17. Complex inheritance (p10)

Question 1

Frequency of genetic diseases of different inheritance

Answer 1

Chromosomal: 4/1000
Monogenic: 20/1000
Multifactorial: 600/1000

Question 2

Environmental influence on inheritance

Answer 2

Major genes:

• Monogenic
• Variable penetrance and expressivity
• Ecogenetic traits

Minor genes:

• Polygenic
• Multifactorial

Question 3

Totally genetic diseases examples

Answer 3

• Cystic fibrosis

- Duchenne muscular dystrophy

Question 4

Characteristics of most of the human traits

Answer 4

• Polygenic
• Continuous - quantitative traits
• Additive effects (not dominant and recessive)
• Multifactorial/complex (environment also involved)

Question 5

Phenotypes distribution

Answer 5

Show continuous, normal distribution in the population.

- As the number of genes increases, so does the number of phenotype categories

Question 6

Skin color inheritance

Answer 6

Supposing 3 additive genes

- Normal distribution

Question 7

Complex disorders (discontinuous)

Answer 7

Frequency of diseases shows ethnic group and sex dependency

• Congenital malformations
• Chronic adult diseases

Question 8

Characteristics of multifactorial traits, diseases

Answer 8

• No Mendelian pattern of inheritance (contradicted by concordance in monoz. and diz. twins)
• Occurs more often in a specific ethnic group and in one gender, but not sex-linked nor sex-limited trait
• Recurrence risk increase with number of affected children in a family and severity of affected
• Marriage between relatives moderately increase the risk
• Risk of affected relatives falls off very quickly with the degree of relationship - First degree relatives of individuals belonging to the more rarely affected gender have a higher risk of bearing the disease)
• Environment can influence the risk of disease (pos/neg)

Question 9

Methods for indentification of genetic background

Answer 9

1) Familial aggregation
2) Twin studies
3) Adoption studies

Question 10

Calculation of familial aggregation

Answer 10

λfamily/λpopulation (λr=1 - no genetics, λr>1 - genetics)

λr: relatives
λs: siblings
λp: parents
Example: CF (λs = 750) definitely genetically determined

Question 11

DM inheritance

Answer 11

• Genetic influence in T1DM higher than in T2DM

- Environment affect both types

Question 12

How identical are monoz. vs diz. twins?

Answer 12

Monoz: 100 %
Dizygotic: 50 %

Question 13

Concordance, discordance analysis in twins

Answer 13

• If genetic factors play more important role - concordance of monozygotic will be higher than dizygotic
• If only environmental factors - concordance values of monozygotic = dizygotic

Question 14

2 theories of genes involved in complex inheritance

Answer 14

1) Many genes with minor effect

2) Few genes with high penetrance

Question 15

Identification of genes involved in multifactorial traits, diseases

Answer 15

1) Hypothesis driven (linkage analysis)
2) Hypothesis free (GWAS)
* Methods: molecular genetic methods, CGH, microarray etc

Question 16

Finding linkage disequilibrium

Answer 16

Two alleles are said to be in linkage disequilibrium if they inherit together more frequently than expected
- Finding genetic markers (SNP, VNTR or known gene)
that inherits together with the given phenotype
*Les mer om linkage equilibrium

Question 17

Haplotype

Answer 17

Allele combinations inheriting together (no recombination between them)

Question 18

Congenital malformation: neural tube defects (NTDs)

Answer 18

Failure of neural tube closure

• Spina bifida
• Anencephaly
• Higher occurence in Hispanics
• Reduce risk: folic acid, multivitamins
• Rates have declined lately - due to screening+diet

Question 19

Effect of folate

Answer 19

Folic acid/B9 vitamin

• DNA methylation => epigenetics
• DNA synthesis
• Synthesis of few amino acids

Question 20

Odds ratio, OD

Answer 20

The ratio of the odds of an event (disease) occurring in one group (influenced by a given factor) vs another group (without the factor)
- OD = (A/C) : (B/D)
A: disease+factor
C: disease - factor
B: factor + no disease
D: no factor + no disease

Question 21

T1DM: polymorphisms and mechanisms - HLA

Answer 21

HLA-DR/DP (MHC II) and HLA-A/B (MHC I)

• Significance of some autoantigen-peptides binding to given HLA alleles
• Autoantigens: preproinsulin, GAD++
• MHC/peptid combo decreases the central and peripheral tolerance and increases the risk of autoimmune diabetes
• MHCI and II alleles can be either sensitizing or protective

Question 22

Sensitizing MHCII alleles

Answer 22

• DRB1*0301
• DQA1*0501
• B10201/DRB10401-DQA10301-DQB0302

Question 23

Sensitizing MHCI alleles

Answer 23

• HLA-B: B*3906

- HLA-A: A*2402

Question 24

Protective alleles (MHCI?)

