interaction of genes and environment
recurrence risk varies and is determined empirically
H = 2(cmz- cdz)
cmz or cdz =concordance mz or dz.
Type I diabetes (Juvenile Onset or IDDM)
Autoimmunity disease in which the insulin-producing b-cells of the pancreas are destroyed.
Requires administration of insulin to prevent death (wasting due to inability to utilize glucose, acidosis, and ketosis).
Chronic, lifelong condition.
Although treatable, difficult to manage. blindness, limb amputations, kidney failure
Major goals in treatment of type 1 diabetes
1) Use genetic screens/tests to identify at risk individuals.
2) Prevent the destruction of the b-cells by modifying environment (eliminate triggers).
DPT Diabetes Prevention Trial
Large, multicenter, multiyear study of individuals at high risk of developing type I diabetes (children, twins, and siblings of diabetics).
Examining the influence of specific environmental factors on the risk these individuals will develop diabetes.
IDDM-1 locus: HLA class II DR gene. 95% of Caucasians with type I diabetes have DR3 and/or DR4 alleles, these occur in only 50% of the general population.
IDDM-2 locus: A VNTR in the 5’ region of the insulin gene itself, accounts for about 10% of the heritability.
HLA DQ alleles confer resistance to diabetes.
Recurrence and transmission patterns
Recurrence risk will change from population to population, and from family to family! Due to differences in genetic load.
Although clearly genetic, risk cannot be calculated based on degree of relationship (probability of shared genes).
Recurrence risks are determined from empirical data (risk based on direct observation of the population data).
Attributes of Polygenic/Multifactorial Inheritance:
1. Recurrence risk decreases rapidly for more distantly related relatives. Risk is less than would be predicted from coefficient of relationship
2. Recurrence risk varies from family to family (genetic load).
3. Recurrence risk increases if more than one family member affected (indicates higher genetic load)
4. The more severe the expression, the higher the risk (indicates higher genetic load)
5. Recurrence risk higher if proband is of the less commonly affected sex
Relationship between risk and relativeness
If disease is multifactorial, risk decreases more rapidly than predicted from coefficient of relationship.
Polygenetic vs. Multifactorial
Polygenic- involves multiple genes.
Multifactorial- environmental trigger as well as genetic causes.
phenotype distributes across a more or less Gaussian (normal) distribution across a population.
Threshold of liability
disease does not have a normal distribution, but is the result of a continuous underlying liability. If threshold is exceeded, then disease results
Membrane Lipid Composition
Lipid rafts has specific proteins. Thus, there are biochemical activities associated with lipid rafts.
Five Major Phospholipids
Which one is negative?
What groups are attached?
Which are found in lipid rafts?
Phosphatidyl-serine (serine) (-)
Function of Ca2+ in activation of PKC
PKC is a soluble protein in the cytoplasm. After Ca2+ binds to it, PKC moves to the membrane where it binds to phosphatidylserine.
No phosphatidylserine -> no binding -> no function.
Phosphatidylserine exposed on the cell surface serves as a signal to induce neighboring cells (macrophage) to phagocytose the dead cell and digest it.
Types of membrane proteins
Structure important in RBC shape
Connected to actin at junctional complex
Holds RBC biconcave
Rate of difussion depends on
gradient * temp * surface are * solubilty / distance / sqrt(MM)
Osmotic pressure equation
Charactersitics and examples of faciliated transport
Channels (fast mln/sec)
Carrier (slow 1-100/sec) e.g. sugars
Energy sources for Active transport
Na+ driven active transport examples
Na+ driven Cl-HCO3- exchange
3x Na+ / 1 Ca2+ exchanger
Where is H+-driven active transport found?
The H+ gradient powers coupled transport of many solutes across plasma membrane of bacteria and yeast and intracellular membranes of eukaryotes.
Pumps that mantain pH
Pump out H+ from the cell (Na+-H+ exchanger)
Bring HCO3- into the cell (Na+-driven Cl- -HCO3- exchanger)
ATP-driven H+ pump
ATP driven pumps
Na+-K+ Pump (3/2)
Ouabain and pumps
Outbain partially inhibits Na+/K+ pump
This leads to inibition of Na+Ca++ exchanger and the increase Ca++ concentration in cells leading to
Three ways to maintain a very low Ca++ in cell
Na+-driven Ca2+ exchanger
Ca2+ pump in ER membrane
Resting Membrane Potential
Membrane potential change generation or change
Ions are flowing
Charged solutes diffuse due to:
The chemical gradients
Why tissue differ in RMP?
K+ leaking out
Negative molecules too large
Permeability vs. Conductance
High permeability indicates that particle mass moves easily through a membrane.
High conductance indicates that electrical charge moves easily through a membrane.
Potassium leak channel
K+ can leak out anytime (not protein dependent)
Characteristics of action potential
Threshold (all or none)
Suprathreshold vs. Subthreshold
Supratreshold to cause action potential
K+ Na+ channels difference
K+ Open slowly
Na+ Open fast
Na+ channel stages