13. Genomic approach of complex inheritance (wk.9) Flashcards
Solely environment affected “diseases”
- Freeze or burn injuries
- Traffic accidents
Examples of genetic diseases (no environment)
- Tay-Sachs
- Marfan syndrome
- Duchenne muscular dystrophy
Multifactorial diseases
Complex diseases
- Genes AND environment contribute
- E.g tumors, Alzheimer disease, birth defects
Diabetes mellitus type 1
- Juvenile autoimmune form
- Cell death
- Insulin deficiency
Diabetes mellitus type 2
- Adult or aged type
- Cell functional defect
- Insulin resistance
MODY
Mature onset diabetes of the young
How to study heritability: family
Comparing frequency in a family to that of the entire population
- λR: frequency family / frequency population
- Higher λR => stronger genetic contribution indicated
- λR=1: no genetic background of trait
- λs: freq. siblings / freq. population
s value of T1DM, T2DM and MODY
T1DM: λs = 15
T2DM: λs = 3.5
*T2 more common, but family clustering of T2 also stronger (?). Both determined also by environment
MODY: s = 50 (monogenic, genetically determined)
How to study heritability
1) Family freq vs population freq
2) Twin studies: discordance vs concordance
- Discordance: one healthy, one sick
- Concordance: both either healthy or sick
- If concordance higher in monoz. twins than diz. twins => suggests genetic role important (e.g diabetes)
How to study environmental effect
1) Adopted children: concordance with biological vs adoptive parents
2) Migration data
3) Epidemiology studies
Possible environmental factors of T1DM
- Enteroviruses (e.g coxsackie B)
- Lack of breast feeding, early exposure to cow milk
- Decreased vitamin D uptake
- Stress
- Aberrant gut biome
- Decreased symbiote exposure
Possible environmental factors of T2DM
- Low exercise
- High fat diet
- Stress
- Social environment
- Smoking
- Soda with added sugar
Inheritance MODY
Monogenic AD
- GCK, HNF-4 alpha and HFN-1 alpha mutations
Increase in no. of genes/alleles => increased no. of…
…possible phenotypes
- Monogenic: 1 gene => 2 allele => 3 phenotype class
- Normal (Gaussian) distriution
- Continuous or discontinuous trait
- Diseases treshold
Frequency of diabetes
T2DM 20x more common than MODY
Frequency of diseases with genetic background
Negative exponential (hoppbakke)
- Polygenic (most frequent)
- Oligogenic
- Monogenic (least frequent)
Hypotheses for obesity
- Some genes were earlier a selection advantage, but disadvantage today
1) Thrifty gene hypothesis - Save food for starvation period
2) Salt-conserving phenotype - Minimal salt-loosing was advantage in warm climate
- Today - more salt - risk of salt sensitive hypertension
Antagonistic pleiotropy
Variants, which are advantageous in younger age, but harmful in older
- Inflammatory response: chronic diseases in older
- APOE gene: E4 variant (better immune system early life, increased susceptibility for Alzheimer, CAD later)
- Opposite: TLR4 D299G SNP - weaker against G- bacteria, but frequent in people over 100yrs
GWAS results T2DM genes
1) CDKAL1, CDKN2A, CDKN2B: Cdk regulators
2) HNF1A, HNF1B: hepatocyte nuclear factor (monogentic diabetes)
3) IRS1: insulin receptor substrate 1
4) FTO: fat mass and obesity-related gene
* Lær tegning over pathways in T2DM
Genes of reduced insulin secretion T2DM
CDKAL1, CDKN2A & -2B: changes mass of beta cells
KCNJ11: potassium channel dysfunction
Genes of insulin resistance T2DM
FTO: hypothalamic FTO expression changes
IRS1: Insulin receptor signaling changes
Pharmacogenomic results T1DM, T2DM, MODY
T1DM: lifelong insulin
T2DM:
- Metformin primary treatment
- KCNJ11, PPARG: sulfonylureas, glitazones
MODY
- GCK: diet modification
- HFN1A: sulfonylureas (low dose)
