Pathophysiology Chapter 5

Lifestyle Modifications

Can alter path of genetic disease: exercise diet stress reduction preventative medication

Nature Clones

Monozygotic Twins

PTPN22

encodes lymphoid-specific tyrosine phospahatase: negatively regulates T cell activation

Diabetes: KCNJ11

encodes potassium channel essential for regulation of insulin secretion by pancreatic beta cells Type II

Concordant Trait

if both members of a twin pair share a trait Table 5-3, page 171 Concordance rates for contagious diseases are similar in MZ and DZ twins (unlikely genetically influenced-measles) Dissimilar for schizophrenia and bipolar (genetic)

Multifactorial Inheritance criteria

1. Recurrence risk is higher if more than one family member is affected. Ex. Ventricular septal defect: increases by number of siblings (recurrence risk for single-gene remains same regardless of number of affected siblings). Increase DOES NOT mean family's risk changed. Means more information about true risk (they had more risk factors-genetic or environmental-so more likely to produce affected child. 2. Expression of disease in the proband is more severe, recurrence risk is higher (because proband is on severe end tail of liability distribution, so relatives are at higher risk for inheriting disease genes) Ex. Bilateral CL/P: higer recurrence risk on family than unilateral cleft. 3. Recurrence risk is higher if proband is of the less commonly affected sex (because usually at a more extreme position of liabilty distribution) 4. Recurrence risk for disease usually decreases rapidly in more remotely related relatives (because many genes and environmental factors must combine to produce trait. Unlikely present in less closely related family members) This decrease occurs more rapidly in multifactorial diseases than single gene. 5. Prevalence of disease in a population is f, the risk for offspring and siblings of probands is the square root of f Does not hold true for single-gene traits because recurrence risks are independent of population prevalence Not an absolute rule for multifactorial traits but many diseases tend to conform Table 5-2: examination of risks Infantile autism is higher than predicted square root f.

Diabetes: Type I Twin Studies

30-50%, not 100% means some environmental factors at play

Diabetes: Type II

90% cases, 10-20% population Table 5-7, page 177 Endogenous insulin production treated with diet and oral drugs insulin resistance (cells have difficulty using insulin) Presents older than 40 Seen in obese (rising) Neither HLA or autoantibodies seen Empirical recurrence risks for first degree relative higher than for type I

Diabetes: Peroxisome proliferator-activated receptor y (PPAR-y)

Association of allele of gene encoding with Type II Transcription factor involved in adipocyte differentiation and glucose metabolism Found in 75% people with type II

Diabetes: Maturity onset diabetes in young (MODA)

Autosomal dominant inheritance: 25 years old Caused by mutation of glucokinase gene which converts glucose to glucose-6-phospate in pancreas five other genes involved in pancreatic development or insulin regulation cause MODA

Obesity

BMI: > 30 (32% American Adults) Overweight: BMI >25 (Additional 35% American Adults) •Incidence among adults and children rapidly increasing •Not a disease, but a risk factor for common diseases (heart disease, stroke, hypertension, and type II diabetes) •Correlation between parents and children-environmental and genetic •Adopted individuals had natural parent body weight even in adopted parents were thin.

Congenital Malformations

Correspond to model for multifactorial disease (genetic and environmental): Isolated cleft lip/cleft palate (Isolated means only observed disease feature) neural tube defects (anencephaly, spina bifida) clubfoot (talipes) congenital heart disease Hypertension Coronary heart disease Stroke Diabetes mellitus (I and II) Cancer

Dizygotic Twins

Double ovulation followed by fertilization of each egg by different sperm. Genetically different Possible to have two fathers rates increase until 40 then drop

Monozygotic Twins

Embryo divides in two separate but identical embryos. Genetically the same. Nature clones differences can be attributed to environment Should always be concordant

Sex Specific Threshold Model

Fits some of the complex disorders but not others: Fits: Pyloric stenosis CL/P Autism Heart disease Doesn't fit: Type I diabetes

Alcoholism: ALDH2 Gene

Gene results in excessive accumulation of acetaldehyde and thus facial flushing, nausea, palpitations, and light headedness. Therefore these people less likely to become alcoholics. Protective allele in Asians but rare in others.

