Complex trait susceptibilities and population diversity in a sample of 4,145 Russians.

The population of Russia consists of more than 150 local ethnicities. The ethnic diversity and geographic origins, which extend from eastern Europe to Asia, make the population uniquely positioned to investigate the shared properties of inherited disease risks between European and Asian ancestries. We present the analysis of genetic and phenotypic data from a cohort of 4,145 individuals collected in three metro areas in western Russia. We show the presence of multiple admixed genetic ancestry clusters spanning from primarily European to Asian and high identity-by-descent sharing with the Finnish population. As a result, there was notable enrichment of Finnish-specific variants in Russia. We illustrate the utility of Russian-descent cohorts for discovery of novel population-specific genetic associations, as well as replication of previously identified associations that were thought to be population-specific in other cohorts. Finally, we provide access to a database of allele frequencies and GWAS results for 464 phenotypes.

Genetic heterogeneity of familial hypercholesterolaemia in two populations from two different countries.

BACKGROUND: Familial hypercholesterolemia (FH) is a genetically determined monogenic disorder of predominantly autosomal dominant inheritance. A number of studies on differences in the genetic profile of patients with FH have demonstrated the importance of a more substantive evaluation of genetic features. The aim of this study was to evaluate the genetic profile of patients with clinical FH among Italian and Russian patients. METHODS: We included 144 Italian and 79 Russian FH patients; clinical diagnosis was based on the same criteria. Patients were divided in: positive to genetic test (one causative variant), inconclusive (only variants of uncertain clinical significance [VUS]), and negative (with likely benign/benign variants, heterozygous variants in LDLRAP1 gene, or without causative variants). RESULTS: The genetic test was positive in 76.4 % of the Italian patients and in 49.4 % of the Russian patients. The presence of VUS alone was detected in 7.6 % and in 19.0 % (p < 0.001), respectively. Among patients with positive genetic diagnosis, pre-treatment LDL-C levels were higher in the Russian cohort (353.5 ± 111.3 vs. 302.7 ± 52.1 mg/dL, p = 0.009), as well as the percentage of treated patients (53.8 % vs. 14.5 %, p < 0.001) and the prevalence of premature coronary heart disease (12.8 % vs. 3.6 %, p = 0.039). Among patients carrying only VUS, mean pre-treatment LDL-C levels were similar between the cohorts (299.5 ± 68.1 vs. 295.3 ± 46.8 mg/dL, p = 0.863). Among pathogenic/likely pathogenic variants and VUS, only 5 % and 4 % was shared between the two cohorts, respectively. CONCLUSION: The genetic background of patients clinically diagnosed with FH in two different countries is characterized by high variability.

The zebrafish model system for dyslipidemia and atherosclerosis research: Focus on environmental/exposome factors and genetic mechanisms.

Dyslipidemias and atherosclerosis play a pivotal role in cardiovascular risk and disease. Although some pathophysiological mechanisms underlying these conditions have been unveiled, several knowledge gaps still remain. Experimental models, both in vitro and in vivo, have been instrumental to our better understanding of such complex processes. The latter have often been based on rodent species, either wild-type or, in several instances, genetically modified. In this context, the zebrafish may represent an additional very useful in vivo experimental model for dyslipidemia and atherosclerosis. Interestingly, the lipid metabolism of zebrafish shares several features with that present in humans, recapitulating some molecular features and pathophysiological aspects in a better way than that of rodents. The zebrafish model may be of help to address questions related to exposome factors as well as to genetic features, aiming to dissect selected aspects of the more complex scenario observed in humans. Indeed, exposome-related dyslipidemia/atherosclerosis research in zebrafish may target different scientific questions, related to nutrition, microbiota, temperature, light exposure at the larval stage, exposure to chemicals and epigenetic consequences of such external factors. Addressing genetic features related to dyslipidemia/atherosclerosis using the zebrafish model is already a reality and active research is now ongoing in this promising area. Novel technologies (gene and genome editing) may help to identify new candidate genes involved in dyslipidemia and dyslipidemia-related diseases. Based on these considerations, the zebrafish experimental model appears highly suitable for the study of exposome factors, genes and molecules involved in the development of atherosclerosis-related disease as well as for the validation of novel potential treatment options.

Integrative Analysis of Multi-Omics and Genetic Approaches-A New Level in Atherosclerotic Cardiovascular Risk Prediction.

Genetics and environmental and lifestyle factors deeply affect cardiovascular diseases, with atherosclerosis as the etiopathological factor (ACVD) and their early recognition can significantly contribute to an efficient prevention and treatment of the disease. Due to the vast number of these factors, only the novel "omic" approaches are surmised. In addition to genomics, which extended the effective therapeutic potential for complex and rarer diseases, the use of "omics" presents a step-forward that can be harnessed for more accurate ACVD prediction and risk assessment in larger populations. The analysis of these data by artificial intelligence (AI)/machine learning (ML) strategies makes is possible to decipher the large amount of data that derives from such techniques, in order to provide an unbiased assessment of pathophysiological correlations and to develop a better understanding of the molecular background of ACVD. The predictive models implementing data from these "omics", are based on consolidated AI best practices for classical ML and deep learning paradigms that employ methods (e.g., Integrative Network Fusion method, using an AI/ML supervised strategy and cross-validation) to validate the reproducibility of the results. Here, we highlight the proposed integrated approach for the prediction and diagnosis of ACVD with the presentation of the key elements of a joint scientific project of the University of Milan and the Almazov National Medical Research Centre.

Sleep Duration, Lipid Profile and Insulin Resistance: Potential Role of Lipoprotein(a).

