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From family history to the From family history to the epigenetics of epigenetics of osteoporosisosteoporosis
National Osteoporosis Society Conference National Osteoporosis Society Conference Birmingham November 2016Birmingham November 2016
Dr Trevor ColeDr Trevor ColeConsultant in Clinical and Cancer Genetics West Midlands Consultant in Clinical and Cancer Genetics West Midlands
Regional Genetics Service and Birmingham Health Partners Regional Genetics Service and Birmingham Health Partners AndAnd
Honorary Reader in Medical Genetics University of Honorary Reader in Medical Genetics University of BirminghamBirmingham
[email protected]@bwnft.nhs.uk
In Clinic ResourcesIn Clinic Resources• Professor Neil Gittoes – Consultant EndocrinologistProfessor Neil Gittoes – Consultant Endocrinologist
• Sue Stewart – Clinical Nurse SpecialistSue Stewart – Clinical Nurse Specialist
• Dr Trevor Cole – Consultant Clinical GeneticistDr Trevor Cole – Consultant Clinical Geneticist
• DEXA scanning (not for all appointments)DEXA scanning (not for all appointments)
• Strong links with BCH and transitionStrong links with BCH and transition
Types of OsteoporosisTypes of Osteoporosis
Primary Secondary
Type 1
Type 2
Type 3
Where do the genetic Where do the genetic factors act on BMD and factors act on BMD and
fragilityfragility
Bone Acquisition
Bone Loss
Genomic-Wide Association Studies Genomic-Wide Association Studies (GWAS) and Heritability Studies(GWAS) and Heritability Studies
Mitchell and Yerges-Armstrong Review 2011Summarised 10 GWAS papers
29 Loci “robustly” associated with BMD
These single nucleotide polymorphism accounts for only about 2-6% of variance in spine and femoral neck BMD
By definition each SNP associated with variance in one direction the opposite SNPwill be associated with the opposite effect
What are Single nucleotide What are Single nucleotide Polymorphisms (SNPS)Polymorphisms (SNPS)
A T C G T T T C G C T A ……………………….. GENE OF INTERESTT A G C A A A G C G A T
A T C G T T G C G C T A ……………………….. GENE OF INTERESTT A G C A A C G C G A T
“SLIGHTLY GREATER CHANCE”
“POPULATION CHANCE OR EVEN REDUCED CHANCE
SNP’s may be away from the possible candidate gene or even if within the gene may not have detectable effect on gene function
Will these SNP’s be clinically Will these SNP’s be clinically significant?significant?
Patient 1
Patient 2
Genomic-Wide Association Studies Genomic-Wide Association Studies (GWAS) and Heritability Studies(GWAS) and Heritability Studies
Slemenda et al 1992 Kelly et al 1993111 Male Twin Pairs
Compared MZ and DZ twins
BMD modestly higher MZ twins
Most of heritability eliminated once adjusted for non genetic factors
40 Twin pairs, predominantly female
Studied BMD changes femur and lumber spine in MZ and DZ twins
Estimated 60-80% heritability
Wide confidence interval and only lumber spine values significant
A lot of non genetic noiseA lot of non genetic noise(how much is non genetic?)(how much is non genetic?)
• BMIBMI• SmokingSmoking• AlcoholAlcohol• ActivityActivity• Chronic DiseaseChronic Disease• DrugsDrugs
Type 3 osteoporosisType 3 osteoporosis
• MalignancyMalignancy• CushingsCushings• Gastrointestinal disease, malabsorbtion and Gastrointestinal disease, malabsorbtion and
nutritionalnutritional• Chronic renal failureChronic renal failure• Inflammatory disease – especially RAInflammatory disease – especially RA• Endocrinopathies – hypertyroidism, hypogonadismEndocrinopathies – hypertyroidism, hypogonadism• Drugs Corticosteroids, chemotherapy, anti-Drugs Corticosteroids, chemotherapy, anti-
convulsants….convulsants….
