Searching for new genes associated with the familial hypercholesterolemia phenotype using whole-genome sequencing and machine learning

One of the most common congenital metabolic disorders is familial hypercholesterolemia. Familial hyper-cholesterolemia is a condition caused by a type of genetic defect leading to a decreased rate of removal of low-density lipoproteins from the bloodstream and a pronounced increase in the blood level of total cholesterol. This disease leads to the early development of cardiovascular diseases of atherosclerotic etiology. Familial hypercholesterolemia is a monogenic disease that is predominantly autosomal dominant. Rare pathogenic variants in the LDLR gene are present in 75–85 % of cases with an identified molecular genetic cause of the disease, and variants in other genes (APOB, PCSK9, LDLRAP1, ABCG5, ABCG8, and others) occur at a frequency of < 5 % in this group of patients. A negative result of genetic screening for pathogenic variants in genes of the low-density lipoprotein receptor and its ligands does not rule out a diagnosis of familial hypercholesterolemia. In 20–40 % of cases, molecular genetic testing fails to detect changes in the above genes. The aim of this work was to search for new genes associated with the familial hypercholesterolemia phenotype by modern high-tech methods of sequencing and machine learning. On the basis of a group of patients with familial hypercholesterolemia (enrolled according to the Dutch Lipid Clinic Network Criteria and including cases confirmed by molecular genetic analysis), decision trees were constructed, which made it possible to identify cases in the study population that require additional molecular genetic analysis. Five probands were identified as having the severest familial hypercholesterolemia without pathogenic variants in the studied genes and were analyzed by whole-genome sequencing on the HiSeq 1500 platform (Illumina). The whole-genome sequencing revealed rare variants in three out of five analyzed patients: a heterozygous variant (rs760657350) located in a splicing acceptor site in the PLD1 gene (c.2430-1G>A), a previously undescribed single-nucleotide deletion in the SIDT1 gene [c.2426del (p.Leu809CysfsTer2)], new missense variant c.10313C>G (p.Pro3438Arg) in the LRP1B gene, and single-nucleotide deletion variant rs753876598 [c.165del (p.Ser56AlafsTer11)] in the CETP gene. All these variants were found for the first time in patients with a clinical diagnosis of familial hypercholesterolemia. Variants were identified that may influence the formation of the familial hypercholesterolemia phenotype

Gender and age features of dyslipidemia in the population of the Nizhny Novgorod region

Aim. To study the gender and age characteristics of dyslipidemia in the population of the Nizhny Novgorod region.Material and methods. A total of 2501 people aged 35-74 among the population of the Nizhny Novgorod region were examined, selected by stratified multi-stage random sampling. The study was performed as part of the third epidemiological study ESSE-RF3. All respondents underwent an anthropometric survey, a questionnaire to identify chronic non-communicable diseases and related risk factors. The following laboratory tests were performed: total cholesterol (TC), low-density lipoproteins (LDL-C), high-density lipoproteins (HDL-C), triglycerides (TG). Among the entire cohort of patients at the time of blood sampling, 276 people (11,0%) were receiving lipid-lowering drugs. They were excluded from further analysis. Hypercholesterolemia (HCL) was recorded with a total cholesterol ≥5,0 mmol/l, an increased level of LDL-C — with a level ≥3,0 mmol/l, hypertriglyceridemia (HTG) — with a TG ≥1,7 mmol/l, a reduced level of HDL-C — with a level in males ≤1,0 mmol/l, in women ≤1,2 mmol/l.Results. The prevalence of HCL was 65,1%. In the young cohort (40-44 years), men were significantly more likely to have hypercholesterolemia, but in the middle (50-54 years) and older (60 years or more) age groups, this lipid metabolism disorder was observed with greater frequency among females. In addition, 68,9% of the respondents had elevated LDL-C levels. When studying the prevalence of this type of dyslipidemia in different age groups among men and women, a similar trend can be noted with similar TC values, but significant gender differences in the prevalence of elevated LDL-C levels l were revealed only in the 60-64 and 65-69 years groups. The prevalence of HTG among the adult population of the Nizhny Novgorod region was 42,6%. Among the 35-49 years and 55-59 years age groups, the prevalence of elevated TG levels was significantly more common among men. The incidence of decreased HDL-C levels was 13,3%. This type of dyslipidemia was significantly more often detected among men only in the youngest subgroup (35-39 years).Conclusion. Among the population of the Nizhny Novgorod region, hypercholesterolemia occurred in 65,1% of respondents, an increased level of LDL-C — in 68,9%, a HTG — in 42,6%, a reduced level of HDL-C — in 13,3%. The data obtained determine a high cardiovascular risk and require the development of prevention and treatment measures for lipid metabolism disorders