Polygenic predisposition to increased LDL-cholesterol concentration and Carotid Artery Intima Media Thickness in childhood and early adulthood

Abstract

Background: High polygenic risk score (PRS) for LDL-cholesterol (LDL-C), due to a burden of LDL-C-raising genetic variants, has been associated with increased concentration of LDL-C and risk of coronary heart disease (CHD) in adults. However, the effect of LDL-C PRS on LDL-C in childhood, when the cumulative lifetime effect of genetic risk is lower, remains largely unknown. Using data from the cross-sectional study of the Avon Longitudinal Study of Parents and Children (ALSPAC) we aimed to examine the LDL-C PRS association with LDL-C in children and to assess the genetic predisposition to higher carotid intima media thickness (CIMT), using LDL-C PRS and CIMT PRS. Methods: Genotyping and cholesterol data were available for seven (n=5424), nine (n=5076), 15 (n=3484), 17 (n=3282) and 24 (n=3248) year olds. CIMT was measured at 17 (n=4633) and 24 (n=2029) years of age. Previously established LDL-C PRS (n=223 SNPs) and CIMT PRS (n=11,600 SNPs) were computed using Plink. Regression analyses were performed in R. Results: LDL-C PRS was associated with LDL-C concentration across all age groups, with the strongest correlation at the age of seven years (p< 1.3x10-57). A significant difference in mean (SD) LDL-C between children with LDL-C PRS in 1st vs. 10th decile was observed as early as seven years of age (p<8x10-15). CIMT was measured at 17 or 24 years and was not associated with LDL-C or LDL-C PRS. However, the CIMT PRS showed association with CIMT at 17 and 24 years of age, after adjusting for covariates (gender, BMI, blood pressure and body fat). Average right/left CIMT in 17-year-olds with CIMT PRS in 1st decile was significantly lower than in those with CIMT PRS in 10th decile (p<1.25x10-5). Conclusions: LDL-C PRS influences LDL-C concentration as early as seven years of age. CIMT PRS correlates with measures of CIMT at ages 17 and 24 years. Polygenic scores testing in childhood might provide the opportunity to assess future CHD risk before the emergence of clinical risk factors of CHD later in life.