Genetic Factors for Anorexia Nervosa

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13th Dec 2019 Dissertation Reference this

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Abstract

Introduction & Background: Anorexia Nervosa (AN) is a chronic psychiatric eating disorder characterised by restricted eating, a relentless pursuit of weight loss and having a distorted body image. Epidemiological studies have shown the incidence of AN to rising significantly over the decade with an estimated of 0.16 million people affected by the disorder in the UK. The peak onset of AN occurs between 15-19 years of age, and the disorder is predominantly common in females than in males; with prevalence rate of 2.5% and 0.24% respectively. AN has profound medical and psychological complications including cardiovascular and skeletal problems. The aetiology of AN is complex and multifactorial with combination of psychosocial and genetic factors contributing to its development.  The extent to which genetic polymorphisms contribute towards AN is controversial and is a major subject of current research.

Aims & Objective: The overall aim of this systematic review is to investigate the extent genetic polymorphisms contribute towards development of AN. The aim is achieved through four specific objectives that focuses on four different single nucleotide polymorphisms (SNPs): BDNF gene polymorphism- Val66Met, 5-HT2 receptor gene polymorphism- 1438G/A, COMT gene polymorphisms –Val158Met and 5-HTTLPR gene polymorphism –S allele. Understanding the aetiology of AN in relation to genetic polymorphisms can provide a potential biomarker which can have significant implications in terms of future treatments.

Methods: The database MEDLINE, PUBMED, EMBASE, PSYCHINFO, CINAHL and WEB OF SCIENCE were searched using key terms:  ‘anorexia nervosa’ ‘genetic’ ‘polymorphism’, then using more specific search terms (‘5-HT2A’ ‘1548G/A’ ‘Val158Met’ ‘BDNF’ ‘Val66Met’ ‘5HTTLPR’ COMT’ and ‘Val158Met’) and applying inclusion and exclusion criteria 16 eligible studies were identified for the analysis of this systematic review.

Results: Most of the studies conferred the association of genetic polymorphisms and AN, although the percentage linkage varied amongst the studies ranging from 3% to 68%. Few studies found insignificant relationship between AN and genetic polymorphisms.

Conclusion: Despite the inconsistency in some of the studies; overall there is significant evidence to indicate the strong role of genetic polymorphisms in aetiology of AN. However, further research is required to confer and strengthen the validity of the findings of this review.

Introduction

Anorexia Nervosa (AN) is a debilitating psychiatric eating disorder characterised by restricted eating and a compulsive pursuit of weight loss, where individuals have a distorted body image.1 According to the fifth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-V) criteria, individuals with AN display three common characteristics; a persistent restriction of energy intake, intense fear of gaining weight and denial of the seriousness of their current low body weight.2 Additionally, AN patients often have a lack of recognition to the severity of their condition where in most cases their weight falls below 85% of their ideal body weight.3

Population-based studies have estimated that around 1.6 million people are affect by Eating Disorder (ED) in the UK, of which 10% of the incidence contribute to AN.3 The onset of AN typically occurs during adolescence with peak onset at around 15-19 years of age, and the disorder is predominantly common in females than in males; with prevalence rate of 2.5% and 0.24% respectively.1,2  

AN have disruptive consequences both medically and psychosocially which persists throughout the patient’s life; such as depression, anxiety, social withdrawal and multiple medical complications including osteoporosis, cardiovascular disturbance, fertility and pregnancy problems.4,5 Additionally, AN has the highest mortality rate amongst all the psychiatric disorders contributing to an overall death rate of 5% per decade.4 The impact of AN is not only detrimental for the patient themselves, but it also places a significant burden on the community, hospital services and on the families of those affected.3

Epidemiological studies has found the incidence of AN to be rising significantly over the past 50 years which is thought to be linked to cultural, social, emotional and psychological factors including narrow interpretation of beauty, influence of media, and the desire for certain body shape and weight.6 Despite these vast environmental risk factors of AN; recent studies have found genetic polymorphism to be a major contributor in predisposing an individual to develop AN, where some studies have shown a strong link of up to 68%.6 Evidence-based studies and literature reviews have revealed four common Single Nucleotide Polymorphisms (SNPs) which have been extensively investigated and been recognized for their role in development of AN. These common polymorphic genes of AN are Brain-derived neurotrophic factor (BDNF)-Val66Met, Catechol-O-methyltransferase (COMT)-Val158Met, 5-hydroxytryptamine- 2 (5-HT2a) receptor-1438G/A, and 5-serotonin-transporter-linked polymorphic region (5-HTTLPR) transporter-S allele.7,8

Improved understanding of the genetic polymorphisms in development of AN could be a potential biomarker to predict who might be predisposed to the condition, therefore, this will enable to inform future treatment options and early interventions, as well as providing new perspective for treating the condition.9

Aims and Objectives

The overall aim of this systematic review is to provide a comprehensive and updated overview of anorexia nervosa, specifically focusing on genetic polymorphisms and predisposing of AN. The aim is divided into four specific objectives:

Objective 1: To investigate the association between BDNF gene polymorphism- Val66Met and predisposition towards AN.

