Feb 11, 2011 ... Fevers, Genes, and Targeted Therapy: Adventures in the Genomics of
Inflammation. Dan Kastner, MD, PhD. NHGRI/NIH/DHHS. February 11 ...
Fevers, Genes, and Targeted Therapy: Adventures in the Genomics of Inflammation
Dan Kastner, MD, PhD NHGRI/NIH/DHHS February 11, 2011
Charting a Course for Genomic Medicine
Charting a Course for Genomic Medicine
Familial Mediterranean Fever (FMF) p13.3 p13.2p13.13
Chromosome 16p
v57c7 OR1F1
NK4
v57c7x4 FPM315
ZNF213 D16S468/ S3070
Telomere
ZNF205 (ZNF210) D16S3082
v9 D16S3405
OR1F2
D16S3373 AFMef101 D16S3275
Centromere
PKD1, TSC2
v57c10
bZIP
NH2
D16S2617
PYD
ZNF200
MEFV
CREBBP
B-Box Coiled-coil
Pyrin / Marenostrin
B30.2
COOH Cell 90:797, 1997
Extending the Pyrin Pathway: Proline Serine Threonine Phosphatase Interacting Protein 1 (PSTPIP1/CD2BP1) 30
1
FCH
A230T
E250 261 Q
* * CC
SH3
413
PSTPIP1
1
Pyrin domain
B-BOX
pyrin
CC
B30.2 781
NLRP3 Mutation in NOMID/CINCA
D303N
Aksentijevich et al, Arthritis Rheum 46:3340, 2002
Aksentijevich et al Arthritis Rheum 56:1273, 2007
Mutations in IL1RN, IL-1 Receptor Antagonist Gene
Aksentijevich I et al. N Engl J Med 360:2426-2437, 2009
Deficiency of the IL-1 Receptor Antagonist (DIRA)
TNFRSF1A Mutations Can Cause Dominantly Inherited Periodic Fever CRD1
CRD1 13
TNFRSF1A CRD2
12
CRD3 11.12
CRD4 12
13
14
CRD2 Death domain
15
21
22 23 24.1
24.3
Rheumatology 5th edn, 1637-57, 2011
14
15
21
22
23
24.1 24.2
24.3
12 q
Mutations in the Mevalonate Kinase Gene Cause HIDS Mevalonate kinase (MK) HMGCoA
Mevalonate
Mevalonate-P
Geranyl-PP
Farnesyl-PP
Farnesylated proteins (Ras, lamin B) Dolichol Haem A
Squalene Ubiquinones
7-Dehydrocholesterol
Vitamin D Bile Acids
Cholesterol
Rheumatology 5th edn, 1637-57, 2011
Steroids Hedgehog proteins
Behçet’s Disease:
The Classic Triad of Clinical Findings
ls > 10
Association of an IL10 Variant with Behçet’s Disease # cases
# controls
Allele freq cases
Discovery - Turkish
1161
1221
0.38
0.30
31.62
1.88E-08
1.41
(1.25 - 1.59)
Replication - Turkish
110
224
0.30
0.31
(0.02)
0.689
0.97
(0.69 - 1.38)
Replication - Middle Eastern
188
163
0.35
0.26
7.15
0.007
1.56
(1.12 - 2.16)
Replication - Greek
107
84
0.40
0.27
7.21
0.007
1.41
(1.26 - 1.59)
Replication - UK Caucasian
120
119
0.31
0.22
4.49
0.034
1.56
(1.03 - 2.34)
77
52
0.71
0.66
0.57
0.450
1.23
(0.78 - 2.10)
611
737
0.76
0.67
29.40
5.89E-08
1.60
(1.35 - 1.90)
2374
2600
75.56
3.54E-18
1.45*
(1.34 - 1.58)
Discovery - Turkish
1213
1275
0.67
0.61
20.71
5.35E-06
1.31
(1.17 - 1.47)
Replication - Turkish
110
220
0.64
0.65
(0.05)
0.818
0.96
(0.69 - 1.35)
Replication - Middle Eastern
165
146
0.65
0.59
2.60
0.107
1.31
(0.94 - 1.81)
Replication - Greek
102
82
0.58
0.58
0.00
0.956
1.01
(0.67 - 1.53)
Replication - UK Caucasian
119
118
0.55
0.53
0.30
0.585
1.11
(0.77 - 1.59)
Replication - Japanese
597
720
0.76
0.70
13.54
2.34E-04
1.39
(1.17 - 1.65)
Replication - Korean
77
54
0.79
0.74
0.72
0.397
1.28
(0.72 - 2.28)
CMH-Meta-analysis
2383
2615
33.62
6.69E-09
1.28*
(1.18 - 1.39)
Sample Collection
Allele freq ctrls Chi-squared
ChiSq P- value
Odds ratio
(95% CI)
rs1518111 (IL10) A/G
Replication - Korean Replication - Japanese CMH-Meta-analysis
rs924080 (IL23R/IL12RB2) A/G
*Breslow-Day Test for Homogeneity of the Odds Ratios: P =0.54 and 0.71, for rs1518111 and rs924080, respectively.
