The Combined Effect of Common Genetic Risk Variants on Circulating Lipoproteins Is Evident in Childhood: A Longitudinal Analysis of the Cardiovascular Risk in Young Finns Study

PLoS One. 2016 Jan 5;11(1):e0146081. doi: 10.1371/journal.pone.0146081. eCollection 2016.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Cardiovascular Diseases / blood*
  • Cardiovascular Diseases / epidemiology
  • Cardiovascular Diseases / genetics*
  • Child
  • Child, Preschool
  • Cholesterol, HDL / blood*
  • Cholesterol, HDL / genetics
  • Cholesterol, LDL / blood*
  • Cholesterol, LDL / genetics
  • Female
  • Finland / epidemiology
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Genome-Wide Association Study
  • Humans
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Triglycerides / blood*
  • Triglycerides / genetics
  • Young Adult

Substances

  • Cholesterol, HDL
  • Cholesterol, LDL
  • Triglycerides

Grants and funding

The Young Finn study was financially supported by the Academy of Finland (grants 126925, 121584, 124282, 129378, 117797, 265877, and 41071), the Social Insurance Institution of Finland, the Turku University Foundation, Paavo Nurmi Foundation, Juho Vainio Foundation, Sigrid Juselius Foundation, Maud Kuistila Foundation, Research funds from the Kuopio, Turku and Tampere University Hospitals, the Finnish Foundation of Cardiovascular Research, the Finnish Medical Foundation, the Orion-Farmos Research Foundation, and the Finnish Cultural Foundation. CGM holds a National Health and Medical Research Council Early Career Fellowship (Public Health Fellowship, APP1037559). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the present manuscript. Fimlab Ltd provided support in the form of salaries for author TL, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.