Familial Hypercholesterolemia in Russia: Three Decades of Genetic Studies

Abstract

The first studies of familial hypercholesterolemia (FH) in Russia go back to late 1980-ies. For more than 10 years the research in this field was carried out in Saint-Petersburg, the megapolis in the North-West Russia. Studies were focused on the search for causative mutations in low-density lipoprotein receptor gene (LDLR). Gradually the research was spread to Petrozavodsk in Karelia and in the XXI century two more centers contributed in investigations of genetics of FH, i.e., in Moscow and Novosibirsk. The best studied is the spectrum of mutations in LDLR, though genetic abnormalities in APOB and PCSK9 genes were also considered. Despite that some 40% mutations in LDLR found in Saint-Petersburg and Moscow are referred to as specific for Russian population, and this proportion is even higher in Karelia (ca. 70%), rapid introduction of NGS and intensifying genetic research all over the world result in continuous decrease of these numbers as “Slavic” mutations become documented in other countries. The samplings of genetically characterized patients in Russia were relatively small, which makes difficult to specify major mutations reflecting the national specificity of FH. Moreover, the majority of studies accomplished so far did not explore possible associations of certain mutations with ethnic origin of patients. By now the only exception is the study of Karelian population showing the absence of typical Finnish mutations in the region that borders on Finland. It can be concluded that the important primary research partly characterizing the mutation spectrum in FH patients both in the European and Siberian parts of Russia has been done. However, it seems likely that the most interesting and comprehensive genetic studies of FH in Russia, concerning various mutations in different genes and the variety of ethnic groups in this multi-national country, are still to be undertaken.

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

“…All missense variants were heterozygous. Some of the identified variants (Cys352Tyr, Cys340Phe, and Leu401His) have been described in patients with familial hypercholesterolemia in Russia [26][27][28][29][30]. The variant most common in our participations-rs121908038-was found in three unrelated families (six subjects total).…”

“…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].…”

“…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].…”

“…The most common limitation of such studies is a small sample size [29]. We should also mention low accessibility of molecular genetic testing in some regions of Russia and the high cost of these tests.…”

Analysis of the low density lipoprotein receptor gene (<i>LDLR</i>) mutation spectrum in Russian familial hypercholesterolemia

“…Already in 2018, the ClinVar database (Landrum et al, 2016) included 4973 variants of the LDLR gene (Iacocca et al, 2018) associated with FH, of which 2351 variants were classified as pathogenic, and 1525 as probably pathogenic, the rest considered as benign variants or variants of uncertain clinical significance. The history of FH research in Russia has recently been reviewed (Vasilyev et al, 2020;Meshkov et al, 2021a). Most of the mutations leading to FH, as expected, were found in the LDLR gene, 187 pathogenic or likely pathogenic variants of which were identified in Russia (Meshkov et al, 2021a); 67 out of 187 were not described in other populations of the world.…”