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New genetic approaches in understanding susceptibility for metabolic syndrome in
Mediterranean populations
(FP7-279171-1)
2012 - 2015
DIABESITY - A WORLD WIDE CHALLANGE
9-10 February 2012 - Brussels
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MEDIGENE Objectives
Finality: improve genetic markers (clinical scale); better explain heritability; offer a new basis for personalized medicine
Insulin resistance syndrome - metabolic syndrome (MetS) in immigrant populations in Europe (host and home countries)
Unravel new susceptibility genes for MetS considering the genetic variability (stratification) in case-control Genome Wide Association Studies (GWAS) and gene environment interaction
Consortium of 13 countries in the Mediterranean area : clinical endocrinologists, geneticists, anthropologists and archeologists
Obesity gene
GWAS
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1.2% 17-20 % 40 %
Modern migrations (immigration)
Host Total % Composition
France 6,471,000 10.18 Algeria, Morocco, China
Spain 4,790,000 10.79 Romania, Morocco, Bolivia
Italy 2,519,000 4.28 Romania, Albania, Ukraine
Greece 974,000 8.66 Albania, Bulgaria, Romania
Specificity of MEDIGENE Visceral obesity, hyperlipidemia, hypertension and diabetes
International Diabetes Federation (IDF)
Questionable candidate for GWAS (heterogeneous)
Insulin resistance - unique feature (fundamental biological process)
MetS correlated with health indices in population (CV mortality)
Vulnerable, health status (assistance), low income
9% of world population, 8% of European community
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Relationship between migration and Health
Genetic
background ?
Home
1st
GEN Host
(NATIVES) Salmon
theory
Selection
theory
Statistically
immortal
Contact
2nd
GEN
Vulnerable
populations
Epidemiological
paradoxes Age of
migration
Refugee Acculturation
Life style Stress
Modern, historical and ancestral migration
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Modern migrations (Immigrants)
Albanese (Illyrians ),
Turkish (Altaic populations
with Central Asians
components), Romanian
(Geto-Thracic populations
from the Carpato-Danubian
basin), North African
immigrants (Berbers
admixed with Bedouin tribes
or Canaanite-Phoenicians in
historical times) - Algerians,
Tunisians and Moroccans.
MEDIGENE
populations
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Historical migrations in Mediterranean
Antiques Romans
(IV-I Century AD)
(n = 3800)
Phoenicians
Black Sea
Atlantic
Ocean
Maures
Numidians
Libyans
Ligurians
Celts
Traces
Scythians
Massalia
Hemeroscopion
Neapolis
Mylai
Alalia
Malaca Hippone
Sulcis
Utique Carthage
Leptis
Magna Egyptians
TYR
Apollonia
Thera
Kourion
Salamine
Sinope
Kimmericon
Pontus
euxinus
Ionians
Tarragona
Romans
Dorians
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Capsian culture
Franco- Cantabrian
Refugia
Carpato- Danubian
basin
Indo-Europeans
Aterian culture
40 kya
40 kya
40 kya
20 kya 20 kya
Azilian culture
North Africa
Europe
Black Sea
Atlantic Ocean
Archeo-genetics of Europe (Paleolithic)
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Haplotyping approach in MEDIGENE mutation
Genetic drift
Evolution
Admixture
Natural selection
Haplotypes
Haplotype 1 Haplotype 2
Haplotype 3 Haplotype 4 Haplotype 5
Ancestral haplotype
Recombination
Linkage disequilibrium
SNP
c t g g c t t a g c c a t a c c
a
t
g
a
g
c
t
t
c
a
g
Unphased DNA
Phased DNA
Classical GWAS
(“frequentist”)
112
h14 h15
h4
h11
h5
h7
h1
h2
h9
h10
111
112 221
211
121
122 112
121 111
Phylogeny
Rare SNP
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Working packages
WP1 1st STAGE
GWAS
600 000 SNPs
• • • • • • • • • • • • • •
140
genes
mtDNA
Y Chr
13 000 SNP
WP2 Ancient DNA study
In historical Romans
Ancient DNA Available DNA
WP3 Locus refining WP4 1st STAGE analysis
CC association in
host countries
WP8 Replication in
Home countries
Rare SNPs
[mutation]
Replication
Filtered
SNPs
WP5 Epidemiology in host and home countries &
novel recruitment for G x E interaction
WP6 2nd STAGE - Replication
Genotyping with filtered SNPs
WP7 2nd stage analysis
and meta-analysis
New DNA sampling
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Methods of MEDIGENE
Next Generation Sequencing
BC-platforms
Design of 600 000 SNP + 13 000 customized SNP
GeneTitan (Barcelona)
Mirrored
Barcelona Montpellier
Genome Wide Association studies
Replication
Data integration
Bioinformatics & statistics
GS Junior (Montpellier) FLX 454
Discovery
AXIOM Chip Primary analysis
Secondary analysis
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Expected results
New genes or allelic variants specific to populations - may help diagnosis, treatment and predictive actions
Alternative for classical GWAS - considering rare variants (SNP) - ethnic specific and explaining better association (OR) and heritability in population
Explain a series of epidemiological paradoxes - e.g. lower mortality in immigrants from Maghreb in France (men but not women) - differences in MetS between North and South in France - low CV mortality in Greeks at the first generation - role of the Mediterranean diet
Alternative explanation of insulin resistance - energy allocation mechanism versus adaptation of humans in relation with fertility, population density, social competitiveness, rural to urban transition
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Consortium Florin Grigorescu (CO), Michel Pugeat (France), Ramon Gomis, Josep M. Macias (Spain), Mihai Coculescu (Romania), Renato Pasquali, Giorgio Sesti, Vincenzo Trischitta, Davide Lauro (Italy), Agathocles Tsatsoulis (Greece), Elza Khusnutdinova (Russia), Sonia Abdelhak (Tunisia), Akila Zenati (Algeria), Abdelhamid Barakat (Morocco), IIly Agron (Albania), Timo Kanninen (Finland), Robert Hermann (Hungary), Ilhan Satman (Turkey)
Nathalie VERCUYSSE
Clelia CASALINO
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Human genetic diversity is a source of persistence and increase in the
differences in health seen in various EU citizens disadvantaged by inequalities and low-income. Understanding and accepting human genetic diversity, in opposition
to biological egalitarism represents a major advance in current thinking and a positive attitude. Group differences will help t o understand how genetic and environmental factors produce biological outcomes. We should bear in
mind that genetic diversity is a virtue of mankind not a defect, and a source of evolutionary resilience and adaptation assuring survival and health with potential
positive economic consequences on agriculture and environment.
Understanding the way of life of different people in native countries, consideration of their way of life, natural (ancestral) ecological niche, consequences of migration in a broader perspective as a potential factor of global increase in prevalence of diabetes/obesity, impact of deregulation of food supplies in modern times.
Perspectives and ethical considerations
Recommended