Association of GCLM -588C/T and GCLC -129T/C Promoter Polymorphisms of Genes Coding the Subunits of Glutamate Cysteine Ligase with Ischemic Heart Disease Development in Kazakhstan Population

Abstract

Background Glutamate cysteine ligase (GCL) is a rate-limiting enzyme in synthesis of glutathione. Evidence suggests that genetic variations in the promoter region of genes coding a catalytic subunit (GCLC -129T/C) and a modifier subunit (GCLM -588C/T) of GCL have a functional impact on their transcriptional activity and were associated with various disorders. Hence, we hypothesize whether these two polymorphic variants of GCLM and GCLC genes are associated with the risk of ischemic heart disease (IHD) development in the population of Kazakhstan. Methods We evaluated 360 patients with IHD and 341 control subjects. Allele frequencies of studied promoters' polymorphisms were detected by PCR-RFLP analysis. Multiple logistic regression analysis was applied to assess the risk for different genotypes obtained. Results The presence of -588T allele in GCLM and -129T allele in GCLC gene genotypes was associated with an increased risk of IHD (GCLM -588T: OR = 3.92, p = 0.003; GCLC -129T: OR = 3.22, p = 0.03) for general ethnically mixed group. Analysis of each ethnical groups separately showed the higher risk tendency for Kazakhs as for GCLM -588T (OR = 4.79; p = 0.03) and as for GCLC -129T (OR = 4.79, p = 0.03). For Russians, statistically differences for two polymorphisms were not observed. Conclusion The two promoter polymorphisms of GCLM (-588C/T) and GCLC (-128T/C) are associated with an increased risk of IHD in Kazakhstan population.

Expression Profile Analysis of Selenium-Related Genes in Peripheral Blood Mononuclear Cells of Patients with Keshan Disease

“…GCLC is a subunit of the first rate-limiting enzyme of glutathione synthesis. Promoter polymorphisms of GCLC have been associated with increased risk of ischemic heart disease in the Kazakhstani population [26]. Uthus and Ross showed that the expression of GCLC was upregulated by selenium deprivation in both rat and mouse liver [27], while increased levels of glutamate-cysteine ligase ( GCL ) may drive glutathione ( GSH ) synthesis in response to oxidants, providing a protective mechanism against oxidative stress [28].…”

Quantitative trait mapping in Diversity Outbred mice identifies novel genomic regions associated with the hepatic glutathione redox system

“…Other studies have examined the disease relevance of polymorphisms in genes involved in glutathione biosynthesis, notably glutathione cysteine ligase (GCL) and glutathione synthetase (GS), which directly affect cellular GSH concentrations [ 29 ]. Polymorphisms in the catalytic subunit of GCL ( GCLC ) have been associated with cystic fibrosis [ 30 ], chronic obstructive pulmonary disease [ 31 ], pulmonary tuberculosis [ 32 ], drug sensitivity in human tumor cell lines [ 33 ], methylmercury retention [ 34 ], vasomotor function and myocardial infarction [ 35 , 36 ]. Functional polymorphisms in the GCL modifier subunit ( GCLM ) have been linked with ischemic heart disease and vasomotor function [ 36 , 37 ], and in some cases, schizophrenia [ [38] , [39] , [40] ].…”

“…Polymorphisms in the catalytic subunit of GCL ( GCLC ) have been associated with cystic fibrosis [ 30 ], chronic obstructive pulmonary disease [ 31 ], pulmonary tuberculosis [ 32 ], drug sensitivity in human tumor cell lines [ 33 ], methylmercury retention [ 34 ], vasomotor function and myocardial infarction [ 35 , 36 ]. Functional polymorphisms in the GCL modifier subunit ( GCLM ) have been linked with ischemic heart disease and vasomotor function [ 36 , 37 ], and in some cases, schizophrenia [ [38] , [39] , [40] ]. Lastly, polymorphisms in GS have been associated with susceptibility to lung dysfunction and lung cancer, as well as patient survival [ 41 , 42 ].…”

The role of polymorphisms in glutathione-related genes in asbestos-related diseases

“…Among the most commonly investigated promoter polymorphisms of the GCLC and GCLM genes are GCLC rs17883901 (c.-129C>T) and GCLM rs41303970 (c.-590 C>T). 17 , 18 , 19 , 20 Some studies indicated that polymorphisms in GCLC and GCLM genes are associated with low levels of reduced GSH in vitro , which may explain susceptibility to certain diseases related to oxidative stress. 17 , 18 The GCLC rs17883901 polymorphism has been suggested to suppress the GCLC gene induction response to oxidants and it has been implicated in coronary endothelial dysfunction and myocardial infarction.…”

“… 21 The presence of GCLC rs17883901 T allele and GCLM rs41303970 T allele has also been associated with an increased risk of ischemic heart disease. 19 However, according to the available literature the association between GCLC and GCLM polymorphisms and asbestos-related diseases has not been studied so far.…”