Objective 2: To investigate the association between 5-HT2 receptor gene polymorphism- 1438G/A and predisposition towards AN

Objective 3: To investigate the association between COMT gene polymorphisms –Val158Met and predisposition towards AN.

Objective 4: To investigate the association between 5-HTTLPR gene polymorphism –S allele and predisposition towards AN.

Background

Brief History of Anorexia Nervosa

Anorexia nervosa has been recognised as a medical disorder for centuries.1 Sir Richard Morton, a British physician, was the first person to coin the term ‘anorexia nervosa’ which literally means ‘nervous loss of appetite’. In 1689, Morton provided the first medical description of the condition where he described AN as a ‘nervous consumption’.10 In 1874 AN was introduced as distinct clinical diagnosis where clinical reports described the illness as a ‘nervous’ disease characterised by self-starvation.10 Over the decades with clinical experience of AN together with its increasing incidence, the psychologists and clinicians has recognised the disorder as a serious psychiatric illness where numerous literatures have been published explaining the condition and its severe medical complications.3,4

Definition/Diagnosis and Prevalence

Anorexia nervosa is a chronic psychological disorder with profound medical and psychological complications; it is characterised by restricted eating, relentless pursuit of thinness, intense fear of gaining weight and a distorted body image where individuals refuse to maintain a normal body weight (patient typically weigh <85% of their ideal body weight).1 The diagnostic criteria for AN has been modified over the decades with better understanding of its pathophysiology.3 AN is one of the three recognised form of eating disorder reported by the American Psychiatric Association in DSM-5 as shown in  Table 1.11 Additionally, laboratory analysis can be carried out to diagnose AN; routine test includes urinalysis, measurement of serum electrolytes and complete blood count.11 In order to confirm the diagnosis further tests are carried out, such as dual-energy x-ray absorptiometry of bone, MRI or computed tomography of the brain as well as neuropsychological assessments to determine atypical features, such as hallucination and cognitive impairment.5 The severity of AN depends on the individuals Body Mass Index (BMI) as shown in Table 1.12  

Table 1. DSM-5 Diagnostic Criteria for Anorexia Nervosa and severity of condition based on BMI. The table shows a summary of diagnostic criteria for AN, which has been introduced by the American Psychiatric Association. The severity of condition depends on the BMI as highlighted in the table.11,12

The incidence of AN has significantly increased over the past 50 years.13 Although some of the factors for rise in incidence of AN  could be due to greater awareness of the condition and better diagnostic criteria, however, evidence-based studies has shown that psychosocial factors are a major contributing factor, especially in the developed countries where the most substantial increase was among females aged 15-24 years.14 Population-based studies from General Practitioner Database has found a mean incidence for AN in people aged 10-39 years to be 0.3% in the UK, similarly, systematic reviews have shown similar incidence rate around Europe.14 The onset of AN most frequently begins during adolescence (14-19 years) which is thought to be due to significant hormonal changes during this period.15

The American Psychiatric Association has reported Eating Disorder (ED) to have the highest morbidity and mortality of any psychiatric disorder and it is the third most common chronic illness among adolescence after obesity and asthma.16 In terms of prognosis, while most people with AN will recover completely after 5-10 years; longitudinal studies have shown a mortality rate of between 5-10% within first 4 years of diagnosis and 20% where the illness lasts >20 years, additionally, 20% of patients will eventually develop a chronic ED.17 The high mortality rate of AN is explained by significant delay from the onset of symptoms to time of diagnosis and treatment, where studies have found >50% of patient with ED to have gone undiagnosed; possibly due to reluctance of patients to seek help or comply with treatment as majority of AN patients are in denial of their illness.18

Complications of Anorexia Nervosa

 The long-term complications of AN varies considerably depending on the severity of the condition, where outcomes range from full recovery to chronic psychosocial difficulties accompanied by physical and medical complications, such osteoporosis, bradycardia and psychological disturbance (Table 2).19,20,21,22 Although significant number of individuals with AN (>60%) will achieve full psychological and physical recovery, however, at least 20% will develop a severe chronic condition.23

Table 2. The common complication associated with chronic anorexia nervosa. The long-term complications of anorexia nervosa develop in majority of patients; although, the severity of the complications vary significantly depending on the BMI of the individual and their general physical health.19,20,21,22   

Aetiology / Risk Factors

The aetiology of AN is widely complex and multifactorial with predisposing factors ranging from genetic polymorphisms, psychosocial and cultural influences (Figure 1).24 However, the extent to how much exactly various risk factors contribute to development of AN is not clearly determined and is the subject of a controversial debate, with most studies being sceptical of their findings.25  


Figure 1. Predisposing and precipitating factors for anorexia nervosa. Genetic polymorphisms create a predisposition towards development of AN whereas the psychosocial factors trigger the onset of the condition. Additionally, puberty can act as a trigger for AN development due to hormonal changes that can cause anxiety and stress.24 

