Polygenic Disease And Major Histocompatability Complex Flashcards
Monogengic disease features
Pedigree is diagnostic 100% concordance in mz twins High risk to relatives Low pop freq Environmental factors insignificant
Define polygenic diseases
Influenced by combined actions of two of more genes
Multifactoral/complex
Exhibit complex inheritance patterns
May be considerable environmental influence
Many chronic diseases
Having the gene increases your risk of getting the disease
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 Diabetes Epilepsy Hypertension Schizophrenia Manic depression Systemic lupus erythematosus MS Rheumatoid arthritis Psoriasis Beckets disease Crohns
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