Genetics Of Pulmonary Disorders 2023-2024 PDF

GENETICS OF PULMONARY DISORDERS DR.İLTER GÜNEY MARMARA UNIVERSITY SCHOOL OF MEDICINE DEPARTMENT OF MEDICAL GENETICS 2023-2024 OUTLINE INTRODUCTION DISEASES ALPHA-1-ANTITRYPSIN DEFICIENCY CYSTIC FIBROSIS ASTHMA LUNG CARCINOMA INT...

GENETICS OF PULMONARY DISORDERS DR.İLTER GÜNEY MARMARA UNIVERSITY SCHOOL OF MEDICINE DEPARTMENT OF MEDICAL GENETICS 2023-2024 OUTLINE INTRODUCTION DISEASES ALPHA-1-ANTITRYPSIN DEFICIENCY CYSTIC FIBROSIS ASTHMA LUNG CARCINOMA INTRODUCTION The respiratory system plays a vital role in delivering oxygen to the body — fuel for all the body's functions. It also * removes carbon dioxide waste, * eliminates toxic waste, * regulates temperature, * stabilizes blood acid-alkaline balance (pH). The lungs are the largest part of the respiratory system and have both "respiratory" and "nonrespiratory" functions. * The respiratory function involves gas exchange — the transfer of oxygen from the air into the blood and the removal of carbon dioxide from the blood. * Non-respiratory lung functions are mechanical, biochemical, and physiological. INTRODUCTION The lungs - provide a defense against bacterial, viral and other infectious agents - remove various metabolic waste products, control the flow of water, ions, and large proteins across its cellular structures, manufacture a variety of essential hormones and chemical agents that have important biological roles. INTRODUCTION Respiratory diseases can arise from a number of causes Inhalation of toxic agents, accidents, and harmful lifestyles, such as smoking Infections Genetic factors Anything else that affects lung development, either directly or indirectly, can cause respiratory symptoms. INTRODUCTION Genetics and Respiratory Diseases : Hereditary lung diseases can affect * airways (asthma, COPD, cystic fibrosis and primary ciliary dyskinesia), * parenchyma (pulmonary fibrosis, Birt Hogg Dube syndrome and tuberous sclerosis) * vasculature (hereditary heamorrhagic telangiectasia) of the lung. Such conditions include simple monogenic disorders such as Kartagener syndrome and α1-antitrypsin, wherein mutations of critical genes are sufficient to induce well‐defined disease phenotypes.. INTRODUCTION Genetics and Respiratory Diseases : However, many are complex genetic traits in which inheritance subtly affects pathogenesis, for example asthma and idiopathic pulmonary fibrosis. A greater understanding of the genetic basis of pulmonary conditions has provided new insights into their underlying pathophysiology and helped in some cases to shed light on more common sporadic forms. Importantly, the identification of causative genes has also enabled prenatal diagnosis and genetic counselling to be introduced for many diseases Systems biology approaches to identify developmental bases for lung diseases Soumyaroop Bhattacharya & Thomas J. Mariani Pediatric Research (2013) DISEASES ALPHA-1-ANTITRYPSIN DEFICIENCY CYSTIC FIBROSIS ASTHMA LUNG CARCINOMA ALPHA-1-ANTITRYPSIN DEFICIENCY Alpha-1 antitrypsin deficiency is an inherited disorder that may cause lung disease and liver disease. The signs and symptoms of the condition and the age at which they appear vary among individuals. Alpha-1 antitrypsin deficiency occurs worldwide, but its prevalence varies by population. This disorder affects about 1 in 1,500 to 3,500 individuals with European ancestry. It is uncommon in people of Asian descent. People with alpha-1 antitrypsin deficiency usually develop the first signs and symptoms of lung disease between ages 20 and 50. The earliest symptoms are shortness of breath following mild activity, reduced ability to exercise wheezing. Other signs and symptoms can include unintentional weight loss, recurring respiratory infections, fatigue, and rapid heartbeat upon standing. Affected individuals often develop emphysema, which is a lung disease caused by damage to the small air sacs in the lungs (alveoli). ALPHA-1-ANTITRYPSIN DEFICIENCY Mutations in the SERPINA1 gene cause alpha-1 antitrypsin deficiency. This gene provides instructions for making a protein called alpha-1 antitrypsin, which protects the body from a powerful enzyme called neutrophil elastase. Neutrophil elastase is released from white blood cells to fight infection, but it can attack normal tissues (especially the lungs) if not tightly controlled by alpha-1 antitrypsin. Cytogenetic Location: 14q32.13, which is the long (q) arm of chromosome 14 at position 32.13 ALPHA-1-ANTITRYPSIN DEFICIENCY Mutations in the SERPINA1 gene can lead to a shortage (deficiency) of alpha-1 antitrypsin or an abnormal form of the protein that cannot control neutrophil elastase. Without enough functional alpha-1 antitrypsin, neutrophil elastase destroys alveoli and causes lung disease. Abnormal alpha-1 antitrypsin can also accumulate in the liver and damage this organ. ALPHA-1-ANTITRYPSIN DEFICIENCY alpha 1 antitirosin deficinecy s a dominant trait.flase Environmental factors, such as exposure to tobacco smoke, chemicals, and dust, likely impact the severity of alpha-1 antitrypsin deficiency. This condition is inherited in an autosomal codominant or a recessive pattern. Codominance means that two different versions of the gene may be active (expressed), and both versions contribute to the genetic trait. The most common version (allele) of the SERPINA1 gene, called M, produces normal levels of alpha-1 antitrypsin. Most people in the general population have two copies of the M allele (MM) in each cell. Other versions of the SERPINA1 gene lead to reduced levels of alpha-1 antitrypsin. For example, the S allele produces moderately low levels of this protein, and the Z allele produces very little alpha-1 antitrypsin. Individuals with two copies of the Z allele (ZZ) in each cell are likely to have alpha-1 antitrypsin deficiency. Those with the SZ combination have an increased risk of