Community based studies have found media to be the major contributing factor for development of AN, where advertisement of certain body shapes by models tend to have a great influence on young people’s attitude towards their body image and causes negative self-evaluation and feeling of worthlessness, particularly on teenage girls.14 Therefore, individuals with negative self-body image are provoked to unhealthy lifestyle including excessive dieting and strenuous exercise which induces a cascade of pathophysiological reactions associated with complications of AN (Table 2). The social risk factors for AN that is reinforced by media and advertisement are predominantly common in western countries; where emphasis on slimness is portrayed as beauty and ideal body shape in the society.2,3 In addition to this, long-term follow up studies have found that AN patients feel extremely isolated during their illness as consequences of social anxiety and fear of social acceptance, thereby this impacts their self-esteem and self-worthiness which ultimately further contribute to the severity of their condition.26

Furthermore, puberty is shown to be the peak period of onset for majority cases of AN, where the influence of puberty on development of AN has been reported extensively in the literature with several possible explanation.27 Firstly, various genes are switched on at the age of puberty which influences the regulation of gonadotropin-releasing hormones (hormones that control release of gonadotrophins), thus these hormonal changes contribute to mood disorders and anxiety, which are the key risk factors for AN.28 In addition to this, case-control studies have demonstrated that puberty is associated with an increased stressful live events (could be due relationship problems and work demand), and rise in mental disorders; consequently leading to development of AN.27 Likewise, recent meta-analysis on pathogenesis of AN suggests that the disorder often occurs in individuals with certain characteristic personality traits, such as perfectionism, obsessive traits and marked anxiety where the peak onset of these traits generally occur during puberty (linked with hormones).29

Genetic Links

The prevalence rate of AN evidently indicates that despite the fact that majority of people are exposed to psychosocial and cultural risk factors of the condition, however, not everyone will be affected by it; therefore, this emphasises the influence of genetic polymorphisms for development of AN.30 Genome-wide association studies (GWAS) and twin studies have produced substantial evidence which indicates genetic polymorphism to be a major predisposing risk factor for development of AN.31 Leading researches in the field of EDs have found genetic components to have a contributing factor of between 50%-68% in development of AN, with twin studies finding a heritability risk of between 58% and 74%.30 Additionally, longitudinal familial studies have shown a strong evidence for genetic link of AN; an individual with a first-degree relative with AN has shown to have a lifetime risk of ten times greater than families of healthy controls. Similarly, meta-analysis of twin studies have found a liability rate of up to 75% for AN in more than 80% of cases, thereby further emphasising the genetic link of AN.30

AN is a polygenic condition, the nature of how genetic polymorphisms create a predisposition to development of AN is the subject of an ongoing research with controversial findings, however, a few genes have been extensively investigated and identified with clear evidence for its contribution to development of AN as discussed thoroughly in the followings.31

  • Brain-derived neurotrophic factor (BDNF) – Val66Met

BDNF is the most abundant multifactorial neurotrophin in the brain and it has a crucial role in proliferation, differentiation and survival of neurones during the development as well as being involved in synaptic efficiency and neuronal plasticity.30 The critical role of BDNF in relation to regulation of energy balance have been recently recognised; BDNF consist of tyrosine kinase receptors that are expressed in various hypothalamic nuclei implicated in eating behaviour.32

Val166Met, also referred to as Rs6265, is a single nucleotide polymorphism (SNP) in the BDNF gene which influence the function of hypothalamus in relation to eating behaviour.32 The role of Val166Met polymorphism in regulation of eating behaviour was first determined in rodents, where chronic intra-cerebral-ventricular delivery of Val166Met was associated with increased body weight gain, whereas BDNF mutant mice were found to develop ED at young age whereby low-level of Val166Met were found to be to associated with restricted eating behaviour and development of AN.33 Likewise, similar trends have been found in human studies which supports the critical role of BDNF in regulation of energy balance.30

In humans, BDNF exhibits its action on the hypothalamus.30 The hypothalamus has an essential role in energy balance where it integrates hunger, satiety and monitors adiposity signals to inform energy status of the individual; and in response to these cues expression and secretion of hypothalamic peptides and neurotransmitters are elicited to determine caloric intake and energy utilization.34 Moreover, arcuate nucleus (Arc) is a hypothalamic nuclei which influences feeding behaviour, the Arc contains neuropeptide Y (NPY); an agonistic appetite-regulating neurone which induces eating. Increased level of Val166Met in the paraventricular nuclei suppresses elevation of NPY expression in the Arc, thereby preventing NPY-induced feeding.35,36

