulto , Biomarcadores , Femenino , Humanos , Masculino , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
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