Cresci Sharon, Zhang Ruibo, Yang Qiong, Duncan Meredith S, Xanthakis Vanessa, Jiang Xuntian, Vasan Ramachandran S, Schaffer Jean E, Peterson Linda R
Diabetic Cardiovascular Disease Center, Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Department of Biostatistics and Epidemiology, Boston University School of Public Health, Boston, MA, USA.
J Lipid Atheroscler. 2020;9(1):172-183. doi: 10.12997/jla.2020.9.1.172. Epub 2020 Jan 3.
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.
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.
The multivariable-adjusted heritability for C22:0 and C24:0 ceramides was 0.42 (standard error [SE], 0.07; =1.8E-9) and 0.25 (SE, 0.08; =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 . The lead SNP (rs4814175) significantly associated with 3% lower plasma C22:0 concentrations (=2.83E-11). Nine SNPs, all on chromosome 20 and close to , 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 (=9.94E-09).
SNPs near the gene, which encodes serine palmitoyltransferase long chain base subunit 3 (SPTLC3; part of the enzyme that catalyzes the rate-limiting step of 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.
总神经酰胺浓度与胰岛素抵抗增加及心脏功能障碍有关。然而，最近的研究表明，特定的超长链脂肪酸神经酰胺（C24:0和C22:0）的血浆浓度与冠心病发病率降低和全因死亡率降低有关。我们推测特定的基因位点与血浆C22:0和C24:0浓度有关。
在弗雷明汉心脏研究后代队列的2217名参与者中，对血浆C24:0和C22:0神经酰胺浓度进行遗传力和全基因组关联研究，并对心血管危险因素协变量和心血管药物治疗进行调整。
C22:0和C24:0神经酰胺的多变量调整遗传力分别为0.42（标准误[SE]，0.07；P = 1.8E-9）和0.25（SE，0.08；P = 0.00025）。19个单核苷酸多态性（SNP）均位于20号染色体上，与C22:0浓度显著相关；与这些变异最接近的基因是 。主效SNP（rs4814175）与血浆C22:0浓度显著降低3%相关（P = 2.83E-11）。9个SNP均位于20号染色体上且靠近 ，与C24:0神经酰胺浓度显著相关。所有9个SNP也与血浆C22:0水平显著相关。主效SNP（rs168622）与血浆C24:0神经酰胺浓度显著降低10%相关（P = 9.94E-09）。
编码丝氨酸棕榈酰转移酶长链碱基亚基3（SPTLC3；催化鞘脂合成限速步骤的酶的一部分）的 基因附近的SNP与血浆C22:0和C24:0神经酰胺浓度有关。这些结果在生物学上是合理的，表明SPTLC3可能是调节C24:0和C22:0神经酰胺的潜在治疗靶点。
