GENES & SLE

8/3/2019 GENES & SLE

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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


22/22

Sunrise ByronBay

THANK YOU

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GENES & SLE