Association between parental history and genetic risk scores for coronary heart disease prediction: The population-based CoLaus study

Antiochos, Panagiotis; Marques‐Vidal, Pedro; McDaid, Aaron; Waeber, Gérard; Vollenweider, Péter

doi:10.1016/j.atherosclerosis.2015.10.104

Cited by 29 publications

(18 citation statements)

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“…To identify the responsible ⌬14Z desaturase, we used genome-wide SNP data, which were available for all European individuals of the cohort (11). As the enzyme converts d18:1 into d18:2, we hypothesized that genetic variations in the desaturase gene will be reflected by changes in the d18:1/d18:2 ratio.…”

Section: Resultsmentioning

confidence: 99%

FADS3 is a Δ14Z sphingoid base desaturase that contributes to gender differences in the human plasma sphingolipidome

Karsai

Lone

Kutalik

et al. 2020

Journal of Biological Chemistry

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Sphingolipids (SLs) are structurally diverse lipids that are defined by the presence of a long-chain base (LCB) backbone. Typically, LCBs contain a single Δ4E double bond (DB) (mostly d18:1), whereas the dienic LCB sphingadienine (d18:2) contains a second DB at the Δ14Z position. The enzyme introducing the Δ14Z DB is unknown. We analyzed the LCB plasma profile in a gender-, age-, and BMI-matched subgroup of the CoLaus cohort (n = 658). Sphingadienine levels showed a significant association with gender, being on average ∼30% higher in females. A genome-wide association study (GWAS) revealed variants in the fatty acid desaturase 3 (FADS3) gene to be significantly associated with the plasma d18:2/d18:1 ratio (p = −log 7.9). Metabolic labeling assays, FADS3 overexpression and knockdown approaches, and plasma LCB profiling in FADS3-deficient mice confirmed that FADS3 is a bona fide LCB desaturase and required for the introduction of the Δ14Z double bond. Moreover, we showed that FADS3 is required for the conversion of the atypical cytotoxic 1-deoxysphinganine (1-deoxySA, m18:0) to 1-deoxysphingosine (1-deoxySO, m18:1). HEK293 cells overexpressing FADS3 were more resistant to m18:0 toxicity than WT cells. In summary, using a combination of metabolic profiling and GWAS, we identified FADS3 to be essential for forming Δ14Z DB containing LCBs, such as d18:2 and m18:1. Our results unravel FADS3 as a Δ14Z LCB desaturase, thereby disclosing the last missing enzyme of the SL de novo synthesis pathway.

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Section: Resultsmentioning

confidence: 99%

FADS3 is a Δ14Z sphingoid base desaturase that contributes to gender differences in the human plasma sphingolipidome

Karsai

Lone

Kutalik

et al. 2020

Journal of Biological Chemistry

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“…Several SNPs in the Ormdl3/GSDMB locus have been shown to be associated with childhood asthma (23, 24). To investigate whether these SNPs are also associated with changes in the plasma sphingoid bases, we analyzed the levels in samples from a population‐based cohort (47–49) for which SNP data were available ( N = 971). We observed no significant association of the sphingoid bases in plasma in response to the respective SNP genotype (Fig.…”

Section: Resultsmentioning

confidence: 99%

ORMDL3 expression levels have no influence on the activity of serine palmitoyltransferase

Zhakupova

Debeuf

Krols³

et al. 2016

FASEB j.

