مسیرهای ژن مرتبط با سروتونین مرتبط با اختلال شبه جسمی تمایز نیافته

It has been suggested that serotonergic hypofunction and serotonergic pathway genes underlie the somatic symptoms of somatoform disorders. We examined a variety of serotonin-related gene polymorphisms to determine whether undifferentiated somatoform disorder is associated with specific serotonin-related gene pathways. Serotonin-related polymorphic markers were assessed using single nucleotide polymorphism (SNP) genotyping. One hundred and two patients with undifferentiated somatoform disorder and 133 healthy subjects were enrolled. The genotype and allele frequencies of tryptophan hydroxylase (TPH)1 A218C, TPH2 rs1386494, serotonin receptor 2A-T102C (5-HTR 2A-T102C), 5-HTR 2A-G1438A and serotonin transporter (5HTTLPR) gene were compared between the groups. The Hamilton Rating Scale for Depression and the somatization subscale of the Symptom Checklist-90-Revised (SCL-90-R) were used for psychological assessment. Patients with undifferentiated somatoform disorder had higher frequencies of the TPH1 C allele than healthy controls (p = 0.02) but the difference was not significant after Bonferroni correction. The frequency of TPH1 genotype also did not differ significantly between the patients and the healthy controls, nor did TPH2 rs1386494, 5-HTR 2A-T102C, 5-HTR 2A-G1438A or 5HTTLPR allele and genotype frequencies differ significantly between the two groups. These findings suggest that a variety of serotonin-related gene pathways are unlikely to be definite genetic risk factors for undifferentiated somatoform disorder. Therefore, the pathogenesis of the disorder may be related to epigenetic factors, including psychosocial and cultural factors. Nonetheless, future studies need to include a larger sample of subjects and polymorphisms of more serotonin-related gene variants.

Somatoform disorders tend to be chronic and can cause significant social problems and financial burden. In particular, undifferentiated somatoform disorder, a subtype of somatoform disorders is characterized by one or more unexplained physical complaints lasting for at least six months but below the threshold for diagnosing somatization disorder (Guggenheim, 2000). The prevalence of undifferentiated somatoform disorder is known to be quite high, ranging from 10.2% to 30.6% (De Waal et al., 2004, Chang et al., 2005 and LeiKeiknes et al., 2007). Treating somatoform disorders is challenging because they cannot be treated according to the existing biomedical model (Koh, 2002). However, antidepressants are commonly used in the treatment of somatoform disorders because these disorders often coexist with depressive symptoms (Belous et al., 2001). Serotonin is believed to play an important role in depression, and a number of serotonergic pathway genes have been examined (Owens and Nemeroff, 1994) including the tryptophan hydroxylase (TPH) gene, which is involved in catalysis of the rate-limiting step for serotonin biosynthesis (Peters et al., 2004) and regulates levels of serotonin (Mann, 1999). Therefore, variations in the TPH gene could contribute to the predisposition to low serotonergic neurotransmission (Rujescu et al., 2002). TPH1 is regarded as a candidate gene for major depressive disorder and is believed to influence antidepressant response (Pickar and Rubinow, 2001). Recently, genetic variants of the TPH2 gene were also reported to be involved in the pathogensis of major depressive disorder (Zill et al., 2004a). In humans TPH1 and TPH2 are expressed in nearly equal amounts in several brain regions (the frontal cortex, thalamus, hippocampus, hypothalamus and amygdala). However, TPH2 is predominantly expressed in the brain stem, the major locus of serotonin-producing neurons (Zill et al., 2004b). The serotonin receptor 2A (5-HTR 2A) gene is also believed to be a candidate gene for depression, because 5-HTR 2A binding potential is associated with major depressive disorder and suicidal behavior (Oquendo and Mann, 2001). Du et al. (2000) reported that the C allele of the 5-HTR 2A T102C gene polymorphism is related to depression and suicidal behavior However, Eley et al. (2004) suggested that the T allele is a more likely risk factor for depression. Other serotonin-related gene polymorphism candidates for depression include the A1438G polymorphism in the promoter region of the 5-HTR 2A gene, which is significantly associated with major depressive disorder (Choi et al., 2004) and seasonal affective disorder (Enoch et al., 1999). In addition, a functional polymorphism located in the promoter region of the serotonin transporter gene (5-HTTLPR), has been shown to be associated with seasonal affective disorder (Rosenthal et al., 1998). However, the 5-HTTLPR s allele was reported to be linked to suicidal behavior (Anguelova et al., 2003a, Lin and Tsai, 2004 and Li and He, 2007) but not to unipolar depression (Anguelova et al., 2003b and Lasky-Su et al., 2005). In addition, somatic symptoms of somatoform disorders are thought to be connected to serotonergic neurotransmission because serotonin is known to regulate the functions relevant to one of these disorders, such as pain disorder (Guggenheim, 2000 and Hennings et al., 2009). There is also some evidence suggesting that an abnormality in processing immunoreactive serotonin transporter protein (IR-STP) is involved in somatoform disorders (Belous et al., 2001). In contrast to the large body of research examining genetic risk factors for depressive disorders, research into the genetic etiology of somatoform disorders is in its infancy. Genetic data indicate that somatization disorder has genetic components because it tends to run in families (Sadock and Sadock, 2003). In addition, another study found that somatic symptoms of somatoform disorder patients might be associated with functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) (Hennings et al., 2009). Therefore, it was suggested that serotonergic hypofunction and serotonergic pathway genes are likely to underlie the somatic symptoms of somatoform disorders. However, few studies have investigated the relationship between the variety of serotonin-related gene polymorphisms and somatoform disorders. In the present study, we examined TPH1 A218C, TPH2 rs1386494, 5-HTR 2A-T102C, 5-HTR 2A-A1438G and 5-HTTLPR gene polymorphisms in patients with undifferentiated somatoform disorder and healthy subjects to determine if the disorder is associated with specific serotonin-related gene pathways.