Key result
Carriage of the rare APOC3 variant rs138326449-A was associated with a significant reduction in plasma triglyceride levels by 1.13 standard deviations compared to non-carriers.
Why the study?
Is the rare variant rs138326449-A in APOC3 associated with altered plasma triglyceride levels in European populations?
Observational (n=16,033)
Yes
Is the rare variant rs138326449-A in APOC3 associated with altered plasma triglyceride levels in European populations?
Standardized Mean Difference: -1.13
p-value: p=6.9 x 10^-15
A rare splice donor variant in APOC3 (rs138326449-A) identified via whole-genome sequencing is significantly associated with reduced plasma triglyceride and altered HDL levels in European populations.
Should not change TG management; hypothesis-generating for APOC3 as therapeutic target.
The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ~0.25% (UK)) associated with plasma triglyceride (TG) levels (-1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 10(-8))) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (-1.0 s.d. (s.e.=0.173), P-value=7.32 × 10(-9)). This is consistent with an effect between 0.5 and 1.5 mmol l(-1) dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale.
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Timpson et al. (2014) conducted an observational in Plasma lipid levels (n=16,033). APOC3 rare variant rs138326449-A vs. Non-carriers (reference allele) was evaluated on Plasma triglyceride (TG) levels (-1.13 s.d., p=6.9 x 10^-15). Carriage of the rare APOC3 variant rs138326449-A was associated with a significant reduction in plasma triglyceride levels by 1.13 standard deviations compared to non-carriers.
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