Genetic Determinants of Circulating Sphingolipid Concentrations in European Populations

Abstract

Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipid metabolism are being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic β-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matched metabolite ratios measured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08×10−66. The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1–3. Variants in 3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of three German MI studies. An additional 70 variants across 23 candidate genes involved in sphingolipid-metabolizing pathways also demonstrate association (p = 10−4 or less). Circulating concentrations of several key components in sphingolipid metabolism are thus under strong genetic control, and variants in these loci can be tested for a role in the development of common cardiovascular, metabolic, neurological, and psychiatric diseases.

Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

“…Such reagents would be especially powerful in combination with inducible enzymatic constructs that can be used to locally produce or degrade specific sphingolipid metabolites. Lastly, advances in human genetics may provide new insights into factors that regulate sphingolipid levels in health and disease (Hicks et al 2009;Demirkan et al 2012).…”

Plasma deoxysphingolipids: a novel class of biomarkers for the metabolic syndrome?

“…Genome-wide association studies have shown a strong association of genetic SPTLC3 variants with alterations in lipid metabolism [29] and increased risk for myocardial infarction [30]. Therefore, lower C 16 SO levels might be directly or indirectly related to the increased risk of diabetic patients for developing cardiovascular complications.…”

Predictive Value of 8 Genetic Loci for Serum Uric Acid Concentration

“…One such study reported increased odds of nephrolithiasis in isolated populations (25), which was attributed to the existence of consanguinity in some of the island populations (18,(26)(27)(28)(29)(30). Subsequent efforts in gene mapping in two of the Croatian Adriatic islands (Vis and Korčula) yielded a number of interesting results, including findings on genetic influence on height determination (31,32), lung function (33), chronic kidney disease (34), and levels of fasting glucose (35), serum lipids (36)(37)(38), creatinine (39), and plasma N-glycans (40), supporting the initial proposal that isolated populations present a very valuable and fundamentally advantageous research resource (17,18,41).…”