Cyprus: a case study - Carsten W. Lederer

Cyprus Case StudyWhat can other countries learn from this experience?Carsten W. LedererThe Cyprus Institute of Neurology and Genetics The Cyprus School of Molecular [email protected]

The Cyprus Institute of Neurology and Genetics

UNESCO HeadquartersParis, France

30 – 31st May 2016

Human Variome Project Consortium

6th Biennial Meeting GG2020 Fringe Meeting

http://mycyprusinsider.com/wp-content/uploads/2015/06/Tzelefos-Bridge.jpg



The Cyprus Institute of Neurology

and GeneticsOutline

Thalassaemia Provision, Needs, Prevention Result Societal Parameters in Cyprus

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and Genetics

Thalassaemia

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and GeneticsHaemoglobin Two loci for H.s. globin genes

Haemoglobin, a tetrameric metalloprotein

2 α-like globin chains 2 β-like globin chains 4 haeme molecules with central Fe2+/3+

Human adult haemoglobins

α

ε

γChr. 16 Chr. 11

ζ δ

β

β

α

α

β HbA >95 % δ

α

α

δ HbA2 <3.5 %

γα

αγHbF <1.0 %

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and GeneticsKey Features of β-thalassaemia

β

α

α

β

α

α

α

α

γα

αγ

γγ

Toxicity of α-globin (Myeloid) ineffective

erythropoiesis (Splenic) haemolysis

Iron overload ( iron chelation) Secondary endocrinopathology Organ failure (liver, pancreas, heart)

δα

αδ

Anaemia ( blood transfusions) Tissue hypoxia & myeloid expansion

Osteoporosis Skeletal deformities

Diagnostic: HbF & HbA2 increase

Modifier: high HbF Genetic (HPFH) Pharmacological induction Gene-therapeutic induction

Modifier:low/high α

ε δ βAγGγβ-globin locus

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and GeneticsCritical Factors

Blood transfusions Supply Biosafety Increased iron absorption

Iron chelation Risk of noncompliance Cost

Genotype-phenotype correlation & HPFH Known and unknown modifiers, mutations and variants Personalised therapies

http://thetab.com http://bernsteincrisism

anagement.com

creativebits.org genius.com

€£


and Genetics

Provision, Needs, Prevention(Provision Needs Prevention.)

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and GeneticsProvision of Care 1969 Governmental policy for thalassaemia

Iron chelation (defer(ri)oxamine) and transfusion to [Hb]=11 g/dL 1 paediatrician/government hospital responsible for thalassaemia

1977 Introduction of a voluntary blood donation scheme Committee for blood donation with political, medical and patient representatives Provision of deferoxamine by the government Increased societal awareness of blood requirements Voluntary blood donations rise from 6% to 50%

1981 Thalassaemia outpatient clinics with dedicated premises Addition of experts for complications in puberty and adulthood

1983 Deferoxamine 44% of governmental drug cost 1999 Introduction of oral chelator deferiprone

Increase in compliance and rate of successful chelation

2007 Introduction of 2nd oral chelator deferasirox

Angastiniotis et al. 1986; Kolnagou et al. 2015

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and GeneticsNeed to Act

Status quo 1969 1/7 of Cypriots carriers for β-thalassaemia 1/49 couples are at risk (i.e. both partners carriers) 1/158 birth expected to be affected 1/1000 disease prevalence

Projected rise for thalassaemics by 2010 Unmanageable drug cost Impossible transfusion requirements

To maintain level of care and quality of life for existing patients:Need for a national prevention programme

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and GeneticsPrevention 1973 Testing of patients’ relatives

High detection rate No prenatal diagnosis The “stigma” implicit discouragement for carrier couples

of pregnancies of marriages

1977 Foetal diagnosis abroad Gradual removal of the “stigma”

1981 Foetal diagnosis in Cyprus 1983 Introduction of a premarital certificate 1984 National cost/benefit analysis On-going education of patients, public and clinicians

Undiminished need for screening and blood donations Disease-management, reproductive, and diagnostic options

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and GeneticsPrevention Ministry of Health

4 Branches of the Thalassaemia Centre Disease Management Patient counselling

1 central haematological laboratory Sample referral

CING (a not-for-profit, semi-GO) – Department of Genetics Thalassaemia

>800 test cases/year β-thalassaemia α-thalassaemia Hb Variants δβ-thalassaemias δ-thalassaemias HPFH


and Genetics

chorionic villus sampling

ultrasoundsensor

placenta

Diagnostic Methods Diagnostic methods for routine CVS & PB samples

For α-thalassaemia Sequencing MLPA GAP-ARMs

For β-thalassaemia Sequencing MLPA

NIPD (cf-mDNA-based) RHD status Thalassaemia

(SNP-based, experimental) PGD (in conjunction with IVF)

qPCR- and HRM-based

Online list of services

Immunosuppression! 2004 – 2011Total cases: 52Pregnancies: 14Births: 12

PMID23362932 Papasavva et al. 2013


and GeneticsDecision Trees (Simplified!)

