what are the next steps in understanding the role of the genome in ibd? judy h. cho icahn school of...
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What are the next steps in understanding the role of the genome in IBD?
Judy H. Cho
Icahn School of Medicine in New York
Dec 2013
Concepts
1. Common variants and systems biology
2. Less common variants and direct therapeutic targeting
3. Functional biomarkers and Mendelian randomization
Concepts
1. Common variants and systems biology
2. Less common variants and direct therapeutic targeting
3. Functional biomarkers and Mendelian randomization
Population differences: principal components
East Asian
African
European ancestry
Inga PeterItsik Pe’er Plos Genetics 2012
Ashkenazi Jews with similar association directions, but higher absolute risk allele frequencies
Prediction: Risk alleles should be higher in Ashkenazim vs. non-Jewish risk alleles
57 CD SNPs tested (Kenny et al., Plos Genetics 2012) 54/57 loci (95%) : risk allele same in AJ and NJ
(same direction of effect) 36/54 loci (67%): higher risk allele frequency in AJ
Most recently: of 116 CD SNPs tested-- 94/116 (81%) risk allele same in AJ and NJ (same
direction of effect) 63/94 loci (67%, p=0.0012) higher risk allele
frequency in AJ vs. NJHypothesis: polygenic adaptation—positive selection at many loci simultaneously in AJs
Polygenic adaptation
“Polygenic adaptation: occurs by simultaneous selection on variants at many loci (perhaps tens or hundreds or more)…..due to small frequency shifts of many alleles…..
To make real progress on these problems will require much greater integration of selection studies with biological information.”
Prichard J.K. et al., Current Biology 2010
Modeling the relevant selection factors
Improved models of chronic mycobacterial infection of macrophages
MΦ Differentiation IFN-γ Priming BCG Infection Plating Count CFUs1 2 3 4
Day 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 33
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Vogt and Nathan. J. Clin. Invest. 121, 3889–3901 (2011).
1. Macrophage differentiation Growth factor: GMCSF—control lost with MCSF Reduced oxygen concentation TNF during 7d differentiation
2. Priming with IFNg--premature introduction of IFNg impairs macrophage survival
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10
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AJEA
Pece
ntag
e of
BCG
Kill
ed
CD controls
Trend toward greater fraction of BCG killed in AJ vs. non-Jewish EA cases and controls
Monica Bowen
Bayesian network analysis: drivers and hubs
cis eQTL
HCK
IL10NOD2
Eric Schadt
In vitro differentiation of M1/M2 macrophages recreates gene cluster observed in omental adipose tissue
Macrophages, 0 hoursMacrophages, 6 hours IL4Macrophages, 24 hours IL4Macrophages, 6 hours IFNgMacrophages, 24 hours IFNg
NOD2HCK
IL10LGALS9RIPK2SLC11A1CARD9
Higher expressionLower expression
M2 M1
Omental adipose tissue co-expression subnetwork
Peripheral blood derived monocytes M1 (IFNg)/M2(IL4)
Regulation of hub expression by TNF
Hubs (squares) regulate gene expression of many genes around them
Hubs near NOD2: Regulate cellular
morphology & cytoskeleton: WAS, AIF1, NCKAP1L
Down-regulated by TNF 2° neighbors: 6.0-fold 3 ° neighbors: 2.7-fold More distant: 1.6 fold
Nature 2012; Supplementary info—cytoscape file
Concepts
1. Common variants and systems biology
2. Less common variants and direct therapeutic targeting
3. Functional biomarkers and Mendelian randomization
AJ-based custom exome chip study
Sequenced 50 AJ CD cases added unique variants to base exome chip
Genotyped: 1,477 AJ cases and 2,614 controls
Goal: to identify rare variants associated to IBD in AJs
Ken HuiDermot McGovernInga Peter
Value of uncommon, loss-of-function protective alleles in precisely defining therapeutic targets
PCSK9, LDL cholesterol & coronary artery disease
IL23R (Arg381Gln) in IBD/psoriasis/ankylosing spondylitis
Cohen JC, N Engl J Med 2006
Using genetics directly to identify new drug targets
Concepts
1. Common variants and systems biology
2. Less common variants and direct therapeutic targeting
3. Functional biomarkers and Mendelian randomization
Coronary artery disease & lipid profiles High LDL correlates with CAD risk.
Lowering LDL decreases CAD Low HDL correlates with CAD risk
Increasing HDL does NOT decrease CAD risk
Genetic markers modulating biomarkers 13 genetic markers associated with LDL 14 genetic markers associated with HDL
Hingorini, Lancet 2005Voight, Lancet 2012
Mendelian randomization & treating (intermediate) biomarkers
Treat LDL, not HDL to lower CAD risk
Relevance to IBD?? Needs: biomarker of relevance in large numbers;
genetic factors that modulate variability. Vitamin D? Anti-GMCSF Ab? fecal calprotectin? Key transcript levels?
Voight, Lancet 2012
More broadly…
Better, faster, cheaper
Leveraging existing resources—archived blood specimens, pathology specimens, EMRs
Massive numbers
Central power of genetic approaches: primary drivers of disease pathogenesis