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Polymorphisms of rs2483205 and rs562556 in the PCSK9 gene are associated with coronary artery disease and cardiovascular risk factors.

ABSTRACT: PCSK9 plays a crucial role in lipid metabolism. This case-control study explored the associations of novel single nucleotide polymorphisms (SNPs) of the PCSK9 gene with coronary artery disease (CAD) (≥ 1 coronary artery stenosis ≥ 50%) and its risk factors in the Han population in Xinjiang, China. Four tag SNPs (rs11583680, rs2483205, rs2495477 and rs562556) of the PCSK9 gene were genotyped in 950 CAD patients and 1082 healthy controls. The distributions of genotypes in rs2483205 and rs562556 were significantly different between the groups (all p < 0.05). The TT genotype of rs2483205, GG genotype of rs562556, and their H4 (T-G) haplotype were associated with CAD [odds ratio (OR) 0.65, confidence interval (CI) 0.45-0.95, p = 0.024; 0.63, 0.45-0.90, p = 0.011; 0.50, 0.35-0.70, p < 0.001, respectively]. Additionally, the model (TT + CT vs. CC) of rs2483205 was associated with increased risk of obesity, and the G allele of rs562556 was associated with lower low-density lipoprotein cholesterol (LDL-C), blood glucose, body mass index (BMI), and mean platelet volume (MPV) (all p < 0.05). rs2483205, rs562556, and their H4 haplotype of the PCSK9 gene were associated with CAD. Additionally, rs2483205 is associated with obesity, and rs562556 is associated with LDL-C, blood glucose, BMI, and MPV.

SUBMITTER: Gai MT

PROVIDER: S-EPMC8169929 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Coronary artery disease (CAD) is a multifactorial and polygenic disorder that results from an excessive inflammatory response. We analyzed whether interleukin-24 (IL-24) gene polymorphisms are associated with premature CAD in a case-control association study. Four polymorphisms (rs1150253, rs1150256, rs1150258, and rs3762344) of the IL-24 gene were analyzed by 5' exonuclease TaqMan genotyping assays in a group of 952 patients with premature CAD, 284 individuals with subclinical atherosclerosis (SA), and 912 controls. The studied polymorphisms were not associated with the risk of premature CAD or SA (P>0.05). Under dominant models adjusted for age, sex, body mass index, and medication, the polymorphisms were associated with cardiometabolic parameters and cardiovascular risk factors. Three polymorphisms (rs1150253, rs1150256, and rs3762344) were associated with hypertension and increased levels of systolic blood pressure in controls. In SA, 2 polymorphisms (rs1150256 and rs3762344) were associated with type 2 diabetes mellitus, gamma-glutamyl transpeptidase (GGT), and alkaline phosphatase, whereas rs1150253 was associated with GGT and type 2 diabetes mellitus and rs1150258 with GGT and alkaline phosphatase. In premature CAD, the 4 polymorphisms were associated with total cholesterol >200?mg/dL, low-density lipoprotein cholesterol (LDL-C), and GGT, whereas rs1150256 was associated also with ApoA. On the other hand, rs1150258 was associated with ApoA, LDL-C >100?mg/dL, and apoB/apoA ratio, and rs3762344 with ApoA, apoB/apoA ratio, LDL-C >100?mg/dL, and total cholesterol. On the basis of single-nucleotide polymorphism functional prediction software, rs1150253 and rs1150258 polymorphisms seem to be functional. The 4 studied polymorphisms were in linkage disequilibrium and had a similar haplotype distribution in patients and controls. Our study demonstrates the association of IL-24 polymorphisms with metabolic and cardiovascular risk factors in individuals with premature CAD, SA, and controls.

Project description:RationaleCoronary artery disease (CAD) is a critical determinant of morbidity and mortality. Previous studies have identified several cardiovascular disease risk factors, which may partly arise from a shared genetic basis with CAD, and thus be useful for discovery of CAD genes.ObjectiveWe aimed to improve discovery of CAD genes and inform the pathogenic relationship between CAD and several cardiovascular disease risk factors using a shared polygenic signal-informed statistical framework.Methods and resultsUsing genome-wide association studies summary statistics and shared polygenic pleiotropy-informed conditional and conjunctional false discovery rate methodology, we systematically investigated genetic overlap between CAD and 8 traits related to cardiovascular disease risk factors: low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, type 2 diabetes mellitus, C-reactive protein, body mass index, systolic blood pressure, and type 1 diabetes mellitus. We found significant enrichment of single-nucleotide polymorphisms associated with CAD as a function of their association with low-density lipoprotein, high-density lipoprotein, triglycerides, type 2 diabetes mellitus, C-reactive protein, body mass index, systolic blood pressure, and type 1 diabetes mellitus. Applying the conditional false discovery rate method to the enriched phenotypes, we identified 67 novel loci associated with CAD (overall conditional false discovery rate <0.01). Furthermore, we identified 53 loci with significant effects in both CAD and at least 1 of low-density lipoprotein, high-density lipoprotein, triglycerides, type 2 diabetes mellitus, C-reactive protein, systolic blood pressure, and type 1 diabetes mellitus.ConclusionsThe observed polygenic overlap between CAD and cardiometabolic risk factors indicates a pathogenic relation that warrants further investigation. The new gene loci identified implicate novel genetic mechanisms related to CAD.

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Polymorphisms of rs2483205 and rs562556 in the PCSK9 gene are associated with coronary artery disease and cardiovascular risk factors.

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