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Metabolic Characterization of a Rare Genetic Variation Within APOC3 and Its Lipoprotein Lipase – Independent Effects

View Article: PubMed Central - PubMed

ABSTRACT

Background—: Plasma triglyceride levels have been implicated in atherosclerosis and coronary heart disease. Apolipoprotein C-III (APOC3) plays a key role in the hydrolysis of triglyceride-rich lipoproteins to remnant particles by lipoprotein lipase (LPL) and their uptake by the liver. A rare variant in APOC3(rs138326449) has been associated with triglyceride, very low–density lipoprotein, and high-density lipoprotein levels, as well as risk of coronary heart disease. We aimed to characterize the impact of this locus across a broad set of mainly lipids-focused metabolic measures.

Methods and results—: A high-throughput serum nuclear magnetic resonance metabolomics platform was used to quantify 225 metabolic measures in 13 285 participants from 2 European population cohorts. We analyzed the effect of the APOC3 variant on the metabolic measures and used the common LPL(rs12678919) polymorphism to test for LPL-independent effects. Eighty-one metabolic measures showed evidence of association with APOC3(rs138326449). In addition to previously reported triglyceride and high-density lipoprotein associations, the variant was also associated with very low–density lipoprotein and high-density lipoprotein composition measures, other cholesterol measures, and fatty acids. Comparison of the APOC3 and LPL associations revealed that APOC3 association results for medium and very large very low–density lipoprotein composition are unlikely to be solely predictable by the action of APOC3 through LPL.

Conclusions—: We characterized the effects of the rare APOC3(rs138326449) loss of function mutation in lipoprotein metabolism, as well as the effects of LPL(rs12678919). Our results improve our understanding of the role of APOC3 in triglyceride metabolism, its LPL independent action, and the complex and correlated nature of human metabolites.

No MeSH data available.


Expected and observed APOC3–metabolites associations for the subset of metabolites with a lipoprotein lipase (LPL)–independent effect. The coefficients and confidence interval (CIs) are scaled by the SE of the observed effect. ALSPAC indicates The Avon Longitudinal Study of Parents and Children; BWHHS, the British Women Heart Health Study; and VLDL, very low–density lipoprotein.
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Figure 3: Expected and observed APOC3–metabolites associations for the subset of metabolites with a lipoprotein lipase (LPL)–independent effect. The coefficients and confidence interval (CIs) are scaled by the SE of the observed effect. ALSPAC indicates The Avon Longitudinal Study of Parents and Children; BWHHS, the British Women Heart Health Study; and VLDL, very low–density lipoprotein.

Mentions: There was evidence for APOC3 effects being mediated through LPL in the majority of the metabolic measures considered. Of the 225 measures tested in the ALSPAC young participants, 6 had no overlapping 95% confidence intervals between the directly observed APOC3(rs138326449) effects and those predicted by LPL(rs12678919; Table VI in the Data Supplement). The ALSPAC mothers and the BWHHS results confirmed 2 of the suggested 6 APOC3-specific effects as independent from LPL (Table 2 and Figure 3). When all 3 samples were combined, 8 measures showed evidence of nonoverlapping estimates (Table VI in the Data Supplement). Those measures which maintained evidence of an effect outside the action of LPL inhibition were both measures of VLDL composition characterizing the percentage of triglyceride in very large and medium VLDL. All results on the comparison of the LPL predicted and observed APOC3 effects are provided in Table VI in the Data Supplement.


Metabolic Characterization of a Rare Genetic Variation Within APOC3 and Its Lipoprotein Lipase – Independent Effects
Expected and observed APOC3–metabolites associations for the subset of metabolites with a lipoprotein lipase (LPL)–independent effect. The coefficients and confidence interval (CIs) are scaled by the SE of the observed effect. ALSPAC indicates The Avon Longitudinal Study of Parents and Children; BWHHS, the British Women Heart Health Study; and VLDL, very low–density lipoprotein.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4920206&req=5

Figure 3: Expected and observed APOC3–metabolites associations for the subset of metabolites with a lipoprotein lipase (LPL)–independent effect. The coefficients and confidence interval (CIs) are scaled by the SE of the observed effect. ALSPAC indicates The Avon Longitudinal Study of Parents and Children; BWHHS, the British Women Heart Health Study; and VLDL, very low–density lipoprotein.
Mentions: There was evidence for APOC3 effects being mediated through LPL in the majority of the metabolic measures considered. Of the 225 measures tested in the ALSPAC young participants, 6 had no overlapping 95% confidence intervals between the directly observed APOC3(rs138326449) effects and those predicted by LPL(rs12678919; Table VI in the Data Supplement). The ALSPAC mothers and the BWHHS results confirmed 2 of the suggested 6 APOC3-specific effects as independent from LPL (Table 2 and Figure 3). When all 3 samples were combined, 8 measures showed evidence of nonoverlapping estimates (Table VI in the Data Supplement). Those measures which maintained evidence of an effect outside the action of LPL inhibition were both measures of VLDL composition characterizing the percentage of triglyceride in very large and medium VLDL. All results on the comparison of the LPL predicted and observed APOC3 effects are provided in Table VI in the Data Supplement.

View Article: PubMed Central - PubMed

ABSTRACT

Background—: Plasma triglyceride levels have been implicated in atherosclerosis and coronary heart disease. Apolipoprotein C-III (APOC3) plays a key role in the hydrolysis of triglyceride-rich lipoproteins to remnant particles by lipoprotein lipase (LPL) and their uptake by the liver. A rare variant in APOC3(rs138326449) has been associated with triglyceride, very low–density lipoprotein, and high-density lipoprotein levels, as well as risk of coronary heart disease. We aimed to characterize the impact of this locus across a broad set of mainly lipids-focused metabolic measures.

Methods and results—: A high-throughput serum nuclear magnetic resonance metabolomics platform was used to quantify 225 metabolic measures in 13 285 participants from 2 European population cohorts. We analyzed the effect of the APOC3 variant on the metabolic measures and used the common LPL(rs12678919) polymorphism to test for LPL-independent effects. Eighty-one metabolic measures showed evidence of association with APOC3(rs138326449). In addition to previously reported triglyceride and high-density lipoprotein associations, the variant was also associated with very low–density lipoprotein and high-density lipoprotein composition measures, other cholesterol measures, and fatty acids. Comparison of the APOC3 and LPL associations revealed that APOC3 association results for medium and very large very low–density lipoprotein composition are unlikely to be solely predictable by the action of APOC3 through LPL.

Conclusions—: We characterized the effects of the rare APOC3(rs138326449) loss of function mutation in lipoprotein metabolism, as well as the effects of LPL(rs12678919). Our results improve our understanding of the role of APOC3 in triglyceride metabolism, its LPL independent action, and the complex and correlated nature of human metabolites.

No MeSH data available.