Introduction and methods

First large-scale study of the genetics of human plasma lipid species

Presented at EAS 2019 in Maastricht, by Rubina Tabassum (Institute for Molecular Medicine Finland, University of Helsinki, Finland).

Human plasma comprises hundreds of lipid species that differ in chemical structure and function. Many of these are known risk factors for human diseases. Advances in mass spectrometry-driven lipid analysis –lipidomics–has made it possible to study the patient lipidome to a greater extent than is possible with conventional analytical methods. Genetic investigation of the detailed lipidomic profiles could provide deeper insight into lipid metabolism and its link to clinical outcomes. To date, understanding of the genetic regulation of molecular lipid species is, however, limited. Unravelling this information could help in the personalized management of atherosclerosis and heart disease.

Centres in Finland, Germany and the USA collaborated to integrate information from the lipidome, genome and phenome to answer key questions relating to the heritability of lipid species, for instance which what the genetic contribution is to the lipodome, and what are genetic determinants of the lipidome. And the researchers are interested in mechanistic insights into lipid variants and their relationship with disease outcomes.

A genome-wide association study (GWAS) of 141 lipid species was performed in 2181 individuals. This was followed by phenome-wide scans (PheWAS) of 37 lipid-related outcomes, including CV, gastrointestinal and neurological disease, in up to 511.700 individuals.

Main results

• Lipid species are heritable to different extents, ranging from 10 to 54 per cent, with the highest heritability in lipids containing polyunsaturated fatty acids (PUFAs). These lipid species with PUFAs also had greater genetic sharing with each other.
• The analyses revealed that traditional lipid measures reflect only a fraction of lipidome.
• The GWAS analyses identified 35 gene variants that were associated with 74 lipid species. Using clinical outcome data from the FinnGen and UK Biobank cohorts, the investigators showed that 10 of these variants (at the APOA5, ABCG5/8, BLK, LPL, FADS2, COL5A1, GALNT16, GLTPD2, MBOAT7 and SPTLC3 genes) were associated with CV disease.
• Gene variants at the BLK, GALNT16 and LPL genes were associated with T2DM.
• The study also provided clues to the underlying mechanisms of well-known lipid loci on lipid metabolism and CV disease risk. Notably, the rs11570891variant in the intron of the gene encoding lipoprotein lipase (LpL) is known to be associated with reduced risk of CV disease T2DM.

Conclusion

This first large-scale study identified novel lipid-associated genetic variants, some of which were linked with risk for cardiovascular disease, such as MI and stroke. This approach gives additional information as compared with traditional lipid measures. In a press release, Tabassum noted: ‘This study has identified new genomic loci associated with lipid species and disease risks in humans. In addition to enhancing the current understanding of genetic determinants of circulating lipids, our study also highlights the potential of lipidomics in gene mapping for lipids and cardiovascular disease over the traditional lipid measures. These insights into the genetic regulation of lipid metabolism and its link to human diseases might help guide future biomarker and drug target discovery and disease prevention strategies.’ The study generates a publicly available knowledgebase.

Our reporting is based on the information provided at the EAS 2019 congress