Answer 24

HLA-B: B*5701

HLA-A: A*1101

Question 25

T1DM: polymorphisms and mechanisms

Answer 25

1) HLA-DR/DP (MHCII) and HLA-A/B (MHCI) 2) PTPN22 (prot tyrosine phosphatase, non-R type 22) 3) INS (insulin) 4) IL2RA (IL2 R alpha chain, CD25) 5) CTLA-4 (cytotoxic T-cell Ag 4, CD152)

Question 26

T1DM: polymorphisms and mechanisms - PTPN22

Answer 26

Protein tyrosine phosphatase, non-R type 22 - Regulates T cell activation (dephosp kinases involved in TCR signal transduction) - Gain-of-function mutation (AA subst - R620W) - Cause abnormal T cell prolif. and cytokine prod. - Can be a therapeutic target

Question 27

T1DM: polymorphisms and mechanisms - INS

Answer 27

Insulin - VNTR polymorphism close to insulin gene - Decreased insulin expression in thymus => decreased central tolerance => more autoreactive cells in periph * Above caused by Class I alleles, while Class III alleles are protective (and dominant)

Question 28

T1DM: polymorphisms and mechanisms - IL2RA

Answer 28

IL2 receptor alpha chain, CD25 - Mainly expressed in Treg, naive and memory T cells - Its regulated expression is involved in supression on T cell response - Noncoding variants decrease CD25 expression and disturb T cell regulation

Question 29

T1DM: polymorphisms and mechanisms - CTLA-4

Answer 29

Cytotoxic T cell Ag 4, CD 152 - Inhibitory T cell costim. R - Polymorphism at the 3' end of CTLA-4 gene modify expression level of soluble forms of CTLA-4 => decreased tolerance

Question 30

T1DM - known or suspected environmental factors

Answer 30

- Early childhood events: cow milk, too early nursing - Drugs: streptozotocin, pentamidin, interferons, some interleukins - Infections: mumps, coxsacckie, rubella, enterovirus, echovirus, sometimes HepB and MMR vaccines

Question 31

Atherosclerosis genes

Answer 31

- ALOX5AP and ALOX5 - ANGPTL3 - OX40L or TNFSF4

Question 32

Atherosclerosis genes - ALOX5AP and ALOX5

Answer 32

"Arachidonate 5-lipoxygenase-activating protein" - ALOX5AP translocates from cytoplasm to the plasmamembrane and activates ALOX5 enzyme - ALOX5 synthesizes LTB4 - are in macrophages - Macrophages support plaque formation (recruit inflammatory cells) - ALOXAP polymorphisms => MI and stroke - ALOX5 promoter polymorphisms => ALOX5 expression => CIMT (carotid intima-media thickness)

Question 33

Atherosclerosis genes - ANGPTL3

Answer 33

"Angiopoietin-like 3" - Polymorphism => coronary atherosclerosis - ANGPTL3 inhibits lipoprotein lipase activity => increasing cholesterol and TAG levels - Binds to integrin a(v)b(5) => plaque formation (change endothel activation and binding to ECM)

Question 34

Atherosclerosis genes - OX40L or TNFSF4

Answer 34

"Tumor necrosis factor ligand superfamily, member 4" - In endothels: cross binding of OX40L causes CCL5 chemokine and IL-6 release => T cell and macrophage infiltration => plaque formation

Question 35

Atherosclerosis - known/suspected environmental factors

Answer 35

- Lifestyle: smoking, unbalanced diet, low activity, stress - Other diseases: dyslipoproteinemia, diabetes, high blood pressure, obesity, depression (?) - Infection: chlamydia pneumonia (?)