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The Role of Genetics in Obesity: What You Need to Know Before Surgery
Table of Contents
Introduction
Obesity has become a global health crisis, affecting millions of people worldwide and contributing to numerous health complications [1]. Whilst lifestyle factors such as diet and physical activity play a significant role in weight gain, research has increasingly highlighted the complex interplay between genetics and obesity [2]. As more individuals consider surgical interventions to combat severe obesity, understanding the genetic underpinnings of this condition has become crucial for both patients and healthcare providers.
Genes, the fundamental units of heredity, can significantly influence an individual’s predisposition to weight gain and fat distribution [3]. Some people may find it more challenging to maintain a healthy weight due to their genetic makeup, which can affect factors such as metabolism, appetite regulation, and fat storage. However, it’s essential to recognise that genetic predisposition doesn’t necessarily dictate destiny; rather, it interacts with environmental factors to influence obesity risk.
Recent advancements in genetic research have identified several genes strongly associated with obesity, such as FTO, MC4R, and POMC [4]. These discoveries have not only enhanced our understanding of the biological mechanisms underlying weight gain but have also opened new avenues for personalised treatment approaches. Additionally, rare genetic disorders like Prader-Willi syndrome and Bardet-Biedl syndrome can cause severe obesity, further highlighting the genetic component of this condition [5].
For individuals considering obesity surgery, understanding their genetic profile can be invaluable. Genetic factors may influence surgical outcomes, guide the selection of the most appropriate surgical technique, and inform post-operative care plans. As we move towards an era of precision medicine, integrating genetic information into obesity management strategies, including surgical interventions, holds promise for more effective and personalised treatments.
This article aims to elucidate the role of genetics in obesity, providing essential information for those contemplating surgical interventions. By exploring the interplay between genes and environment, discussing available genetic tests, and examining the implications for obesity surgery, we hope to empower readers with the knowledge needed to make informed decisions about their health and treatment options.
The Basics of Genetics and Obesity
What are genes?
Genes are the fundamental units of heredity, composed of DNA sequences that encode instructions for producing proteins, the building blocks of our bodies [6]. Each person inherits a unique combination of genes from their parents, which influences various traits, including those related to body weight and metabolism.
Within our cells, genes reside on structures called chromosomes. Humans typically have 23 pairs of chromosomes, with one set inherited from each parent. This genetic inheritance forms the basis of our biological predispositions, including our susceptibility to certain health conditions like obesity.
How genes influence body weight and fat distribution
The influence of genes on body weight and fat distribution is complex and multifaceted. Genetic factors can affect various physiological processes that contribute to weight regulation, including:
1. Metabolism: Genes can influence how efficiently our bodies convert food into energy and how quickly we burn calories at rest (basal metabolic rate).
2. Appetite regulation: Certain genes play a role in controlling hunger and satiety signals, affecting how much we eat and how often we feel hungry [7].
3. Fat storage and distribution: Genetic factors can determine where our bodies tend to store fat and how easily we accumulate or lose fat in different areas.
4. Response to diet and exercise: Our genes can influence how our bodies respond to different types of foods and physical activities, affecting weight loss or gain.
5. Hormonal balance: Genes involved in hormone production and regulation can impact weight, as hormones like insulin, leptin, and ghrelin play crucial roles in metabolism and appetite control.
It’s important to note that while genes can predispose individuals to obesity, they rarely act alone. Environmental factors, lifestyle choices, and gene-environment interactions all play significant roles in determining an individual’s weight [8].
The concept of genetic predisposition to obesity
Genetic predisposition to obesity refers to an increased likelihood of becoming obese due to inherited genetic factors. This predisposition doesn’t guarantee that a person will become obese, but it does mean they may be more susceptible to weight gain under certain environmental conditions.
Research has identified numerous genes associated with obesity risk. Some of the most well-studied include:
1. FTO (Fat Mass and Obesity-Associated) gene: Variations in this gene have been strongly linked to increased body mass index (BMI) and risk of obesity [9].
2. MC4R (Melanocortin 4 Receptor) gene: Mutations in this gene can lead to severe obesity, often beginning in childhood.
3. POMC (Pro-Opiomelanocortin) gene: Defects in this gene can result in early-onset obesity and adrenal insufficiency.
These genes, among others, can influence factors such as appetite, metabolism, and fat storage. However, it’s crucial to understand that having a genetic predisposition to obesity doesn’t mean obesity is inevitable. Lifestyle factors, including diet and physical activity, play a significant role in whether these genetic predispositions are expressed.
