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Variation of Genes Encoding Tryptophan Catabolites Pathway Enzymes in Stroke

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Variation of Genes Encoding Tryptophan Catabolites Pathway Enzymes in Stroke Journal of Clinical Medicine Article Variation of Genes Encoding Tryptophan Catabolites Pathway Enzymes in Stroke Paulina Wigner 1, Joanna Saluk-Bijak 2, Ewelina Synowiec 1, Elzbieta Miller 3 , Tomasz Sliwinski 1 , Natalia Cichon 2 and Michal Bijak 2,* 1 Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland; [email protected] (P.W.); [email protected] (E.S.); [email protected] (T.S.) 2 Department of General Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland; [email protected] (J.S.-B.); [email protected] (N.C.) 3 Department of Neurological Rehabilitation, Medical University of Lodz, Poland, Milionowa 14, 93-113 Lodz, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-42-635-43-36 Received: 10 November 2019; Accepted: 27 November 2019; Published: 3 December 2019 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. Keywords: stroke; TRYCATs; tryptophan; polymorphism 1. Introduction 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]. The World Health Organization defines stroke as a “neurological deficit of cerebrovascular cause that persists beyond 24 h or is interrupted by death within 24 h” [2]. There were 6.5 million stroke deaths in the world in 2013, making stroke the second-leading cause of death behind ischemic heart disease. Approximately 795,000 J. Clin. Med. 2019, 8, 2133; doi:10.3390/jcm8122133 www.mdpi.com/journal/jcm J. Clin. Med. 2019, 8, 2133 2 of 17 strokes occur in the United States each year. Interestingly, someone has a stroke on average every 40 s in the United States, and someone dies of a stroke every 4 min [3]. There was an estimated number of 10.3 million new strokes in 2013, and 67% of them were ischemic strokes. Incidence for both ischemic and haemorrhagic strokes is higher among males than females [4]. Moreover, stroke is associated with high costs of treatment. 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 [5–7]. Moreover, the activation of the TRYCATs pathway was increased after a stroke and may be linked with stroke severity and poor prognosis [7,8]. So far, research findings suggest that patients after an ischemic stroke have a lowered concentration of tryptophan and kynurenine acid. Tryptophan is an amino acid which is also a precursor to the neurotransmitter serotonin and hormone melatonin, while kynurenine acid is its neuroprotective metabolite and an antagonist of the N-methyl-D-aspartate (NMDA) receptor [9,10]. Moreover, 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]. IDO is a rate-limiting enzyme, which initiates tryptophan metabolism through O2-dependent oxidation, whereas KAT catalyses irreversible transamination of kynurenine acid in the brain and peripheral tissues [12–14]. Furthermore, an animal-based study confirmed that ischemia, which is observed during a stroke, increased the expression of TDO as compared to control animals [15]. Interestingly, the TRYCATs pathway is closely linked with inflammatory modulation. IDO may be activated by pro-inflammatory cytokines, whereas anti-inflammatory cytokines may act as inhibitors of the enzyme [16,17]. Thus, an inflammatory response to an acute ischemic stroke may cause the activation of IDO and, consequently, may lead to tryptophan depletion and increased generation of kynurenine [18]. Additionally, previous findings suggest that Interleukin 10 (IL-10) may reduce the capability of 5-TH synthesis in the brain, which is observed in patients after a stroke [19,20]. Moreover, Ormstad et al. [21] revealed that high levels of interleukin 1β are positively correlated with decreased bioavailability of TRP in the patients after an acute ischemic stroke. More details about the TRYCATs pathway were presented elsewhere [22]. The next study indicated that the activation of the kynurenine pathway plays a crucial role in the acute phase of a stroke as well as in fatigue and depression following a stroke. Patients with Fatigue Severity Scale (FSS) 4 at 12 months post-stroke, ≥ were characterized by a reduced tryptophan (TRP) index as compared to patients with FSS < 4 [21]. The index indicates the bioavailability of TRP in the plasma for serotonin (5-TH) synthesis in the brain [23]. Thus, the reduced TRP index confirmed lower bioavailability of TRP for 5-TH synthesis in patients during the acute stroke phase. Serotonin is important for wakefulness and inhibits rapid eye movement sleep [24]. Therefore, a low level of 5-TH synthesis may lead to abnormal tiredness and a need for long-lasting sleep [25]. In addition, an animal-based study showed that the level of kynurenine (a neurotoxic metabolite of tryptophan) during ischemia was increased in the brain [15]. Interestingly, kynurenine may activate an aryl hydrocarbon (Ah) receptor (ligand-activated transcription factor), and the activation is deleterious to cerebral ischemia. Accordingly, the study showed that the Ah receptor was overexpressed in the mouse brain after an experimental stroke, mainly in the neurons located at the peri-infarct and ischemic core. Similarly, increased expression of the Ah receptor was found in cultured rat cortical neurons after in vitro experimental ischemia [26]. Besides kynurenine, the level of another neurotoxic metabolite, i.e., quinolinic acid, was increased after transient ischemia in gerbils. This study was aimed to further elucidate the role of the TRYCATs pathway during a stroke in the Polish population. Therefore, single-nucleotide polymorphisms (SNPs) were investigated in the presented study. The studied SNPs were localized in the genes encoding the enzymes involved in the TRYCATs pathway, including tryptophan hydroxylase, kynurenine aminotransferase, and indoleamine 2,3-dioxygenase. Moreover, in this study, the further analysis included gen-gen interaction, haplotype and risk of stroke. J. Clin. Med. 2019, 8, 2133 3 of 17 2. Materials and Methods 2.1. Subjects We recruited 107 patients with stroke and 107 age- and sex-matched control subjects (without stroke) in our case-control study. The case group comprised patients after an ischemic stroke hospitalized at the Neurorehabilitation Department of the 3rd General Hospital in Lodz, Poland, in the years 2015–2017. The cerebral ischemic event in each patient had been documented using computed tomography (CT) of the brain. Neurological and CT findings were interpreted by two or more independent and experienced neurologists. All the patients had been diagnosed with an ischemic stroke; we did not include patients having other types of strokes. Among the selected individuals, the people with a history of cranial trauma, cerebral haemorrhage, atrial fibrillation, other major sources of cardioembolism, coagulation disorders, tumours, chronic inflammatory diseases, and autoimmune diseases were excluded from the study. Having excluded all such cases, 107 subjects (50 males and 57 females) with a clinically overt stroke were selected and classified into
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