Lecture 4- Multiple Sclerosis

Question 1

multiple sclerosis

Answer 1

most common CNS demyelinating disease- accumulating disability

Question 2

epidemiology of MS

Answer 2

~23 000 cases in australia (1:1000)

Question 3

onset of MS

Answer 3

most commonly in early adulthood (25-40yrs)

Question 4

subtypes of MS

Answer 4

relapsing-remitting (60%)
secondary progressive (30%)- followup to relapsing remitting
primary progressive (10%)- w/o relapsing remitting

Question 5

describe MS progression

Answer 5

CNS inflammation–>demyelination–> remyelination–> progressive neurodegeneration

Question 6

inflammatory phase

Answer 6

immune cells led by T-cell mediated autoimmunity cross BBB, have reaction against myelin (target ODs)

Question 7

demyelination and remyelination of axons

Answer 7

after inflammatory phase- OD progenitor cell make new myelin

process continues until pool of progenitor cells depleted

Question 8

progressive neurodegeneration

Answer 8

failure for new myelin synthesis

Question 9

periventricular plaques

Answer 9

95% of MS patients

white spots on MRI- water filled holes in brain due to demyelination and cell death in white matter tract

Question 10

more common in which gender?

Answer 10

females 2-3 times fold

Question 11

more common in which ethnicity?

Answer 11

north european ancestry

Question 12

environmental risk factors

Answer 12

EBV, sunlight/vitD

Question 13

treatments

Answer 13

are disease modifying; modulate course of disease and slow it down
e.g. Ocrelizumab- humanized anti-CD20 mAb

Question 14

coding and non coding DNA in genome

Answer 14

1% protein coding; rest non-coding DNA

non coding- important in gene regulation

Question 15

SNPs

Answer 15

most common known genetic variation
can be used as genetic markers in mapping
usually bi-allelic- both alleles of a gene

Question 16

GWAS

Answer 16

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

Question 17

why is identifying genes from GWAS hits hard?

Answer 17

• 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

Question 18

SNPs effect on predisposition of gene

Answer 18

small effects to predisposition on its own

- lots together increase genetic burden and predisposition

Question 19

ANZgene

Answer 19

GWAS identified two MS susceptibility genes

Question 20

the two MS susceptibility genes identified by ANZgene GWAS

Answer 20

CD40 and CYP27B1

Question 21

HLA (DR2) association with MS

Answer 21

interaction with T cell receptor

Question 22

why did we use GWAS?

Answer 22

family based genetic studies not successful in identifying highly penetrant genetic mutations

Question 23

GWAS results

Answer 23

false positive associations really high, therefore replication very important
validation cohort important

Question 24

CD40

Answer 24

associated with susceptibility to MS
chr 20q13
involved in Ag presentation
member of TNF receptor family

Question 25

function of CD40

Answer 25

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

Question 26

CYP27B1 gene

Answer 26

associated with MS chr 12q13-14 involved in vitD synthesis

Question 27

function of CYP27B1 gene

Answer 27

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

Question 28

MS risk

Answer 28

mainly driven by genes with immune function; dysregulation

Question 29

what triggers onset of MS?

Answer 29

unclear- combination of genetic and environmental

Question 30

major genetic risk locus

Answer 30

HLA complex

Question 31

MS loci identified so far?

Answer 31

explain 25% of variance in risk | 1/3rd of loci associated with other autoimmune diseases

Question 32

genetic associations for MS phenotype?

Answer 32

no genetic basis for clinical heterogeneity i.e. subtypes

Question 33

NGS

Answer 33

detection and analysis of known (SNPs) and unknown pathogenic mutations

Question 34

targeted DNA sequencing

Answer 34

specific genomic regions

Question 35

whole exome sequencing

Answer 35

only protein coding regions

Question 36

whole genome sequencing

Answer 36

all protein coding and non coding regions | e.g. look for particular mutations that has allowed neurons to survive as long as it has

Question 37

targeted RNA sequencing

Answer 37

specific gene transcripts

Question 38

whole genome RNA sequencing

Answer 38

entire transcriptome