For individuals considering obesity surgery, understanding their genetic predisposition can be valuable. It can help explain why traditional weight loss methods may have been challenging and inform post-surgical care plans. For instance, patients with certain genetic variants might require more intensive dietary counselling or closer monitoring of nutritional status after surgery [10].
Moreover, as the field of obesity genetics advances, there’s potential for more personalised approaches to obesity treatment, including tailored surgical interventions based on an individual’s genetic profile. While we’re not yet at the point of routinely using genetic information to guide obesity surgery decisions, ongoing research in this area holds promise for more effective, individualised treatment strategies in the future.
Understanding the basics of genetics and its role in obesity is crucial for anyone considering surgical interventions. It provides context for why some individuals struggle more with weight loss than others and underscores the importance of comprehensive, personalised approaches to obesity management.
Key Genetic Factors in Obesity
Common genetic variants associated with obesity
Whilst obesity is a complex condition influenced by numerous factors, research has identified several common genetic variants that play a significant role in its development. These genetic variants, often referred to as single nucleotide polymorphisms (SNPs), can affect an individual’s susceptibility to weight gain and obesity.
1. FTO gene: The Fat Mass and Obesity-Associated (FTO) gene was one of the first to be strongly linked to obesity risk. Variants of this gene are associated with increased body mass index (BMI), body fat percentage, and waist circumference. Individuals carrying certain FTO variants may have a 20-30% higher risk of obesity compared to those without these variants [11].
2. MC4R gene: The Melanocortin 4 Receptor (MC4R) gene plays a crucial role in regulating energy balance and food intake. Mutations in this gene are the most common genetic cause of severe obesity that runs in families. People with MC4R mutations often experience increased hunger and reduced satiety, leading to overconsumption of food [12].
3. POMC gene: The Pro-Opiomelanocortin (POMC) gene is involved in the production of several hormones that regulate appetite and energy balance. Mutations in this gene can lead to severe, early-onset obesity, often accompanied by adrenal insufficiency and red hair colour.
Rare genetic disorders causing obesity
While common genetic variants contribute to obesity risk in the general population, certain rare genetic disorders can cause severe obesity, often beginning in childhood. These disorders are typically caused by mutations in single genes and can have profound effects on weight regulation.
1. Prader-Willi syndrome: This genetic disorder is characterised by weak muscle tone feeding difficulties in infancy, followed by excessive eating and obesity in later childhood. It’s caused by the loss of function of specific genes on chromosome 15 and affects approximately 1 in 10,000 to 30,000 people [13].
2. Bardet-Biedl syndrome: This is a rare genetic disorder that affects multiple body systems. Obesity is a primary feature, along with retinal degeneration, cognitive impairment, and extra fingers or toes. It’s caused by mutations in at least 14 different genes and affects about 1 in 140,000 to 160,000 people in North America and Europe.
Epigenetics and obesity
Epigenetics refers to changes in gene expression that don’t involve alterations to the DNA sequence itself. These changes can be influenced by environmental factors and can be passed down through generations. In the context of obesity, epigenetic modifications can affect how genes related to metabolism and fat storage are expressed.
Several environmental factors can induce epigenetic changes that influence obesity risk:
1. Maternal nutrition: A mother’s diet during pregnancy can affect her child’s epigenetic profile, potentially influencing their future risk of obesity.
2. Early life experiences: Factors such as stress or overfeeding in early childhood can lead to epigenetic changes that affect long-term weight regulation.
3. Diet and lifestyle: Certain foods and physical activity patterns can induce epigenetic changes that influence metabolism and fat storage.
Understanding these epigenetic mechanisms is crucial for developing more effective obesity prevention and treatment strategies. For instance, research has shown that weight loss interventions, including bariatric surgery, can lead to epigenetic changes that may help maintain weight loss in the long term [14].
For individuals considering obesity surgery, understanding these key genetic factors is important for several reasons:
1. It can help explain why traditional weight loss methods may have been challenging.
2. It can inform expectations about surgical outcomes and the potential need for additional support.
3. It may guide post-surgical care plans, including nutritional and behavioural interventions.
4. In the future, it may help in tailoring surgical approaches based on an individual’s genetic profile.
As our understanding of obesity genetics continues to evolve, it’s likely that genetic and epigenetic information will play an increasingly important role in personalising obesity treatments, including surgical interventions [4].
