Multifactorial Diseases Flashcards
What ratio is used in studies to determine heritability of a disease?
λR - disease frequency among relatives / disease frequency in entire population
higher value = stronger genetic contribution
λR = 1 means no genetic background
How can the λR ratio be measured differently to assess disease “accumulation” within a family?
(And what is the value of this different ratio in different forms of diabetes?)
λS - freq. among siblings / frequency in population
MODY = 50 (very heritable)
T1DM = 15
T2DM = 3.5
(bc of higher incidence of T2 overall, but family clustering is actually stronger for T2)
What are the terms for investigating heritability among identical twins?
(What can differences btwn mono-/dizygotic twin’s tendencies to share a disease indicate about its heritability?)
Discordance - when twins don’t both have the same diseased/healthy state
Concordance - when twins share the diseased/healthy state
(higher concordance in mono- than dizygotic twins suggests genetic factors)
How can environmental factors be investigated in the development of multifactorial disease?
Adoption Studies
if there is strong concordance with adopted parents, environment is likely decisive in disease development
What are some environmental factors possibly involved in T1DM development?
(6)
- Enteroviruses (Coxsackie B)
- No breastfeeding / early cow milk exposure
- Low vitamin D intake
- Stress
- Gut Microbiome Issues
- Low Symbiote Exposure
How is MODY inherited?
(what genes are involved?)
AD inheritance
glucokinase and hepatocyte nuclear factor (HNF-1/4 alpha)
What is a continous vs. a discontinous trait?
continuous - has a scale/spectrum of expression, usually with a normal/Gaussian distribution (ex = height)
discontinous - is either present or absent
How do the frequencies of poly-, oligo- and monogenic diseases compare?
poly > oligo > monogenic
What is antagonistic pleiotropy?
example?
when a variant is advantageous at one age, but harmful at another
(technically just when one gene controls for >1 trait, and one trait is beneficial, while the other is harmful)
ex: strong inflammatory responses are helpful in young, but harmful in old when inflammatory diseases like atherosclerosis, RA + Alzheimers are more common; TLR4 Asp299Gly SNP > weak Gram(-) response, frequent in centenarians
What are some genes with variants related to reduced insulin secretion in T2DM?
+ their mechanisms
- CDKs (AL1/N2A/N2B) - variants can result in decreased B-cell mass
- KCNJ11 - can cause K+ channel closure dysfunctions
What are 2 genes with variants related to insulin resistance in T2DM?
+ their mechanisms?
- FTO - “fat mass and obesity-related gene”, codes for a hypothalamic protein; deficiency contributes to T2DM
- IRS1 - “insulin receptor substrate 1”, variants > insuling signaling changes > T2DM
Pharmacogenomic studies have shown increased efficacy of certain drugs for certain forms of T2DM and MODY.
Which drugs for which forms/gene variants?
- KCJN1/PPARG in T2DM - sulfonylureas + glitazones
- GCK-MODY - diet
- HNF1A-MODY - low dose sulfonylurea
How does a continous trait “become” discontinous?
when it passes a certain threshold to produce disease
ex: fasting blood sugar levels are on a continous spectrum, but above a certain point will qualify as DM
In multifactorial diseases…
- how are they related to gender?
- how at-risk are first-degree relatives of the less-affected gender?
- how is the concordance rate in mono/dizygotic twins?
- occur more frequently in one gender, but not sex-linked/limited
- first degree relatives of individual of less-affected gender have higher disease risk
- concordance rate in twins contradicts Mendelian proportions
In multifactorial diseases…
- what influence can environmental factors have?
- how does ethnicity play a role?
- how does degree-of-relationship affect risk?
- environment can increase or decrease risk
- disease occurs more frequently in certain ethnicities
- risk of affected relatives decreases quickly with degree of relationship