Lipoprotein (a) (Lp(a)) is considered a genetic factor for cardiovascular disease playing an important role in atherogenesis and thrombosis, but the evidence about its association with sleep duration is controversial. We evaluated the relation between self-reported sleep duration and Lp(a). Among 1600 participants of the population-based sample, we selected 1427 subjects without previously known cardiovascular events, who answered the questions about their sleep duration; had valid lipid profile results (total cholesterol, low- and high-density lipoproteins, Lp(a), apolipoprotein AI (ApoAI), ApoB, and ApoB/ApoAI); and did not take lipid-lowering drugs (mean age 46 ± 12 years). We performed a structured interview, which included questions about lifestyle, medical history, complaints, and sleep duration (How long have you been sleeping per night during the last month?). Sleep duration was classified as follows: <6 h/night-short, 6-9 h/night-normal, and ≥10 h/night-long. Overall, 73 respondents (5.2%) were short-sleepers and 69 (4.8%) long-sleepers. Males were slightly more prevalent among short-sleepers. The groups matched by age, body mass index, blood pressure, diabetes mellitus, and hypertension rate. Short-sleepers had lower rates of high total cholesterol (≥5.0 mmol/L), lower Lp(a) levels and lower rates of increased Lp(a) ≥0.5 g/L, and higher insulin and insulin resistance (assessed by the homeostatic model assessment for insulin resistance (HOMA-IR)). ApoAI, ApoB, their ratio, and other lab tests were similar in the groups. The multinomial logistic regression demonstrated that only the short sleep duration was independently (odds ratio (OR) 0.29, 95% confidence interval (CI) (0.09-0.91), p = 0.033) associated with Lp(a) (χ2 = 41.58, p = 0.003). Other influencing factors were smoking and HOMA-IR. Such an association was not found for long-sleepers. In conclusion, a short-sleep duration is associated with Lp(a). The latter might mediate the higher insulin resistance and higher cardiometabolic risks in short-sleepers.

Prevalence and relationship between metabolic syndrome and risk of cardiovascular disease: Evidence from two population-based studies.

BACKGROUND AND AIM: The metabolic syndrome (MetS) has become one of the most important clinical issues in the cardiovascular field for this decade because of the marked increase in cardiovascular (CV) risk associated with a clustering of risk factors. The aim of the current study was to evaluate the relationship between MetS and its components and cardiovascular disease (CVD). METHODS: This population-based cross-sectional study was based on data from two studies carried out in Russia (ESSE-RF) and Italy (PLIC). One sample from each cohort was selected, matching individuals by sex and age. A comparison between samples of MetS components distribution and CV risk, according to SCORE chart, has been conducted. RESULTS: A total of 609 individuals (mean [SD] age 55 [8] years, about 39% males) for each cohort were selected. Almost half of PLIC cohort participants belonged to the moderate CV risk group (47% vs 27%), while in ESSE-RF cohort a relatively higher prevalence of individuals classified in the high and very high risk group was observed (19% vs 11%, 21% vs 6%, respectively). Overall, 43% of ESSE-RF participants were diagnosed with MetS, compared with the 27% of PLIC members (the difference in prevalence becomes 37% vs 21%, considering a more conservative cut-off for waist circumference). Both cohorts showed a trend towards the increase of MetS components moving from the lowest to the highest CV risk class, with a high prevalence of patients with four or five MetS determinants allocated in the high/very high CV risk group. CONCLUSIONS: Developing effective public health strategies for the prevention, detection and treatment of MetS should be an urgent priority to reduce the burden of CVD, not only in subjects at high/very high CV risk, but also in those characterized by a lower risk, as even rare CV events that come from low risk group bring a tangible burden to healthcare systems.

Lipid Clinics Network. Rationale and design of the EAS global project.

The evidence of the causal role of low-density lipoprotein cholesterol in the development of atherosclerotic cardiovascular disease is well-established. The clearly identified common position of the European guidelines proclaims necessity to decrease LDL-C concentrations based on a proper risk stratification. However, current worldwide situation with the lipid management still demonstrates inadequate dyslipidemia control, that is probably related to a healthcare system issues. As the need to standardize and implement approaches following the guidelines into clinical practice remains a challenge, the EAS initiates the Lipid Clinics Network project, aiming to provide a structure to establish uniform EU-wide standards of diagnosis, management and treatment of patients with lipid disorders, based on the ESC/EAS Guidelines on management of dyslipidaemias.

Epidemiology of cardiovascular risk factors in two population-based studies.

We aimed to compare cardiovascular risk factors prevalence in Italy and Russia through cross-sectional database analysis. The study has been based on data from ESSE-RF and from baseline of PLIC study, two population-based epidemiological studies aimed to investigate prevalence of risk factors and evaluating contribution of traditional and new risk factors into morbidity and cardiovascular mortality. A total of 2203 patients with left and right intima-media thickness (IMT) measurements constituted the source population (1205 from PLIC study and 998 from ESSE-RF study). Sample of ESSE-RF study had slightly more diabetic and hypertensive individuals, while the percentage of subjects with high cholesterol value was lower than in the other sample (67.1% vs 79.9%). The median LDL-C value was higher among individuals not treated with statins in the PLIC sample (p < 0.001), while was comparable among subjects receiving statin therapy. On the other hand, the percentage of individuals with positive cardiovascular history was higher in ESSE-RF sample. This could also explain the higher mean IMT value (0.71 ±â€¯0.17 vs 0.63 ±â€¯0.13) in the whole sample, and among patients without past cardiovascular events (regardless of statin treatment), despite some differences in major risk factors. Despite Russian and Italian populations are culturally and geographically different, they are not so different based on characteristics analyzed.