Lecture 4- Multiple Sclerosis Flashcards
multiple sclerosis
most common CNS demyelinating disease- accumulating disability
epidemiology of MS
~23 000 cases in australia (1:1000)
onset of MS
most commonly in early adulthood (25-40yrs)
subtypes of MS
relapsing-remitting (60%) secondary progressive (30%)- followup to relapsing remitting primary progressive (10%)- w/o relapsing remitting
describe MS progression
CNS inflammation–>demyelination–> remyelination–> progressive neurodegeneration
inflammatory phase
immune cells led by T-cell mediated autoimmunity cross BBB, have reaction against myelin (target ODs)
demyelination and remyelination of axons
after inflammatory phase- OD progenitor cell make new myelin
process continues until pool of progenitor cells depleted
progressive neurodegeneration
failure for new myelin synthesis
periventricular plaques
95% of MS patients
white spots on MRI- water filled holes in brain due to demyelination and cell death in white matter tract
more common in which gender?
females 2-3 times fold
more common in which ethnicity?
north european ancestry
environmental risk factors
EBV, sunlight/vitD
treatments
are disease modifying; modulate course of disease and slow it down
e.g. Ocrelizumab- humanized anti-CD20 mAb
coding and non coding DNA in genome
1% protein coding; rest non-coding DNA
non coding- important in gene regulation
SNPs
most common known genetic variation
can be used as genetic markers in mapping
usually bi-allelic- both alleles of a gene
GWAS
compare SNP allele frequencies between groups of individuals e.g. cases and controls across genome
statistically significant difference in allele frequencies implies SNP in close genomic proximity to causal genetic locus
- diseases from families not applicable
- applicable to genetically complex common diseases
why is identifying genes from GWAS hits hard?
- top GWAS SNPs do not reside in genes, only 5% in protein coding regions
- tend to be found in regulatory regions which influence gene regulatory sites
SNPs effect on predisposition of gene
small effects to predisposition on its own
- lots together increase genetic burden and predisposition
ANZgene
GWAS identified two MS susceptibility genes
the two MS susceptibility genes identified by ANZgene GWAS
CD40 and CYP27B1
HLA (DR2) association with MS
interaction with T cell receptor
why did we use GWAS?
family based genetic studies not successful in identifying highly penetrant genetic mutations
GWAS results
false positive associations really high, therefore replication very important
validation cohort important
CD40
associated with susceptibility to MS
chr 20q13
involved in Ag presentation
member of TNF receptor family
function of CD40
Ag presentation
- important regulatory of cellular and humoral immunity
- co stimulatory molecule expressed on Ag presenting cells
- CD40-CD40L binding expressed on surface of activated CD4 helper T cells, activates APCs
CYP27B1 gene
associated with MS
chr 12q13-14
involved in vitD synthesis
function of CYP27B1 gene
involved in vitD synthesis
- provides instructions for making vitD enzyme (hydroxylase) which converts vitD to active form, regulates calcium metabolism and and immune system via VDR
MS risk
mainly driven by genes with immune function; dysregulation
what triggers onset of MS?
unclear- combination of genetic and environmental
major genetic risk locus
HLA complex
MS loci identified so far?
explain 25% of variance in risk
1/3rd of loci associated with other autoimmune diseases
genetic associations for MS phenotype?
no genetic basis for clinical heterogeneity i.e. subtypes
NGS
detection and analysis of known (SNPs) and unknown pathogenic mutations
targeted DNA sequencing
specific genomic regions
whole exome sequencing
only protein coding regions
whole genome sequencing
all protein coding and non coding regions
e.g. look for particular mutations that has allowed neurons to survive as long as it has
targeted RNA sequencing
specific gene transcripts
whole genome RNA sequencing
entire transcriptome