  • Serotonin 5-hydroxytryptamine-2A(5-HT2) receptor- 1438G/A

Serotonin 5-HT2A receptor is a subtype of serotonin 5-HT2 receptor group which are a family of G protein-coupled receptor (GPCR), located primarily in the neocortex, caudate nucleus, hippocampus and smooth muscles.37 Serotonin 5-HT2 regulates various central nervous system (CNS) physiological activities ranging from food intake, sleep cycle, cognition and emotional behaviours.38 Numerous studies have found that polymorphism in serotonin 5-HT2a to be involved in various psychiatric disorders such as obsessive compulsive disorder, depression and schizophrenia as well as in the regulation of the feeling of satiety.37 Consequently, polymorphism in 5-HT2a receptor is a key indicated in the physiopathology of AN. The genetic variation 1438G/A (also called rs6311), is a SNP in the human 5-HT2a receptor, which has been investigated for its role in eating disorders, personality traits and compulsive behaviours.39   

Genetic epidemiological studies have shown serotonin 5HT2 to be the main excitatory receptor subtype among the GPRCs which exerts its excitatory effects on various sites including smooth muscles of the gastrointestinal tract.40 Positron Emission Tomography (PET) scans are used to investigate the brain serotonin 5-HT2 receptor levels in patients with AN, where results have revealed presence of 1438G/A SNP to be associated with a decreased level of 5-HT2 receptor binding in various location of on the brain including in the hippocampus, amygdala and cingulate cortex.41 The amygdala and cingulate cortex are involved in emotional and autonomic response and disturbance of these regions have been associated with mood disorders such as depression, anxiety and compulsive behaviours – which are all the key risk factors for developing AN.41,42

  • 5-serotonin-transporter-linked polymorphism regions (5-HTTLPR)- S allele

5-HTTLPR is a dysfunctional repeat polymorphism region in SLC6A4 – a gene that encodes for the serotonin transporter.43 The serotonin transporter (5-HTT) is involved into similar functions as to 5-HT2A which includes a broad range of psychological traits and physical behaviours, as well as regulation of mood, sleep, sexual activity and appetite.44 Since the recognition of the polymorphism in 5-HTT its role has been extensively investigated in relation to various psychiatric disorders.6  

The 5-HTTLPR consists of two common alleles; S-allele and L-allele, where the S-allele is involved in regulation of the serotonin transporter reuptake system.44  Polymorphism of the S-allele is found to lead to reduce transcription efficiency for the 5-HTT gene, which in turn reduces expression of 5-HTT.45 The 5-HTT gene is encoded by 5-HTTLPR and the mechanism underlying S-allele induced AN is taught to be due to S-allele polymorphism exhibiting reduced expression of serotonin transporter, which means reduced reuptake of 5-HT from the synapse , thus ultimately leading to stronger psychological reaction to stressful situations than those with L-allele.44 Case-control studies have demonstrated a positive trend between increased frequency of the S-allele polymorphism in S-HTTLPR and incidence of a number of serotonin related psychological disorders including AN.45

  • Catechol-O-methyltransferase (COMT) – Val158Met

COMT is a methyl-transferase enzyme catalysing the transfer of methyl group from S-adenosylmethionin to catecholamine, which in turn activates dopamine in the prefrontal cortex (PFC).46 COMT metabolizes more than 60% of released dopamine in the brain, dopamine is the main neurotransmitter of the brain and consists of 5 receptors including dopamine D2 receptor (DRD2), which is a G-protein coupled auto-receptor that inhibits adenylyl activity.47 DRD2 is predominantly located in the caudate putamen, nucleus accumbens and striatum, consequently, these areas are involved in food-anticipatory behaviour, food administration, response to stressful stimuli, reward and motivation.48

Recent studies in Molecular Psychiatry have shown Val158Met SNP (also known as rs4680) to be the most common variation of the COMT gene, whereby a single G/A base-pair substitution (valine to methionine) lead to reduced activity of COMT.49 Therefore, COMT polymorphism, VAL158Met, influences cortical dopamine degradation, which in turn affects the concentration of dopamine in the prefrontal cortex. The VAL allele is associated with increased COMT enzyme activity and increased dopamine degradation than the Met allele of the COMT.46,50 The fluctuation of dopamine in the PFC and striatum influences essential cognitive process as well as physical behaviours associated with predisposition of AN.47   

Current Treatments  

The treatment of anorexia nervosa remains an incredible challenge despite the increased understanding of its pathophysiology and aetiology.3 The multifactorial risk factor nature of AN is the greatest threat to development of effective treatment for the condition, where studies have shown that approximately 50% of patients who receive treatment continue to remain below their expected body weight even several years after their treatment course.51,52 Despite the poor treatment outcomes for AN, researches have shown that majority of patients tend to benefit from the therapy to some extent.53

Weight restoration is emphasised by the current guidelines for AN treatment since the hallmark symptoms of AN are the results of starvation, therefore the initial focus of all treatment options are to restore weight; particularly for those patients with body weight <85% of their ideal weight.54 Various forms of psychotherapy and nutrition therapy are used in an attempt to prompt weight restoration. Since most patients are reluctant to comply with treatments, therefore enhance motivation techniques such as coercion as well as cognitive behaviour therapy (CBT) forms an essential part of the treatment.54 Additionally, educating patients and their families regarding the nature of the condition, such as the risk factors and the serious health consequences, as well as the effective treatment options available will raise their awareness and insight about the condition so they are able to make more informed lifestyle choices.55