Sounds a mess? Don’t Sounds a mess? Don’t Despair Despair
A way forwardA way forward
For Primary Osteoporosis – a simple solution
For Secondary Osteoporosis – a few illustrative exemplars
London Morphology DatabaseLondon Morphology Database>250 conditions associated with >250 conditions associated with
osteoporosisosteoporosis• Complex syndromes – eg Barakat Complex syndromes – eg Barakat
19961996
• Metabolic - aromatase deficiencyMetabolic - aromatase deficiency
• Mechanical – arthrogryphosis Mechanical – arthrogryphosis syndromessyndromes
Array-CGH methodArray-CGH method
TestGenomic
DNA
Reference Genomic
DNA
Rati
o
Position on Sequence
Cot-1 DNA
Genomic clones or
oligosspotted on glass slide
DNA gain
DNA loss
“Dye-flip” experiments commonly employed
Hadju-Cheney Syndrome and response Hadju-Cheney Syndrome and response to Bisphosphonatesto Bisphosphonates
Examples of Disorders in 2016Examples of Disorders in 2016• Stuve-WiedemannStuve-Wiedemann• Schimke Immuno-osseous dystrophySchimke Immuno-osseous dystrophy• Osteoporosis – pseudogliomaOsteoporosis – pseudoglioma• Kenny-CaffeyKenny-Caffey• TMEM38B OITMEM38B OI• OI/Bone fragilityOI/Bone fragility• Skeletal DysplasiasSkeletal Dysplasias• Hyperparathyroid disordersHyperparathyroid disorders
The effect of next generation The effect of next generation sequencingsequencing
Why has this happenedWhy has this happened The effect of NGSThe effect of NGS• MEN1MEN1• CDC73CDC73• CASRCASR• CDKN1ACDKN1A• CDKN1BCDKN1B• CDKN2BCDKN2B• RET (exons 8,10-RET (exons 8,10-
11,13-16)11,13-16)• AP2S1 (pArg15)AP2S1 (pArg15)
Large MEN1 pedigreeLarge MEN1 pedigree
Menin and CASR mutation studies Menin and CASR mutation studies normalnormal
2015 Oxford hyper- parathyroid panel
Confirmed CDC73 mutation
Why is it important to recognise Why is it important to recognise CDC73 hyperparathyroidism (HPRT2)? CDC73 hyperparathyroidism (HPRT2)?
• Non PenetranceNon Penetrance• Different spectrum of tumoursDifferent spectrum of tumours• Therefore not just managing HPTTherefore not just managing HPT• Parathyroid carcinomaParathyroid carcinoma• Jaw tumoursJaw tumours• Uterine tumoursUterine tumours• Renal tumoursRenal tumours
CDC73 can be variable and the CDC73 can be variable and the genetics doesn’t always give the genetics doesn’t always give the
answeranswer
Heterozygous c26delG(pArg9fs)
Biochemically and Genetically both Biochemically and Genetically both have hypophosphatasiahave hypophosphatasia
Very low AlkPhosVery low AlkPhosCompound heterozygous mutations TNALPCompound heterozygous mutations TNALPLong term Paediatric ITU and Asfotase alphaLong term Paediatric ITU and Asfotase alpha
Very low AlkPhosVery low AlkPhosHomozygous mutations TNALPHomozygous mutations TNALPAsymptomaticAsymptomatic
Patient seen in Joint Endocrine Patient seen in Joint Endocrine Genetic ClinicGenetic Clinic
OsteoporosisOn Bisphosponate
History Obtained in the History Obtained in the Endocrine Genetic ClinicEndocrine Genetic Clinic
OI and Osteoporosis On Bisphosponate
a few # as childAge 45
a few # as a childAge 41
History of #Childrens Hospital
History of #Childrens Hospital
Family Members at risk of OIFamily Members at risk of OI
271
140 127
442
0
50
100
150
200
250
300
DefinitelyAffected
StatusUncertain
at 50% risk PossiblyAffected
Obligatorycarriers
OI phenotypes and genotypesOI phenotypes and genotypesOI Type Inheritance Phenotype Gene Defect
Classical –Silence Type
IIIIIIIV
ADADADAD
MildLethalProgressiveModerate
Nul Col1A1Col7A1/Col1A2Col1A1/Col 1A2Col1A1/Col1A2
Other V
VI
AD
?AR
Distinctive histology/callusMineralisation defect
IFITM5
SERPINF1
3 hydroxylation defects
VII
VIIIIX
AR
ARAR
Hypomorphic (S)null (L)Severe to lethalModerate – severe
CRTAP
LEPRE1PP1B
Chaperone Defects
XXI
ARAR
Severe to lethalBRUCK progressive
SERPINH1FKBP10
Unclassified typesBruck Type II AR Contractures PLOD2Caffey Disease AD Cortical
hyperostosisCol1A1
Osteoblast maturation defect
AD Moderate SP7
The Reality – the answer to these The Reality – the answer to these questions was mostly NO!questions was mostly NO!