developing lung diseases (such as emphysema), particularly if they smoke. Worldwide, it is estimated that more than 161 million people have one copy of the S or Z allele and one copy of the M allele in each cell (MS or MZ). Individuals with an MS (or SS) combination usually produce enough alpha-1 antitrypsin to protect the lungs. People with MZ alleles, however, have a slightly increased risk of impaired lung or liver function. ALPHA-1-ANTITRYPSIN DEFICIENCY ALPHA-1-ANTITRYPSIN DEFICIENCY ALPHA-1-ANTITRYPSIN DEFICIENCY CYSTIC FIBROSIS Cystic fibrosis is an inherited disease that causes mucus in the body to become thick and sticky. This glue-like mucus builds up and causes problems in the lungs and the pancreas. People who have cystic fibrosis can have serious breathing problems and lung disease. They can also have problems with nutrition, digestion, growth, and development. There is no cure for cystic fibrosis. But with advances in treatment, people with cystic fibrosis are living longer. CYSTIC FIBROSIS People with cystic fibrosis also lose large amounts of salt when they sweat. This can cause an unhealthy imbalance of minerals in your body. It can lead to: Dehydration Fatigue Weakness Increased heart rate Low blood pressure Heat stroke Death in rare cases More than 30,000 Americans have cystic fibrosis. Each year about 1,000 new cases are diagnosed. Ireland not only has the highest incidence of cystic fibrosis in the world, but also the largest proportion of families with more than one child suffering from condition. Sixty years ago, the disease killed most people who had it before they reached elementary school. Nowadays people with cystic fibrosis have an average lifespan of about 37 years. CYSTIC FIBROSIS People with cystic fibrosis inherit a defective gene on chromosome 7q31.2 called CFTR (cystic fibrosis transmembrane conductance regulator). The protein produced by this gene normally helps salt (sodium chloride) move in and out of cells. If the protein doesn't work correctly, that movement is blocked and an abnormally thick sticky mucus is produced on the outside of the cell. The cells most seriously affected by this are the lung cells. This mucus clogs the airways in the lungs, and increases the risk of infection by bacteria. CYSTIC FIBROSIS CYSTIC FIBROSIS Well over two thousand mutations have been described that affect the CFTR gene in different ways. The most common CFTR mutation is a deletion of just three DNA nucleotides, which leads to the deletion of an amino acid (phenylalanine) at position 508 of the protein sequence. This is denoted as ΔF508, and is found in around 90% of CF patients. The disease spectrum has broadened as it has become clear that there are a large number of CFTR mutations. Some conditions caused by two CFTR mutations might cause only mild lung disease with or without affecting the pancreas – these conditions can be described as “atypical CF.” Other conditions do not meet the usual diagnostic criteria for classical CF and can be referred to as “CF-related disease,” for example congenital bilateral absence of the vas deferens, which can cause sterility in males. Though the biological effects of many CFTR mutations are known, there continue to be mutations for which scientists have incomplete knowledge of the health effects. CYSTIC FIBROSIS In cystic fibrosis, mutations affect the composition of the mucus layer lining the epithelial surfaces in the lungs and pancreas. The disruption of ion transport affects the salt concentration in sweat which is used in the CF “sweat test.” CYSTIC FIBROSIS Cystic fibrosis is an inherited disease. For someone to get cystic fibrosis, both parents must be carriers of the gene that causes it and then pass it on. That means 25% of the children of such parents will have cystic fibrosis. Boys and girls are equally likely to get the disease. About 10 million Americans carry the gene and do not know it. More whites get the disease than do people of other races. ASTHMA Asthma is a chronic lung disease that causes wheezing, breathlessness, chest tightness and coughing. It can affect adults or children. According to the Centers for Disease Control and Prevention, approximately 1 in 12 adults and 1 in 11 children have asthma. Bronchial asthma is the most common chronic disease affecting children and young adults. It is a complex genetic disorder with a heterogeneous phenotype, largely attributed to the interactions among many genes and between these genes and the environment. Multifactorial Inheritance ASTHMA ASTHMA Having a family history of asthma or allergies increases the chance that you might have asthma; so does smoking or breathing in tobacco smoke. You can’t change your family history, but you can control your exposure to smoke. Understanding asthma risk factors may help you prevent or minimize asthma. The most common risk factors for asthma are: Family history of asthma. If your mother or father has asthma, you’re three to six times more likely to develop asthma than someone who doesn’t have a parent with asthma. As many as three-fifths of all asthma cases may be inherited. Allergies. Smoking/Tobacco Exposure. Pollution. Obesity. ASTHMA Susceptibility genes for asthma ASTHMA With each successive wave of new technology, more genes are being identified. The next steps in the research agenda are to determine the actual functional variants in these genes and to figure out how the novel genes are involved in asthma pathogenesis. Although asthma can be controlled by pharmacologic treatment, some patients do not respond to therapy, and genetic variation has been shown to have a role in treatment response. Response to short-acting beta-agonists and inhaled corticosteroids has been evaluated in a number of studies that have validated the association of genes to asthma treatment response (eg, ADRB2, GSDMB, FCER2, VEGFA, SPAT2SL, ASB3, and COL2A1)