Hospitalization is considered for certain patients, depending on their physiological and psychiatric status, for example, for a patient with a weight of more than 25% below the expected weight, those with severe psychiatric or medical conditions and children who are losing weight rapidly hospitalization is generally required.56 Hospital-based treatment of AN includes medical monitoring of the patient such as laboratory assessments, psychological support as well nutritional counselling from dietitians.57   

Methodology

Search strategy and selection criteria

The aim of this study is to determine to what extend genetic polymorphisms contributes towards development of anorexia nervosa. To identify the relevant studies, the electronic databases MEDLINE, PUBMED, EMBASE, PSYCHINFO, CINAHL and WEB OF SCIENCE were searched on February 2017. The initial search terms used were ‘anorexia nervosa’ ‘genetic’ ‘polymorphism’, once appropriate level of searches were reached, then a more specific focused key search terms were used including ‘anorexia nervosa’ ‘5-HT2A’ ‘1548G/A’ ‘Val158Met’ ‘BDNF’ ‘Val66Met’ ‘5HTTLPR’ COMT’ and ‘Val158Met’; thus identifying the most relevant studies. The inclusion criteria’s were then applied to further narrow down the search.  The criteria are shown in Table 3 and the results for the database search are highlighted in Figure 2, whereas Tables 4-7 presents the summary of the final 16 relevant studies after inclusion and exclusion criteria were applied.

Table 3. The criteria to establish final studies required for systematic review. The above inclusion and exclusion criteria were applied after search terms to select the relevant studies for the final review.

I excluded the studies that examines anorexia bulimia or studies on anorexia nervosa in combination with other conditions such as schizophrenia or any other psychiatric disorders as this will affect the primary aim of this review.

Figure 2. Flow chart of study selection process. This flow chart highlights the process of study selection demonstrating where and why studies were excluded from initial search of 13,169 to the final 16 studies after application of inclusion and exclusion criteria.

Table 4. A summary of the four studies investigating the role of BDNF polymorphism in AN. The table highlights the key information including study methodology and main findings of the studies used for the analysis of this review.58-61
Table 5. A summary of the three studies investigating the role of 5-HT2 receptor polymorphism in AN. The table highlights the key information including study methodology and main findings of the studies used for the analysis of this review.62-64
Table 6. A summary of the four studies investigating the role of COMT polymorphism in AN. The table highlights the key information including study methodology and main findings of the studies used for the analysis of this review.65-68
Table 7. A summary of the five studies investigating the role of 5-HTTLPR polymorphism in AN. The table highlights the key information including study methodology and main findings of the studies used for the analysis of this review.69-73 

Outcome Measures

This review used various criteria to determine the genetic link of anorexia nervosa as shown in Table 3. The primary study outcomes of each research is to determine association of genetic polymorphism with anorexia nervosa, the secondary outcomes are to elaborate the pathophysiology and mechanisms of the identified genes in relation to anorexia nervosa.

Data Extraction  

Variables extracted from each data included the followings: author name, year of publication, genes investigated, study methodology and key findings as illustrated in Tables 4-7. Moreover, genetic polymorphism in relation to anorexia nervosa was extracted to explain pathophysiology and aetiology of AN in relation to genetics. Additionally, details of each study were extracted such as number of participants, study design, duration of study, participant gender and age in order to critically review each study in light of credibility.

Data Analysis

From the objectives of this review the analysis could be divided into different sections focusing on separate genetic polymorphism which contribute to aetiology of anorexia nervosa. Theses genetic polymorphisms associated with AN consist of four types; serotonin transporter (5-HTTLPR), serotonin receptor (5-HT2), catechol-O-methyltransferase (COMT), and brain-derived neurotrophic factor (BDNF). Additionally, the review has categories pathophysiology, aetiology, epidemiology and prevalence into different sections to enable systematic review and evidence-based qualitative analysis of each data.

Results

Results for Objective 1

The aim of objective 1 was to investigate the link between BDNF gene promoter polymorphism-Val66Met and predisposition towards AN. To achieve the objective aim four studies were identified which altogether looked at 2,118 people, the study design varied amongst the researches; one study used pre-screening for BDNF gene polymorphism in patients who already had AN, whereas two studies used case-control comparing genotypes of AN patients against healthy group. The final study used long-term follow up cohort study, where a group of AN predisposed individuals with Val66Met SNP were followed up for six years to determine if they develop AN. The outcome measures also varied amongst the studies, ranging from ELISA method, BMI measure, serum BDNF count and PCR technique. all of the studies reported their findings descriptively in combination with quantitative report (Table 8).

