PCSK9 genetic (rs11591147) and epigenetic (DNA methylation) modifications associated with PCSK9 expression and serum proteins in CAD patients

被引：11

作者：

Shyamala, Nivas ^{[1
]}

Gundapaneni, Kishore Kumar ^{[1
]}

Galimudi, Rajesh Kumar ^{[1
,2
]}

Tupurani, Mohini Aiyengar ^{[1
]}

Padala, Chiranjeevi ^{[1
,3
]}

Puranam, Kaushik ^{[1
]}

Kupsal, Keerthi ^{[1
]}

Kummari, Ramanjaneyulu ^{[1
]}

Gantala, Srilatha Reddy ^{[1
]}

Nallamala, Krishna Reddy ^{[4
]}

Sahu, Sanjib K. ^{[4
]}

Hanumanth, Surekha Rani ^{[1
]}

机构：

[1] Osmania Univ, Dept Genet & Biotechnol, Hyderabad, Telangana, India

[2] Inst Recerca Biomed Lleida IRBLleida, Vasc & Renal Translat Res Grp, Lleida, Spain

[3] Univ Hyderabad, Sch Life Sci, Dept Biochem, Hyderabad, Telangana, India

[4] Durgabai Deshmukh Hosp & Res Ctr, CARE Cardiac Ctr, Hyderabad, Telangana, India

来源：

JOURNAL OF GENE MEDICINE | 2021年 / 23卷 / 08期

关键词：

genotypes; LDL‐ C; methylation‐ specific PCR; promoter DNA methylation; proprotein convertase subtilisin; kexin type 9; qPCR; CORONARY-ARTERY-DISEASE; LIPOPROTEIN CHOLESTEROL LEVELS; FAMILIAL HYPERCHOLESTEROLEMIA; PROMOTER METHYLATION; SNP RS11591147; RISK; STABILITY; R46L; LDL;

D O I：

10.1002/jgm.3346

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Introduction Proprotein convertase subtilisin/kexin type 9 (PCSK9) genetic polymorphisms play a significant role in cholesterol homeostasis. Therefore, we aimed to investigate the association of PCSK9 genetic variations NM_174936.3:c.137G>T (R46L, rs11591147) and NM_174936.3:c.1120G>T (D374Y, rs137852912), as well as promoter DNA methylation status, with mRNA expression and circulating serum protein levels in coronary artery disease (CAD) patients. Methods The present study includes 300 CAD cases and 300 controls from South India. Biochemical assays were performed using commercially available kits. PCSK9 rs11591147 and rs137852912 polymorphisms were analyzed by the polymerase chain reaction (PCR)-restriction fragment length polymorphism method, whereas promoter DNA methylation status and gene expression were determined using methylation specific PCR and quantitative PCR respectively. Results The genotypic distribution of PCSK9 rs11591147 revealed that individuals with the TT-genotype and T-allele have a reduced risk for CAD. Furthermore, patients with the PCSK9 rs11591147 TT genotype have a significantly lower total cholesterol and low-density lipoprotein-cholesterol levels and also higher high-density lipoprotein-cholesterol levels than individuals with the GG genotype. Logistic regression analysis has shown that the GG and GT (p = 1.51 x 10(-8), p = 1.47 x 10(-9)) genotypes predicted the risk for CAD with an odds ratio of 5.8 and 7.3 respectively. In addition, individuals with the TT genotype were hypermethylated at promoter DNA of PCSK9, resulting in lower mRNA expression and circulating serum proteins than in individuals with the GG genotype. In silico analyses revealed that rs11591147 T-allele has protein destabilizing capacity. Conclusions In conclusion, the present study indicates that the PCSK9 gene expression and circulating serum protein levels are not only associated with rs11591147 genotype, but also with promoter DNA methylation. Furthermore, the findings with respect to both single nucleotide polymorphism and promoter DNA methylation may open avenues for novel treatment possibilities targeting PCSK9 for CAD management.

引用

页数：15

共 37 条

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