13. Genomic approach of complex inheritance (wk.9)

Question 1

Solely environment affected “diseases”

Answer 1

• Freeze or burn injuries

- Traffic accidents

Question 2

Examples of genetic diseases (no environment)

Answer 2

• Tay-Sachs
• Marfan syndrome
• Duchenne muscular dystrophy

Question 3

Multifactorial diseases

Answer 3

Complex diseases

• Genes AND environment contribute
• E.g tumors, Alzheimer disease, birth defects

Question 4

Diabetes mellitus type 1

Answer 4

• Juvenile autoimmune form
• Cell death
• Insulin deficiency

Question 5

Diabetes mellitus type 2

Answer 5

• Adult or aged type
• Cell functional defect
• Insulin resistance

Question 6

MODY

Answer 6

Mature onset diabetes of the young

Question 7

How to study heritability: family

Answer 7

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

Question 8

s value of T1DM, T2DM and MODY

Answer 8

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)

Question 9

How to study heritability

Answer 9

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)

Question 10

How to study environmental effect

Answer 10

1) Adopted children: concordance with biological vs adoptive parents
2) Migration data
3) Epidemiology studies

Question 11

Possible environmental factors of T1DM

Answer 11

• 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

Question 12

Possible environmental factors of T2DM

Answer 12

• Low exercise
• High fat diet
• Stress
• Social environment
• Smoking
• Soda with added sugar

Question 13

Inheritance MODY

Answer 13

Monogenic AD

- GCK, HNF-4 alpha and HFN-1 alpha mutations

Question 14

Increase in no. of genes/alleles => increased no. of…

Answer 14

…possible phenotypes

• Monogenic: 1 gene => 2 allele => 3 phenotype class
• Normal (Gaussian) distriution
• Continuous or discontinuous trait
• Diseases treshold

Question 15

Frequency of diabetes

Answer 15

T2DM 20x more common than MODY

Question 16

Frequency of diseases with genetic background

Answer 16

Negative exponential (hoppbakke)

• Polygenic (most frequent)
• Oligogenic
• Monogenic (least frequent)

Question 17

Hypotheses for obesity

Answer 17

• 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

Question 18

Antagonistic pleiotropy

Answer 18

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

Question 19

GWAS results T2DM genes

Answer 19

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

Question 20

Genes of reduced insulin secretion T2DM

Answer 20

CDKAL1, CDKN2A & -2B: changes mass of beta cells

KCNJ11: potassium channel dysfunction

Question 21

Genes of insulin resistance T2DM

Answer 21

FTO: hypothalamic FTO expression changes
IRS1: Insulin receptor signaling changes

Question 22

Pharmacogenomic results T1DM, T2DM, MODY

Answer 22

T1DM: lifelong insulin

T2DM:

• Metformin primary treatment
• KCNJ11, PPARG: sulfonylureas, glitazones

MODY

• GCK: diet modification
• HFN1A: sulfonylureas (low dose)