Academic journal article Advances in Mental Health

Development of Reelin Biomarkers to Measure Psychological Resilience and Their Interaction with 5-HTTLPR in Depression

Academic journal article Advances in Mental Health

Development of Reelin Biomarkers to Measure Psychological Resilience and Their Interaction with 5-HTTLPR in Depression

Article excerpt

Introduction

Serotonin or 5-hydoxytryptamine (5-HT) levels have been reported to play an important role in depression by a very large number of studies from the late 1960s onwards, and is based on active modulation of serotonergic system of prefrontal brain areas, which affects the cognitive and behaviour dysfunction (Goldman-Rakic, 1999). Serotonin concentration is regulated by various factors involved in the serotonergic system, such as the 5-HT receptors, tryptophan hydroxylase isoform 2 (TPH2) and the serotonin transporter (5-HTT) (Dannlowski et al., 2007). The 5-HTT or SLC6A4 is a key player in the serotonergic neurotransmission as it enables reuptake of 5-HT from the synaptic cleft. Heils et al. (1995, 1996) first reported the 5-HTT promoter region polymorphism identified at the promoter site of approximately 1 kb and demonstrated that the polymorphism could alter transcriptional levels of 5-HTT whilst, Collier et al. (1996) reported that the polymorphism (44 bp insertion and deletion) affected the expression efficiency of 5-HT, and proposed that it was linked to various mental disorders. The short (s) and long (l ) allele variants of 5-HTT functional length promoter polymorphic region are called 5-HTTLPR and it has been shown that subjects with s allele (s/s or s/l) have lower 5-HT levels in blood platelets, lymphoblast cell and brain (Hanna et al., 1998; Lesch et al., 1996; Little et al., 1998). These studies prompted several research groups to investigate the role of 5-HTTLPR in depression and other neuroticism, of which some of the studies showed 5-HTTLPR association with anxiety, agreeableness, other neuroticism (Lesch et al., 1996, Greenberg et al., 2000, Melke et al., 2001), anticipatory worry and fear of uncertainity (Mazzanti et al., 1998) while others did not (Gustavsson et al., 1999; Jorm et al., 1998).

Several research groups have studied 5-HTTLPR in association with depression and stress and/or stress factors. There have been more than 80 studies over the last few decades, but the results have been inconsistent and contradictory. For example, in cross-sectional studies some have showed an association of the ss allele with depression (Cervilla et al., 2007), others with the ll and ls allele (Sharpley, Palanisamy, & McFarlane, 2013) or with ss or ll alleles depending on the stressor and gender (Sjoberg et al., 2006), while others have found no association of the any 5-HTTLPR polymorphisms with depression (Surtees et al., 2006). In longitudinal studies, an association of s or ss allele with depression was reported (Jacobs et al., 2006), while others have demonstrated no association with the s allele (Middeldorp et al., 2007). Others (Chorbov et al., 2007) have reported an association with the la alleles when results are analyzed using the sa /sg /la /lg method described by Wendland, Martin, Kruse, Lesch, & Murphy (2006).

The first systematic reviews and meta-analysis studies of Munafo, Durrant, Lewis and Flint (2009; five studies) and Risch et al. (2009; 14 studies) concluded that there was no supporting evidence for 5-HTTLPR s allele association with depression. However, a few years later Karg and colleagues (2011) analyzed the data from 54 studies and concluded there was a significant effect for the ss allele association between stress, stressful environment (Gene x Environment) and depression. However, in the 54 studies, 15 reported no association of ss allele between stress and depression and six studies reported a ll allele interaction between stress and depression. A recent 5-HTTLPR meta-analysis including 81 studies (Sharpley, Palanisamy, Glyde, Dillingham, & Agnew, 2014) supported the work of Karg et al. (2011) but found a number of methodological flaws in many of these studies, such as low subject numbers and subjective depressive questions. A recent 5-HTTLPR study on a Chinese Han population found that the l allele is more prone to depression and anxiety (Long et al., 2013) compared to the Caucasian population. …

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