The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia

Мешков, А. Н.; Ершова, А. И.; Киселева, А. В.; Zotova, Evgenia; Sotnikova, Evgeniia A.; Петухова, А. В.; Zharikova, Anastasia A.; Малышев, П. П.; Рожкова, Т. А.; Блохина, А. В.; Лимонова, А. С.; Ramensky, Vasily; Divashuk, Mikhail G.; Khasanova, Zukhra B.; Букаева, А. А.; Курилова, О. В.; Скирко, О. П.; Pokrovskaya, M. S.; Mikova, Valeriya M.; Snigir, Ekaterina A.; Akinshina, Aleksandra I.; Mitrofanov, Sergey I.; Kashtanova, Daria A.; Makarov, Valentin V.; Кухарчук, В. В.; Boytsov, S. А.; Yudin, S. M.; Drapkina, О. М.

doi:10.3390/genes12010066

Cited by 38 publications

(23 citation statements)

References 33 publications

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“…Moreover, this whole-exome study demonstrated the overrepresentation of several disease-causing variants for Mendelian disorders, such as phenylketonuria (PAH, rs5030858), Wilson's disease (ATP7B, rs76151636), factor VII deficiency (F7, rs36209567), and the kyphoscoliosis type of Ehlers-Danlos syndrome (FKBP14, rs542489955). For the Russian population, however, pathogenic variant frequencies were reported mostly for relatively small cohorts including patients and their families and targeted at specific genes and disorders, for example, familial hypercholesterolemia (Meshkov et al, 2021;Miroshnikova et al, 2021); cystic fibrosis, phenylketonuria, alpha-1 antitrypsin deficiency, and sensorineural hearing loss (Kiseleva et al, 2020;Petrova et al, 2020); cardiomyopathy (Marakhonov et al, 2019;Zaklyazminskaya et al, 2019;Kulikova et al, 2021;Shestak et al, 2021); and breast and ovarian cancer (Brovkina et al, 2018;Solodskikh et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Targeted Sequencing of 242 Clinically Important Genes in the Russian Population From the Ivanovo Region

et al. 2021

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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.

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Section: Introductionmentioning

confidence: 99%

Targeted Sequencing of 242 Clinically Important Genes in the Russian Population From the Ivanovo Region

et al. 2021

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“…Molecular genetic research on familial hypercholesterolemia in Russia has been conducted for more than 30 years in different regions of the country [29]. It is worth mentioning some variants of the LDLR gene that not only occur in most regions of Russia but are also the most common variants of this gene: rs121908038 and rs761954844 [28][29][30][31][32]57]. Additionally, these variants have been found in populations of Northern and Central Europe (rs121908038) and in populations of Central and Eastern Europe, Southeast Asia, and North America (rs761954844) [40].…”

Section: Discussionmentioning

confidence: 99%

“…The small sample sizes do not allow us to assess clinicalcourse features of the disease that are associated with various pathogenic variants in lipid metabolism genes and to evaluate the spectrum of pathogenic variants in lipid metabolism genes in the population of Russia. Targeted sequencing can be useful not only for rapid and cost-effective diagnosis of familial hypercholesterolemia, but also for investigation of rare variants of lipid metabolism genes and their influence on the patients' phenotype [30,57,58]. This method may help to combine the efforts of physicians and investigators from different regions for the research on familial hypercholesterolemia.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Rare Variants in Genes Related to Lipid Metabolism in Patients with Familial Hypercholesterolemia in Western Siberia (Russia)

Shakhtshneider

Ivanoshchuk

Тимощенко

et al. 2021

JPM

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The aim of this work was to identify genetic variants potentially involved in familial hypercholesterolemia in 43 genes associated with lipid metabolism disorders. Targeted high-throughput sequencing of lipid metabolism genes was performed (80 subjects with a familial-hypercholesterolemia phenotype). For patients without functionally significant substitutions in the above genes, multiplex ligation-dependent probe amplification was conducted to determine bigger mutations (deletions and/or duplications) in the LDLR promoter and exons. A clinically significant variant in some gene associated with familial hypercholesterolemia was identified in 47.5% of the subjects. Clinically significant variants in the LDLR gene were identified in 19 probands (73.1% of all variants identified in probands); in three probands (11.5%), pathogenic variants were found in the APOB gene; and in four probands (15.4%), rare, clinically significant variants were identified in genes LPL, SREBF1, APOC3, and ABCG5. In 12 (85.7%) of 14 children of the probands, clinically significant variants were detectable in genes associated with familial hypercholesterolemia. The use of clinical criteria, targeted sequencing, and multiplex ligation-dependent probe amplification makes it possible to identify carriers of rare clinically significant variants in a wide range of lipid metabolism genes and to investigate their influence on phenotypic manifestations of familial hypercholesterolemia.

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“…Разработка полигенных шкал риска развития ХНИЗ (атеросклероза, АГ, СД, ожирения, остеопороза и др.) [21][22][23].…”

Section: распространенность семейной гиперхолестеринемииunclassified

Epidemiology of Cardiovascular Diseases and their Risk Factors in Regions of Russian Federation (ESSE-RF) study. Ten years later

Бойцов

Драпкина²,

Шляхто

et al. 2021

Cardiovasc Ther Prev

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The growing weight of noncommunicable diseases, primarily cardiovascular diseases (CVDs), is a great threat to the health of population worldwide, worsening the quality of life and reducing life expectancy. Realization of this threat led to initiation of epidemiological study by the Russian Ministry of Health to investigate the prevalence of CVDs and their risk factors, since it is CVDs that specify the high allcause mortality in Russia. In the modern history of epidemiology of non-infectious disease, the Epidemiology of Cardiovascular Diseases and their Risk Factors in Regions of Russian Federation (ESSE-RF) study occupies a special place. This is the largest epidemiological study, which is considered as a continuation of preventive activity in order to obtain unbiased information on epidemiological characteristics of population in Russian regions. To conduct the study, the Research Organizing Committee of ESSE-RF study was created and a protocol was developed. All interested scientists and experts from following three centers took part in the work: National Medical Research Center for Therapy and Preventive Medicine, Almazov National Medical Research Center, National Medical Research Center of Cardiology. The Russian regions were justified and selected for participation. In 2012-2014 ESSE-RF study, 13 following Russian regions took part: Volgograd, Vologda, Voronezh, Ivanovo, Kemerovo, Tyumen Oblasts; Krasnoyarsk and Primorsky Krai; the Republic of North Ossetia (Alania); cities of Orenburg, Samara, St. Petersburg and Tomsk. All participated regions used a single study protocol, while biochemical parameters were determined in Federal centers using the same equipment and reagent kits. The paper presents some of the most interesting results that indicate a change in Russian epidemiological situation over the past few years. After the end of cross-sectional study, a field of priority research areas was formed in each center.Conclusion. Epidemiological studies are the most important scientific tool for assessing the prevalence of diseases, their risk factors, as well as predicting adverse events. Based on the results obtained, healthcare system and medical community determine priorities and develop related strategies (population-based and high-risk strategies). For their implementation, a regulatory and legal framework is being created.

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The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia

Cited by 38 publications

References 33 publications

Targeted Sequencing of 242 Clinically Important Genes in the Russian Population From the Ivanovo Region

Targeted Sequencing of 242 Clinically Important Genes in the Russian Population From the Ivanovo Region

Analysis of Rare Variants in Genes Related to Lipid Metabolism in Patients with Familial Hypercholesterolemia in Western Siberia (Russia)

Epidemiology of Cardiovascular Diseases and their Risk Factors in Regions of Russian Federation (ESSE-RF) study. Ten years later

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