Rare variants in cholesterol transporter genes in patients with lipid metabolism disorders

Cardiovascular diseases are the leading cause of death both in Russia and in the world. One of the factors predisposing to the development of cardiovascular diseases is lipid metabolism disorders (dyslipidemias), which contribute to the progression of atherosclerosis. Currently, there are known genes associated with the development of monogenic forms of lipid metabolism disorders characterized by marked changes in lipid levels. However, identifying individuals with an increased genetic risk of dyslipidemia remains an unsolved problem, due to the polygenic nature of most cases. The aim of this work was to study the spectrum of rare variants in the cholesterol transporter genes ABCA1, ABCG1, ABCG5, ABCG8 and NPC1L1 that occur in patients with lipid metabolism disorders in the population of the Northwestern region of Russia. The search for rare variants (gnomAD frequency less than 1 %) in the ABCA1, ABCG1, ABCG5, ABCG8 and NPC1L1 genes was performed using targeted sequencing data for 169 patients with lipid metabolism disorders. 14 variants were identified in the ABCA1 gene (17 patients); 4 variants, in the ABCG1 gene (5 patients); 11 variants, in the ABCG5 gene (18 patients); and 7 variants, in the ABCG8 gene (11 patients). The frequency of some of them, according to the RUSeq database, is higher than in the global population. 19 patients (11 %) were carriers of the p.(Val177Ile)/p.(His221Tyr)/p.(Ala271Phe) haplotype in the NPC1L1 gene, which may be specific to the Russian population, meaning that these variants are not rare, but polymorphic, and occur more frequently in patients with impaired lipid metabolism. Influence of the p.(Val177Ile) variant of the NPC1L1 gene on the development of atherosclerosis was assessed using additional sample sets (a group of patients with atherosclerosis, a control group), but no significant differences in genotype frequencies were revealed. Thus, at present, there are insufficient data to support the role of the p.(Val177Ile)/p.(His221Tyr)/p.(Ala271Phe) haplotype of the NPC1L1 gene in the development of dyslipidemia and atherosclerosis. The study draws attention to the population specificity of a number of variants in cholesterol transporter genes, in particular in the NPC1L1 gene, for the Northwestern region of Russia. The data can be further used for design and calculation of genetic risk scores for dyslipidemia.