The Interplay Between Genetics and Environment
Gene-environment interactions
The development of obesity is not solely determined by genetics or environment alone but rather by the complex interplay between these factors. This interaction, known as gene-environment interaction, explains why individuals with similar genetic predispositions may have different outcomes depending on their lifestyle and environment.
Gene-environment interactions in obesity can manifest in various ways:
1. Dietary responses: Some genetic variants may influence how an individual’s body responds to different types of diets. For instance, people with certain variants of the FTO gene may be more susceptible to weight gain when consuming a high-fat diet [15].
2. Physical activity effects: Genetic factors can influence how effectively exercise contributes to weight loss or maintenance. Some individuals may see more significant benefits from exercise due to their genetic makeup.
3. Stress responses: Certain genes may modulate the relationship between stress and weight gain, with some individuals being more prone to stress-induced eating or metabolic changes.
Understanding these interactions is crucial for developing personalised approaches to obesity prevention and treatment, including tailored dietary and lifestyle recommendations based on an individual’s genetic profile.
Lifestyle factors that can “activate” genetic predispositions
While genetic predispositions to obesity exist, they often require specific environmental conditions to be “activated” or expressed. Several lifestyle factors can interact with genetic risk to increase the likelihood of obesity:
1. Sedentary behaviour: A lack of physical activity can exacerbate the genetic risk for obesity. Studies have shown that the effect of obesity-related genes is stronger in individuals with sedentary lifestyles compared to those who are physically active [16].
2. High-calorie diets: Consumption of energy-dense foods, particularly those high in sugar and saturated fats, can amplify the genetic risk for obesity. The abundance and accessibility of such foods in modern environments have been linked to the rising prevalence of obesity.
3. Sleep deprivation: Poor sleep patterns can interact with genetic factors to increase obesity risk. Some studies suggest that the effect of certain obesity-related genes is stronger in individuals who get insufficient sleep.
4. Chronic stress: Prolonged stress can lead to hormonal changes that interact with genetic factors to promote weight gain. This interaction may be particularly relevant in our fast-paced, high-stress modern society.
The role of diet and exercise in managing genetic risk
Despite genetic predispositions, lifestyle modifications remain crucial in managing obesity risk. Diet and exercise play vital roles in mitigating genetic susceptibility to obesity:
1. Balanced diet: Adopting a balanced, nutrient-rich diet can help manage weight even in individuals with a high genetic risk for obesity. Some studies suggest that adherence to a Mediterranean-style diet may attenuate the effect of obesity-related genes [17].
2. Regular physical activity: Engaging in regular exercise can significantly reduce the impact of genetic risk on BMI and obesity. Even moderate levels of physical activity have been shown to blunt the effect of obesity-related genetic variants.
3. Personalised nutrition: Emerging research in nutrigenomics suggests that tailoring diets based on an individual’s genetic profile may enhance weight loss efforts. While this field is still developing, it holds promise for more effective, personalised approaches to weight management.
4. Behavioural interventions: Cognitive-behavioural strategies can help individuals develop healthier eating habits and lifestyle patterns, which can be particularly beneficial for those with genetic predispositions to obesity.
For individuals considering obesity surgery, understanding the interplay between genetics and environment is crucial. While surgery can be an effective tool for weight loss, long-term success often depends on adopting and maintaining healthy lifestyle habits. Patients with certain genetic predispositions may require more intensive post-surgical support in areas such as dietary management and physical activity [18].
Moreover, recognising the role of gene-environment interactions can help set realistic expectations for surgical outcomes. While surgery can lead to significant weight loss, the interplay between an individual’s genes and their post-surgical environment will influence long-term results.
As our understanding of gene-environment interactions in obesity continues to grow, it’s likely that pre-surgical assessments and post-surgical care plans will increasingly incorporate genetic information. This could lead to more personalised approaches to obesity surgery, with interventions tailored to an individual’s genetic risk profile and environmental factors [19].
