2. Regulation of LncRNA and Determinants of Statin Efficacy
While the underlying mechanisms of variations in statin response are not completely understood, the association of certain lncRNAs with currently accepted determinants of statin efficacy (i.e., gene polymorphisms, P450 enzyme, efflux and uptake transporters) provides a rationale for further research into how lncRNA regulation might be associated with response to statins. Although only a few studies have directly examined the association of certain statins together with lncRNAs and determinants of statin efficacy to date, the association of the latter two has been more frequently reported.
LncRNAs have emerged as critical players in cellular cholesterol metabolism. Previous studies have reported on the role of lncRNAs LASER, LeXis, MeXis, GAS5, and CHROME in cholesterol metabolism (cholesterol efflux, synthesis etc.) and have been reviewed above [
13,
15,
16,
18,
19,
20]. Cai et al. also reported that overexpression lncRNA ENST00000602558.1 downregulated ABCG1 mRNA and protein expression in VSMCs, leading to decreased ABCG1-mediated cholesterol efflux and increased lipid accumulation [
53]. This process might promote VSMC phenotype switching to foam cells, a major mechanism of atherosclerosis [
54]. Similarly, Tang et al. also reported that lncRNA ZFAS1 was upregulated in an in vitro model of atherosclerosis (THP-1 macrophage-derived foam cells). Overexpression of ZFAS1 promoted inflammatory responses and decreased cholesterol efflux by upregulating ADAM10/RAB22A expression [
55].
In a separate study, Lan et al. identified an lncRNA named lnc-HC that negatively regulated cholesterol metabolism in hepatocytes of an experimental metabolic syndrome rat model [
56]. By binding to hnRNPA2B1, the lnc-HC–hnRNPA2B1 complex decreased Cyp7a1 or Abca1 (both on mRNA and protein levels)—both of which are implicated in cellular cholesterol excretion—thus augmenting cholesterol accumulation within hepatocytes [
56]. Given that the abovementioned lncRNAs were shown to be important regulators of cholesterol efflux and metabolism, these lncRNAs may represent targets to increase statin efficacy in nonresponders.
In addition, certain lncRNAs have been found to regulate cytochrome P450 [
57], and since most statins are metabolized through cytochrome P450, further research is needed to investigate whether certain lncRNAs might be targets for enhancing the response in statin nonresponders.
Genome-wide studies have also demonstrated that combination of certain polymorphisms might be important predictors of statin response [
58]. Polymorphisms in lncRNAs have recently been associated with increased risk of cardiovascular events. In particular, Zheng et al. demonstrated that a deletion polymorphism (rs145204276) in the promoter of lncRNA GAS5—implicated in cholesterol efflux and metabolism as noted above [
19]—was related to an increased risk of ischemic stroke in humans [
59]. Similarly, polymorphisms in lncRNA MEG3 (i.e., rs7158663 and rs4081134) were associated with increased risk of ischemic stroke jointly with polymorphisms in miR-181b rs322931 [
60]. In a case–control study, a single nucleotide polymorphism rs4977574 of CDKN2BAS was shown to be a risk factor for coronary heart disease in both females and males under the age of 65 [
61]. These results were confirmed in a meta-analysis of 36,452 cases and 39,781 controls which showed that patients with the polymorphism rs4977574 had 27% higher odds of coronary heart disease (OR = 1.27, 95%CI 1.22–1.31) compared with their counterparts [
61]. Another case–control study from Pakistan revealed a strong association of polymorphism rs1333049:C > G of lncRNA ANRIL with myocardial infarction [
62]. Finally, Li et al. demonstrated that polymorphisms rs9632884 of lncRNA ANRIL and rs3200401 of lncRNA MALAT1 were significantly associated with increased cholesterol and triglyceride levels among both healthy and myocardial infarction patients without necessarily being associated with an increased risk of myocardial infarction [
63]. Collectively, given the association of certain lncRNA polymorphisms with a higher frequency of adverse events as well as lipid levels, variations in statin efficacy might be associated with certain lncRNA and other gene polymorphisms.