Alzheimer: Heterogeneous Disorder

Half early-onset attributed to mutations in three genes that affect amhyloid beta disposition: 1. presenilin 1 (PS1): cleavage of amyloid beta precursor protein (APP) 2. Presenilin 2 (PS2) 3. Chromosome 21: location of gene that encodes APP. Disrupt normal cleavage sites in APP, lead to accumulation. Present in three copies in trisome 21 individuals (increase AD with down syndrome)

Genetic Lesion

Identification can lead to effective prevention and treatment of disease Ex. Identification of mutations causing autosomal dominant breast cancer enable early screening and prevention metastasis Ex. Pinpointing gene responsible for neurotransmitter defect in behavior disorder (schizophrenia) lead to development of more effective drug treatment Ex. Gene therapy in people with familial hypercholesterolemia may treat disease.

Diabetes: Type I

Insulin-dependent: IDDM T cell infiltration of pancreas and destruction of insulin-producing beta cells Occurs before age 40 Receive exogenous insulin to survive Autoantibodies formed against pancreatic cells before symptoms show Autoimmune disease-presence human leukocyte antigens (HLA) and class II alleles Siblings of individuals with type I at increased risk. Recurrence risk elevated with affected parent (affects genders equally) Some viral infections can cause (autoimmune response)

Diabetes Mellitus

Leading cause: blindness, heart disease, kidney failure Heterogeneous group of disorders characterized by elevated blood sugar Two types: Type I Type II

Relative Risk

Measure effect of a specific risk factor: Incidence rate of disease among individuals exposed/incidence rate of disease among individuals not exposed Ex. Cigarette smoking and lung cancer: British Study: incidence death from lung cancer in physicians who smoked with those that did not. Relative Risk: 23.7 deaths. 24-fold increase in deaths related to cigarettes

Quantitative Trait

Measured on continuous numeric scale and is multifactorial Ex. Blood pressure Caused by additive effects of genetic and environmental factors Follow bell curve Mendelian principles of segregation and independent assortment: act together to influence trait

Gene-Environmental Interaction

Most common diseases are due to genetic and nongenetic factors Predisposition may interact with environmental factors to increase risk of disease to higher level than genes are environmental factor alone Ex. Alpha antitrypsin deficiency: genetic condition that causes pulmonary emphysema and greatly exacerbated by cigarette smoking. Ex. Congenital malformations, heart disease, cancer, diabetes, psychiatric disorders

Diabetes: Type II Risk Factors

Most important: 1. obesity (increases insulin resistance) 2. family history *Exercise lowers risk of type II even if have family history (increases insulin sensitivity and improves glucose tolerance)

Schizophrenia Genetics

No gene has been identified as contributer, but suspect brain-expressed genes with products interacting with glutamate receptors: dysbindin 1 (chromosome 6p), neuregulin 1 (chromosome 8p), and G72 (chromosome 13q)

Prevalence varies by...

Population Ex. Cystic fibrosis common in Europeans and rare in Asians Ex. Sickle Cell common in African Americans, rare in European Americans Due to disease-causing mutations more/less common in different populations Nongenetic (environmental) factors have little influence on prevalence.

Congenital Disease

Present at birth and multifactorial in etiology Table 5-4, page 172 Sibling recurrence risk range from 1-5% Environmental factors cause some congenital malformations. Ex. Thalidomide (sedative) when ingested during early pregnancy caused Phocomelia (shortened limbs) Ex. Maternal exposure to retinoic acid-treats acne-cause congenital defects of heart, ear, CNS Ex. Maternal rubella infection can cause congenital heart defects Easy to repair: CL/P and pyloric stenosis Hard to repair: neural tube defects (severe consequences) Common to be associated with other disorders: Hydrocephaly and clubfood seen secondary to spina bifida CL/P is seen in babies with trisomy 13 Congenital heart defects seen in children with down syndrome

Alzheimer Disease

Responsible for 60-70% cases of progressive cognitive impairment among older adults •Described by: progressive dementia and memory loss. •Formation of amyloid plaques an neurofibrillary tangle in the brain (cerebral cortex and hippocampus) •Leads to progressive neuronal loss and death within 7 to 10 years of symptoms •Risk doubles in individuals with affected first degree relative. •Do not appear to be caused by single loci •10%: autosomal dominant mode of transmission •Early onset: before age 65-inherited in autosomal dominant fashion

