Patho Chap 5

diabetes I

-genes, insulin gene on chromosome 11 -env.(pg.174&177 Is caused by the autoimmune destruction of insulin-producing beta cells in the pancreas. T-cell activation and autoantibody production Individuals with type 1 diabetes need insulin for life. Siblings of individuals with type 1 diabetes face a substantial elevation in risk. *Incidence is higher in the offspring of diabetic fathers*.

alzheimer disease

-genetically heterogeneous disorder, presinilin 1 and presinilin 2, chromosome 21 -env. (pg.178) Characterized by progressive dementia and a loss of memory. Produces amyloid plaques and neurofibrillary tangles. Risk doubles if a first-degree relative has AD. Mutations for early-onset affect amyloid-beta deposition. Presenilin 1 (PS1), presenilin 2 (PS2), and amyloid-beta precursor protein (APP) gene, which is the primary cause of AD Mutations for late-onset AD Allelic variation (ε2, ε3, and ε4) in apolipoprotein E (APOE) One copy of the ε4 allele: at least two to five times at greater risk Two copies of the ε4 allele: at least five to ten times more likely to develop AD

basic model

Because these are additive effects, the traits form a normal, bell shaped distribution in population.

Differentiate Congenital malformations versus multifactorial disorders of adult population

Congenital disease occurs at birth ex. Clubfoot Multifactorial disorders occur later in life ex CHD (coronary heart disease) Congenital malformations are common at birth Multifactorial disorders present whereas in the adult population these disorders are later diagnosed found in adolescents and adults. An example of congenital malformation would be clubfoot and an example of an adult disorder is heart disease.

Identifty the variables that influence relative risk (eg. Lung cancer)

Diet, Smoking, exposure to cancer causing substances in the air, cancer, diabetes, high blood pressure. (pg.165)

recurrence risks

Given with confidence for single-gene diseases (50% autosomal dominant, 25% autosomal recessive), not so for multifactorial. Empirical risks - risks based on direct observation of data has been created for multifactorial diseases. Families are examined in which 1 child developed a disease. In the US, 3% of siblings of individuals with neural tube defects also have neural tube defects. This makes the recurrence risk for parents that have a child with the defect have a 3% risk. Can be given with confidence for single-gene diseases. But with multifactorial diseases, the risks can change substantially from one population to the next because gene frequencies as well as environmental factors can differ among populations. First, the recurrence risk becomes higher if more than one family member is affected. Second, if the expression of the disease in the proband is more severe, the recurrence risk is higher Third, the recurrence risk is higher if the proband is of the less commonly affected gender Fourth, the recurrence risk for the disease usually decreases rapidly in more remotely related relatives Finally, if the prevalence of the disease in a population is f, the risk for offspring and siblings of probands is approximately sqrt(f).

hypertension

Important environmental factors include sodium intake, lack of exercise, stress, and obesity

Discuss the use of twin studies and adoption studies in measuring gene-environment interactions

In twin studies there are comparisons made between monozygotic (MZ, identical twins) and dizygotic (DZ, fraternal twins). If both members *share a trait =concordant trait*. If both members *DO NOT share a trait = discordant*. (pg.169)

threshold model

Includes diseases that do not follow the bell-shaped distribution, rather, they're either present or absent in individuals without following the expected patterns of single-gene diseases. An individual must cross a threshold of liability - when the liability distribution is on the low end, the person had little exposure to environmental factors or a small amount of the alleles. High end exposure means they have more of the disease-causing genes and environmental factors. An example of the threshold model is pyloric stenosis, a disorder expressed shortly after birth, causing a narrowing of the pylorus, the area between the stomach and intestine. It affects 3/1000 live births in whites, affected 1/200 males but 1/1000 females.

Relative risk

Is the incidence rate of a disease among individuals exposed to a risk factor divided by the incidence rate of the disease among individuals not exposed to a risk factor indicates the chance of developing a disease relative to an exposure Many factors, including age, gender, diet, exercise, and family history of the disease, can influence the risk.

Prevalence rate

Is the proportion of the population affected by a disease at a specific point in time. Varies from population to population.

Cancer

Is the second leading cause of death in the United States. Many major cancers occurs in families. Environmental and lifestyle choices affect the risk for cancer. Tobacco use accounts for one-third of all cancers.

Know the factors that influences risk of acquiring common adult diseases (include genetic and nongenetic variables).

There are many factors, such as age, gender, diet, exercise, and family history of the disease. Genetic variables: inherited genes that contribute to the risk of developing common diseases. Ex: family history. Nongenetic variables: environmental factors that contribute to the risk of developing common diseases. Ex: diet, exercise. (pg.165)

Discuss the impact of the environment and gene interactions on disease (know examples)

This involves nature (the gene) and nurture (the environment). The two are not mutually exclusive most traits are influenced by both. Example is lung cancer.

