Abstract
The abnormal activation of the tryptophan catabolites pathway (TRYCATs) is observed in patients suffering from cerebrovascular disease, including stroke. A previous study confirmed that lower bioavailability of tryptophan for serotonin synthesis was characterized in the patients during the acute stroke phase. Interestingly, according to various studies, polymorphisms of the genes involved in the TRYCATs pathway may modulate the risk of stroke occurrence. Therefore, this study aimed to investigate the association between the occurrence of TPH1, TPH2, KAT1, KAT2 and IDO1 polymorphisms and the risk of stroke development.The following 10 polymorphisms of the genes encoding enzymes of the TRYCATs pathway were selected: c.804-7C > A (rs10488682), c.-1668T > A (rs623580), c.803+221C > A (rs1800532), c.-173A > T (rs1799913) – TPH1, c.-1449C > A (rs7963803), and c.-844G > T (rs4570625) – TPH2. c.*456G > A of KAT1 (rs10988134), c.975-7T > C of KAT2 (rs1480544), c.-1849C > A (rs3824259) and c. -1493G > C (rs10089084) of IDO1. The study was carried out on DNA isolated from the peripheral blood taken from 107 patients after a stroke and 107 healthy volunteers. All DNA samples were genotyped using TaqMan probes. The genotypes of eight studied polymorphisms modulated the risk of stroke. No significant difference in genotype and allele frequencies of the c.804-7C > A –TPH1 (rs10488682) and c.*456G > A – KAT1 (rs10988134) polymorphisms were found between patients and controls. Having performed haplotype and gen-gen analyses, it was possible to determine that patients after a stroke and controls differed in terms of the frequency of selected genotypes and haplotypes. Among the studied polymorphisms, eight SNPs were linked with stroke risk modulation. The results obtained confirmed our hypothesis regarding the involvement of the TRYCATs pathway in the pathogenesis of stroke.
Highlights
Stroke is considered and classified as a cardiovascular disease, next to coronary artery diseases, heart failure, hypertensive heart disease, valvular heart disease, and carditis [1]
A statistical analysis of disturbances in the genotypes and alleles of the c.803 + 221C > A – TPH1 polymorphism confirmed that the C/C and A/A homozygotes were linked with an increased frequency of stroke occurrence by 20 times, while the heterozygote of the same single-nucleotide polymorphisms (SNPs) showed a protective character and reduced the risk
The results demonstrated that the T/T genotype and T allele of c.-1668T > A – TPH1 were negatively correlated with stroke, whereas the A/A, T/A and A allele of the same polymorphism were positively correlated with the disease
Summary
Stroke is considered and classified as a cardiovascular disease, next to coronary artery diseases, heart failure, hypertensive heart disease, valvular heart disease, and carditis [1]. There were 6.5 million stroke deaths in the world in 2013, making stroke the second-leading cause of death behind ischemic heart disease. There was an estimated number of 10.3 million new strokes in 2013, and 67% of them were ischemic strokes. It was estimated that the annual cost of treating CVD and strokes in the United States amounted to $316.1 billion from 2012 to 2013 [3]. Studies conducted in recent years demonstrated that the tryptophan catabolites pathway (TRYCATs) might be associated with the prevalence of cardiovascular diseases, including stroke [5,6,7]. Research findings suggest that patients after an ischemic stroke have a lowered concentration of tryptophan and kynurenine acid. The kynurenine/tryptophan (KYN/TRP) ratio, meaning kynurenine transaminase (KAT) activity, was lower, while the kynurenic acid/kynurenine (KYNA/KYN) ratio, meaning indoleamine-2,3-dioxygenase IDO activity, was higher in patients when compared to healthy volunteers [11]
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