Effect of E670G Polymorphism in PCSK9 Gene on the Risk and Severity of Coronary Heart Disease and Ischemic Stroke in a Tunisian Cohort

Abstract

The association of E670G (rs505151) polymorphism in PCSK9 gene with an increased risk of coronary artery disease (CAD) and ischemic stroke (IS) was reported in previous studies. We investigated the effect of the E670G (rs505151) on the risk of CAD and IS in a Tunisian cohort. Genotyping of the PCSK9 E670G was performed using polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) and then confirmed by direct sequencing. The frequency of the 670G allele was significantly higher in the CAD than in the no-CAD subgroup (0.132 vs. 0.068, p = 0.030). As expected, the incidence of E670G was significantly important in IS subgroup than control group (0.122 vs. 0.073, p = 0.032). Furthermore in CAD patients, the 670G carriers showed significantly increased plasma total cholesterol and LDL-cholesterol levels compared to E670 carriers (6.78 [6.47-7.00] vs. 4.92 [4.02-5.46] mmol/l, p < 0.0001 and 4.60 [4.00-5.04] vs. 3.00 [2.22-3.70] mmol/l p = 0.001, respectively). The risk and severity of CAD were significantly increased in 670G carriers between no-CAD subgroup and CAD patients presenting a stenosis ≥50 % in two or three major coronary arteries (0.068 vs. 0.198, p = 0.001, OR = 3.39 [1.55-7.37]). The E670G polymorphism of the PCSK9 gene is mainly associated with a increased risk and severity of CAD and IS in Tunisian cohort.

Combined PCSK9 and APOE Polymorphisms are Genetic Risk Factors Associated with Elevated Plasma Lipid Levels in a Thai Population

“…Our findings were inconsistent with the previous studies in Germany [27], which showed that the association of E670G with increased LDL-C in men, but not in women. However, our results were consistent with previous studies conducted in Brazilian [26] and Tunisian populations [28], as well as in the Belgium stroke study [29], the PLIC study [25], and the LCAS [30], all which showed the association of E670G with an increased risk of CVD. In the present study, the association of PCSK9 E670G with lipid parameters was not observed in the rural subjects.…”

“…However, PCSK9 I474V was not associated with lipid levels in healthy UK men [15], Brazilian subjects [26], and the PLIC study [25]. Moreover, in German [27], Brazilian [26], and Tunisian populations [28], as well as in the Belgium Stroke Study [29], the PLIC study [25], and the LCAS [30], PCSK9 E670G was associated with increased TC and/or LDL-C levels or an increased risk of atherosclerosis. In healthy UK men [15], Taiwanese [31], Guangxi Bai Ku Yao, and Han Chinese populations [32], and in the PROSPER study group [14], PCSK9 E670G was not associated with increased TC and/or LDL-C levels or increased risk of atherosclerosis.…”

Large-scale phenome-wide association study of PCSK9 loss-of-function variants demonstrates protection against ischemic stroke

“…We compiled two sets of phenotypes to study associations between PCSK9 loss-of-function variants and diverse outcomes across the whole phenome. First, we created a hypothesis-driven set of 11 phenotypes informed by concurrent literature, 12,17,21,26,27 including cholesterol medication status, coronary heart disease, all stroke, ischemic stroke, hemorrhagic stroke, T2D, cataracts, heart failure, atrial fibrillation, epilepsy, and a cognitive function test (detailed definitions in Table S1). Next, we created a hypothesis-generating phenome-wide set comprising blocks of ICD-10 codes, groups of procedure (OPCS-4) codes, self-reported variables reflecting medical information, symptoms and environmental factors, and physical and functional measurements.…”

“…PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors are an important new class of LDL-C lowering drugs that were discovered based on human genetic studies. 10,11 The gene product of PCSK9 binds to the low-density lipoprotein receptor ( LDLR ) and promotes its degradation, thereby increasing levels of circulating LDL-C. 12 Genetic studies have established the association of variants in the PCSK9 locus with hypercholesterolemia and atherosclerotic CVD (ASCVD), 10,13,14 and fine-mapping efforts have revealed multiple independent signals within the locus. 15,16 PCSK9 variants can independently influence lipid levels 11,17 and also act to modify therapeutic response to statins.…”

Next-generation gene discovery for variants of large impact on lipid traits

“…Often, the most highly associated SNVs do not have a direct effect, but mark a region containing causal variation. These regions generally contain several genes, requiring fine sequencing, additional samples, and animal and cell models to pinpoint the likely causal variants or genes [18,21,28–31]. Methods incorporating genome annotations within GWAS in order to prioritize variants is an active area of research [32▪▪].…”