Blood lipid levels are an important etiological contributor to CVD. CVD is the leading cause of death among individuals with T2D, in which lipid abnormalities are characterized by hypertriglyceridemia, reduced levels of HDL-C, and elevated levels of LDL-C. These lipid-related traits, including ~14-54% for TG, ~34-42% for HDL-C, and ~28-50% for LDL-C, are highly heritable in familial T2D or diabetic patients [19
]. These estimates indicate that genetic variants play important roles in explaining inter-individual variations in blood lipid levels.
Although systematic reviews have reported relationships between childhood obesity and adult CVD risk [21
], there is not a shred of evidence that blood lipid status in adults is an independent or dependent risk factor in a childhood obesity group. Early childhood obesity might be the best time for dyslipidemia intervention, including screening, early detection, and management. The aim of this study was to consolidate the associations of 16 GWAS-based candidate variants with blood lipid concentrations across the lifespan.
In GWAS-based candidate approaches, the well-known LPL
gene was significantly associated with low TG and high HDL-C levels in a childhood obesity study, respectively. This finding is well matched to the negative correlation between blood TG and HDL-C concentrations [23
]. In addition, the LIPC
gene was further observed in decreased HDL-C. In analyses of the joint effects of these variants, we found that GRSs on the two risk alleles (rs10503669 at LPL
and rs16940212 at LIPC
) were associated with a cumulative effect of TG and HDL-C levels. However, these facts indicate that currently identified risk variants might have low discriminatory ability and modest genetic contribution to disease prediction [24
Lipoprotein lipase (LPL
) plays an important role in lipid metabolism by hydrolyzing TGs of circulating chylomicrons and very low-density lipoproteins. In addition, LPL
is expressed in the brain regions that are functionally relevant to learning, memory, and other cognitive functions. Many GWASs and meta-analyses have shown that variations in the well-known LPL
gene for multiple lipid-related traits are implicated in multiethnic populations [2
]. An increasing number of studies have suggested an association of LPL
gene variants with the risk of cerebrovascular as well as CVD [29
]. Recent genome-wide investigations identified schizophrenia-associated loci in the chromosome 8p22 region, including LPL
]. It was suggested that LPL
is an attractive candidate gene that might be involved in the potential role of lipid metabolism in schizophrenia. Stages of early childhood development can be taken into account when considering a diagnosis of mental illness [33
Hepatic lipase (LIPC
) gene encodes hepatic triglyceride lipase, which is expressed in liver. LIPC
has a dual function as a triglyceride hydrolase and ligand/bridging factor for receptor-mediated lipoprotein uptake. A GWAS has identified a possible role of LIPC
in advanced age-related macular degeneration (AMD) [34
]. AMD is an eye condition affecting the central part of the retina. Although a condition that is commonly associated with the elderly, macular degeneration affects younger people through a rare inherited condition [35
]. Based on a lack of direct relationships between HDL-C and AMD risk, the LIPC
association may not be the result of an effect on HDL-C levels, but it could represent a pleiotropic effect as a functional component, such as a lipoprotein transporter, underlying the biological mechanisms involving the cholesterol pathway.
Taken together, our findings demonstrate that the genetic architecture of circulating lipid levels (TG and HDL-C) overlap to a large extent in childhood as well as in adulthood. A genetic risk assessment by incorporating two risk alleles suggests encouraging evidence that identified genetic risk variants for lipid phenotypes have cumulative effects on lipid concentrations. Post-GWAS functional characterization of these variants is further required to elucidate the pathophysiological role and biological mechanisms.