The spectrum of mutations in the low-density lipoprotein receptor gene in the Russian population

Воевода, М. И.; Kulikov, I. V.; Shakhtshneider, E.; Максимов, В. Н.; Pilipenko, I. V.; Tereschenko, I. P.; Кобзев, В. Ф.; Romaschenko, A. G.; Nikitin, Yu. P.

doi:10.1134/s1022795408100074

Cited by 12 publications

(17 citation statements)

References 6 publications

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“…The search strategy described above yielded 665 citations; 474 remained after duplicate removal. After the analysis of the abstracts referring to genetic testing or LDLR , APOB and PCSK9 variants in FH patients, 27 articles were selected, of which 25 contained data on the LDLR , APOB , and PCSK9 variants, including three of previously published articles by our group [ 6 , 7 , 8 , 9 , 10 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. These articles describe 91 causal variants of LDLR gene, one variant of APOB, and one variant of PCSK9 ( Figure 1 , Table A1 , Table A2 and Table A3 in Appendix A ).…”

Section: Resultsmentioning

confidence: 99%

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

Мешков

Ершова

Киселева

et al. 2021

Genes

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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.

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Section: Resultsmentioning

confidence: 99%

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

Мешков

Ершова

Киселева

et al. 2021

Genes

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“…The considerable difference in allele frequencies in different populations and even within the same population residing in different regions is potentially the key reason for the poor replicability of the results obtained in individual studies [ 33 ]. In particular, ε3/ε3 turned out to be the risk genotype in our study involving Russians living in Central Russia, while ε2/ε3 was the risk genotype among Siberian males [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Multilocus Analysis of Genetic Susceptibility to Myocardial Infarction in Russians: Replication Study

Kukava¹,

Titov²,

Osmak³

et al. 2017

Acta Naturae

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In search of genetic markers of myocardial infarction (MI) risk, which have prognostic significance for Russians, we performed a replication study of MI association with genetic variants of PCSK9 (rs562556), APOE (epsilon polymorphism, rs7412 and rs429358), LPL (rs320), MTHFR (rs1801133), eNOS (rs2070744), and the 9p21 region (rs1333049) in 405 patients with MI and 198 controls. Significant MI association was observed with variants of the lipid metabolism genes (PCSK9, APOE and LPL), and of eNOS. The SNPs in the MTHFR gene and the 9p21 region were not significantly associated with MI one by one but were included in several different MI-associated allelic combinations identified by multilocus analysis. Since we have not revealed nonlinear epistatic interactions between the components of the identified combinations, we postulate that the cumulative effect of genes that form a combination arises from the summation of their small independent contributions. The prognostic significance of the additive composite model built from the PCSK9, APOE, LPL, and eNOS genes as genetic markers was assessed using ROC analysis. After we included these markers in the previously published composite model of individual genetic risk of MI, the prognostic efficacy in our sample reached AUC = 0.676. However, the results obtained in this study certainly need to be replicated in an independent sample of Russians.

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“…In conclusion, the mutation spectrum for FH in Russian individuals is similar to that of other European countries. Evidence of this conclusion is that certain LDLR mutations that had initially been found in Russian individuals (12,64) were subsequently identified in European populations, such as p.(Cys249*), p.(Trp422*), p.(Asp601Asn) and p.(Arg410Gly) (39,40,50,51). Mutations in the LDLR gene are very diverse and can be present in any part of the gene; therefore, it was not unexpected that through using NGS, novel LDLR variants were discovered in the present study.…”

Section: Number In Dbsnp or Position --------------------------------mentioning

confidence: 99%

Identification of novel variants in the LDLR gene in Russian patients with familial hypercholesterolemia using targeted sequencing

et al. 2020

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Familial hypercholesterolemia (FH) is caused by mutations in various genes, including the LDLR , APOB and PSCK9 genes; however, the spectrum of these mutations in Russian individuals has not been fully investigated. In the present study, mutation screening was performed on the LDLR gene and other FH-associated genes in patients with definite or possible FH, using next-generation sequencing. In total, 59 unrelated patients were recruited and sorted into two separate groups depending on their age: Adult (n=31; median age, 49; age range, 23-70) and children/adolescent (n=28; median age, 11; age range, 2-21). FH-associated variants were identified in 18 adults and 25 children, demonstrating mutation detection rates of 58 and 89% for the adult and children/adolescent groups, respectively. In the adult group, 13 patients had FH-associated mutations in the LDLR gene, including two novel variants [NM_000527.4: c.433_434dupG p.(Val145Glyfs*35) and c.1186G>C p.(Gly396Arg)], 3 patients had APOB mutations and two had ABCG5/G8 mutations. In the children/adolescent group, 21 patients had FH-causing mutations in the LDLR gene, including five novel variants [NM_000527.4: c.325T>G p.(Cys109Gly), c.401G>C p.(Cys134Ser), c.616A>C p.(Ser206Arg), c.1684_1691delTGGCCCAA p.(Pro563Hisfs*14) and c.940+1_c.940+4delGTGA], and 2 patients had APOB mutations, as well as ABCG8 and LIPA mutations, being found in different patients. The present study reported seven novel LDLR variants considered to be pathogenic or likely pathogenic. Among them, four missense variants were located in the coding regions, which corresponded to functional protein domains, and two frameshifts were identified that produced truncated proteins. These variants were observed only once in different patients, whereas a splicing variant in intron 6 (c.940+1_c.940+4delGTGA) was detected in four unrelated individuals. Previously reported variants in the LDLR, APOB, ABCG5/8 and LIPA genes were observed in 33 patients. The LDLR p.(Gly592Glu) variant was detected in 6 patients, representing 10% of the FH cases reported in the present study, thus it may be a major variant present in the Russian population. In conclusion, the present study identified seven novel variants of the LDLR gene and broadens the spectrum of mutations in FH-related genes in the Russian Federation.

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The spectrum of mutations in the low-density lipoprotein receptor gene in the Russian population

Cited by 12 publications

References 6 publications

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

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

Multilocus Analysis of Genetic Susceptibility to Myocardial Infarction in Russians: Replication Study

Identification of novel variants in the LDLR gene in Russian patients with familial hypercholesterolemia using targeted sequencing

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