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Abstract
The critical role of blood lipids in a broad range of health and disease states is well recognised but less explored is the interplay of genetics and environment within the broader blood lipidome. We examined heritability of the plasma lipidome among healthy older-aged twins (75 monozygotic/55 dizygotic pairs) enrolled in the Older Australian Twins Study (OATS) and explored corresponding gene expression and DNA methylation associations. 27/209 lipids (13.3%) detected by liquid chromatography-coupled mass spectrometry (LC-MS) were significantly heritable under the classical ACE twin model (h2 = 0.28-0.59), which included ceramides (Cer) and triglycerides (TG). Relative to non-significantly heritable TGs, heritable TGs had a greater number of associations with gene transcripts, not directly associated with lipid metabolism, but with immune function, signalling and transcriptional regulation. Genome-wide average DNA methylation (GWAM) levels accounted for variability in some non-heritable lipids. We reveal a complex interplay of genetic and environmental influences on the ageing plasma lipidome.
Highlights
As the field of lipidomics has grown, hundreds to thousands of complex lipids have been characterised (Fahy et al, 2005; Quehenberger et al, 2010), with many linked to health and disease states, such as metabolic syndrome (Meikle and Christopher, 2011), cardiovascular disease (Meikle et al, 2014; Harmon et al, 2016), obesity (Barber et al, 2012; Rauschert et al, 2016), and dementiaWong et al eLife 2020;9:e58954
Data from 70 independent genome-wide association study (GWAS) with sample sizes ranging from ten thousand to several hundred thousand participants have identified associations of traditional lipid levels with 500 single nucleotide polymorphism (SNPs) in 167 loci that explain up to 40% of individual variance in these traditional lipid measures (Matey-Hernandez et al, 2018). This number suggests that low density lipoprotein (LDL), high density lipoprotein (HDL), total cholesterol and triglyceride levels undergo a substantial degree of genetic regulation, and highlights that much of the lipid variance is still unaccounted for, possibly related to rare variants or environmental factors (Matey-Hernandez et al, 2018; Garcıa-Giustiniani and Stein, 2016)
Plasma lipidomics was performed on n = 330 individuals, 260 of these were used for heritability analyses
Summary
As the field of lipidomics has grown, hundreds to thousands of complex lipids have been characterised (Fahy et al, 2005; Quehenberger et al, 2010), with many linked to health and disease states, such as metabolic syndrome (Meikle and Christopher, 2011), cardiovascular disease (Meikle et al, 2014; Harmon et al, 2016), obesity (Barber et al, 2012; Rauschert et al, 2016), and dementia. Data from 70 independent GWAS with sample sizes ranging from ten thousand to several hundred thousand participants have identified associations of traditional lipid levels with 500 single nucleotide polymorphism (SNPs) in 167 loci that explain up to 40% of individual variance in these traditional lipid measures (Matey-Hernandez et al, 2018) This number suggests that LDL, HDL, total cholesterol and triglyceride levels undergo a substantial degree of genetic regulation, and highlights that much of the lipid variance is still unaccounted for, possibly related to rare variants or environmental factors (Matey-Hernandez et al, 2018; Garcıa-Giustiniani and Stein, 2016). To examine heritability of the broad plasma lipidome among healthy older – aged twins and explore putative genetic, transcriptomic and epigenetic associations of these lipids
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