Define and calculate relative risk

a common measure of the effect of a specific risk factor. It is expressed as a ratio of the incidence rate of the disease among individuals exposed to a risk factor divided by the incidence of the disease among individuals NOT exposed to a risk factor(pg.165)

schizophrenia

gene, dysbindin (chromosome 6), neurogulin (chromosome 8), D amino acid oxidase activator G30 (chromosome 13). (pg.179&180) -Recurrence risk among offspring of one affected parent is 10 times higher than the general population. -If an individual has an affected sibling and an affected parent, then the risk is approximately 17%. -If an individual has two affected parents, then the risk is 46%. -Twin and adoption studies: MZ and DZ pairs have a risk of 47% and 12%, respectively. -If the offspring of a schizophrenic parent are adopted by normal parents, then the risk is approximately the same as the risk when raised by a schizophrenic biologic parent. -Brain-expressed genes whose products interact with glutamate receptors have been implicated.

coronary heart disease

genes involved in lipid coagulation, variation and hypertension -env. high-fat diet, lack of exercise, smoking, and obesity increase risk - risk factors: obesity, cigarette smoking, hypertension, elevated cholesterol level, and positive family history - leading killer of Americans, accounting for approximately 25% of all deaths in the United States. Risk increases if: More affected relatives exist 2-7x more likely Affected relatives are female rather than male. Age of onset is younger than 55 years.

bipolar disorder

genes that encode MAOA, 5HTT, COMT, NRG1, and DISC1. (pg.180) Is also called manic depressive disorder. Risk rises between 5% and 10% if an individual has an affected first-degree relative, as compared with the normal risk of 0.5%. Concordance rates are 79% and 24% for MZ and DZ twins, respectively. Genes that affect serotonin, dopamine, and noradrenaline systems have been implicated. Schizophrenia and bipolar disorder Both are heterogeneous—reflects the influence of numerous genetic and environmental factors, making the phenotype hard to identify and genetic analysis complicated.

alcoholism

genes, alcohol dehydrogenases (ADH), aldehyde dehydrogenase (ALDHs), gamma aminobutyric acid (GABA) NOTE, this disease requires an ENVIORNMENTAL component. (pg.179) Risk is three to five times higher in the individual with an alcoholic parent. Adoption studies Offspring of an alcoholic parent, even when raised by nonalcoholic parents, have a fourfold increased risk. Offspring of nonalcoholic parents, when reared by alcoholic parents, did not have an increased risk. Twin studies: MZ and DZ pairs have a >60% and <30%, respectively, increased risk. Genes Individuals with ALDH2*2 allele are much less likely to become alcoholics. Allelic variation of gamma-aminobutyric acid (GABA) receptors increase the risk.

Breast cancer

genes, chromosome *17 and 13*, mutation in any 6 genes -env. Low fiber or high fat diet. (pg.172) Affects 12% of American women who live to 85 years of age. If a woman has a *first-degree relative* with breast cancer, then her *risk doubles*. Recurrence risk increases if the age of onset in the affected relative is early and if the cancer is bilateral. An autosomal dominant form (5%) has been linked to chromosomes 13 (BRCA2) and 17 (BRCA1). This form causes a 50% to 80% lifetime risk of developing breast cancer and *increases the risk for ovarian cancer*. Other genes are implicated.

diabetes II

genes, insulin resistance gene TCF7L2 which codes for a transcription factor involved in the secretion of insulin -env. Obesity. (pg.177) More than 90% of all individuals with diabetes have type 2. Neither HLA nor autoantibodies are present. Insulin resistance is present, or insulin production is diminished. Risk factors include obesity and a positive family history. Exercise has a preventive effect. Recurrence risk MZ twins have a 90% risk First-degree relatives have a 15% to 40% risk. Genes Variant of TCF7L2 is associated with a 50% increased risk. Other genes: PPAR-γ and KCNJ11 are associated with increased risk. Glucokinase gene is associated with maturity-onset diabetes of the young.

hypercholesterolemia

genes, renin-angiotensin system -env. Increased sodium intake. (pg.172)

obesity

genes, that encode leptin and genes that affect appetite -env. overeating, not exercising. (pg.178) Is a BMI greater than 30. BMI = weight in kilograms (W) divided by height in meters squared (H2) (BMI = W/H2) Presents a substantial risk factor for heart disease, stroke, hypertension, and type 2 diabetes. Adoption studies Body weights of adopted individuals correlated significantly with their natural parents' body weights. Twin studies Genetics have an effect on body weight: most studies yielded heritability estimates between 0.60 and 0.80. Gene for leptin and its receptors are related to obesity

multifactorial inheritance

means that many factors are involved in causing a birth defect. The factors are usually both genetic and environmental, where a combination of genes from both parents, in addition to unknown environmental factors, produce the trait or condition. Often one gender (either males or females) is affected more frequently than the other in multifactorial traits. Multifactorial traits do recur in families, because they are partly caused by genes. The chance for a multifactorial trait or condition to happen again depends upon how closely the family member with the trait is related to you. For example, the risk is higher if your brother or sister has the trait or disease, than if your first cousin has the trait or disease. Family members share a certain percentage of genes in common, depending upon their relationship.

transmission patterns

observable patterns that occur during transmission

Incidence rate

the number of new cases of a disease reported during a specific period (~1 year) divided by the number of individuals in the population; the denominator is often expressed as person-years

Multifactorial traits

when environmental factors are also believed to cause variation in the trait; include quantitative traits - blood pressure and others that are measured on a continuous numeric scale.