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Abstract
Low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are modifiable risk factors for cardiovascular disease. Several genetic loci for predisposition to abnormal LDL-C, HDL-C and TG have been identified. However, it remains unclear whether these loci are consistently associated with serum lipid levels at each age or with unique developmental trajectories. Therefore, we assessed the association between genome wide association studies (GWAS) derived polygenic genetic risk scores and LDL-C, HDL-C, and triglyceride trajectories from childhood to adulthood using data available from the 27-year European ‘Cardiovascular Risk in Young Finns’ Study. For 2,442 participants, three weighted genetic risk scores (wGRSs) for HDL-C (38 SNPs), LDL-C (14 SNPs) and triglycerides (24 SNPs) were computed and tested for association with serum lipoprotein levels measured up to 8 times between 1980 and 2011. The categorical analyses revealed no clear divergence of blood lipid trajectories over time between wGRSs categories, with participants in the lower wGRS quartiles tending to have average lipoprotein concentrations 30 to 45% lower than those in the upper-quartile wGRS beginning at age 3 years and continuing through to age 49 years (where the upper-quartile wGRS have 4–7 more risk alleles than the lower wGRS group). Continuous analyses, however, revealed a significant but moderate time-dependent genetic interaction for HDL-C levels, with the association between HDL-C and the continuous HDL-C risk score weakening slightly with age. Conversely, in males, the association between the continuous TG genetic risk score and triglycerides levels tended to be lower in childhood and become more pronounced after the age of 25 years. Although the influence of genetic factors on age-specific lipoprotein values and developmental trajectories is complex, our data show that wGRSs are highly predictive of HDL-C, LDL-C, and triglyceride levels at all ages.
Highlights
Cardiovascular disease (CVD) is the leading cause of death and a major health burden worldwide [1]
Additional descriptive statistics showed that the weighted genetic risk scores (wGRSs) were not strongly linearly correlated with the lipoproteins overall when ignoring the effect of participants age (Pearson’s r = 0.21 for low-density lipoprotein cholesterol (LDL-C), 0.19 for high-density lipoprotein cholesterol (HDL-C) and 0.18 for triglycerides)
For HDL-C we found a significant linear and quadratic age-dependent interactions between participants belonging to the high and low wGRS group (β[wGRS Ãf(age)] = 0.022 and β[wGRS Ãf(age-square) = -2.6 x10-04) (Table 2), suggesting that genetic group membership is a modifier of the HDL-C trajectory
Summary
Cardiovascular disease (CVD) is the leading cause of death and a major health burden worldwide [1]. Recent findings have questioned the causal relationship between genetically-defined HDL-C levels and atherosclerosis [7, 8], numerous prospective and case-control epidemiological studies have reported an inverse association between HDL-C levels and the risk of CVD[9,10,11]. Recent evidence suggests that genetically-defined plasma TG levels are associated with coronary artery disease risk, even after correcting for confounding effects due to LDL-C or HDL-C levels[16]. In light of these associations, managing dyslipidemia remains a continuing trend both in primary and secondary prevention and risk reduction of CVD worldwide[17]
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