Colorectal Cancer

Second to lung cancer in deaths. 1 in 20 will develop Strong in families Risk in people with one affected first-degree relative two-three times higher than general population Family aggression caused by inherited single-gene trait: familial adenomatous polyposis (1 in 8000 whites) Gene responsible: APC from chromosome 5. Functions as tumor suppressor. Found in 85% of all colon tumors Hereditary nonpolyposis colorectal cancer: accounts for 5%: caused by mutations of any six genes. Cloning of genes shows all are involved in process of DNA repair. Colorectal cancer can be caused by interaction of multiple genes and environmental factors (high-fat, low-fiber diet)

Polygenic

Traits in which variation is thought to be caused by combined effects of multiple genes

Studies about influence of genes and environment on disease

Two types: 1. Twin Studies 2. Adoptive Studies

Twin Studies

Two types: 1. Monozygotic Twins (identical) 2. Dizygotic Twins (fraternal)

Diabetes: Human Leukocyte Antigens (HLA)

accounts for 40% family clustering of type I 95% whites with HLA DR3 have type I

Environmental Factors

affect etiology of cancers of colon and stomach in study involving Japanese and Japanese-Americans. Diet high in fat, low in fiber increases colon cancer, preservation of fish leads to stomach cancer. Genes can also play a role though.

Alzheimer: Apolipoprotein E (APOE) locus

allele variation=risk factor for late onset AD 2-5 times more likely to develop AD. Higher associated risk in Europeans and Japanese than Hispanics and African Americans. Despite association, half individuals developing do not have copy of the allele and many who do, do not get AD in advanced age. Apolipoprotein E associated with clearance of amyloid from brain

Diabetes: DR3 and DR4

alleles seen in individuals with type I diabetes-20% more likely if have allele

Empirical Risks

based on direct observation of data: derived for most multifactorial diseases: Specific to the multifactorial disease in question Recurrence risks can change from one population to another (unlike single gene diseases) because gene frequencies and environmental factors differ To estimate: large series of families examined: one child has developed disease (proband). Siblings of each proband surveyed to calculate the percentage who have also developed disease. Ex. Neural tube defects: estimated for the offspring of affected parents (30%) Can be difficult to distinguish polygenic or multifactorial diseases from single-gene with reduced penetrance or variable expression. Need large data sets and epidemiologic data to distinguish

Infantile Autism

behavioral disorder in which male/female ratio=4:1. Multifactorial disorder. •Recurrence risks for siblings of male probands is lower than siblings of female probands. •If sex ratio for disease reversed females would expect higher recurrence risk when proband is male.

hypercholesterolemia

benefits from gene therapy

Alcoholism: gamma-aminobutyric acid (GABA) receptors

brain's primary inhibitory neurotransmitter. GABA receptor genes are contributing to genetic susceptibility to alcoholism.

Congenital Malformations are due to...

complex interplay of genetic and environmental factors, NOT because of a single gene or chromosome defect

Laterality

component of bilateral forms are more likely to cluster strongly in families: Breast cancer CL/P

Prevalence Rate

contrasts with incidence rate. Proportion of population affected by a disease at a specific point in time. Prevalence is determined by incidence rate and length of survival period in affected individuals. Ex. AIDS: larger than the yearly incidence rate b/c can survive years after diagnosis

Pyloric Stenosis

corresponds to threshold model presents after birth: narrowing/obstruction of pylorus (stomach) Causes: chronic vomiting, constipation, weight loss, electrolyte imbalance Can resolve spontaneously or correct through surgery More common in white males. This difference in prevalence reflects two thresholds in liability distribution: lower threshold=males, high threshold=females Low threshold means fewer disease-causing factors are required to generate disorder in males.

