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APOA5 genetic variants are markers for classic hyperlipoproteinemia phenotypes and hypertriglyceridemia


Background Several known candidate gene variants are useful markers for diagnosing hyperlipoproteinemia. In an attempt to identify other useful variants, we evaluated the association of two common APOA5 single-nucleotide polymorphisms across the range of classic hyperlipoproteinemia phenotypes.

Methods We assessed plasma lipoprotein profiles and APOA5 S19W and −1131T>C genotypes in 678 adults from a single tertiary referral lipid clinic and in 373 normolipidemic controls matched for age and sex, all of European ancestry.

Results We observed significant stepwise relationships between APOA5 minor allele carrier frequencies and plasma triglyceride quartiles. The odds ratios for hyperlipoproteinemia types 2B, 3, 4 and 5 in APOA5 S19W carriers were 3.11 (95% CI 1.63–5.95), 4.76 (2.25–10.1), 2.89 (1.17–7.18) and 6.16 (3.66–10.3), respectively. For APOA5 −1131T>C carriers, the odds ratios for these hyperlipoproteinemia subtypes were 2.23 (95% CI 1.21–4.08), 3.18 (1.55–6.52), 3.95 (1.85–8.45) and 4.24 (2.64–6.81), respectively. The overall odds ratio for the presence of either allele in lipid clinic patients was 2.58 (95% CI 1.89–3.52).

Conclusions A high proportion of patients with four classic hyperlipoproteinemia phenotypes are carriers of either the APOA5 S19W or −1131T>C variant or both. These two variants are robust genetic biomarkers of a range of clinical hyperlipoproteinemia phenotypes linked by hypertriglyceridemia.

Key Points

  • Hyperlipoproteinemia types 2B, 3, 4 and 5 feature elevated plasma triglyceride concentration as part of their definition

  • We found that APOA5 variants S19W and −1131T>C are frequently present in and are strongly associated with hyperlipoproteinemia 2B, 3, 4 and 5 and also with hypertriglyceridemia in lipid clinic patients

  • These two APOA5 variants are robust genetic biomarkers of a range of complex hyperlipoproteinemia phenotypes, which had been considered distinct and disparate but which share hypertriglyceridemia as a defining feature

  • These strong genetic associations might help predict susceptibility to hypertriglyceridemia or identify interindividual differences in response to interventions to lower plasma triglyceride

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Figure 1: Frequency of carriers of APOA5 variants according to quartile of plasma triglycerides.
Figure 2: Forest plot of odds ratios for patients with APOA5 S19W, −1131T>C or either for classic primary triglyceride-containing hyperlipoproteinemia phenotypes.


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R Provost provided outstanding technical assistance. Supported by the Jacob J Wolfe Distinguished Medical Research Chair (RAH), the Edith Schulich Vinet Canada Research Chair (Tier I) in Human Genetics (RAH), a Career Investigator award from the Heart and Stroke Foundation of Ontario (RAH), and operating grants from the Canadian Institutes for Health Research (MOP-13430, MOP-39533, MOP-39833), the Heart and Stroke Foundation of Ontario (grants PRG-5967, NA-6059, T-6018) and the Ontario Research Fund and by Genome Canada through the Ontario Genomics Institute.

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Correspondence to Robert A Hegele.

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Wang, J., Ban, M., Kennedy, B. et al. APOA5 genetic variants are markers for classic hyperlipoproteinemia phenotypes and hypertriglyceridemia. Nat Rev Cardiol 5, 730–737 (2008).

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