Table 8.  A summary of the methodology and key findings of the four studies assessing the association between AN and Val166Met BDNF gene polymorphisms. As highlighted in the table, studies used various designs and outcome measure to determine the association between Val166Met BDNF gene polymorphism and development of AN. 58-61

The findings of all the four studies have shown BDNF gene polymorphism to be linked with development of anorexia nervosa to varies extents, although the study methodology and measure outcomes varied in most cases.58-61 For example, one case-control study shows average serum BDNF protein to positively correlate with BMI whereby a difference of 68 ng/ml were found between AN and obese individuals.59 Likewise, the randomly selected study shows over half of subjects with BDNF polymorphism to have lower BMI than the healthy subjects.62 Another case-control study measuring the frequency of Val166Met polymorphism found its prevalence to be higher (by 6%) in AN subjects than healthy controls.61 Similarly, the results of a six-year follow-up study shows that individuals who had the inheritance of Val166Met gene polymorphism to be 49% more likely to develop AN later in life than the healthy controls.60.62        

Results for Objective 2

 The aim of objective 2 was to investigate the link between 5-HT2 receptor gene polymorphism- 1438G/A and predisposition towards AN. A total of 3 studies were identified to achieve the objective aim, altogether the studies looked at 1020 subjects across seven different countries and included both genders. The study designs consist of population screening, family-based transmission disequilibrium and case-control modelling. The outcome measures for each study also varied, which included genotyping, DNA sample extraction analysis using PCR and clinical assessments (Table 9).


Table 9. A summary of the methodology and key findings of the three studies assessing the association between AN and 5-HT2 receptor polymorphism- 1438G/A. the studies used different study designs and measure outcomes to determine the association between 1438G/A polymorphism and predisposition towards AN. 62-64

The results of the comparisons studies shows the prevalence of 1438G/A polymorphisms to be higher in the AN subjects in comparisons to the healthy controls whereby a difference of 46% was found in on study62 and 22% in another study,64 between the two cohorts. Similarly, the screening study shows 1438G/A polymorphism to be present in 47% of AN subjects.63  

Results for Objective 3

The aim of objective 3 was to investigate the association between COMT gene polymorphism –Val158Met and predisposition towards AN. To achieve the objective aim four eligible studies were identified, altogether the studies investigated 2179 subjects using various case-control comparison methods (Table 10).

Table 10. A summary of the methodology and key findings of the four studies assessing the association between AN and COMT gene polymorphism Val1158Met. The table highlights key information of the methods for each stud including number of subjects, study design, measure outcomes and their overall findings. 65-68

The findings of all of the four studies shows various percentage association between presence of COMT Val158Met polymorphism and AN.65-68 The family-based study shows the highest percentage link association between AN and Val158Met polymorphism with a frequency of 68%; 66 whereas, a slightly lower linkage of 62% (56% higher than healthy controls) is found in one case-control study68 and 47% linkage (3 times higher than healthy controls) in another.67Likewise, the combined family trio shows 54% of AN subject to have the Val158Met Polymorphisms in comparison to 10.5% of the healthy controls.68

Results for Objective 4

The aim of objective 4 was to investigate the link between 5-HTTLPR gene polymorphism –S allele and predisposition towards AN. In order to achieve the objective aim five eligible studies were identified through world-wide web search, altogether the studies examined 1933 subjects. The study designs included 3 case-controls, a follow up study and a genotyping. The method of investigation and the outcomes of the studies reported varied amongst the studies as summarised in Table 11.  

Table 11. A summary of the methodology and key findings of the five studies assessing the association between AN and polymorphism S-allele in 5-HTTLPR gene.  As highlighted in the table, the five studies have used various forms of designs and outcome measures to determine an association link between S-allele of 5-HTTLPR gene and AN. 69-73

The association of S-allele polymorphism and development of AN has been supported in all five of these studies, where variable frequency of S-allele has been present in all the cases. For example, the cohort study have demonstrated a strong link of 65% between AN and presence of S-allele polymorphism,71 whereas follow up study has shown 60% of subjects with predisposed S-allele polymorphism to develop AN.69 Additionally, a combination of case-control study and 3 year followed up monitoring have shown S-allele frequency to increase by 17% which is associated with increased severity of AN from moderate to severe.72 Similarly, the 5-year follow up study have shown 3% of subjects with S-allele polymorphism to meet the DSM-V criteria for AN, in comparison to 0% of subjects with the healthy gene.73

Discussions

Objective 1 Analysis

Objective 1 assessed the association of the Val66Met polymorphism of the BDNF gene and development of anorexia nervosa. Three out of four studies confer strong susceptibility of Val166Met polymorphism in BDNF gene towards the development of AN.58,59,61 The method on investigations varied amongst the studies, for example, the case-control study measured average serum protein BDNF level and found that it positively correlates with BMI (a difference of 23ng/ml were found between AN subjects and healthy controls. On the other hand, screening study by Josep M et al used a combination of genotyping and case-control study to determine the difference in average serum BDNF between healthy controls and AN subjects – the findings supported the case-control study results whereby a positive correlation between BMI and serum BDNF levels were found.58,61 However, the final genotyping study showed a difference of 6% in serum BDNF level of healthy subjects in comparisons to AN subjects, thus indicating an insignificant relationship.60