Remmers et al. Nature Genet 42:698-702, 2010
The PYRIN Domain: A Cognate Interaction Motif
Richards et al., J Biol Chem 276:39320, 2001
Pyrin PYRIN
ASC PYRIN CARD
pro-IL-1b
CARD Caspase-1
IL-1b Converting Enzyme (ICE)
IL-1b
Human and Mouse NLR Family Members
Schroder and Tschopp, Cell 140:821, 2010
FMF Knockin Mice: IL-Dependent Inflammation WT
V726A
WT
V726A
IL-1b Activation Disorders
Masters et al. Annu Rev Immunol 27:621, 2009
Protein-Misfolding in TRAPS
Rheumatology 5th edn. 1637-57, 2011
Kastner et al., Cell 140:784-790, 2010.
Adaptive and Innate Immunity
Hoebe et al. Nature Immunol 5:971, 2004
Kastner et al., Cell 140:784-790, 2010.
Gout as an Autoinflammatory Disease
Martinon and Glimcher JCI 116:2073-2075, 2006
Atherosclerosis as an Autoinflammatory Disease
Duewell et al. Nature 464:1357-1361, 2010
MEFV Mutations: The Case for Selection
Masters et al. Annu Rev Immunol 27:621, 2009
Frequency of the mutation in the founder population
Caucasian Controls (NY) Population of origin
Newfoundland 0.4%
p.N52Kfs25 p. E77X p.Q54X c.156-157delCA c.229G>T c.160C>T Father Mother Neg in 364 Neg in 364 Neg in 364 DNA samples DNA samples DNA samples 2:555 DNA samples
0:351 DNA samples
The Netherlands
Not done
175kB deletion Neg in 364 DNA samples 3:119 DNA samples
Puerto Rico 2.6%
The Silk Route and Behçet’s Disease
Treatment of 18 NOMID Patients with the IL-1 Receptor Antagonist Anakinra
Goldbach-Mansky R et al. N Engl J Med 2006;355:581-592
Anakinra Treatment of DIRA
Age 9 months, before therapy
3 days post treatment initiation
7 days post treatment initiation
IL-1 Inhibition in FMF Amyloidosis
Chae et al PNAS 103:9982, 2006
Type 2 Diabetes Mellitus as an Autoinflammatory Disease
Larsen CM et al. N Engl J Med 356:1517-1526, 2007
An Inflammasome Signature in PFAPA Flares
Anakinra in PFAPA
The NIH Autoinflammatory Cohort
NIH Intramural Research Program
Ivona Aksentijevich
Raphaela Goldbach-Mansky
JaeJin Chae
Elaine Remmers
Seth Masters
Richard Siegel
NHGRI Inflammatory Disease Section, 2010
“It’s a genome world . . . “
NIH Clinical Center
[email protected] [email protected], referrals
