Genetic aspects of decreased low-density lipoprotein cholesterol values

Aim. To study genetic causes of decreased low-density lipoprotein cholesterol (LDL-C) in Russian patients.Material and methods. The study included the following Epidemiology of Cardiovascular Diseases and their Risk Factors in Regions of Russian Federation (ESSE-RF) participants: individuals with LDL-C<5th percentile, taking into account sex and age (n=52), who underwent targeted sequencing of protein-coding regions of 6 genes (APOB, PCSK9, MTTP, ANGPTL3, SAR1B, APOC3) and determination of the genetic risk score (GRS) for hypercholesterolemia; and a representative sample of the Ivanovo region population (ESSEIvanovo, n=1667), for which only GRS was determined. Genetic testing was performed using next generation sequencing.Results. In 10 (19,2%) of 52 participants with decreased LDL-C levels, the following rare variants potentially associated with hypocholesterolemia were identified: 8 — leading to a premature termination codon in the APOB gene, 1 — leading to a premature termination codon in the APOC3 gene and 1 missense variant in the PCSK9 gene. Of the 10 identified variants, 6 are described by us for the first time. GRS in the LDL-C group (0,27±0,25) was significantly lower than in the ESSE-Ivanovo population sample (0,43±0,27) (p=4,7×10-06).Conclusion. Genetic reasons explain decreased LDL-C levels (<5th percentile) in 32,7% of patients, of which only monogenic variants were identified in 13,5%, a combination of monogenic and polygenic hypocholesterolemia — in 5,7%, and polygenic hypocholesterolemia — in 13,5%.