Genes, Environment, Lifestyle and Common Diseases PDF

GENES, ENVIRONMENT LIFESTYLE AND COMMON DISEASES Derek Owens DrAP, CRNA Module 2 Guyton chapter 3 McCance 4, 5, 6 Learning objectives 1. Describe how genes influence all aspects of body structure and function. 2. Compare how defects in genes can lead to recognizable gene...

GENES, ENVIRONMENT LIFESTYLE AND COMMON DISEASES Derek Owens DrAP, CRNA Module 2 Guyton chapter 3 McCance 4, 5, 6 Learning objectives 1. Describe how genes influence all aspects of body structure and function. 2. Compare how defects in genes can lead to recognizable genetic diseases. McCance chapter 5  Incidence of disease in populations Incidence rate- the number of new cases of disease reported during a specific period (typically one year) Prevalence rate- proportion of the population affected by disease at a specific point in time – Comparison of these two numbers depends on length of the survival period – The prevalence rate of AIDS is larger than the incident rate because most people with aids survive for several years – Many diseases vary in prevalence from one population to another Cystic fibrosis- common in Europeans, rare in Asians Sickle cell disease- one in 600 American blacks but much less frequency and whites Colon cancer is rare in Japan but is the second most common cancer in the United States, stomach cancer is common in Japan but rare in the United States – As Japanese have immigrated to the US we have been able to observe what happens to the rates of stomach and colon cancer Indicate an important role for environmental factors for a colon and stomach cancer Risk factors Relative risk- increased rate of the disease among individuals exposed – = 24 fold risk of death from lung cancer for heavy smoking Risk factors of developing a disease can be genetic or lifestyle related – Age, gender, diet, amount of exercise, family history – Smokers who have variance in genes that are involved in the metabolism of tobacco smoke components are at significantly increased risk of developing lung cancer  Multifactorial inheritance Polygenic- traits in which variation is thought to be caused by the combine effects of multiple genes Multifactorial trait- when environmental factors are also believed to cause variation in the trait – Height is affected by more than one gene, as well as environmental factors and therefore there are many more possibilities than tall medium or short – Blood pressure is influenced by parents blood pressure but also environmental factors such as diet exercise and stress – Many adult diseases- hypertension, coronary heart disease, stroke, diabetes and some cancers Threshold of liability- there doesn’t seem to be a normal distribution with some diseases, they are either present or absent. – A number of different genes along with a number of environmental variables act as risk or protective factors Recurrence risk and transmission patterns Risk estimation is difficult with multifactorial diseases – For most multifactorial diseases empirical risk have been derived It is difficult to distinguish polygenic or multifactorial diseases from single gene diseases that have reduced penetrance or variable expression 1. The recurrence becomes higher if more than one family member is affected This does not mean the families risk has actually changed. It means there’s only more information about the families true risk 2. If the expression of disease in the proband is more severe the recurrence risk is higher 3. The recurrence risk is higher if the proband is of the less commonly affected sex 4. The recurrence risk for the disease usually decreases rapidly in more remote relatives The recurrence risk for single gene disease is decreases by 50% with each degree of relationship – Decreases much more quickly for multifactorial diseases  Twin studies Twins occur about one and 100 births in white populations – More common in blacks and less common in Asians Monozygotic (MZ, identical)- when the developing embryo divides to form two separate but identical embryos Dizygotic (DZ, fraternal)- double ovulation followed by fertilization of each egg by a different sperm – It is possible for each DZ twin to have a different father – MZ twins are constant across populations whereas DZ twinning rates vary somewhat MZ twins are genetically identical so any differences should be caused only by environmental factors DZ twins are genetically different but their environment differences should be similar – Genetically the same as siblings Twin studies Concordant- if both members of the twin pair share a trait Discordant- they do not share the trait – If a trait is solely determined by genes MZ twins should always be concordant The concordance rate for contagious diseases such as measles are quite similar in MZ and DZ twins The concordance rate is quite dissimilar for schizophrenia and bipolar affective disorder – Sizable genetic component Table page 166 in McCance Twins were once thought to provide a perfect natural laboratory but several difficulties arose – The assumptions that the environments are equally similar Adoption studies Children born to parents who have a disease but are then subsequently adopted by parents lacking the disease can be studied to find out whether these children develop the disease – When such children develop the disease more often than a comparative control population this provides some evidence that genes may be involved in the causation of that disease. 