Genetic Testing for Obesity
Types of genetic tests available
Genetic testing for obesity has advanced significantly in recent years, offering individuals and healthcare providers valuable insights into genetic predispositions to weight gain. Several types of genetic tests are available:
1. Single gene tests: These focus on specific genes known to be associated with severe, early-onset obesity, such as mutations in the MC4R or POMC genes. These tests are typically used when a rare genetic disorder is suspected.
2. Panel tests: These examine multiple genes associated with obesity risk, metabolism, and related conditions. They can provide a broader picture of an individual’s genetic susceptibility to weight gain.
3. Genome-wide association studies (GWAS): While not typically used in clinical settings, GWAS have been crucial in identifying common genetic variants associated with obesity risk in large populations [20].
4. Direct-to-consumer tests: Some companies offer genetic tests directly to consumers, which may include information about obesity risk. However, these tests often have limitations and should be interpreted cautiously.
Pros and cons of genetic testing
Genetic testing for obesity can offer valuable insights, but it’s important to consider both the benefits and limitations:
Pros:
1. Personalized risk assessment: Genetic testing can provide individuals with information about their personal risk for obesity, which may motivate lifestyle changes.
2. Tailored interventions: Understanding genetic predispositions can help healthcare providers develop more personalised treatment plans, including specific dietary or exercise recommendations.
3. Early intervention: For individuals with genetic variants associated with severe obesity, early identification can lead to prompt intervention and management.
Cons:
1. Psychological impact: Learning about genetic risk factors for obesity may cause anxiety or a sense of fatalism in some individuals.
2. Limitations of current knowledge: Our understanding of obesity genetics is still evolving, and current tests may not capture all relevant genetic factors.
3. Potential misinterpretation: Without proper guidance, individuals may misinterpret genetic test results, leading to unnecessary worry or false reassurance.
4. Privacy concerns: Genetic information is highly personal, and there are concerns about data privacy and potential discrimination based on genetic information [21].
Interpreting genetic test results
Interpreting genetic test results for obesity requires careful consideration and often the expertise of healthcare professionals:
1. Risk assessment: Genetic test results typically provide information about relative risk – how an individual’s risk compares to the general population. It’s crucial to understand that increased genetic risk doesn’t guarantee obesity development.
2. Context is key: Genetic risk should be interpreted in the context of an individual’s overall health, family history, and lifestyle factors. A high genetic risk doesn’t negate the importance of environmental factors in obesity development.
3. Actionable insights: The most valuable genetic information is that which can inform actionable steps, such as specific dietary modifications or targeted preventive measures.
4. Limitations of prediction: Current genetic tests cannot precisely predict an individual’s future weight or body composition. They provide probabilistic information about risk, not certainty about outcomes.
5. Evolving science: As our understanding of obesity genetics continues to advance, the interpretation of genetic test results may change over time [22].
For individuals considering obesity surgery, genetic testing may offer additional insights:
1. Surgical planning: Genetic information might inform the choice of surgical procedures or help predict potential outcomes. For instance, certain genetic variants have been associated with greater weight loss after bariatric surgery [18].
2. Post-surgical care: Understanding genetic predispositions can help tailor post-surgical dietary and lifestyle recommendations, potentially improving long-term outcomes.
3. Managing expectations: Genetic information can help set realistic expectations for surgical outcomes, recognising that genetic factors may influence the degree of weight loss and weight maintenance after surgery.
4. Identifying comorbidities: Genetic testing might reveal predispositions to obesity-related comorbidities, allowing for more comprehensive pre-surgical evaluation and post-surgical monitoring.
While genetic testing can provide valuable insights, it’s important to remember that obesity is a complex condition influenced by multiple factors. Genetic information should be considered as one piece of a larger puzzle, informing but not determining treatment decisions. As the field of obesity genetics continues to advance, it’s likely that genetic testing will play an increasingly important role in personalizing obesity treatment, including surgical interventions [4].
Genetic Testing for Obesity
How genetic factors may influence surgery outcomes
Genetic factors can play a significant role in determining the outcomes of obesity surgery. Understanding these genetic influences is crucial for both patients and healthcare providers when considering surgical interventions:
1. Weight loss variability: Studies have shown that genetic variants can influence the amount of weight loss achieved after bariatric surgery. For instance, variants in the FTO gene have been associated with differences in post-surgical weight loss outcomes [18].
2. Metabolic improvements: Certain genetic factors may predict the degree of improvement in obesity-related metabolic conditions, such as type 2 diabetes, following surgery.
