Key result
APOA5 p.S19W linked to ~130% higher premature CAD risk, partly mediated by HDL-C and triglycerides.
Why the study?
APOA5 variants have been linked to coronary artery disease, but their causal roles in premature CAD are not well studied.
Do APOA5 variants increase the risk of premature CAD?
Case-Control (n=1,007)
Do APOA5 variants increase the risk of premature CAD?
Odds Ratio: 2.3
p-value: p=0.008
The APOA5 p.S19W variant is causally associated with an increased risk of premature CAD, partially mediated through its effects on HDL-C and triglyceride levels.
May support APOA5 inclusion in premature CAD risk models; leaves open therapeutic targeting pending replication.
Apolipoprotein A5 (APOA5) regulates the metabolisms of triglyceride and HDL. APOA5 variants have been linked to coronary artery disease (CAD), but their causal roles are not well studied yet. This study aims to identify the causal effects of APOA5 variants on premature CAD. Sequencing analysis of APOA5 in 128 premature, familiar CAD patients from GeneQuest identified 11 genomic variants, including p.S19W (rs3135506). SKAT analysis showed that all sequenced variants, in aggregate, significantly increased the risk of premature CAD (P-skat = 0.037). Individually, the p.S19W variant was significantly associated with risk of premature CAD (OR = 2.30, P = 0.008) in an independent set of 342 premature CAD patients and 537 controls after adjusting for covariates of sex, age, hypertension, body mass index, triglycerides (TGs), and total, LDL-, and HDL-cholesterol levels. Meanwhile, p.S19W significantly correlated with HDL-C levels (P = 0.048) and TG levels (P = 0.025). Mediation analysis yielded a mediation effect of p.S19W on risk of premature CAD through HDL-C (OR = 0.98, P = 0.040) and TG (OR = 0.98, P = 0.042), suggesting a causal relationship between p.S19W and premature CAD partially through its effects on HDL-C and TG levels. These results suggest that APOA5 variation regulates TG and HDL levels, thus displaying a causal role in the development of CAD.
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Wang et al. (2018) conducted a case-control in Premature coronary artery disease (n=1,007). APOA5 p.S19W variant (rs3135506) vs. Controls without premature CAD was evaluated on Risk of premature CAD (OR 2.30, p=0.008). The APOA5 p.S19W variant was significantly associated with an increased risk of premature coronary artery disease (OR 2.30; P=0.008), partially mediated through HDL-C and triglyceride levels.
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