J Lipid Atheroscler.  2020 Jan;9(1):172-183. 10.12997/jla.2020.9.1.172.

Genetic Architecture of Circulating Very-Long-Chain (C24:0 and C22:0) Ceramide Concentrations

• Cresci S
• Zhang R
• Yang Q
• Duncan MS
• Xanthakis
• Jiang X
• Vasan RS
• Schaffer J
• Peterson L

• KMID: 2470809
• DOI: http://doi.org/10.12997/jla.2020.9.1.172

Abstract

OBJECTIVE
Total ceramide concentrations are linked with increased insulin resistance and cardiac dysfunction. However, recent studies have demonstrated that plasma concentrations of specific very-long-chain fatty ceramides (C24:0 and C22:0) are associated with a reduced incidence of coronary heart disease and all-cause mortality. We hypothesized that specific genetic loci are associated with plasma C22:0 and C24:0 concentrations.
METHODS
Heritability and genome-wide association studies of plasma C24:0 and C22:0 ceramide concentrations were performed among 2,217 participants in the Framingham Heart Study Offspring Cohort, adjusting for cardiovascular risk factor covariates and cardiovascular drug treatment.
RESULTS
The multivariable-adjusted heritability for C22:0 and C24:0 ceramides was 0.42 (standard error [SE], 0.07; p=1.8E-9) and 0.25 (SE, 0.08; p=0.00025), respectively. Nineteen single nucleotide polymorphisms (SNPs), all on chromosome 20, significantly associated with C22:0 concentrations; the closest gene to these variants was SPTLC3. The lead SNP (rs4814175) significantly associated with 3% lower plasma C22:0 concentrations (p=2.83E-11). Nine SNPs, all on chromosome 20 and close to SPTLC3, were significantly associated with C24:0 ceramide concentrations. All 9 were also significantly related to plasma C22:0 levels. The lead SNP (rs168622) was significantly associated with 10% lower plasma C24:0 ceramide concentrations (p=9.94E-09).
CONCLUSION
SNPs near the SPTLC3 gene, which encodes serine palmitoyltransferase long chain base subunit 3 (SPTLC3; part of the enzyme that catalyzes the rate-limiting step of de novo sphingolipid synthesis) were associated with plasma C22:0 and C24:0 ceramide concentrations. These results are biologically plausible and suggest that SPTLC3 may be a potential therapeutic target for C24:0 and C22:0 ceramide modulation.

Keyword

Genomics; Lipidomics; Cardiovascular disease; Genome-Wide Association Study

MeSH Terms

Cardiovascular Diseases
Ceramides
Chromosomes, Human, Pair 20
Cohort Studies
Coronary Disease
Genetic Loci
Genome-Wide Association Study
Genomics
Heart
Incidence
Insulin Resistance
Mortality
Plasma
Polymorphism, Single Nucleotide
Risk Factors
Serine C-Palmitoyltransferase
Ceramides
Serine C-Palmitoyltransferase

Figure

• 

  Fig. 1 Manhattan plot of associations between SNPs and plasma C22:0 ceramide concentrations in 2,217 Framingham Heart Study subjects. SNPs are plotted on the x-axis according to their position on each chromosome, with the −log10 p-value on the y-axis. The upper dashed horizontal line indicates the threshold for genome-wide significance, 5×10−8. SNP, single-nucleotide polymorphism.

• 

  Fig. 2 Regional association and recombination plot for SNPs associated with plasma C22:0 ceramide concentrations. The −log10 p-values for associations with C22:0 ceramide concentrations are presented on the left y-axis. The chromosome 20 position in megabases (Mb) is presented on the x-axis. The plotted SNPs are presented in the top panel and the relative positions of genes in the region are presented in the bottom panel. The purple diamond indicates the SNP (rs4814175) with the most significant association with C22:0 ceramide concentrations. The surrounding SNPs are colored according to their pairwise correlation (r2) with rs4814175. Estimated recombination hotspots in HapMap (i.e., recombination rates) are represented by blue lines (quantified on the right y-axis). SNP, single-nucleotide polymorphism.

• 

  Fig. 3 Manhattan plot of associations between SNPs and plasma C24:0 ceramide concentrations in 2,217 Framingham Heart Study subjects. SNPs are plotted on the x-axis according to their position on each chromosome, with the −log10 p-value on the y-axis. The upper dashed horizontal line indicates the threshold for genome-wide significance, 5×10−8. SNP, single-nucleotide polymorphism.

• 

  Fig. 4 Regional association and recombination plot for SNPs associated with plasma C24:0 ceramide concentrations. The −log10 p-values for association with C24:0 ceramide concentrations are represented on the left y-axis. The chromosome 20 position in megabases (Mb) is presented on the x-axis. The plotted SNPs are presented in the top panel and the relative positions of genes in the region are represented in the bottom panel. The purple diamond indicates the SNP (rs168622) with the most significant association with C22:0 ceramide concentrations. Surrounding SNPs are colored according to their pairwise correlation (r2) with rs168622. Estimated recombination hotspots in HapMap (i.e., recombination rates) are represented by blue lines (quantified on the right y-axis). SNP, single-nucleotide polymorphism.

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