• Did we know where were they now?Did we know where were they now?• Did we know how many more children had been born?Did we know how many more children had been born?• Did we know the type / severity of their OI?Did we know the type / severity of their OI?• Did we need expensive genetic testing?Did we need expensive genetic testing?• Did we know if they were on any treatment?Did we know if they were on any treatment?• Was anybody monitoring adults? Was anybody monitoring adults?
• Did we need a very complex / expensive overhaul of Did we need a very complex / expensive overhaul of our pathways?our pathways?
Types of OsteoporosisTypes of OsteoporosisA very simple suggestionA very simple suggestion
Primary Secondary
Type 1
Type 2
Type 3
3 Simple actions3 Simple actions• Take a family historyTake a family history
• Assess if medical history in patient or relative is Assess if medical history in patient or relative is indicative of an underlying disorderindicative of an underlying disorder
• See if a joint clinic with a genetics colleague is See if a joint clinic with a genetics colleague is realisticrealistic
• But has genetics anything to really add?But has genetics anything to really add?
Audit of referrals to clinical genetics Audit of referrals to clinical genetics 20062006
GP27%
Genetics12%Obs &
Gynae15%
Paediatrics3%
Other34%
Endocrin-ology3%
Unknown6%
Figure 1. Referral source – OI Patients Referred to Genetics
Figure 2. Referral source – CAH Patients Referred to Genetics
GP17%
Obs & Gynae25%
Other13%
Paediatrics28%
Endocrin-ology1%
Ortho-paedics
8%
Unknown8%
GP27%
Genetics12%Obs &
Gynae15%
Paediatrics3%
Other34%
Endocrin-ology3%
Unknown6%
Figure 1. Referral source – OI Patients Referred to Genetics
Figure 2. Referral source – CAH Patients Referred to Genetics
GP17%
Obs & Gynae25%
Other13%
Paediatrics28%
Endocrin-ology1%
Ortho-paedics
8%
Unknown8%
Important Gene PathwaysImportant Gene Pathways
• Wnt / Beta CateninWnt / Beta Catenin
• RANKL/RANK/OPGRANKL/RANK/OPG
• Oestrogen and TestosteroneOestrogen and Testosterone
• PTH Calcium homeostasisPTH Calcium homeostasis
Fascinating science but just do not Fascinating science but just do not know how to apply clinically know how to apply clinically but :-but :-
• Wnt / Beta CateninWnt / Beta Catenin
• RANKL/RANK/OPGRANKL/RANK/OPG
• Oestrogen and TestosteroneOestrogen and Testosterone
• PTH Calcium homeostasisPTH Calcium homeostasis
Epigenetics and Future TherapyEpigenetics and Future Therapy
• Change of gene expression without changing the Change of gene expression without changing the coding sequencecoding sequence
• Three main mechanismsThree main mechanisms– Post transcriptional histone modificationPost transcriptional histone modification– MicroRNA’s (miRNA’s) in regulation of gene expressionMicroRNA’s (miRNA’s) in regulation of gene expression– DNA methylation in regulaion of gene expressionDNA methylation in regulaion of gene expression
Vrtanik, Marc and Ostanek 2014. Epigeneticc mechanisms in bone; Clin Chem Lab Medicine 52; 589-608
From Family History to EpigeneticsFrom Family History to Epigeneticsoror
A Holistic Approach made SimpleA Holistic Approach made Simple• Different clinical structures to match clinical serviceDifferent clinical structures to match clinical service
• A route to consider the unusual cases or rare A route to consider the unusual cases or rare disorders with secondary osteoporosisdisorders with secondary osteoporosis
• A mechanism to identify and follow up extended A mechanism to identify and follow up extended familyfamily
• Identifying cohorts for future researchIdentifying cohorts for future research
My Thanks to :-My Thanks to :-• Professor Neil GittoesProfessor Neil Gittoes
• Sue Stewart – Clinical nurse specialistSue Stewart – Clinical nurse specialist
• Lisa Cooper-Charles –W Mids Regional Genetics LaboratoryLisa Cooper-Charles –W Mids Regional Genetics Laboratory
• Authors of 2 excellent reviews – Authors of 2 excellent reviews – • Vrtacnik et al (2014) Epigenetics mechanisms in bone. Clin ChemLab Vrtacnik et al (2014) Epigenetics mechanisms in bone. Clin ChemLab
Med 52:589-608Med 52:589-608• Mitchell and Streeten (2013). Clinical impact of recent genetic Mitchell and Streeten (2013). Clinical impact of recent genetic
discoveries in osteoporosis. App of clinical genetics 6: 75-85 discoveries in osteoporosis. App of clinical genetics 6: 75-85