3. Nutrient absorption: Genetic variations can affect how the body absorbs and metabolises nutrients post-surgery, potentially influencing the risk of nutritional deficiencies.
4. Appetite regulation: Genes involved in appetite control may influence eating behaviours after surgery, affecting long-term weight maintenance.
Tailoring surgical approaches based on genetic profiles
As our understanding of obesity genetics advances, there’s growing potential to personalise surgical approaches based on an individual’s genetic profile:
1. Procedure selection: Genetic information might help guide the choice between different surgical procedures (e.g., gastric bypass vs. sleeve gastrectomy) based on predicted outcomes.
2. Risk stratification: Genetic profiling could help identify patients at higher risk of complications or suboptimal outcomes, allowing for more intensive pre- and post-surgical support.
3. Pharmacogenomics: Genetic data may inform the use of adjunct medications before or after surgery to enhance outcomes or mitigate risks.
4. Nutritional planning: Understanding an individual’s genetic predispositions could help tailor post-surgical nutritional recommendations to prevent deficiencies and optimise weight loss [13].
Potential for personalized post-surgery care plans
Genetic information can be valuable in developing personalised post-surgery care plans:
1. Dietary interventions: Genetic variants associated with nutrient metabolism can guide dietary recommendations. For example, individuals with certain genetic profiles might benefit from specific macronutrient ratios or particular types of dietary fats.
2. Exercise prescriptions: Genetic factors influencing response to different types of physical activity could inform personalised exercise plans to maximise weight loss and metabolic health improvements.
3. Behavioural support: Understanding genetic predispositions to eating behaviours or addictive tendencies could help tailor cognitive-behavioural interventions for better long-term outcomes.
4. Supplementation strategies: Genetic variations affecting nutrient absorption or metabolism could guide personalised supplementation plans to prevent deficiencies common after bariatric surgery.
5. Follow-up intensity: Patients with genetic profiles suggesting a higher risk of weight regain or complication might benefit from more frequent or intensive follow-up care [28].
While the integration of genetic information into obesity surgery protocols is still evolving, it holds significant promise for improving outcomes. However, it’s crucial to remember that genetics is just one factor among many that influence surgical success. Environmental factors, adherence to post-surgical recommendations, and overall health status remain critical determinants of outcomes.
Moreover, the field of obesity genetics is rapidly advancing, and our understanding of how specific genetic variants influence surgical outcomes is continually refining. As such, genetic information should be considered as part of a comprehensive assessment rather than a sole determinant of surgical decisions or post-operative care plans.
For patients considering obesity surgery, discussing genetic factors with healthcare providers can provide valuable insights. While genetic testing is not routinely required before bariatric surgery, it may be recommended in certain cases, particularly for individuals with early-onset severe obesity or strong family history of obesity-related conditions.
Looking ahead, ongoing research in this field promises to further refine our ability to predict and optimise surgical outcomes based on genetic profiles. Large-scale studies combining genetic data with detailed information on surgical outcomes are helping to identify new genetic markers of surgical success and refine our understanding of known genetic influences [25].
As we move towards an era of precision medicine in obesity treatment, the integration of genetic information with other clinical and lifestyle factors holds the potential to significantly enhance the effectiveness and safety of obesity surgery, leading to more personalised and successful interventions for individuals struggling with severe obesity [4].
Genetic Testing for Obesity
Emerging gene therapies
The field of gene therapy holds significant promise for the treatment of obesity, particularly for cases with strong genetic components:
1. Gene editing: CRISPR-Cas9 and other gene-editing technologies are being explored as potential tools to correct obesity-causing genetic mutations. While still in the early stages, this approach could potentially offer a ‘cure’ for certain genetic forms of obesity [26].
2. Gene silencing: RNA interference (RNAi) techniques are being investigated to suppress the expression of genes that promote obesity. This approach could potentially mitigate the effects of obesity-promoting genetic variants.
3. Gene activation: Conversely, researchers are exploring ways to activate genes that protect against obesity or promote energy expenditure. This could involve using engineered transcription factors or other molecular tools to enhance the expression of beneficial genes.
While these approaches show promise in preclinical studies, significant challenges remain in translating them into safe and effective human therapies. Ethical considerations and long-term safety concerns will need to be carefully addressed as these technologies advance.
