Glutathione Transferase P1 Polymorphism Might Be a Risk Determinant in Heart Failure

Abstract

Disturbed redox balance in heart failure (HF) might contribute to impairment of cardiac function, by oxidative damage, or by regulation of cell signaling. The role of polymorphism in glutathione transferases (GSTs), involved both in antioxidant defense and in regulation of apoptotic signaling pathways in HF, has been proposed. We aimed to determine whether GST genotypes exhibit differential risk effects between coronary artery disease (CAD) and idiopathic dilated cardiomyopathy (IDC) in HF patients. GSTA1, GSTM1, GSTP1, and GSTT1 genotypes were determined in 194 HF patients (109 CAD, 85 IDC) and 274 age- and gender-matched controls. No significant association was found for GSTA1, GSTM1, and GSTT1 genotypes with HF occurrence due to either CAD or IDC. However, carriers of at least one variant GSTP1∗Val (rs1695) allele were at 1.7-fold increased HF risk than GSTP1∗Ile/Ile carriers (p=0.031), which was higher when combined with the variant GSTA1∗B allele (OR=2.2, p=0.034). In HF patients stratified based on the underlying cause of disease, an even stronger association was observed in HF patients due to CAD, who were carriers of a combined GSTP1(rs1695)/GSTA1 “risk-associated” genotype (OR=2.8, p=0.033) or a combined GSTP1∗Ile/Val+Val/Val (rs1695)/GSTP1∗AlaVal+∗ValVal (rs1138272) genotype (OR=2.1, p=0.056). Moreover, these patients exhibited significantly decreased left ventricular end-systolic diameter compared to GSTA1∗AA/GSTP1∗IleIle carriers (p=0.021). Higher values of ICAM-1 were found in carriers of the GSTP1∗IleVal+∗ValVal (rs1695) (p=0.041) genotype, whereas higher TNFα was determined in carriers of the GSTP1∗AlaVal+∗ValVal genotype (rs1138272) (p=0.041). In conclusion, GSTP1 polymorphic variants may determine individual susceptibility to oxidative stress, inflammation, and endothelial dysfunction in HF.

Expression Signatures of Long Noncoding RNAs in Left Ventricular Noncompaction

“…The significance of the G2M pathway is relevant to the LVNC since many stress-responsive genes often play a role in heart development and pathogenesis ( 30 ). The glutathione-S-Transferase pi 1 (GSTP1) gene is highly polymorphic and involved in many diseases including cancer and heart failure ( 31 ). Its role in LVNC could be further investigated.…”

A novel gene associated with small bowel bleeding in patients taking low-dose aspirin

“…Almost all members of the GST family exhibit genetic polymorphisms, which can result in a complete lack or reduction of enzyme activity [38] . Two genetic variants in the GSTP1 gene have been shown to confer altered catalytic and noncatalytic activity [39] . These are the GSTP1 * G allele (rs1695), encoding a protein in which amino acid isoleucine (Ile) is substituted with valine (Val) at position 105, and the GSTP1 * allele (rs1138272), in which alanine (Ala) is substituted with (Val) at position 114.…”

“…These are the GSTP1 * G allele (rs1695), encoding a protein in which amino acid isoleucine (Ile) is substituted with valine (Val) at position 105, and the GSTP1 * allele (rs1138272), in which alanine (Ala) is substituted with (Val) at position 114. Simeunovic et al [39] reported that the GSTP1 G allele (rs1695) was significantly associated with an increase in the levels of soluble intracellular adhesion molecule-1 (ICAM-1) in patients with heart failure. In an animal study, NSAID induced a rapid increase in ICAM-1 expression in blood vessels, probably because of inhibition of prostaglandin synthesis [40] .…”

Identification of biomarkers, pathways and potential therapeutic targets for heart failure using bioinformatics analysis

“…GO [76], SLC16A9 [77], ACADSB (acyl-CoA dehydrogenase short/branched chain) [78], IMPA1 [79], CD300LG [80], CIRBP (cold inducible RNA binding protein) [81], PIK3R1 [82], YEATS4 [83], USP2 [84], NEDD9 [85], CHCHD5 [86] and ERAP1 [87] promotes hypertension. HSPB1 [88], CRYAB (crystallin alpha B) [89], ANXA5 [90], CCR2 [91], RGS4 [92], TNFRSF1A [93], XBP1 [94], NKX2-5 [95], NEU1 [96], GSTP1 [97], COMT (catechol-O-methyltransferase) [98], LIMK1 [99], CAMKK1 [100], CD276 [101], SMARCA4 [102], ADORA2B [103], ACOT1 [104], RGN (regucalcin) [105], PPA2 [106], KAT2B [107], PDK1 [108], CS (citrate synthase)…”