Association of Monoamine-Synthesizing Genes with the Depression Tendency and Personality in Chronic Fatigue Syndrome Patients
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Life Sciences 92 (2013) 183–186 Contents lists available at SciVerse ScienceDirect Life Sciences journal homepage: www.elsevier.com/locate/lifescie Association of monoamine-synthesizing genes with the depression tendency and personality in chronic fatigue syndrome patients Sanae Fukuda a,b, Mieko Horiguchi c,d, Kouzi Yamaguti e,f, Yasuhito Nakatomi b,e, Hirohiko Kuratsune e,f,g, Hiroshi Ichinose d, Yasuyoshi Watanabe b,f,⁎ a Department of Medical Science on Fatigue, Osaka City University, Graduate School of Medicine, Osaka, Japan b Center for Molecular Imaging Science, RIKEN, Kobe, Hyogo, Japan c Department of Domestic Science, Junior College Division, Otsuma Women's University, Tokyo, Japan d Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan e Department of Metabolism, Endocrinology and Molecular Medicine, Fatigue Clinical Center, Osaka City University Graduate School of Medicine, Osaka, Japan f Department of Physiology, Osaka City University Graduate School of Medicine, Osaka, Japan g Department of Health Welfare, Kansai Welfare University, Kashiwara, Japan article info abstract Article history: Aims: Tyrosine hydroxylase (TH) and GTP cyclohydrolase I (GCH) are the rate-limiting enzymes for the Received 19 June 2012 biosynthesis of catecholamines and tetrahydrobiopterin (BH4), respectively. Since catecholamines and BH4 Accepted 20 November 2012 are thought to be involved in the pathophysiology of CFS, we explored the genetic factors that influence CFS development and examined the possible association between the SNPs of the TH and GCH genes and Keywords: the various characteristics of CFS patients. Personality Main methods: After drawing venous blood from CFS patients and controls, genomic DNA was then extracted Chronic fatigue syndrome from whole blood in accordance with standard procedures. Digestion patterns of the PCR products were used GCH1 − Tyrosine hydroxylase for genotyping the SNPs of GCH (rs841; C+243T) and TH (rs10770141; C 824T). We also performed ques- Single nucleotide polymorphism tionnaires consisting of fatigue-scale and temperament and character inventory scale (TCI) to CFS patients. Key findings: Our results demonstrated that the allele differences for the GCH and TH SNPs were not associated with CFS patients. We did find that the GCH gene with the C+243T polymorphism affected harm avoidance, while the TH gene with the C−824T polymorphism affected persistence in the CFS patients. The concept of per- sistence has been linked to specific personality, such as perfectionism, in CFS. Significance: Our results suggest that the biosynthetic pathways of the monoamine neurotransmitters that are mediated by TH and GCH might be associated with the CFS clinical findings, because persistence is one of the typical personality traits observed in CFS and patients with major depressive disorder exhibit a higher harm avoidance score. © 2012 Elsevier Inc. All rights reserved. Introduction is a deep involvement of monoaminergic neural function with tempera- ment (Cloninger, 1987; Cloninger et al., 1993). Chronic fatigue syndrome (CFS) is a disorder diagnosed following Dysfunction in monoaminergic system has been suggested to be at least 6 months of disabling, unexplained mental and physical one of the mechanisms involved in the development of CFS. Several fatigue accompanied by other physical and psychological symptoms 5HT-agonist challenge tests have demonstrated that 5HT may be (Fukuda et al., 1994; Prins et al., 2006). Patients with CFS tend to show involved in the etiology of CFS (Parker et al., 2001). As compared with a different pattern in temperament compared with controls (Fukuda et controls, CFS patients have been shown to have a different genotype al., 2010). Cloninger et al. (1993) have proposed a psychobiological distribution in the serotonin transporter polymorphic region (Narita model of temperament and character, novelty seeking (NS), harm avoid- et al., 2003). Recently the positive effects of an anti-dopamine drug on ance (HA), reward dependence (RD), persistence (P), self-directedness CFS patients were found (Pardini et al., 2011), while there are still few (SD), cooperativeness (C), and self-transcendence (ST) (Cloninger et investigations that have examined the effect of dopamine and its related al., 1993). The model proposed by Cloninger et al. suggests that there pathways in CFS patients. Tetrahydrobiopterin (BH4) is a cofactor for tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH), and nitric oxide synthase (NOS). ⁎ Corresponding author at: RIKEN Center for Molecular Imaging Science, 6-7-3 TH and TPH are the rate-limiting enzymes for the biosynthesis of mono- Minatojima-minamimachi, Chuo-ku, Kobe City, Hyogo 650-0047, Japan. Tel.: +81 78 304 7101; fax: +81 78 304 7112. amine neurotransmitters. It is well known that most therapeutic E-mail address: [email protected] (Y. Watanabe). regimens for patients with depression act via the potentiation of neural 