Overview of Multifactorial Disorders

Multifactorial disorders are diseases that arise from the interaction of multiple genetic and environmental factors. They encompass a broad spectrum of common health problems, such as schizophrenia, diabetes, asthma, depression, high blood pressure, Alzheimer's, obesity, epilepsy, heart disease, hypothyroidism, clubfoot, cancer, birth defects, and even dandruff. Unlike single-gene disorders that follow Mendel's laws of inheritance, multifactorial disorders have complex and obscure inheritance patterns that require statistical analysis. The mechanisms of multifactorial disorders involve various aspects of genetics, such as gene variants, polymorphisms, epigenetics, and gene-environment interactions. The risk of developing multifactorial disorders is influenced by the combination of genetic factors, environmental factors, and complex factors (such as overweight), which may have different effects on different diseases. The diagnosis and treatment of multifactorial disorders are challenging because the specific causes of these diseases remain elusive and each individual may have a different situation. Therefore, the prevention and management of multifactorial disorders need to consider the individual's genetic background, lifestyle, environmental exposure, and other factors, as well as the possible interactions among them.

Classification and Examples of Multifactorial Disorders

Multifactorial disorders can be classified according to different criteria, such as disease type, affected organ, age of onset and so on. Classified by disease type, several common multifactorial disorders include metabolic disease, cardiovascular disease, cancer, neuropsychiatric disease, and birth defects.

• Metabolic Disease

Metabolic diseases are a group of diseases caused by abnormalities in metabolic pathways or regulatory mechanisms, including metabolic disorders, endocrine disorders, malnutrition, etc. Metabolic diseases are usually multifactorial, that is, they are influenced by both genetic and environmental factors.

For example, metabolic syndrome is a multifactorial disease with multiple risk factors caused by insulin resistance accompanied by abnormal fat deposition and function. It has a combination of risk factors for coronary heart disease as well as diabetes, fatty liver, and several cancers. The diagnostic criteria for metabolic syndrome include: increased waist circumference, high blood pressure, high blood sugar, high triglycerides, and low high-density lipoprotein cholesterol. The treatment of metabolic syndrome is mainly to improve lifestyle, such as by reducing weight, increasing exercise, controlling diet, etc., to reduce insulin resistance and cardiovascular risk. There is currently no gene therapy program for metabolic syndrome, but there are some gene therapy trials for its related factors in progress, such as angiotensin-converting enzyme 2 (ACE2) gene therapy for hypertension.

As another example, non-alcoholic fatty liver disease (NAFLD) is a liver injury caused by excessive accumulation of fat in the liver, which may develop into non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, and liver cancer. The occurrence of NAFLD is related to many factors, such as genetics, diet, weight, insulin resistance, etc. The diagnosis of NAFLD mainly relies on imaging and histological examination. The treatment of NAFLD is mainly to improve lifestyle, such as by reducing weight, increasing exercise, controlling diet, etc., to reduce liver lipid deposition and oxidative stress. There is currently no gene therapy program for NAFLD, but there are some gene therapy trials for its related factors in progress, such as transforming growth factor β1 (TGF-β1) gene therapy for NASH.

Fig.1 The Influencing Factors of NAFLD and Its Possible Consequences. (Zarghamravanbakhsh, 2021)

In addition to the above two more common metabolic diseases, there are many other types of metabolic diseases, such as hypercholesterolemia, hyperthyroidism, hypothyroidism, pituitary insufficiency, Cushing’s syndrome, etc. These metabolic diseases are also multifactorial, that is, they are influenced by both genetic and environmental factors. The diagnosis and treatment methods for these metabolic diseases vary depending on the specific situation and need to be evaluated and selected accordingly. There are also some gene therapy trials for these metabolic diseases or their related factors in progress, such as low-density lipoprotein receptor (LDLR) gene therapy for hypercholesterolemia.

• Cardiovascular Disease

Cardiovascular diseases refer to a group of diseases that affect the heart and blood vessels, including coronary heart disease, hypertension, heart failure, arrhythmias, atherosclerosis, etc. The occurrence and development of these diseases are influenced by multiple factors, including genetic and environmental factors. Genetic factors refer to the risk associated with gene mutations or polymorphisms; environmental factors refer to the risk associated with lifestyle, diet, smoking, alcohol, pollution, infection, etc. These factors may interact or synergize with each other, leading to the complexity and diversity of cardiovascular diseases. The common symptoms of cardiovascular diseases include chest tightness, chest pain, shortness of breath, palpitations, dizziness, nausea, vomiting, etc. These symptoms may lead to serious consequences such as myocardial ischemia, myocardial infarction, cardiac arrest, cardiogenic shock, etc. Cardiovascular diseases are one of the main causes of death worldwide and a major cause of disability and poverty.

The treatment plans for cardiovascular diseases mainly include drug therapy, interventional therapy, and surgery. Drug therapy mainly aims to control blood pressure, blood lipids, blood sugar, and other risk factors, improve cardiac function, and relieve symptoms. Interventional therapy mainly aims to dilate or support blocked or narrowed blood vessels by using devices such as catheters or stents to restore blood flow. Surgery mainly aims to reconstruct or replace damaged or defective cardiac structures or tissues by means of bypass or transplantation. Gene therapy is a novel method that uses genes or gene vectors to treat or prevent genetic or non-genetic cardiovascular diseases. Gene therapy can be divided into two major categories: somatic gene therapy and germline gene therapy. Somatic gene therapy refers to transfecting normal or modified genes into specific cells or tissues in the patient's body to achieve the purpose of repairing or enhancing function. Germline gene therapy refers to transfecting normal or modified genes into reproductive cells or embryos in the patient's body to achieve the purpose of changing the genetic information of offspring. At present, gene therapy is mainly applied in several aspects of the field of cardiovascular diseases: monogenic hereditary cardiovascular diseases, polygenic or multifactorial cardiovascular diseases, and immune-related cardiovascular diseases.