8 to 10% of adopted children of a schizophrenic parent develop schizophrenia Only 1% of adopted children of unaffected parents develop schizophrenia Caution must be exercise interpreting the results – Prenatal environmental influences could have long lasting affects on adopt a child – Children can be adopted after they are several years old ensuring some environmental influence has been imparted Twins and adoption studies take away Most common diseases are not the result of either genetics or environment Genetic and non-genetic factors usually interact to influence one’s likelihood of developing a disease Genetics of common diseases Some common multifactorial disorders are present at birth, others are seen in adolescents and adults and unraveling genetics is a daunting task – Congenital malformations – Heart disease, cancer and diabetes Coronary heart disease is the leading killer of Americans – Approximately 25% of all deaths in the US – Risk factors- obesity, cigarette smoking, hypertension, elevated cholesterol, and positive family history An individual with a positive family history is 2 to 7 times more likely to have heart disease – More affected relatives – Affected relative or relatives are female – Age of onset of the effected relative younger than 55 – Environmental factors Cigarette smoking and obesity Exercise and a diet low in saturated fats  Hypertension Worldwide prevalence of approximately 25 to 30% – Key risk factor for heart disease and stroke and kidney disease – 20 to 40% of the variation in systolic and diastolic blood pressure is caused by genetic factors This indicates that environmental factors must be an important cause of hypertension Due to the complexity of blood pressure regulation much research is now focused on specific components – The renin-angiotensin system, vasodilators like NO, and ion transport systems  Cancer Second leading cause of death in the United States – Many types of cancer cluster strongly in families Caused both by genes and shared environmental factors – Tobacco use accounts count for 1/3 of all cancer cases – Breast cancer- the most common cancer among women, affecting approximately 12% of American women who lived to 85 or older Strong family correlation One affected first degree relative doubles the risk – Risk is increased if the affected relative has a young age of onset and bilateral cancer – BRCA1 and 2- the gene responsible for an autosomal dominant form of breast cancer which accounts for approximately 5 to 10% of cases in the US Women who inherit a mutation of this gene experience a 50 to 80% lifetime risk of developing breast cancer BRCA1 mutations also carry a 20 to 50% lifetime risk of ovarian cancer 6% the males who inherit BRCA2 will develop breast cancer, a 100 fold increase over the general population – Colorectal cancer- Second only to lung cancer number of cancer deaths annually Risk is 2 to 3 times higher if there is one affected first-degree relative – Prostate cancer- Second most commonly diagnosed cancer in men Risk is 2 to 3 times higher if there’s an affected first degree relative Heritability is approximately 40%  Diabetes Type 1 diabetes – Auto immune disorder- T cell infiltration of the pancreas along with antibody formation against pancreas cells and a histocompatibility complex – 0.3 to 0.5% risk in the general population Siblings - 6% Diabetic parent- 1-3% (mothers) 4-6% (fathers) Identical twins- 30 to 50% Dizygotic twins 5 to 10% – Since identical twins are not 100% concordant genetic factors are not solely responsible for disorder – There’s good evidence that specific viral infections contribute to the cause in at least some individuals possibly by activating an auto immune response  Diabetes Type 2 diabetes – Accounts for 90% of all diabetics cases – There are several distinguishing factors Caused by insulin resistance Nearly always some endogenous insulin production Can often be treated successfully with dietary modification and or oral drugs Typically occurs among people older than 40 Higher incidence of obesity – Monozygotic twin concordance rates are 70 to 90% – First-degree relative concurrence are 15 to 40% – The two most important risk factors for type two diabetes are positive family history and obesity Obesity increases insulin resistance – There is a rise in prevalence when populations adopt a diet and exercise pattern typical of US and European nations – Exercise can substantially lower ones risk of developing type two diabetes even among individuals with family history Partially because exercise reduces obesity but even in the absence of weight loss exercise increases  Obesity A body mass index greater than 30 – More than 1/3 of American adults are obese an