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Flashcards in Polygenic Disease And Major Histocompatability Complex Deck (21)

Define polygenic diseases

Influenced by combined actions of two of more genes
Exhibit complex inheritance patterns
May be considerable environmental influence
Many chronic diseases
Having the gene increases your risk of getting the disease


Monogengic disease features

Pedigree is diagnostic
100% concordance in mz twins
High risk to relatives
Low pop freq
Environmental factors insignificant


Polygenic features

Pedigree is not diagnostic
Concordance is less than 100% in mz twins
Risk to relatives often low
High freq in pop
Significant environmental influences
Polymorphisms present in pop
Genes have a cumulative effect to increase risk


Examples of polygenic diseases

Coronary heart disease
Manic depression
Systemic lupus erythematosus
Rheumatoid arthritis
Beckets disease


Genetic associations, Threshold model

Several but not unlimited number of genes involved in phenotype
No dominance or recessivity
Genes act in an additive way-> add or detract from phenotype
Environment produces final phenotype
Distribution of gene variations shows standard distribution curve
Increasing the number of disease alleles moves you closer to or over the threshold for having the disease
Relatives share genes-> at higher risk


What is a Major Histocompatability Complex

Same as human leukocyte antigen
Multigene complex
Contains MHC class 1 and 2 genes and other immune function related genes
Polymorphic-> multiple variants of each gene
Polygenic-> each individual has a set of MHC protiens with different ranges of peptide binding
Co dominant expression of maternal and paternal halo types
Important in responses to pathogens/self tollerance
Key role in susceptibility to autoimmune disease


MHC Class 1

In all nucleated cells
Types A,B and C
Antigen presentation of self peptides for immune surveillance-> self tolerance
Relate to chronic autoimmune disease


MCH Class 2

Leukocytes-> phagocytotic cells, dendritic cells, b lymphocytes
Types DP, DQ, DR
Specific antigen presenting cells for stimulation of T cell activation-> response to pathogens


MHC and peptide presentation

Anchor residues-> from floor of peptide binding cleft of its walls
Interact with peptide-> select peptide that can bind
Dictate which peptides are presented
Strong selective favour of pathogens that can escape presentation


Ankylosing spondylitis overview

Chronic autoimmune arthritic inflammation
Affects spine to pelvis with possible involvement of other joints-> fusion of spine
Targets fibrocartilage enthesis-> attatchment points of tendons etc
Onset early adult life


Ankylosing spondylitis HLA allele and risks

HLA allele-> B27 gives relative risk of 87.4% chance
31 different B27 alleles
3:1 male to female
MZ twin concordance 63%
DZ twin concordance 12%
90% of ankylosing spondylitis patients of B27 positive
4-8% of pop B27 positive only 5% if them develope AS
Therefore B27 only contributes 40-50% of risk
Relative risk to 1st degree relative is 5-16x higher than another B27 positive person
Heritability is >90%


AS B27 mechanism

Possibly by T cell activation
B27 allele variant alters peptide presented to immune system?
Poor presentation in thymus may lead to escaped autoreactive cells?
Presenation of microbial antigen mimicking self antigen?
Overall auto reactivity to self antigens is triggered in the periphery


AS non HLA influences

GWAS suggests a number of non-HLA AS associated-> around 10 other genes-> all genes with immune functions
IL23R is receptor for proinflammatory IL23
ERAP/ARTS 1 is an ER aminopeptidase involved in antigen processing
TNFR1 is the receptor for TNF alpha-> medicates inflammation


Rheumatoid arthritis overview

Most common inflammatory joint disease
1% of pop
Chronic inflammation and destruction of synovial joints and other tissue involvement


RA, HLA and risk factors

HLA allele-> DR4-> relative risk of 4.2
MZ concordance 12-16%
DZ concordance 3.5%
Genetic factors 60% of risk, 40% of this is from HLA DR4
DR4-> DRB1 and other alleles


RA HLA shared epitope

Some DRB alleles demonstrated a shared epitope
5 AA
Associated with RA positive for anti citrullinated peptide antibodies


RA and autoimmunity. Rheumatoid factor and citrullinated protien antibodies

Rheumatoid factor:
IgG-IgM complexes
Not specific for RA
Don't appear to cause RA
Citrullinated protien antibodies:
Anti cp
50-70% of RA patients
<2% of healthy
Detectable long before disease onset
May have a causal role as 90-95% specific for RA


RA potential mechanisms

SE motif alters peptides presented to T cells?
Citrullinated peptides load into DRB1 variants better?
Second risk factor-> PAD4
30 other risk loci located by GWAS
Smoking is a significant risk factor for APC+RA DRB1+
Periodontal disease produces PAD4


Ischaemic heart disease

Leading causes of death
Occurs secondary to atherosclerosis in most cases
Increased LDL decreased HDL in most cases
Monogenean form-> familial
Apo-A 1 gene-> low HDL apo A-1 and C-3
Apo C-3-> hypertriglyceridaemia
Hypervariable region near insulin gene
Apo-E altered LDL
Risk increased by:
Type 2


Diabetes mellitus

General pop 0.3%
Relatives 6%
HLA identical relative 18%
Identical twins 30%
HLA DR3/4 highly significant-> 25x increased risk
But actual association is with DQB which is linked to DR3
Homozygous for ASP at 57th AA in DQB -> resistant to type 1
Homozygous for non-ASP at 57th AA susceptible


Diabetes mellitus HLA mechanisms

Involves autoreactive T-Cells and destruction of islet cells
T cell recognition of islet peptides
-> DQB alleles present self peptide to autoreactive T cells?
-> DQB alleles don't present self peptides well during thymic education?
Environmental triggers
Other genes:
Insulin gene-> reduced insulin expression in thymus
PTPN22-> tyrosine phosphate involved in suppression of T cell activation
CTLA-4-> reduced inhibition of T cell activation and/or reduced Treg activity

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