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12 July 2018
APOA5 genetic variability, triglycerides and coronary heart disease risk in Chinese subjects

This case–control study in Chinese subjects showed that variants in apolipoprotein A5 (APOA5) were significantly associated with an increased risk of coronary heart disease (CHD) which was mediated by elevated plasma triglycerides.

You Y, Wu Y-H, Zhang Y, et al. Effects of polymorphisms in APOA5 on the plasma levels of triglycerides and risk of coronary heart disease in Jilin, northeast China: a case–control study. BMJ Open 2018;8:e020016. doi:10.1136/bmjopen-2017-020016
Summary
Comments & References
STUDY SUMMARY
Objective: To investigate the associations of APOA5 polymorphisms with CHD in a Chinese population
Study design: Case control study. Three single nucleotide polymorphisms (SNPs), i.e.  rs2075291, rs662799 and rs651821, were selected to identify the association between APOA5 gene polymorphism and CHD.
Study population: 710 subjects (355 patients with CHD and 355 controls) from Jilin, northeast China, who were recruited from a cross-sectional study.  Inclusion criteria for CHD subjects were 1) angiographically confirmed coronary artery disease with ≥50% occlusion of at least one major coronary artery; 2) a confirmed myocardial infarction (MI); and 3) no diagnosis of liver, thyroid, pituitary or renal disease or history of acute or chronic inflammatory disease.
Efficacy variables:

·  Plasma lipids

·  Risk for CHD, as define above, according to carriage of the specified APOA5 variants

Methods: The χ2 test and haplotype analysis were used to analyse the associations between carriage of the APOA5 SNPs and CHD. A mediation model, incorporating three multivariate linear regression models adjusted for age and gender, was used to investigate whether levels of triglycerides act as a mediator of the associations between APOA5 polymorphisms and coronary artery disease. The level of statistical significance was p <0.05.
Results:

The study showed that two SNPs in APOA5, rs662799 and rs651821, had significant differences in genotype and allele distributions between CHD cases and control subjects. The risk for CHD with carriage of these variants is shown in Table 1.

Table 1. APOA5 variants and risk for CHD

APOA5 Variant

Model

Risk of CHD

Odds ratio (95% CI)

P-value*

rs662799

(TC or CC alleles)

Dominant

1.61 (1.09 to 2.37?

<0.001

rs651821

Codominant

For GA: 1.49 (1.04 to 2.16)

For GG: 2.23 (1.43 to 3.47)

P<0.001

* versus wild type, either TT or AA, and adjusted for age, gender, body mass index, smoking status, drinking, systolic blood pressure and diastolic blood pressure

For the APOA5 rs651821 variant, G alleles positively correlated with CHD risk (p<0.001). There was also a positive correlation between the number of APOA5 rs651821 G alleles and levels of triglycerides (p<0.05), indicative of a significant mediation effect of triglycerides on CHD risk.
Triglycerides also exerted a partial mediation effect on the association between the APOA5 rs662799 variant and CHD risk.

Conclusion: Based on these data, variants of the APOA5 gene are associated with CHD susceptibility and may modulate levels of plasma triglycerides among a Chinese population.

COMMENT

Genetic insights into the regulation of triglyceride-rich lipoproteins has offered alternative therapeutic approaches. In over 15 years since its discovery, there is now accumulating evidence that APOA5 is an important determinant of plasma triglycerides.1 Loss-of-function APOA5 variants have been shown to be associated with reduced lipolysis, poor remnant clearance and concomitantly, hypertriglyceridaemia, and also increased the risk of CHD in some but not all studies.2-5

The current study adds to evidence that APOA5 variants are associated with CHD risk in a Chinese cohort.  The study was unique in using a mediation model to investigate whether the plasma level of triglycerides mediated the association of these two variants, rs651821 and rs662799, with CHD risk. Despite the limitations of a case-control study design and smaller sample size, the results from mediation modelling implicate triglycerides in the CHD risk associated with APOA5 loss-of-function variants in this Chinese cohort, and thus, reinforce evidence for the atheroprotective role of apolipoprotein A5.

References

1. Pennacchio LA, Olivier M, Hubacek JA et al. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science 2001;294:169–73.

2. Pennacchio LA, Olivier M, Hubacek JA et al. Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride levels. Hum Mol Genet 2002;11:3031–8.

3. Talmud PJ, Hawe E, Martin S, et al. Relative contribution of variation within the APOC3/A4/A5 gene cluster in determining plasma triglycerides. Hum Mol Genet 2002;11:3039–46.

4. Hubacek JA. Apolipoprotein A5 fifteen years anniversary: Lessons from genetic epidemiology. Gene 2016;592:193-9.

5. Lee KW, Ayyobi AF, Frohlich JJ et al. APOA5 gene polymorphism modulates levels of triglyceride, HDL cholesterol and FERHDL but is not a risk factor for coronary artery disease. Atherosclerosis 2004;176:165–72.

Key words apolipoprotein A5, coronary heart disease risk; triglycerides; genetic study; mediation analysis