Diabetes: Genes associated with Type I

cytotoxic lymphocyte associated-4 (CTLA4): endcodes protein involved in regulation of T cell proliferation PTPN22: encodes lymphoid-specific tyrosine phospahatase: negatively regulates T cell activation Variation results in other autoimmune diseases: systemic lupus erythematosus, rheumatoid arthritis, autoimmune thyroid disease

Diabetes: TCF7L2

encodes transcription factor associated with blood glucose homeostasis Type II

cytotoxic lymphocyte associated-4 (CTLA4)

endcodes protein involved in regulation of T cell proliferation

Multifactorial Trait

environmental factors cause variation in trait

Adoptive Studies

estimate genetic contribution to multifactorial trait. Born to parents who have disease but adopted by parents who don't. See if children develop. •See if in different environment they still develop the disease •Still develop schizophrenia-no environmental factor, it's genetic •Prenatal environmental influences can have long-lasting effects •Children adopted after several years old have some environmental influence from birth parents •Adoption agencies try to match adoptive parents with natural parents in terms of background, socioeconomic status-can exaggerate apparent influence of biologic inheritance.

Gene therapy

for people with familial hypercholesterolemia may treat disease.

Nature and Nurture

genes and environment affect children of parents affected Ex. blood pressure

Multifactorial Disease Recurrence

harder to determine than with single gene disease because: Number of genes contributing to disease is usually not known Extent of environmental effects can vary substantially

Genetic research goal...

identify and measure the relative roles of genes and environment in causation of multifactorial diseases

Obesity

increases insulin resistance

Excercise

increases insulin sensitivity and improves glucose tolerance

Proband

individual from which the pedigree begins: higher when proband is female b/c higher threshold means must be exposed to more disease causing factors *male relatives of female probands at highest risk

Liability Distribution

individuals on low end of distribution have little chance of developing disease because they have few of the disease causing genes and environmental factors. Individuals on high end do have the genes and environmental factors. Likely to develop disease.

Coronary heart disease

leading cause of death of Americans-25% Caused by atherosclerosis (narrowing as result of formation of lipid-laden leisons) Results in myocardial infarction (destruction of heart tissue from inadequate supply oxygen) Stroke results from atherosclerosis Risk factors: obesity, smoking, hypertension, elevated cholesterol, positive family history-one affective first degree relative) Positive family history is two to seven times more likely to have heart disease. Risk increases if: 1. More affected relatives 2. Affected relative are female (less commonly affected sex) 3. Age of onset in the affected relative is early-prior to 55 Genetic research on relation of genetic lipoproteins: isolation and cloning of the gene for low-density lipoprotein (LDL) receptor defects: cause familial hypercholesterolemia Other genes involved in lipid variation, coagulation, hypertension identified include several genes encoding apolipoproteins

Bipolar Affective Disorder

manic-depressive disorder. Form of psychosis with extreme mood swings and emotional instability. 5-10% chance with affective first-degree relative Treated with lithium Concordance rates of 79% and 24% for MZ and DZ twins Unipolar concordance rates (major depression) were 54% and 19% for MZ and DZ twins Bipolar is more strongly influenced by genetics than unipolar

Obesity: Leptin

means thin Leptin and leptin receptor play role in obesity. Leptin hormone is secreted by adipocytes and binds to receptors in hypothalamus (appetite control center). Mutations to leptin: identified in severely obese (BMI >40) are rare Involved in other components of appetite control: neuropeptide Y and alpha melanocyte stimulating hormone and its receptor (melanocortin-4 receptor MC4R) DNA variant in FTO gene associated with 40-70% increase in risk of overweight and obese

Age of onset

more strongly inherited forms of complex disorders have earlier age of onset: Breast Cancer AD Heart Disease

Breast Cancer

most common among women Strong in families-genetic One affected first-degree relative risk doubles. Doubles again if affected relative is early and bilateral Autosomal dominant form accounts for 5% breast cancer. Mapped to chromosomes 17 (BRCA 1) and 13 (BRCA 2): inherited means 50-80% chance of developing breast cancer and 20-50% chance developing ovarian chance Males who inherit have increased risk of prostate and colon cancer. BRCA 2 increased risk breast cancer. Breast cancer also caused by mutations in tumor-suppressor genes (CHK2 and TP53) PTEN germline mutations responsible for cowden disease-multiple benign tumors increased susceptibility to breast cancer.

