Association study of two serotonin 1A receptor gene polymorphisms and fluoxetine treatment response in Chinese major depressive disorders

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Abstract

The firing rate of dorsal raphe serotonergic neurons is modulated by somatodendritic 5-hydroxytryptamine 1A (HTR1A) autoreceptors. Evidence from animal and clinical studies has suggested that desensitization of HTR1A is implicated in the antidepressant therapeutic mechanism of selective serotonin reuptake inhibitors (SSRIs). Recent studies, including our recent findings, have reported that a functional HTR1A C-1019G polymorphism in the promoter region, as well as a nonsynonymous polymorphism, Gly272Asp, may be associated with SSRI pharmacogenetics. In this study, we tested whether Gly272Asp genetic variants are related to a 4-week fluoxetine antidepressant effect in 222 Chinese major depressive patients. We also tested the linkage disequilibrium (LD) measurement between HTR1A Gly272Asp and C-1019G polymorphisms, and haplotype analysis was conducted to assess the association between the two markers within the HTR1A gene and fluoxetine antidepressant response. The results show that the HTR1A Gly272Asp polymorphism was not associated with fluoxetine therapeutic response. The two markers are in strong LD and the HTR1A haplotype of the two polymorphisms is associated with fluoxetine therapeutic response. This association is gender-specific and mostly arises from the effect of HTR1A C-1019G polymorphism: female patients with -1019C/C genotype showed a better response than -1019G carriers. These findings need to be confirmed in other ethnic populations.

Introduction

Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line agents for treatment of major depression. The mechanisms underlying the antidepressant effects of SSRIs are still unclear. Although all SSRIs share almost no molecular feature, one common feature of SSRIs is that they have specific activity in the inhibition of serotonin reuptake, which leads to a tonic elevation of serotonin levels (Nutt et al., 1999). Since SSRIs induce increased serotonin levels in the extracellular space, their therapeutic effect is probably medicated, at least in part, by action at various serotonin receptors. Currently, at least 14 mammalian serotonin receptor subtypes, differing in structure and distribution, have been identified. Among them, serotonin 1A receptor (HTR1A) is expressed as a postsynaptic receptor as well as the major somatodendritic autoreceptor on serotonergic raphe neurons (Sotelo et al., 1990). Data from both animal and human studies have suggested that SSRI therapeutic effects seem to be related to desensitization of somatodendritic HTR1A in the raphe nuclei, which is induced by the increase in serotonin concentration in the extracellular space (for review, see Newman et al., 1993, Stahl, 1998). This notion is further supported by the finding that there is a significant augmenting effect when the beta-adrenergic/HTR1A receptor antagonist, pindolol, was coadministered with SSRI treatment (Bordet et al., 1998).

Pharmacogenetics investigate individual possible genetic factors involved in response to clinical drug treatment, including those factors related to drug metabolism and those related to drug targeting. Since HTR1A has been implicated in the SSRI therapeutic mechanisms, genetic variants in the HTR1A could be candidates for SSRI pharmacogenetic study. The HTR1A gene, mapped to chromosome 15q11, is intronless and codes a 422-amino-acid protein (Kobilka et al., 1987). Recently, our team and another two research teams have reported a common promoter polymorphism (C-1019G; rs6295 (http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=6295)) of HTR1A as being associated with SSRI treatment efficacy in bipolar or unipolar depression (Serretti et al., 2004, Lemonde et al., 2004, Hong et al., 2006). It is possible that this polymorphism may directly affect the SSRI effect on desensitization of the somatodendritic HTR1A receptor or the association of this HTR1 polymorphism and SSRI antidepressant response is due to linkage disequilibrium (LD) between this polymorphism and a nearby functional polymorphism (Hong et al., 2006). Recently, study of Japanese patients found that a nonsynonymous HTR1A polymorphism (Gly272Asp) was associated with fluvoxamine (an SSRI) antidepressant response (Suzuki et al., 2004). This result prompted us to study whether or not this Gly272Asp polymorphism may play a role in SSRI pharmacogenetics in the Chinese population. In addition, LD measurement between HTR1A Gly272Asp and C-1019G polymorphisms and haplotype analysis were conducted to assess the association between the two markers within the HTR1A gene and SSRI antidepressant response.

Section snippets

Methods and patients

This is an extended study of our previous report (Hong et al., 2006). The study population consisted of 222 patients with major depression (male/female: 94:128; mean age: 44.0 years [SD: 16.3]) who met DSM-IV criteria and completed a 4-week therapeutic evaluation of fluoxetine. A senior psychiatrist (YWY) made the diagnosis by interviewing patients and family members and also by obtaining records whenever possible. Other inclusion criteria were a minimum baseline score of 18 on the 21-item

Results

The mean fluoxetine doses for the 222 patients was 26.0 mg/day [SD: 9.4] at week 4 and 83 (37.3%) of the 222 patients had at least a 50% decrease in HAM-D total score after 4 weeks of taking medication. There were no significant differences in gender or baseline HAM-D score between the responder and the non-responder groups (Table 1); however, the non-responder group had an older mean age compared with the responder group (P = 0.047).

Genotype distributions for all of the two genetic polymorphisms

Discussion

In this study of a Chinese sample population, we cannot replicate the association observed in the Japanese sample between HTR1A Gly272Asp polymorphism and short-term SSRI treatment response (Suzuki et al., 2004). There are several possible explanations for this discrepancy. First, the HTR1A Gly272Asp polymorphism may be in LD with a functional variant, which affects antidepressant response, and the extent of this linkage disequilibrium is not the same for all ethnic populations. Second, this

Acknowledgments

This work was supported by Grant 92-2314-B-075-087 from the National Science Council, Taiwan, ROC, and Grant VGH92-161 from Taipei Veterans General Hospital.

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      Besides 5HTTLPR, serotonin receptor-encoding genes were also extensively studied, especially HTR1A and HTR2A. Although a promoter polymorphism in HTR1A gene has been associated initially with antidepressant treatment response (Hong, Chen, Yu, & Tsai, 2006; Villafuerte et al., 2009; Yu, Tsai, Liou, Hong, & Chen, 2006), recent studies contradict these findings (Antypa et al., 2013; Basu, Chadda, Sood, Kaur, & Kukreti, 2015; Dong et al., 2016; Kato et al., 2009; Serretti et al., 2013; Zhao et al., 2012). Moreover, three meta-analyses found no significant effect on antidepressant side effects or treatment response (Kato & Serretti, 2010; Niitsu et al., 2013; Zhao et al., 2012).

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