Pharmacogenomics in obesity treatment
Pharmacogenomics, the study of how genetic variation affects drug response, is poised to revolutionise obesity treatment:
1. Personalised medication selection: Genetic profiling could help predict which anti-obesity medications are likely to be most effective for each individual, minimising trial-and-error approaches [22].
2. Dosage optimisation: Genetic factors influencing drug metabolism could inform personalised dosing strategies, maximising efficacy while minimising side effects.
3. Novel drug targets: Ongoing genetic research continues to uncover new molecular pathways involved in obesity, potentially leading to the development of novel, more targeted obesity medications.
4. Predicting side effects: Genetic testing might help identify individuals at higher risk of adverse reactions to specific obesity medications, allowing for more informed treatment decisions.
As our understanding of obesity genetics grows, it’s likely that pharmacogenomic approaches will become increasingly integrated into obesity treatment protocols, including pre-and post-surgical care.
Potential for precision medicine approaches
The future of obesity treatment lies in precision medicine – tailoring prevention and treatment strategies to each individual’s unique genetic, environmental, and lifestyle factors:
1. Comprehensive genetic profiling: As genetic testing becomes more affordable and accessible, comprehensive genetic risk assessments for obesity and related conditions may become routine in clinical practice [27].
2. Integration of multi-omics data: Beyond genetics, the integration of other ‘omics’ data (e.g., proteomics, metabolomics, microbiomics) could provide a more complete picture of an individual’s obesity risk and potential treatment responses.
3. AI-driven treatment planning: Advanced algorithms and machine learning techniques could help process complex genetic and clinical data to generate highly personalised treatment recommendations.
4. Lifestyle interventions: Precision approaches to diet and exercise recommendations based on genetic profiles could enhance the effectiveness of non-surgical obesity interventions.
5. Surgical decision-making: In the context of obesity surgery, precision medicine approaches could inform decisions about surgical timing, technique selection, and post-operative care strategies [24].
The move towards precision medicine in obesity treatment holds great promise, but also presents challenges. These include the need for large-scale, diverse genetic studies to improve our understanding of obesity genetics across different populations, as well as the development of robust, clinically validated tools for interpreting complex genetic data.
Moreover, as genetic and precision medicine approaches become more prevalent, there will be an increasing need for healthcare providers to be well-versed in genetics and its clinical applications. This may necessitate additional training for current practitioners and changes to medical education curricula.
Ethical considerations will also be paramount as these technologies advance. Issues of genetic privacy, potential genetic discrimination, and equitable access to genetic testing and precision medicine approaches will need to be carefully addressed [21].
For individuals considering obesity surgery, these future directions highlight the importance of staying informed about advancing treatment options. While many of these approaches are still in development, they underscore the rapidly evolving nature of obesity treatment and the increasing potential for more effective, personalised interventions.
As research progresses, it’s likely that genetic considerations will play an increasingly important role in all aspects of obesity management, from prevention strategies to surgical interventions and post-treatment care. This evolution towards more personalised, genetics-informed approaches holds the promise of improved outcomes and quality of life for individuals struggling with obesity.
Conclusion
The role of genetics in obesity is complex and multifaceted, offering crucial insights for individuals considering obesity surgery. Understanding one’s genetic predispositions can inform treatment decisions, set realistic expectations, and guide post-surgical care strategies [4].
As we’ve explored, obesity results from an intricate interplay between genetic, environmental, and lifestyle factors. While genetic testing can provide valuable information about individual risk and potential treatment responses, it’s important to remember that genes are not destiny. Lifestyle modifications, including diet and exercise, remain cornerstone interventions in managing obesity, even for those with high genetic risk [8].
For those contemplating obesity surgery, genetic insights can help tailor surgical approaches and post-operative care plans. However, the decision to undergo surgery should be made in consultation with healthcare providers, considering a comprehensive range of factors beyond genetics alone.
Looking ahead, the field of obesity genetics promises exciting developments. From gene therapies to precision medicine approaches, future treatments may offer more personalised and effective interventions [28]. As research progresses, it’s likely that genetic considerations will play an increasingly important role in all aspects of obesity management.
Ultimately, while genetics provides valuable insights, successful obesity management—surgical or otherwise—requires a holistic approach that considers genetic, environmental, and personal factors in concert.
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