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ORMDL proteins are believed to be negative regulators of serine palmitoyltransferase (SPT), which catalyzes the first and rate limiting step in sphingolipid (SL) de novo synthesis. Several single-nucleotide polymorphisms (SNPs) that are close to the ORMDL3 locus have been reported to increase ORMDL3 expression and to be associated with an elevated risk for early childhood asthma; however, the direct effect of ORMDL3 expression on SPT activity and its link to asthma remains elusive. In this study, we investigated whether ORMDL3 expression is associated with changes in SPT activity and total SL levels. Ormdl3-knockout (Ormdl3) and transgenic (Ormdl3) mice were generated to study the effect of ORMDL3 on total SL levels in plasma and tissues. Cellular SPT activity was measured in mouse embryonic fibroblasts from Ormdl3 mice, as well as in HEK293 cells in which ORMDL3 was overexpressed and silenced. Furthermore, we analyzed the association of the reported ORMDL3 asthma SNPs with plasma sphingoid bases in a population-based cohort of 971 individuals. Total C-long chain bases were not significantly altered in the plasma and tissues of Ormdl3 mice, whereas C-sphinganine showed a small and significant increase in plasma, lung, and liver tissues. Mouse embryonic fibroblast cells from Ormdl3 mice did not show an altered SPT activity compared with Ormdl3 and Ormdl3 mice. Overexpression or knockdown of ORMDL3 in HEK293 cells did not alter SPT activity; however, parallel knockdown of all 3 ORMDL isoforms increased enzyme activity significantly. A significant association of the annotated ORMDL3 asthma SNPs with plasma long-chain sphingoid base levels could not be confirmed. ORMDL3 expression levels seem not to be directly associated with changes in SPT activity. ORMDL3 might influence de novo sphingolipid metabolism downstream of SPT.-Zhakupova, A., Debeuf, N., Krols, M., Toussaint, W., Vanhoutte, L., Alecu, I., Kutalik, Z., Vollenweider, P., Ernst, D., von Eckardstein, A., Lambrecht, B. N., Janssens, S., Hornemann, T. ORMDL3 expression levels have no influence on the activity of serine palmitoyltransferase.

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“…The baseline study was conducted between 2003 and 2006 and included 6733 participants, with a participation rate of 41%; the first follow-up was conducted between April 2009 and September 2012, five and a half year on average after the baseline and included 5064 participants (75.2%) [ 26 ].…”

Section: Methodsmentioning

confidence: 99%

Prevalence and determinants of polypharmacy in Switzerland: data from the CoLaus study

Castioni

Marques‐Vidal²,

Abolhassani³

et al. 2017

BMC Health Serv Res

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BackgroundPolypharmacy is a frequent condition, but its prevalence and determinants in the Swiss mid-aged population are unknown. We aimed to evaluate the prevalence and determinants of polypharmacy in a large Swiss mid-aged population-based sample.MethodsData from 4938 participants of the CoLaus study (53% women, age range 40–81 years) were collected between 2009 and 2012. Polypharmacy was defined by the regular use of five or more drugs.ResultsPolypharmacy was reported by 580 participants [11.8%, 95% confidence interval (10.9; 12.6)]. Participants on polypharmacy were significantly older (mean ± standard deviation: 66.0 ± 9.1 vs. 56.6 ± 10.1 years), more frequently obese (35.9% vs. 14.7%), of lower education (66.6% vs. 50.7%) and former smokers (46.7% vs. 36.4%) than participants not on polypharmacy. These findings were confirmed by multivariate analysis: odds ratio and (95% confidence interval) for age groups 50–64 and 65–81 relative to 40–49 years: 2.90 (2.04; 4.12) and 10.3 (7.26; 14.5), respectively, p for trend < 0.001; for low relative to high education: 1.56 (1.17; 2.07); for overweight and obese relative to normal weight participants: 2.09 (1.65; 2.66) and 4.38 (3.39; 5.66), respectively, p for trend < 0.001; for former and current relative to never smokers: 1.42 (1.14, 1.75) and 1.63 (1.25, 2.12), respectively, p for trend < 0.001.ConclusionOne out of nine participants of our sample is on polypharmacy. Increasing age, body mass index, smoking and lower education independently increase the likelihood of being on polypharmacy.Electronic supplementary materialThe online version of this article (10.1186/s12913-017-2793-z) contains supplementary material, which is available to authorized users.

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Association between parental history and genetic risk scores for coronary heart disease prediction: The population-based CoLaus study

Cited by 29 publications

References 29 publications

FADS3 is a Δ14Z sphingoid base desaturase that contributes to gender differences in the human plasma sphingolipidome

FADS3 is a Δ14Z sphingoid base desaturase that contributes to gender differences in the human plasma sphingolipidome

ORMDL3 expression levels have no influence on the activity of serine palmitoyltransferase

Prevalence and determinants of polypharmacy in Switzerland: data from the CoLaus study

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