👤 Veronika Skvortsova

Most genomic studies compare the genomes of long-living adults to those of the general population to identify potential genetic markers of longevity. We propose a refined approach: focusing on the genetic makeup of healthy, long-living adults to detect mechanisms promoting both longer lifespan and improved quality of life. To this end, we analyzed medical and genomic data from 3,703 long-living adults aged ≥90 years and 22,354 individuals aged 18-75 years (total N = 26,057). Using whole-genome sequencing (WGS) and a genome-wide association study (GWAS), we found that variants with significant and negative associations with longevity in the GWAS were located in genes such as APOE, APOC1, and CFAP46, which are implicated in an increased risk of age-related diseases. However, the presence or absence of these variants should not be considered a definitive determinant of longevity or sustained health after the age of 90. We found that healthy longevity was positively associated with variants within the MYO18B, TBC1D28, and LOC105376454 genes. To demonstrate the multifactorial nature of the examined phenotypes, we constructed polygenic score models that accounted for nonlinear interactions among the predictors. Trial registration: Clinical Trials NCT06268132 (for long-living adults). Registered 22 February 2024 (retrospectively registered). Show less

Familial hypercholesterolemia (FH) is a prevalent hereditary disorder, with its monogenic form linked to an elevated risk of early-onset ischemic heart disease. Evaluating the prevalence and penetrance of pathogenic and likely pathogenic variants associated with this disorder would provide valuable information supporting routine FH screening of the general population. Such informed screening would facilitate early identification of at-risk individuals, enabling timely intervention and management. We analyzed genetic data from 4,856 individuals with various cardiovascular conditions for pathogenic and likely pathogenic variants in the PCSK9, APOB, and LDLR genes. The evaluation included comprehensive clinical assessments, instrumental examinations, and laboratory tests. All genetic data were obtained through the whole-genome sequencing of blood leukocytes. A total of 1.77% of participants carried pathogenic or likely pathogenic variants in the LDLR or APOB genes, and none in the PCSK9 gene. After adjusting for sex and age, the risk of ischemic heart disease was 1.3 times higher in carriers of pathogenic or likely pathogenic variants [95% CI 1.18-1.46; FH remains significantly underdiagnosed. Only 10.5% of carriers of pathogenic or likely pathogenic variants in the LDLR and APOB genes had a prior diagnosis of FH. Our findings suggest low diagnostic rates for this disorder in Eastern European populations and highlight the need for routine genetic screening of younger individuals. However, further research is needed to assess the clinical applicability and cost-effectiveness of such screening programs. Show less

Long-living adults often maintain cognitive function despite neuropathological changes, which is often attributed to cognitive resilience (CR)-a combined effect of cognitive and cerebral reserves. CR is influenced by genetic, clinical, sociodemographic, and environmental factors. We investigated genetic, clinical, and environmental predictors of CR in 198 dementia-free long-living adults via two neuropsychological examinations over a 2-year period, a geriatric assessment, and a genome-wide association study (GWAS). Limited mobility, reduced walking, hearing impairment, depression, anemia, lower quality of life, and decreased BMI were key accelerators of CI. Depression, hypercholesterolemia, and lack of hobbies increased the risk of mild cognitive impairment (MCI)-to-dementia progression. GWAS identified CR-associated genetic variants, including a missense mutation in Our findings corroborated established risk factors for cardiovascular diseases and identified population-specific patterns, with APOE ε4 showing no significant association. Both protein-coding regions and non-coding elements were implicated in CI, suggesting that it is underlain by complex regulatory mechanisms. Show less

Epithelial to mesenchymal transition (EMT) is clinically relevant in head and neck squamous cell carcinoma (HNSCC). We hypothesized that EMT-transcription factors (EMT-TFs) and an anti-EMT factor, Krüppel-like-factor-4 (KLF4) regulate EMT in HNSCC. Ten control mucosa and 37 HNSCC tissue samples and three HNSCC cell lines were included for investigation of EMT-TFs, KLF4 and vimentin at mRNA and protein levels. Slug gene expression was significantly higher, whereas, KLF4 gene expression was significantly lower in HNSCC than in normal mucosa. In the majority of HNSCC samples, there was a significant negative correlation between KLF4 and Slug gene expression. Slug gene expression was significantly higher in human papilloma virus (HPV) negative HNSCC, and in tumor samples with irregular p53 gene sequence. Transforming-growth-factor-beta-1 (TGF- β1) contributed to downregulation of KLF4 and upregulation of Slug. Two possible regulatory pathways could be suggested: (1) EMT-factors induced pathway, where TGF-β1 induced Slug together with vimentin, and KLF4 was down regulated at the same time; (2) p53 mutations contributed to upregulation and stabilization of Slug, where also KLF4 could co-exist with EMT-TFs. Show less