additional 1/3 or overweight (BMI 25 to 30) Obesity itself is not a disease – It is an important risk factor for several diseases including heart disease, stroke, type 2 diabetes, and cancer of the prostate, breast, and colon There’s a strong familial correlation of obesity – Easily ascribed to common environmental effects: parents and children share similar dietary and exercise habits Four adoption studies show that body weights of adopted individuals correlated significantly with a natural parents body weights but not with those if they’re adopted parents Twin studies showed heritability estimates between 0.6 and 0.8 Alzheimer disease Characterized by progressive dementia and memory loss by the formation of amyloid plaques and Neurofibrillary tangles in the brain AD is a genetically heterogeneous disorder Responsible for 60 to 70% of the cases of progressive cognitive impairment among older adults Affects approximately 5 to 10% of the population older than 65 and 40% of the population older than 85 – 3 to 5% occur before age 65 and are considered early onset These are much more likely to be inherited Death usually occurs within 7 to 10 years after the first appearance of symptoms The risk of developing AD doubles in individuals who have an affected first-degree relative Alcoholism Diagnosed in 10% of adult males and 3 to 5% of adult females in the US The risk of developing alcoholism among individuals with one affected parent is 3 to 5 times higher than those with unaffected parents DZ twins have a concordance rate less than 30% and concordance rates for MZ twins are in excess of 60% Adoption studies show that the offspring of an alcoholic parent when raised by non-alcoholic parents have a fourfold increased risk of developing the disorder – The offspring of non-alcoholic parents when raised by alcoholics did not have an increased risk of developing alcoholism  Alcoholism Alcohol dehydrogenases (ADHs) convert ethanol to acetaldehyde Aldehyde dehydrogenases (ALDHs) convert acetaldehyde to acetate – An allele of the ALDH2 gene (ALDH2*2) results in excessive accumulation of acetaldehyde which causes facial flushing, nausea, palpitations, and lightheadedness Due to these unpleasant effects individuals who have the ALDH2*2 alleles are much less likely to become alcoholics Some genes that encode components of Gamma aminobutyric acid (GABA) are associated with susceptibility to alcohol addiction – Alcohol has been shown to increase GABA release and allelic variation in GABA receptor genes may modulate this effect Genes may increase one susceptibility to alcoholism but this disease requires an environmental component as well  Psychiatric disorders Schizophrenia is a severe emotional disorder characterized by delusions, hallucinations, retreat from reality, and bizarre withdrawn or inappropriate behavior – The recurrence risk is 8 to 10% when there is one affected parent This is 10 times higher than the risk of the general population Risk increases when more relatives are affected – An individual who has a sibling and a parent with schizophrenia has risk approaching 20% – The risk with two affected parents is nearly 50% – Frequency of schizophrenic probands who have a schizophrenic parent is only about 5% This is because people with schizophrenia are less likely to produce children than other individuals MZ twins have a 47% concordance rate compared to only 12% for DZ twins When the offspring of a schizophrenic parent are adopted by normal parents the risk of the disease is about 10% Large scale genetic studies have revealed more than 100 loci that are associated with the risk of schizophrenia – Many of these genes encode components of the dopaminergic and glutamatergic signaling pathways – The major therapeutic drugs used to treat schizophrenia are dopamine receptor antagonist Psychiatric disorders Bipolar disorder- a form of psychosis with extreme mood swings and emotional instability (manic depressive disorder) – Incidence in the general population is approximately 0.5% The risk rises to 5 to 10% for those with an affected first-degree relative Twin studies show that approximately 60% of the risk is attributable to genetic factors Most likely heterogeneous reflecting the influence of numerous genetic and environmental factors – Genetic studies are especially challenging  Conclusions 1. The more strongly inherited forms of complex disorders generally have an earlier age of onset 2. When laterality is a component the bilateral forms cluster strongly in families 3. Although the sex specific threshold model fits some of the complex disorders it fails to fit others Most of the disease discussed in this chapter have both genetic and environmental components – Lifestyle modification (diet, exercise, stress reduction) can reduce risk significantly Especially important for individuals with a family history that may develop disease earlier in life The identification of a specific genetic lesion can lead to more effective prevention and treatment of the disease – Identification of mutations that cause breast cancer may enable early screening and