The inconsistency of these findings are as a result of multiple-factors including variation in study designs and measure outcomes (Table 8). Additionally, the age, gender and nationalities of the subjects in each study varied, therefore all these co-founding factors makes it difficult to compare their findings and draw a logical conclusion.75 Furthermore, the studies failed to control extraneous variables, for example if the participants had other conditions that could potentially alter the results and thereby affect the validity of the findings. Additionally, two of the studies selected their sample size from specific cohort (Chinese origin from medical school, and Caucasian origin),76.77 therefore the samples are not representation of the general population and there is also a possibility of cultural bias.63 Nevertheless, the findings of the three studies provide a strong evidence to suggests that the average serum BDNF may potentially have a crucial role in the regulation of body weight.78

The Mechanisms

The role of BDNF in regulation of energy and appetite is due to its action on the hypothalamus.79 The hypothalamus governs central homeostatic actions including regulation of energy intake and feeding behaviour. BDNF is a widely abundant neurotrophin in the in the hypothalamus which signals through tropomyosin-related kinase (TrkB) receptor.80 There are several interconnected hypothalamic nuclei that influences eating behaviour including the arcuate nuclei (Arc), paraventricular nuclei (PVN), ventromedial nuclei (VMN) and lateral hypothalamus (LH). The concentration of BDNF is abundant in these hypothalamic regions, particularly in the VMN and Arc.79 The Arc contains neuropeptide Y (NPY) and proopiomelanocortin (POMO), which are two functionally distinct neurons that act as a feeding promotor and inhibitor, respectively. The mechanisms of actions in AN is thought that Val66Met polymorphism intensifies the action of TrkB on the POMO neuron, thereby causing a satiety effect despite the low energy intake.80 

Objective 2 Analysis

Objective 2 assessed the linkage between 5-HT2 receptor gene polymorphism- 1438G/A and predisposition towards AN, 3 studies were identified which altogether they looked at 1020 subjects. All of the three studies provides evidence for association of -1438G/A and AN, although the strength of linkage varies in each cases. For example, the finding of community-based screening showed -1438G/A polymorphism to be present in 54% of AN subjects in contrast to 8% of healthy subjects,62 similarly, the statistical analysis found 1438G/A to be present in 47% of AN subjects (in a total of 150 AN subjects).63 In contrast, the case-control study found 1438G/A polymorphism to have a weak associative role in AN with a presence of allele frequency of 24%.64 Overall, all the studies have shown that SNP 1438G/A is more common in AN subjects than healthy controls, therefore suggesting that 1438G/A polymorphism may have a potential link to development of AN.

All of these studies have used a large sample of participants, therefore it is very unlikely for the results to be false-positive.81 In addition to this, the subjects were selected randomly to avoid population bias, moreover, following the first stage of selections all the subjects completed a self-reporting health check questionnaire to ensure only eligible subjects are considered for the study (i.e. Only those with AN and not other health conditions that might interfere with the results).82  The major limitation of all these studies is the unequal proportion of female to male as almost 90% of subjects studied were female, this is a potential drawback as physiological difference can influence the findings.82 Additionally, the sample is not a true representation of the whole population, therefore it cannot be generalised, this potentially poses a great challenge for individualised therapies of AN in the future.81

The Mechanisms

Serotonin (5-HT) has several role in nervous system ranging from regulation of hormones, sleep, body-temperature, appetite and cognitive functions.83 The serotonin 5-HT2A receptor is a part of  G-protein-couple receptors (GPCR) family which is located in several brain regions (amygdala, neocortex and hippocampus) and is associated with regulation of mood, sleep cycle and appetite.84 Serotonin 5-HT2 is the main excitatory receptor of GPCR that exerts its effect of on various sites including smooth muscles of the GI tract. 5-HT2 receptor gene polymorphism 1438G/A weakens the excitatory action of 5-HT2, which means brain regions associated with regulation of mood, sleep, appetite is not activated adequately, consequently leading to mood disorders, anxiety, compulsive behaviours, reduced appetite and disturbance in sleep patterns – these are all the contributing factors for development of AN.84   

Objective 3 Analysis

Objective 3 assessed the association between COMT gene polymorphism –Val158Met and predisposition towards AN. Altogether four studies looked at a total of 2179 subjects from eight different country origins. Each study had different sample size and the participants varied by age and gender. There was a consistency in results across of all the four studies, as the findings show the presence of Val158Met polymorphism to be significantly higher in AN subjects in comparison to healthy controls.65-68 For example, family-based study of AN subjects revealed Val158Met to be present in 68% of the subjects, similarly, combined family trio and case-control shows the frequency of Val158Met to be 43.5% higher in AN group than the control.68

The significance of these findings could potentially be a false-positive result as two of the studies had a very small sample size, thus making the findings insignificant to generalise.82 Additionally, co-founding factors such as age, gender and ethnicity was not taken into consideration, thus further affecting validity of the findings.81 Furthermore, some of the studies relied on self-reporting questionnaires to collect information about the participants, this creates the risk of participant bias, as some subjects might be reluctant to disclose certain information about themselves (such as a health condition).82Another limitation of the findings are that none of the studies considered the multifactorial aetiological nature of AN, as evidence-based researches have shown psychological factors (such as stressful experiences) and personality traits contribute to development of AN.80 Overall, despite the limitations, the finding of these studies provide a strong association between Val158Met polymorphism and AN which requires further research with larger study samples and improved control-measures.

