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GENES AND SLE
Dr M Tahir Chaudhry
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SLE
Archetypal systemic autoimmune disease
Genetically complex disease withheterogeneous clinical manifestations
Understanding its pathogenesis remains aclinical challenge
Multiple abnormalities of both innate and
adaptive immune systems Immunological dysfunction precedes clinical
symptoms by many years
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Genetic basis of SLE
Recognized since 70s observational studies
Concordance rates 24-57% monozygotic Vs.2-5% dizygotic twins
Sibling risk ratio of 20-29
5-12% of relatives of SLE patients havedisease, many more have asymptomatic lupus
antibodies 27% children of 195 mothers with lupus found
to have positive ANA
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MHC and HLA
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Overview
Cluster of genes on short arm of chromosome6
Encode Human Leukocyte AntigensHLA
Broadly 2 classes of HLA present on surface ofWhite Blood Cells and many other tissues
Main role recognition of SELF from NONSELF.
Allows immune system to fight pathogens andmalignancies
BUT also transplant rejections andautoimmunity
Also gene for Complement components,
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Major HistocompatibilityComplex
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The genetic model for SLE
The basics
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Common disease, common
variant
SLE is polygenic, does not follow mendelianrules of inheritance
Some rare cases MUTATIONS e.g.
complement components
Majority due to common variants foundthroughout the population
SNPs - each contributes modestly to diseaserisk
SLE susceptibility defined by geneticvariations at multiple loci
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Contd.
HOWEVER variants much more commonthan prevalence of SLE
Essential pre-requisite but do not cause SLE
per se Protective mechanisms counter the risk
conferred immune redundancy, regulatorypathways and protective genetic variants!
Environmental factors likely trigger for diseaseonset
Likely common triggers in unison orsuccession, over a short period of time in agenetically programmed host
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Threshold Liability
Genetic AND environmental susceptibilityeffects Critical threshold metSLEmanifests
Genetic liability determined from birth bycomplement of inherited susceptibility genes
Many susceptibility genes + minor
environmental trigger = disease threshold Little genetic risk SLE may never develop
even with strong environmental triggers
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SLE candidate genes
1970-2007: slow progress about 9 linkageregions identified by linkage studies
2007 onwards: Advent of high density genome
wide scans, powerful computing technologies andpooling of resources
RESULT- staggering increase in understanding
the genetics of SLE esp. in past 3 years.
>25 susceptibility genes identified
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Genome Wide AssociationStudies GWAS- series of landmark trials
Whole genome scans of patients and controls to
detect differences in SNPs
SLEGEN: Up to half a million SNPs scanned inmore than 10,000 individuals of north European
descent
Many new candidate genes identified, includingsome with no known immune function
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Most Important SLE Genes
MHC: HLA-DR2, HLA- DR3(class II); MSH5(classIII)
Innate immunity: IRF5, STAT4, IRAK1- mostinvolved in interferon pathways
Lymphocyte signaling pathways: BANK-1, LYN,BLK, PTPN22
Complement and immune clearance:
C4A,C2, C1q,B rare mutations, confer highestrisk
ITGAM; FCGR3A
Chromosome X: Klinefelters, IRAK1
Mystery genes: KIAA1542, PXK
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SLE pathogenesis- a genetic
hypothesis
1. Auto-antigen generation: ITGAM, IRF5
2. Auto-antigen recognition: FCGR2A,FCGR3B, ITGAM
3. Auto-antigen presentation: MHC
4. Auto-reactive T cells: STAT4, IRF5, PTPN22
5. Auto-reactive B cells: BLK, BANK1, LYN
6. Auto-antibodies, immune complex generation
7. Tissue damage
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Recent GWAS
Some susceptibility gene variants are common, othersvary amongst ethnic/racial populations
There are individual gene variants that predispose to
multiple autoimmune diseases
Susceptibility genes strongly related to Anti-dsDNAantibody + SLE, but not to antibody SLE
Genotype-Phenotype associations: only some diseasemanifestations relate to susceptibility genes whereasothers do not.
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Interferon
Lupus long recognized as a disease with highactivity of type I Interferons
Many susceptibility genes related to IFN
pathways resulting in increase activity orsensitivity to IFN
Clinical biomarkers based on IFN or its targetsbeing developed. Potential to predict relapses
e.g. lupus nephritis Clinical trials are assessing safety and efficacy
of monoclonal antibody inhibitors of IFN
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Summary
Major advances in identification of SLEsusceptibility genes
Genetic risk conferred by multiple genes
Genes on their own do not result in disease,environmental influences are also important
Little is known about the function of hithertounknown genes, gene-gene interactions and
epigenetic influences Research translating into clinical practice is on
the horizon
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Sunrise ByronBay
THANK YOU
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