Population-wide Screening

Normal Haematology

Go Forth and Multiply

Abnormal Haematology (MCV,

MCH)

Elevated HbA2

Test for β-thalassaemia

Normal HbA2

Test for α-thalassaemia

Test for δ/δβ-thalassaemia

Abnormal CE-HPLC Peaks

Sequence for α/β/δ Variants

Results for Both Partners

Single Carrier or Alternate-locus

Carriers

Go Forth and Multiply

Both Partners Same-locus Carriers

Counselling

Advise: in Case of Pregnancy PD

No Conception / Repeatedly Affected

IVF/PGD


and Genetics

Result

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and GeneticsElectronic Patient Database Knowing your patient population Geographical fine-mapping of epidemiologies

Mutations in patients and patient genotypes Mutation-specific carrier frequencies

Longitudinal nationwide studies Basis for genotype/phenotype studies Feeding into international summary databases, such as IthaGenes Enabling collaborative studies

PMID: 24006929 Kyrri et al. 2013PMID: 25058394 Kountouris et al. 2014PMID: 27199182 Kountouris et al. 2016


and Genetics

16Result! Annual Number of Thalassaemic Births in CyprusActual (x) vs. Expected (x)

0

10

20

30

40

50

60

70

1974

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

Annual Number of Thalassaemic Births % of Expected

Carrier Database α-thalassaemia: 8,412 β-thalassaemia: 2,335 δ-thalassaemia: 428 Cypriot population: 659115

Patient Database H-disease (--/α-): 595 [608] β-thalassaemia: 592 [630]


and GeneticsBeyond the Primary Mutation

β-globin locusδ βAγGγε

HbF

HbA

HbA2

HPFHHbF

HbA

HbA2

Normal

PMID 25737641 Finotti et al. 2015

Patient stratification

Mild and severe thalassaemia

High and low HbF levels

Response in cell culture to chemical and gene-therapeutic HbF induction

Identification of population-wide key modifiers, such as BCL11A and KLF1 variants


and Genetics

Societal Parameters in Cyprus

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and Genetics

Small size (9,251 km2) and population (0.7 / 1.1 Mio) Regular meetings of all key clinicians, molecular researchers and patients Homogeneity and community spirit at the country level Universal awareness of screening requirement and the need for blood donations

Strength of the Greek Orthodox Church Church influence on society and politics Greek Orthodox weddings before (or early during) most pregnancies

Dedicated diagnostic infrastructure of the Thalassaemia Centre Four haematology and care centres in each major city (Nicosia, Larnaca, Limassol and Paphos) Central haematology laboratory Central molecular testing and database at the CING

Integration of diagnostic work and molecular research Availability of sample material for research

(novel diagnostics, e.g. NIPD) Research programs involving all

stakeholders

Family, Church and State 19


and Genetics

Annual Number of Thalassaemic Births in Cyprus

Challenges For Cyprus: changing attitudes

Changing societal structure Secularisation of society Pregnancies out of wedlock

Success its own worst enemy Sinking awareness amongst the young Increasing choice to have thalassaemic children

For others: horses for courses Religious or ethical homogeneity is an exception Coordination problems for larger or geographically dispersed countries Legality and social acceptance of abortion as key factor Compulsory screening (and church interference) untenable elsewhere

EU law: Cyprus as a special case

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www.oecd.org/social/family/database

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7

20

10

182224

16

27

17

36

423940

5452

3739

2932

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121010 9

3 2 30 2

52 1 3 3 2 2 2 2 2 4 2 3 1 0 1

5 4 3 51 2

6

0

10

20

30

40

50

60

1960

1961

1962

1963

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1967

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1971

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1973

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1976

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1980

1981

1982

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1984

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1988

1989

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1994

1995

1996

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1998

1999

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2003

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2009

2010

2011

2012


and GeneticsChallenges! 21

MY

Malay, Peninsular

Han Chinese, Hokkien

Tamil

Han Chinese, Hakka

Han Chinese, Cantonese

Banjar Malay

Han Chinese, Teochew

Han Chinese, Mandarin

Minangkabau

F

French

French by acquisition

Foreigners

Immigrants

NGYoruba

Hausa

Igbo

Fulani

Urhobo-Isoko

Efik-Ibibio

Kanuri

Edo

Tiv

Ijaw

CYGreek Cypriot

Foreign Residents

Illegal immigrants


and Genetics

This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 306201 and from the Research Promotion Foundation of Cyprus under grant agreement ΥΓΕΙΑ/ΒΙΟΣ/0311(ΒΕ).

Acknowledgements CING & ITHANET

Marina Kleanthous Petros Kountouris Pavlos Fanis Coralea Stephanou Xenia Felekki The whole diagnostics team

Ministry of Health/Thalassaemia Centre Soteroulla Christou Maria Sitarou Annita Kolnagou Michael Hadjigavriel Haematology Laboratory

All our collaborators and patients!

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and Genetics

Thank you!

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and GeneticsAcknowledgementsThalassaemia Centre & General

Hospital Σωτηρούλα Χρίστου Ελένη Καλογήρου Μαρία Σίταρου Μιχάλης Ηατζηγαβριήλ Ανίτα Κολνάγου Μάριος Αντωνιάδης Μιχάλης Αγκαστινιώτης

Cyprus Antianaemia Association Ναταλία Μιχαηλίδου Λοΐζος Περικλέους All patients and sample volunteers!

«Genome Editing»University of Freiburg Toni Cathomen Claudio Mussolino

«Advancing Lentiviral Vector»King’s College London, ΗΒ Mike AntoniouUniversity of Ferrara, Italy Roberto Gambari

[email protected]

«ThalaMoSS»University of Ferrara, Italy Roberto GambariErasmus MC, The Netherlands Sjaak Philipsen Ίδρυµα Ιατροβιολογικών Ερευνών της Ακαδημίας Αθηνών, Ελλάδα Eleni KatsantoniWeill Cornell Medical College, ΗΠΑ Stefano RivellaUniversity of Masaryk, Czech Republic Petr Holub University of Cagliari, Italy Paolo MoiKing’s College London, ΗΒ Swee Lay TheinΛαϊκό Γενικό Νοσοκομείο, Ελλάδα Ersi Voskaridou Weill Cornell Medical College, ΗΠΑ Stefano RivellaNovaMechanics, CyprusBioCep Ltd., Israel Harbour Antibodies BV, The NetherlandsIRBM Science Park, Italy

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Cyprus: a case study - Carsten W. Lederer

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