17. Complex inheritance (p10) Flashcards
Frequency of genetic diseases of different inheritance
Chromosomal: 4/1000
Monogenic: 20/1000
Multifactorial: 600/1000
Environmental influence on inheritance
Major genes:
- Monogenic
- Variable penetrance and expressivity
- Ecogenetic traits
Minor genes:
- Polygenic
- Multifactorial
Totally genetic diseases examples
- Cystic fibrosis
- Duchenne muscular dystrophy
Characteristics of most of the human traits
- Polygenic
- Continuous - quantitative traits
- Additive effects (not dominant and recessive)
- Multifactorial/complex (environment also involved)
Phenotypes distribution
Show continuous, normal distribution in the population.
- As the number of genes increases, so does the number of phenotype categories
Skin color inheritance
Supposing 3 additive genes
- Normal distribution
Complex disorders (discontinuous)
Frequency of diseases shows ethnic group and sex dependency
- Congenital malformations
- Chronic adult diseases
Characteristics of multifactorial traits, diseases
- 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)
Methods for indentification of genetic background
1) Familial aggregation
2) Twin studies
3) Adoption studies
Calculation of familial aggregation
λfamily/λpopulation (λr=1 - no genetics, λr>1 - genetics)
λr: relatives
λs: siblings
λp: parents
Example: CF (λs = 750) definitely genetically determined
DM inheritance
- Genetic influence in T1DM higher than in T2DM
- Environment affect both types
How identical are monoz. vs diz. twins?
Monoz: 100 %
Dizygotic: 50 %
Concordance, discordance analysis in twins
- If genetic factors play more important role - concordance of monozygotic will be higher than dizygotic
- If only environmental factors - concordance values of monozygotic = dizygotic
2 theories of genes involved in complex inheritance
1) Many genes with minor effect
2) Few genes with high penetrance
Identification of genes involved in multifactorial traits, diseases
1) Hypothesis driven (linkage analysis)
2) Hypothesis free (GWAS)
* Methods: molecular genetic methods, CGH, microarray etc
Finding linkage disequilibrium
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
Haplotype
Allele combinations inheriting together (no recombination between them)
Congenital malformation: neural tube defects (NTDs)
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
Effect of folate
Folic acid/B9 vitamin
- DNA methylation => epigenetics
- DNA synthesis
- Synthesis of few amino acids
Odds ratio, OD
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
T1DM: polymorphisms and mechanisms - HLA
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
Sensitizing MHCII alleles
- DRB1*0301
- DQA1*0501
- B10201/DRB10401-DQA10301-DQB0302
Sensitizing MHCI alleles
- HLA-B: B*3906
- HLA-A: A*2402
Protective alleles (MHCI?)
HLA-B: B*5701
HLA-A: A*1101
T1DM: polymorphisms and mechanisms
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)
T1DM: polymorphisms and mechanisms - PTPN22
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
T1DM: polymorphisms and mechanisms - INS
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)
T1DM: polymorphisms and mechanisms - IL2RA
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
T1DM: polymorphisms and mechanisms - CTLA-4
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
T1DM - known or suspected environmental factors
- 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
Atherosclerosis genes
- ALOX5AP and ALOX5
- ANGPTL3
- OX40L or TNFSF4
Atherosclerosis genes - ALOX5AP and ALOX5
“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)
Atherosclerosis genes - ANGPTL3
“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)
Atherosclerosis genes - OX40L or TNFSF4
“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
Atherosclerosis - known/suspected environmental factors
- Lifestyle: smoking, unbalanced diet, low activity, stress
- Other diseases: dyslipoproteinemia, diabetes, high blood pressure, obesity, depression (?)
- Infection: chlamydia pneumonia (?)
