Hidden burden of chronic non-communicable diseases. Part 1. Prevalence of germline variants associated with cardiovascular diseases in Russian population

Introduction. Cardiovascular diseases (CVD) are the leading cause of mortality in the Russian Federation. Existing healthcare programs are primarily focused on the treatment of manifest CVD, while the prevalence of genetic risk factors (cardio-germline variants) remains understudied.

Objective. Assessment of the prevalence of pathogenic and likely pathogenic (P/LP) cardio-germline variants in Russian population based on a representative sample.

Materials and methods. The study was conducted using samples from the Genetic Database (GDB) cohort of the Centre for Strategic Planning (FMBA of Russia), comprising 116,794 participants from 86 Russian regions. Whole-genome sequencing (WGS, coverage >30x) of DNA was performed (database of the Centre for Strategic Planning FMBA of Russia). The search and annotation of pathogenic and likely pathogenic (P/LP) variants in 37 genes associated with CVD were performed based on ClinVar. Statistical analysis was conducted using Python (v3.9.12).

Results. P/LP variants in 26 genes were identified in 0.98% (1152) of participants (cumulative allele frequency 0.49%, 424 unique variants). The prevalence by disease groups was as follows: hypercholesterolemia — 0.1704%, structural abnormalities — 0.2218%, arrhythmias — 0.1040%. The most frequent variant was rs5742904 (APOB gene, 0.0545%). When strictly considering only variants with the “reviewed by expert panel” level of evidence (Level A), the prevalence was 0.14%. Significant geographical variations were observed (ranging 321–6250 carriers per 100,000 population), with the highest frequencies in the Chechnya, Khakassia, and Bryansk Oblast. No statistically significant decrease in the proportion of carriers was found in the age group over 75 years, confirming the generally low penetrance of these variants. However, within the group over 75 years, a higher number of carriers was observed among female compared to male subjects (p = 0.013), which may indicate a greater effect of these variants on male carriers.

Conclusions. The study has identified for the first time a significant “hidden burden” of P/LP cardio-germline variants (~1% carriers) in the Russian population. The substantial geographical variations underscore the importance of a regional approach to healthcare resource planning. The absence of an overall decrease in carrier frequency among the elderly, combined with sex-specific differences in age-related dynamics for certain disease groups, highlights the role of modifying factors and variable penetrance. The data obtained are critical for the development of preventive cardiogenetics and the optimization of the CVD prevention system in Russia.

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