Key result
The chromosome 9p21 coronary heart disease risk SNP rs10757274 (GG genotype) is associated with significantly reduced plasma levels of lysophospholipids, lysophosphatidic acids, and autotaxin compared to the AA genotype.
Why the study?
Common chromosome 9p21 SNPs increase coronary heart disease risk independent of traditional lipid risk factors, but whether they alter unmeasured inflammatory lipid molecules was unclear.
Observational (n=3,000)
Yes
This study reveals that the chromosome 9p21 CHD risk SNP rs10757274 is associated with inflammatory phospholipid metabolic dysregulation, independent of traditional lipid risk factors.
Answers are grounded in this paper and cite their sources.
Supports 9p21 variant association with lysoPL dysregulation in CHD models; leaves open human validation and therapeutic targeting.
Aims Common chromosome 9p21 SNPs increase coronary heart disease (CHD) risk, independent of “traditional lipid risk factors”. However, lipids comprise large numbers of structurally-related molecules not measured in traditional risk measurements, and many have inflammatory bioactivities. Here we applied lipidomic and genomic approaches to three model systems, to characterize lipid metabolic changes in common Chr9p21 SNPs which confer ∼30% elevated CHD risk associated with altered expression of ANRIL , a long ncRNA. Methods and Results Untargeted and targeted lipidomics was applied to plasma samples from Northwick Park Heart Study II (NPHSII) homozygotes for AA or GG in rs10757274. Elevated risk GG correlated with reduced lysophosphospholipids (lysoPLs), lysophosphatidic acids (lysoPA) and autotaxin (ATX). Five other risk SNPs did not show this phenotype. Correlation and network analysis showed that lysoPL-lysoPA interconversion was uncoupled from ATX in GG, indicating metabolic dysregulation. To identify candidate genes, transcriptomic data from shRNA downregulation of ANRIL in HEK293 cells was mined. Significantly-altered expression of several lysoPL/lysoPA metabolising enzymes was found ( MBOAT2, PLA2G4C, LPCAT2, ACSL6, PNPLA2, PLBD1, PLPP1, PLPP2 and PLPPR2) . Next, vascular smooth muscle cells differentiated from iPSCs of individuals homozygous for Chr9p21 risk SNPs were examined. Here, the presence of risk alleles was associated with altered expression of several lysoPL/lysoPA enzymes. Importantly, for several, deletion of the risk locus fully or partially reversed their expression to non-risk haplotype levels: ACSL3, DGKA, PLA2G2A, LPCAT2, LPL, PLA2G3, PNPLA3, PLA2G12A LIPC, LCAT, PLA2G6, ACSL1, MBOAT2. Conclusion A Chr9p21 risk SNP associates with complex alterations in immune-bioactive phospholipids and their enzymatic metabolism. Lipid metabolites and genomic pathways associated with CHD pathogenesis in Chr9p21 and ANRIL -associated disease are demonstrated. One sentence summary Inflammatory phospholipid metabolism defines a cardiovascular disease SNP
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Meckelmann et al. (2019) conducted an observational in Coronary Heart Disease Risk (n=3,000). Chromosome 9p21 SNP rs10757274 GG genotype vs. AA genotype was evaluated on Plasma levels of lysophospholipids, lysophosphatidic acids, and autotaxin (p=0.026). The chromosome 9p21 coronary heart disease risk SNP rs10757274 (GG genotype) is associated with significantly reduced plasma levels of lysophospholipids, lysophosphatidic acids, and autotaxin compared to the AA genotype.
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