Smoking

most smokers don't develop lung cancer genetic background affects likeliness of developing it Environmental factors (breathing in other carcinogens)

Cowden Disease

multiple benign tumors increased susceptibility to breast cancer

Threshold of Liablitly

must be crossed before disease is expressed Below threshold: appear normal Above threshold: display disease

Atherosclerosis

narrowing as result of formation of lipid-laden leisons

Bell Curve

not all diseases follow: present or absent in individuals don't follow inheritance patterns expected of single gene disease liability distribution

Incidence Rate

number of new cases of a disease reported during specific period (one year) Divided by number of individuals in population Denominator=person-years

Other complex multifactorial disorders

parkinson disease hearling loss multiple sclerosis amyotrophic lateral sclerosis epilepsy asthma inflammatory bowel disease blindness

Diabetes: Insulin gene on Chromosome 11

polymorphism within and near this gene tested for association with type I Inherited genetic variation accounts for 10% family clustering

Diabetes: Aspartic acid

position 57 of DQ chain associated with resistance to type I (alters shape of HLA class II and ability to bind to present peptides to T cells, preventing autoimmune episodes). If individual doesn't have aspartic acid, at position 57, 100 times more likely to develop DM type I.

Cancer

second cause of death of Americans genetic and environmental factors Tobacco accounts for 1/3 cancer cases in America

Schizophrenia

severe emotional disorder characterized by delusions, hallucinations, retreat from reality, bizarre withdrawn, inappropriate behavior (no split personality). Life time recurrence risk among offspring of one affected parent is 8-10%, ten times higher than general population Treated with drugs that block dopamine receptors Empirical risks increase with more than one relative Empirical risks decrease with affected member being second-degree or more relative Table 5-8 recurrence risks (page 179) Less likely to marry and produce children-substantial selection against the disorder. Which means proband with schizophrenic parent only 5% lower risk than proband with other first-degree relative. Twin and adoption studies indicate genetic factors involved 47% concordance rate for MZ twins and 12% for DZ twins.

Hypertension

systemic: risk factor for heart disease, stroke, kidney disease •Study of blood pressure correlations within families indicate that 20-40% of variation in systolic and diastolic blood pressure is caused by genetic factors. •Less than 100% means environment plays a role as well •Increased sodium, decreased physical activity, psychosocial stress, obesity all relate to environmental factors causing hypertension •Regulation of blood pressure influenced by: kidney function, cellular ion transport, heart function •Research focus is on components that influence blood pressure such as angiotensin, angiotensigen urinary kallikrein, sodium-lithium contertransport: under control of small number of genes Ex. Angiotensinogen gene in causation of both hypertension and preeclampsia (pregnancy induced hypertension)

APC: Chromosome 5

tumor suppressor found in 85% colorectal patients: mutated

Discordant Trait

twins do not share a trait Only compare same-sex DZ twins because certain traits are more dominant in males Ex. Contagious diseases

Alzheimers: APP

when not cleaved properly causes long form to accumulate excessively and deposit in the brain. Primary cause of Alzheimer diesase. Mutations in PS1 result in early onset around 50

Psychiatric Disorders

•Large scale linkage studies to polymorphisms throughout genome carried out and show negative results •Candidate genes include: neurotransmitters, receptors, neurotransmitter-related enzymes in each disease •Tested for: sodium-lithium counter transport, dopaminergic system, and neurotransmitter-related enzymes and none are unequivocally linked. •Heterogeneous disorders reflecting influence of genetics and environment. •Phenotype not always straightforward and may change in time, complicating analysis

Alcoholism

•National cost is $200 billion/year •Clusters in families •Risk with one affected parent is three to five times higher than those with unaffected parents. •Twin studies yield concordance rates for MZ twins in excess of 60% •Adoption studies show the offspring of an alcoholic parent even when raised in absence of alcohol have a fourfold increased risk of developing the disorder. •To prevent prenatal effects of alcoholic mother: studies include only the offspring of alcoholic father. Results remain the same •Physiologic response to alcohol can be influenced by variation in the key enzymes responsible for alcohol metabolism (alcohol dehydraogenases-ADH) which convert ethanol to acetaldehyde, and aldehyde dehydrogenases (ALDH) which convert acetaldehyde to acetate. •Genes increase susceptibility to alcoholism. Requires environmental component regardless of genetic predisposition.