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Common complex diseases -Examples -Morbidity/mortality rate -Pattern of inheritance |
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Definition
•Ex's:congenital birth defects, MI, HTN, CA, mental illness, diabetes, Alzheimer's •Cause morbidity/mortality in nearly 2 of 3 individuals during their lifetime •Inheritance follows a multifactoral (complex) pattern
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| Diseases with complex inheritance often demonstrate ______ which means they cluster and run in families |
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| When 2 related individuals in a family have the same dz, they are said to be _________ for the dz |
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| When only 1 member of a pair of relatives is affected while the other is not, the relatives are ________ for the disease |
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| Greater concordance for disease is expected among ________ versus ________ twin. |
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Complex phenotypes of multifactoral disorders can be divided into 2 major categories: |
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1. Qualitative trait: a genetic disease that is either present or absent; use concordance as an estimate of heritability 2. Quantitative trait: a measurable physiological or biochemical quality (height, BP, serum cholesterol concentration, BMI, etc.); use coefficient of correlation as measure of heritability |
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•Expression of how much of the observed variation in a phenotype is due to differences in genotype •Range = 0-1 -If a trait has a h2 of 1 it means that all phenotypic variation in the population is caused by genotypic differences
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Prevalence of the dz in the relatives of an affected
person Prevalence of the dz in the general population |
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| In case control studies patients with a disease (case) are compared to _____________ with respect to _____________________. |
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Suitably chose individuals without the dz (controls) Family history of the dz |
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•Compares degree of concordance for a trait in MZ vs. DZ twins reared together or apart •The greater the difference, the greater the heritability •Concordance <100% means there must be an environmental component
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| Correlation coefficient (r) |
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Definition
•Ranges from -1 to +1 •-1 = perfect negative correlation •+1 = perfect positive correlation •0 = no correlation •Measures the correlation of particular physiological qualities among relatives
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| Heritability (from twin study) = |
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Variance in DZ pairs - Variance in MZ pairs Variance in DZ pairs |
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Cancer: •In some form will strike more than ____ of the population in their lifetime •The primary risk factor = ______ •Accounts for more than _____ of all deaths •In developed countries, its responsible for more than ___ of the total cost of medical care |
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| Inherited vs. Sporadic cancer |
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Definition
•Inherited = initial cancer causing mutation is inherited through the germline (usually in a dominant pattern) •Sporadic = originates from the accumulation of mutations in a single somatic cell *only about 5% of cancers are hereditary*
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| For a tumor to be cancer it must also be ______ |
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| Cytogenic changes of cancer |
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Definition
•Aneuploidy: deletion or duplication of entire chromosomes •Aneusomy: deletion of duplication of chromosome segments •Gene amplification: segments of chromosomes are replicated multiple times •Chromosomal translocations: exchange of segments b/n chromosomes
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Some CA's (such as CML) are caused by translocation events, creating hybrid genes that activate cell division, such as: |
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Definition
•Philadelphia chromosome (1st example of translocation causing CA) -C-ABL gene (Chr 9) is connected to the BCR gene (Chr 22) -Hybrid gene encodes an abnormal protein that signals CML cells to divide
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Imatibib (Gleevec) Inactivates the BCR-ABL protein, stopping cancer cell division |
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•Expression of BCR-ABL oncogene → clonal expansion of tranformed hematopoietic progenitor cells → increases circulating myeloid cells •Accounts for 15% of adult leukemia •Incidence = 1-2 per 100,000 •Approx. 95% of pts with CML have Philadelphia chromosome •During dz progression 50-80% of pt's will have their tumor cells acquire additional chromosomal changes, another Philadelphia chromosome, or both |
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0 (because somatic mutation)
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Term
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•Arises in retinoblasts (embryonic retinal cells that disappear at ~2 yrs of age) •Usually occurs only in children (b/c more mature retinal cells don't transform into tumors) •Usual dx = 1-3 y.o. •Caused by mutations in the RB1 gene (Chr 13) -Encodes pRB protein (tumor suppressor protein)
that controls the G1/S transition in cell cycle
(without pRB cell division = uncontrolled)
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| Familial vs. Sporadic Retinoblastoma |
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Definition
•Familial -85-95% chance of dvlping the dz if gene inherited
-Usually involves both eyes and occurs earlier in life (30% of pts affected unilaterally)
•Sporadic -Usually involves 1 eye and occurs later in life
(70% of patients affected bilaterally)
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