Val279Phe variant of Lp-PLA2 is a risk factor for a subpopulation of Indonesia patients with acute myocardial infarction.

Lipoprotein-associated phospholipase A2 (Lp-PLA2), a member of the phospholipase A2 superfamily, is an enzyme that hydrolyses phospholipids, is found in blood circulation as a sign of inflammation, and takes a role in atherogenesis. There is an epidemiologic relation between increased Lp-PLA2 levels and coronary heart disease. Lp-PLA2 is an enzyme that is produced by macrophages and takes a role as an independent predictor of a coronary event. A genetic variant of Val279Phe on the Lp-PLA2 gene has been reported with various results in Japan, China, Korea, and Caucasian populations. This study aims to analyse the influence of the Val279Phe genetic variant on acute myocardial infarction (AMI) at Saiful Anwar Hospital, Indonesia. This study was conducted on 151 patients (111 AMI patients and 40 non-AMI patients). The genetic variant of Val279Phe was identified through a genotyping method. There were no significant differences in age, total cholesterol level, LDL-C (low-density lipoprotein cholesterol) level, and family history data between AMI and non-AMI patients. However, AMI patients had low HDL-C (high-density lipoprotein cholesterol), triglyceride levels, dyslipidaemia, and hypertension risk factors compared to non-AMI patients. The frequency of the GG genotype (279Val) was dominant in both AMI and non-AMI groups. Further analysis suggested that the GG genotype has a 2.9 times greater risk of AMI compared to the GT/TT genotype (279Phe). This study concluded that the Val279Phe genetic variant undoubtedly influenced AMI risk, which is a warrant for further development of early detection and improving strategy to prevent AMI in patients.

279(Val→Phe) Polymorphism of lipoprotein-associated phospholipase A(2) resulted in changes of folding kinetics and recognition to substrate.

INTRODUCTION: PLA2G7 encodes Lp-PLA2 having role in the formation of atherosclerotic plaques by catalyzing its substrate, phosphatydilcholine (PC), to be pro-inflammatory substances. The increased risk for coronary artery disease (CAD) in Asian population has been related with this enzyme. 279(Val→Phe) variant was reported to have a protective role against CAD due to, in part, secretion defect or loss of enzymatic function. Therefore, We study folding kinetics and enzyme-substrate interaction in 279(Val→Phe) by using clinical and computational biology approach. METHODS: Polymorphisms were detected by genotyping among 103 acute myocardial infarction patients and 37 controls. Folding Lp-PLA2 was simulated using GROMACS software by assessing helicity, hydrogen bond formation and stability. The interactions of Lp-PLA2 and its substrate were simulated using Pyrx software followed by molecular dynamics simulation using YASARA software. RESULT: Polymorphism of 279(Val→Phe) was represented by the change of nucleotide from G to T of 994th PLA2G7 gene. The folding simulation suggested a decreased percentage of α-helix, hydrogen bond formation, hydrogen bond stability and hydrophobicity in 279(Val→Phe). The PC did not interact with active site of 279(Val→Phe) as paradoxically observed in 279 valine. 279(Val→Phe) polymorphism is likely to cause unstable binding to the substrate and decrease the enzymatic activity as observed in molecular dynamics simulations. The results of our computational biology study supported a protected effect of 279(Val→Phe) Polymorphism showed by the odd ratio for MI of 0.22 (CI 95% 0.035-1.37) in this study. CONCLUSION: 279(Val→Phe) Polymorphism of Lp-PLA2 may lead to decrease the enzymatic activity via changes of folding kinetics and recognition to its substrate.

The Potential effect of G915C polymorphism in regulating TGF-ß1 transport into Endoplasmic Reticulum for cytokine production.

The TGF-ß1 cytokine concentration is known to be higher in nephritis with implied Lupus Nephritis severity. The production of TGF-ß1 cytokine is associated with G915C polymorphism. Therefore, it is of interest to study G915C polymorphism. The G915C polymorphism changes codon 25 which encodes arginine into proline in the signal peptide of TGF-ß1. The amino acid substitution affects signal peptide properties that may inhibit the transport of TGF-ß1 into the endoplasmic reticulum and eventually decline the cytokine production. Hence, the effect of G915C polymorphism on the properties of the signal peptide, the ability of TGF-ß1 transport into the endoplasmic reticulum and the concentrations of urinary TGF-ß1 in Lupus Nephritis patients was studied. The arginine substitution into proline decreased the polarity of the signal peptide for TGF-ß1. The increased hydrophobicity with increased binding energy of the signal peptide for TGF-ß1 to Signal Recognition Particle (SRP) and translocon is shown. This implies decreased protein complex stability in potentially blocking the transport of TGF-ß1 into the endoplasmic reticulum. This transport retention possibly hampers the synthesis and maturation of TGF-ß1 leading to decreased cytokine production.