Transcript The Role of Twin Studies in IBD Research Dr Hannah Gordon Clinical Research Fellow Chelsea and Westminster Hospital.

The Role of Twin Studies in IBD Research
Dr Hannah Gordon
Clinical Research Fellow
Chelsea and Westminster Hospital
Introduction
• Review
• History of twin studies
• Twin studies in IBD
• New molecular techniques in IBD
• UK IBD Nixon Twin and Multiplex Registry and Biobank
History of Twin Studies
• 1st recorded 1875
• Francis Galton (1)
• Description of twin pairs
• Personal traits
• Physical and mental health
“Nature is far stronger than nurture”
• Monozygotic vs dizygotic distinguished 1914 (2)
Twin Studies – study design
• Classical
• Monozygotic vs dizygotic (nature vs nurture)
• Adoption
• Genetically identical individuals reared apart
• Longitudinal
• Correlation between environment and discordance
over time
• Exercise and depression
• Offspring of twins
• Birth weight of children of MZ female twins more
similar than birth weight of children of MZ male twins
Twin Studies in IBD – Inheritance
•
•
Twin study 1988 showed CD MZ concordance 55% DZ concordance
3.8% (3)
Figure 1: Range of Concordance of Crohn’s and UC between Twin Pairs
(from Swedish, UK, Danish, Dutch and German Twin Populations (4))
Crohn’s Disease
Ulcerative Colitis
Monozygotic
20-55%
6.3-17%
Dizygotic
0-3.6%
0-6.3%
•
Variation
• CC defined 1960s
• Genetic differences between populations
•
Crohn’s has stronger genetic basis
•
Strong environmental component
Twin studies:
• UC altered mucosal glycosylation presented in discordant
MZ pairs (9)
• MZ concordance
• CD location and behaviour
• UC extent (5,6)
• monozygotic twin pairs x1CD x1 UC (7)
• X2 concordance DZ twins compared with other siblings (8)
• Shared uterus
• More similar childhood environment
Genome Wide Association Studies
• 163 SNPs associated with IBD (10,11)
The Microbiome – a living active ecosystem
•
•
•
•
•
Trillions of microbes (10x number of human cells) (12)
>1000 species level phylotypes
Microbial genome 150x larger than human host (13)
Changes during life
Interactions with host (and each other)
• Obesity
• DM
• IBD
• CV disease
Study of Microbiota
• Megagenomics
• 16srRNA PCR sequencing and amplification (14)
• Metaproteomics
• Expressed gene products
• Metabolomics
• Metabolites of host-microbiota interactions
• High res NMR spect
• Multivariate statistical analysis
• “Metabolic fingerprint”
Microbiota of MZ twins:
• Healthy MZ twins have similar microbiota (15)
• Twins with CD have differing microbiota (concordant or
discordant) (16)
• Microbiota tends towards phenotype rather than
genotype (17)
• Inactive UC microbiota no different from healthy twin
(18)
Metabolomics – “Fingerprints” in IBD
• Metabolomic profile of faecal water of A) CD (n=10), B)
UC (n=10), C) Healthy control (n=13) (19)
Key:
1, butyrate; 2, leucine; 3,
propionate;
4,
valine;
5,
isoleucine; 6, threonine; 7,
alanine; 8, lysine; 9, acetate;
10, glutamate; 11,
succinate; 12, aspartic acid; 13,
asparagine; 14, trimethylamine;
15, cysteine; 16, proline; 17,
glycerol; 18, methylamine; 19,
5-aminosalicylic
acid; 20,
N
-acetyl-5-aminosalicylic
acid;
21, tyrosine; and 22, uracil
Metabolomic profiles IBD:
• CD
• Depletion of short chain fatty acids
• Decreased methylamine and trimethylamine
• UC
• Increased amino acids
Metabolomic profiles of Twins
• Difference between discordant MZ pairs (ICD and CCD)
(20)
• Similarity between healthy MZ
• Differentiation between ICD and CCD
• ?Metabolites associated with SNPs higher in affected
twin
Epigenetics – Blurring the distinction
between nature and nurture
• “Heritable changes in gene expression that occur without
alterations in DNA sequence” (11)
• Methylation
• gene silencing
• Histone modification
• Changes persist after mitosis
• ?persist after meiosis (transgenerational)
Epigenetics
• IBD – 50 genes with different methylation between
patients with CD and controls (21)
• Twin studies – different methylation patterns SLE MZ
discordant
• Role of twin studies
• ?timing of methylation
• ?Inheritance of methylation in offspring
MicroRNA
• Small non coding RNA molecule
• Transported from nucleus
• Forms protein complex
• Binds with mRNA
• mRNA degraded sooner and translated less
• How does it change in IBD?
• Distinct miRNA signatures in peripheral blood in CD
vs UC vs Control (11)
• MiRNA
• NOD2 controls miRNA expression (24)
• MiRNA 29 deficient mice – worse colitis
Limitations of twin studies
• Sample size
• MZ twins 3/1000 births
• DZ twins 13/1000 births
• IBD prevalence UK 400/100,000
IBD Nixon TAM Registry and Biobank
• History
• Royal Free Dataset
• 250 twin pairs
• Study of MZ vs DZ concordance 1996 (23)
• Database revisited and reanalysed 2011 (6)
• Concordance of disease location and extent
• Childhood infection
• Current
• Contacting Twins from previous dataset
• Recruiting new Twin pairs
• Biobank
Conclusion
• Continuing relevance to twin studies in omics era(2)
• Microbiome
• Epigenetics
• Twin studies to date
• Evidence of genetic component
• Development
• Disease pattern
• Galton wrong – environmental factors predominate
References:
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Tysk C, Lindberg E, Jarnerot G, et al. Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins. A study of heritability
and the influence of smoking. Gut. 1988; 29: 990–996
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monozygotic twins of inflammatory bowel disease patients. Gut. 2006 Jul;55(7):973-7. Epub 2006 Feb 4
Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;490:119–124
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catalogue established by metagemonic sequencing .MetaHIT Consortium Nature 464, 59-65(2010)
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inflammatory bowel disease phenotypes. Gastroenterology 139: 1844–1854
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mechanisms including the Th17 pathway. Inflamm Bowel Dis. 2012;18:889–899
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September 19, 2013
Inflammatory Bowel
Diseases 2014
• Bella Center Copenhagen, Denmark
• EACCME applied
• Register online at www.ecco-ibd.eu
CALLING ALL TWINS!!!!!
If you know of any IBD patients who are part of a twin pair
please contact me:
Email: [email protected]
Tel: +44 (0)7834 705791