0024-3205/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.lfs.2012.11.016 184 S. Fukuda et al. / Life Sciences 92 (2013) 183–186 transmission mediated by monoamines. BH4 is synthesized from forward primer and 5′-TAGCACTTTCGGCACTACACCAC-3′ as the reverse guanosine-triphosphate (GTP) via three enzymatic reactions. GTP primer, and then digested with the restriction enzyme, AfaI(RsaI). The cyclohydrolase I (GCH) catalyzes the first reaction and serves as the DNA fragments of TH surrounding the rs10770141 (C−824T) were rate-limiting enzyme in the biosynthesis of BH4. GCH transcription is first amplified by PCR using 5′-GTTGTCCTCAAGGGAGTTCTCAG-3′ as enhanced by many stimuli, such as nerve growth factor, glucocorticoids, the forward primer and 5′-CCAGGGTTGCCAGGGCGACCAG-3′ as the interleukin-2, and tumor necrosis factor-α (Huang et al., 2005; Ito et al., reverse primer, and then digested with the restriction enzyme, DraI. 2005), implying physiological relevance of the GCH expression. Three genotypes, C/C, C/T, and T/T, were determined from the corre- Many single nucleotide polymorphisms (SNPs) in the GCH gene sponding patterns of the digested DNA fragments. have been reported. GCH activity has been shown to be involved in human mental function and its associated behaviors (Ichinose et al., Statistical analyses 2008). It has also been reported that the polymorphisms of the TH gene are associated with several psychiatric disorders, i.e., schizophrenia Statistical analyses were performed using SPSS 15.0 J software (SPSS and mood disorders (Bellivier et al., 1998; Furlong et al., 1999). Japan Inc., Tokyo, Japan). Since age and gender can influence the TCI It has been found that the T allele of the GCH polymorphism (rs841) scores, the difference for each TCI score between the genotype groups was related to lower luciferase activity in transfected chromaffincells, was analyzed according to gender and then examined using an analysis and that this allele was associated with lower GCH mRNA levels and of covariance for age. All reported P-values were two-tailed. Hardy– reduced BH4 levels (Zhang et al., 2007). The same research group addi- Weinberg equilibrium for the SNPs in the controls and patients was tionally reported that the T allele of the C−824T polymorphism in the examined in order to test the genotype distribution. Statistical signifi- TH gene promoter (rs10770141) was responsible for higher promoter cance was defined as Pb0.05. activity of the TH gene and higher norepinephrine levels (Rao et al., 2007). These reports suggest that these SNPs are functional polymor- Personality assessment phisms that are responsible for the monoamine levels in vivo. We chose these 2 genes and 2 SNPs because TH and GCH are the rate-limiting Personality traits of the subjects were assessed by the Japanese enzymes for biosynthesis of catecholamine and tetrahydrobiopterin, version of the TCI, (Kijima et al., 2000) which has been verified to respectively, and these 2 SNPs were reported to be functional ones have a high reliability and validity. (Rao et al., 2007; Zhang et al., 2007). A previous study has reported associations between both the func- Results tional TH gene promoter and NS, and between the GCH gene and NS in a healthy Japanese population (Sadahiro et al., 2010, 2011). The The genotype distribution for the GCH genotype was in Hardy– current study was designed to examine the association between the Weinberg equilibrium for the SNP C+243T (χ2 =0.153, df=1, P> SNP of the GCH gene (rs841) or the TH gene (rs10770141) and the 0.05). The distribution of the GCH genotypes in CFS patients (C/C= subsequent development of CFS, and the association between the SNPs 30.4%, C/T=48.9%, T/T=20.7%) was similar to that seen in the samples and the personality traits in CFS patients. from other healthy Japanese subjects (Sadahiro et al., 2011). After adjustment for age in the total subject group, a significantly Materials and methods higher score for the HA in the TCI dimension scores was found between subjects with the C allele and those without the allele Subjects (Table 1). Meanwhile, there were no significant main effects of gen- der on the seven TCI dimension scores. In contrast, patients without Subjects for the clinical association study were recruited from the psychiatric diseases exhibited lower P scores when the T allele was Fatigue Clinical Center at the Osaka City University Hospital, Osaka, present as compared with when the allele was absent (Fig. 1). Japan, and from the Osaka University Hospital Department of Psychiatry. The genotype distribution for the TH genotypes was in Hardy– A total of 155 CFS patients (55 menand100womenwithameanageof Weinberg equilibrium for the SNP C−824T (χ2 =1.28, df=1, P> 36.0 years [SD: 8.51 years]) were enrolled in the study. All of the sub- 0.05). The distribution of the T genotypes for the CFS patients (T allele jects were Japanese. Fifty-five of CFS patients completed the question- (−)=78.3%, T allele (+)=21.7%) was similar to that observed in the naire. In the CFS patient group, 58% were diagnosed with psychiatric samples from other healthy Japanese subjects (Sadahiro et al., 2010).