• Cancer

Cancer is a multifactorial genetic disease, which refers to a disease in which abnormal cell proliferation is caused by the joint action of multiple genetic factors and environmental factors (such as ultraviolet rays, cigarettes, and viruses). Cancer is the second-leading cause of death worldwide, accounting for nearly one in six deaths. There are many types of cancer, and different types of cancer have different causes, symptoms, and treatment options. Take breast cancer as an example. Breast cancer is one of the most common malignant tumors in women, and its occurrence is related to factors such as heredity, hormones, and lifestyle. The main symptoms of breast cancer are lumps in the breast, skin changes, nipple discharge, or inversion. The diagnosis of breast cancer mainly relies on breast examination, imaging tests, and a biopsy. The treatment plan for breast cancer is formulated according to factors such as the patient's age, tumor type, stage, and receptor status and generally includes surgery, radiation therapy, chemotherapy, endocrine therapy, and targeted therapy.

Gene therapy is a method of using genes or gene carriers to treat or prevent hereditary or non-hereditary diseases. There are several approaches to the application of gene therapy to breast cancer. Gene replacement therapy is the introduction of normal or repaired genes into cells where the missing or mutated gene resides to restore normal function. For example, introducing normal BRCA1/BRCA2 genes into breast cancer cells that carry mutations in these genes enhances the cells' ability to repair DNA damage. Gene knockout therapy is the use of specific nucleases (such as CRISPR/Cas9) to remove oncogenes or genes that promote tumor growth and metastasis from cells to inhibit tumor development. For example, CRISPR/Cas9 was introduced into breast cancer cells overexpressing HER2 to knock out the HER2 gene, thereby reducing tumor aggressiveness. Suicide gene therapy for breast cancer is a method that introduces a gene that can induce cell apoptosis (suicide) under specific conditions into breast cancer cells, to eliminate the tumor. For example, HSV-TK is an enzyme that can convert a nontoxic antiviral drug (such as ganciclovir) into a toxic metabolite, thereby killing the cell. When the HSV-TK gene is introduced into breast cancer cells that overexpress HER2, and the patient takes ganciclovir, the HER2-positive breast cancer cells will be specifically killed, while normal cells and HER2-negative breast cancer cells will not be affected. This is a selective suicide gene therapy method that targets HER2-positive breast cancer.

• Neuropsychiatric Disease

Neuropsychiatric diseases are a group of diseases that affect human psychology, emotion, cognition, and behavior, including depression, anxiety, autism spectrum disorder (ASD), schizophrenia (SCZ), attention-deficit/hyperactivity disorder (ADHD), bipolar disorder, obsessive-compulsive disorder, Tourette syndrome, and others. The occurrence and development of these diseases involve multiple factors, including genetics, environment, psychology, society, etc. Among them, genetic factors mainly include parental age, de novo mutations, gene polymorphisms, and epigenetic mechanisms. Environmental factors mainly include prenatal exposure, infection, nutrition, toxins, stress, and trauma. Psychological and social factors mainly include personality, emotion regulation, family relationships, education level, social support, and cultural background.

Due to the complexity and heterogeneity of neuropsychiatric diseases, there is no single diagnostic method or treatment plan that can apply to all patients. Generally speaking, diagnosing neuropsychiatric diseases requires a combination of clinical manifestations, psychological assessment, biochemical testing, imaging examination, and genetic testing. Treating neuropsychiatric diseases requires a personalized approach based on the specific situation of the patient, using methods such as drug therapy, psychotherapy, behavioral therapy, rehabilitation training, and social support. Gene therapy is a method that uses genes or gene vectors to repair or replace abnormal genes, thereby improving or curing related diseases. In the field of neuropsychiatric diseases, gene therapy mainly targets diseases that have clear genetic defects or molecular targets, such as ASD, SCZ, and ADHD. Currently, gene therapy is still in the experimental stage and has not been widely used in clinical practice. The main challenges of gene therapy include safety, efficacy, ethics, and feasibility.

• Birth Defects

Congenital heart disease (CHD) is a group of diseases that involve defects in the structure of the heart, including the walls, valves, arteries, and veins of the heart. CHD is one of the most common congenital defects, affecting about 1.5 million babies every year at birth. CHD is related to various factors, including gene mutations, chromosomal abnormalities, maternal infections or exposure to harmful substances during pregnancy, poor nutrition during pregnancy, and so on. The severity of CHD varies; some may not affect normal life, while others may lead to heart failure, arrhythmias, infections, or other complications. The main symptoms of CHD include shortness of breath, cyanosis, chest pain, palpitations, fatigue, and so on.

Fig.2 Physiological Mechanism of Congenital Heart Defect Prognosis & Diagnosis. (Siddiqui, 2021)

The treatment options for CHD depend on the specific type and severity of the disease. Some may not require treatment or only need medication. Some may require surgery or interventional treatment. Surgery or interventional treatment can repair or improve the defects in the heart structure, thereby improving the quality of life and prognosis of patients. Gene therapy is a method that uses genes or gene vectors to treat or prevent genetic or acquired diseases. Currently, gene therapy for CHD is still in its infancy stage, mainly focusing on animal models and the cellular level. Some gene therapy strategies include using gene editing techniques to correct pathogenic gene mutations, using gene transfer techniques to increase the expression of protective genes, using stem cell techniques to promote myocardial regeneration, and so on. However, gene therapy for CHD still faces many challenges and barriers, such as safety, efficacy, and ethics.

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