The Mechanisms

COMT is an important enzyme in monoamine metabolism, it degrades dopamine (DA) via methylation which in turn inhibits the biological action of dopamine notably in the prefrontal-cortex (PFC) and striatum.85 COMT polymorphism Val158Met is the most common variation of the COMT gene and this SNP is responsible for the reduced activity of COMT, thus affecting dopamine degradation in the PFC.86 Decreased levels of DA in the PFC is associated with increased risk of psychotic symptoms including anxiety, depression, impulsive behaviours and disturbance in appetite and sleep cycle, which are all implicated in the development of AN.87,88

Objective 4 Analysis

Objective 4 investigated the association of 5-HTTLPR gene polymorphism –S allele and predisposition towards AN. Altogether five studies were identified that assessed a total of 1933 subjects. All of the five studies shows the SNP S-allele in 5-HTTLPR gene to be associated with AN to various degrees. For example, the six-year followed up study confers a susceptibility risk of 60% for development of AN for individuals with S-allele polymorphism.69 Likewise, a case-control study shows the frequency of S-allele to be associated with severity of AN where after a long period of followed up as the frequency of the SNP increased, consequently, subjects reported higher rate of eating disorder behaviours as well as their BMI being decreased by 25%.71

Although the findings of these studies clearly indicates a correlation between 5-HTTLPR S-allele SNP and AN, however, it cannot be said for certainty that there is a causation between the two – since most of the studies failed to control extraneous variables and co-founding factors. For example, the genotyping study by Hinney A et al did not consider social and psychological risk factors of AN as well as mental health conditions, therefore, these poor study practice can potentially affect the credibility of the findings.89 Similarly, in the case-control studies the age and gender of the subjects varied, thereby making the comparison on the findings insignificant. In addition to this, the occurrence false-positive results are very likely in the case-control studies, because of population stratification, however, to counteract this effect; Jue Chen et al carried out a follow-up family-based study as an effective approach to confirm the findings.90 Overall, the significance of these findings provide a strong case for further research, despite the limitation of the studies.

The Mechanisms

Serotonin-transporter 5-HTT has an important role in transport of sodium ions in the extracellular compartment; the transporter bind to sodium ion then to serotonin, this enables the transport of serotonin from the synaptic cleft to presynaptic neurone.91 Therefore, 5-HTT functions by terminating the effects of serotonin and enables its recycling, ultimately allowing neuronal communications.92 The gene SLC6A4 encodes 5-HTT, variation of this gene results in 5-HTTLPR SNP which is a dysfunctional serotonin transporter associated with hyperactivity. PET scans of the brains of 5-HTTLPR SNP individuals have shown changes in the brain structure including the amygdala and anterior cingulate cortex, which are associated with mood disorders and personality traits, hence, contributing towards the risk factors of AN.92

Conclusion

Understanding the aetiology of AN in relation to genetics will provide a potential biomarker for pre-screening those individuals who are thought to be at risk of developing AN. Once the pre-screening identifies the pre-disposed subjects for AN, then early interventions and individualised treatments can be introduced to prevent the occurrence of the condition. Studies have shown that the earlier the diagnosis of AN the higher the compliance rate, whereby in some cases-control studies an improved compliance rate of 45% was found between six months diagnosis in comparison to 10 years.

Furthermore, understanding the extent genetic polymorphisms contributes towards the development of AN will ease the psychological pressures on the patients, as they will have a better understating of the cause of their behaviours and a greater insight into their condition.93 Additionally, understanding the condition at an early stage means individuals are in a better mental state to make informed decisions from early on before the condition progresses.94 However, genetic pre-screening does create an ethical dilemma, for example, how to prioritise the pre-screening, when to screen an individual and what appropriate action to take once pre-disposed genes are identified? Therefore, it is critical to consider the consequences of the pre-screening diagnostic for AN and implement appropriate interventions to ensure that the clinical benefits outweighs the ethical issues associated with pre-screening.     

In conclusion, the findings of the present review provide a strong evidence to suggest a significant association between the four-studied genetic polymorphism (Val66Met, 1438G/A, Val158Met and 5-HTTLPR gene -S allele) and predisposition towards the development of anorexia nervosa; whereby some studies finding a linkage of 68%. Nevertheless, as most studies failed to control the extraneous variables and co-founding factors, therefore, further studies with larger samples and appropriate monitoring is required to confirm the validity of the current review.

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