Transcript GeneticsJTElder10

Genetics of Psoriasis
and Psoriatic Arthritis
James T. Elder
Department of Dermatology
University of Michigan
PsA Working Group Meeting
New York, NY
April 14, 2003
Genetic Epidemiology: Summary
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•
•
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•
Most data supports polygenic
inheritance
Low penetrance of disease
alleles (low GRR)
“Many genes means common
genes”
Low penetrance and high
frequency cause problems
for linkage
Common genes  founder
effect  LD methods
Published Psoriasis Loci
1
2
3
4
5
6
7
8
9
10
11
13
14
15
16
17
18
19
20
21
22
Y
12
X
Chromosome 16q--the Crohn’s
Disease Connection?
• Psoriasis is 7 times more common in Crohn’s
disease patients than in controls
• Our 16q linkage peak mapped very close to a
confirmed linkage peak for Crohn’s disease
• NOD2 maps to the 16q peak and has been
confirmed as a Crohn’s susceptibility gene
• NOD2 recognizes pathogens and activates
NF-B (innate immunity)
• But--little or no evidence for association with
major Crohn’s disease alleles (3 studies)
Confirmation of Linkage to 17q
Originally reported by Bowcock et al. (Science 1994)
Also found by us in two separate groups of families, and in
Swedish families
Possible gene reported 6/03 by Bowcock--needs
confirmation
Strategy for Identification of PSORS1
(Nair et al, AJHG 66:1833-44,2000)
• 62 microsatellites
spanning the MHC
(more around HLA-C)
• Haplotypes deduced
from pedigrees and
clustered to identify
ancestral chromosomes
• Clusters tested for risk
using TDT
• Find shortest region
common to risk
• Sequence risk region in
risk vs. non-risk
chromosomes
Physical Map of PSORS1 Region
SEEK1
SPR1
0
30
40
50
60
70
80
RH1
90
100
110
120
130
140
150
CDSN
10
20
160 170
RH2
180
190
200 kb
17 5
2
8
13 3 2 3 6 1
3
1 1
9 2
4 3
8
3 10 4 16
-
19 16
3
6
9 3 2 3 6 1
3
1 1
9 3
4 3
1
2
2 2
4
8
21 16
3
6
15 3 2 3 6 1
3
1 1
9 2
4 3
1
2
2 2
4 16
22 16
23 15
3
3
6
6
15 3 2 3 6 1
13 3 2 3 6 1
3
3
1 1
1 1
9 2
8 2
4 3
4 3
1
1
2
2
2 2
2 2
4 16
4 26
25 15
26 7
3
6
13 3 2 3 6 1
3
1 1
8 2
4 3
1
2
2 2
4 20
3
7
15 3 5 3 6 1
3
1 1
10 2
4 3
6
2
1
2 4
1
• RH1 is repeat-rich, encodes no known genes
• 7 known genes found in RH2
• RH1 and RH2 are separated by two closely spaced
markers (M6S111 and M6S169)
Refined PSORS1 Risk Region
• Refined risk interval includes OTF3, TCF19, HCR,
SPR1, and SEEK1, but not CDSN
• Risk interval could be larger depending on risk status
of Cluster 17 (T:NT = 21:10, TDT p value = 0.048)
Cluster 17 Collaboration: Methods
• Objective: to determine whether Cluster
17 is a risk chromosome
• Type marker M6S161, whose allele 3 is
specific for cluster 17--frequency only
1.5%, so many subjects needed
• 10 psoriasis genetics centers [Finland,
Germany, Iceland, Italy, Sweden (2), UK (2),
France, Ann Arbor/Kiel]
• Analysis by transmission disequilibrium
test (TDT)
Refined PSORS1 Risk Region
• Based on conclusion that Cluster 17 is non-risk
• Redefined risk interval includes HLA-C, OTF3, TCF19,
HCR, SPR1, SEEK1, CDSN, and STG
• Region is still small enough to analyze by DNA
sequencing
Sequencing Strategy
Genomic fosmid library (~40 kb inserts)
Screen with region-specific probes
Fosmid clones for each allele
Shear fosmid DNA (~1 kb)
Clone into plasmid
Seq 1000 clones
Assemble
GATCGATC
GATCGATC
GATCCATC
Testing of Candidate Genes
• HLA-Cw6 is specific for risk chromosomes
• If cluster 17 is non-risk, then one combination of 3 variants
in CDSN is specific for risk (“Allele 5”, T619-T1236-C1243)
• No significant association of any coding CDSN variants
with psoriasis in Japan (Tissue Antigens 60:77, 2002) or in
Taiwan (Br J Dermatol 148:418, 2003), despite significant
associations with HLA-Cw6
Is HLA-Cw6 the PSORS1
Disease Allele?
• HLA-Cw1-B46 in
Oriental psoriasis
• HLA-B38/39 in
psoriatic arthritis
HLA Associations with PsV in Thailand
(Choonhakarn et al., Int J Dermatol 41:330, 2002)
• HLA-B46-Cw1 haplotype is strongly associated with
psoriasis in Thailand and Japan (odds ratio  4)
• B46-Cw1 is common in Asians (HF = 14% in
controls), rare in Caucasians (HF <<1%)
• HLA-Cw6 is common in Thai psoriatics, rare in Thai
controls (odds ratio  10)
• B46-Cw1 is equally prevalent in early- and lateonset Thai psoriatics (HF = 24.7 vs 26.7)
• HLA-Cw6 is more common in early-onset Thai
psoriatics (HF = 17.4 vs. 8.9)
• Thus, Cw6 and B46-Cw1risk alleles do not appear to
be identical by descent, and differ in phenotype
HLA-B38/39 in PsV and PsA:
Compilation of 15 Studies
Disease
HLA
Al lele
Cw7
Cw7
Cw7
Population
Al l
Japanese
Ot hers
t ot al
cases
8 59
3 58
5 01
allele (+ )
cases
2 57
1 05
1 52
allele (+ )
cont rols
5 72
1 65
4 07
%
Relat ive Risk
2 9.9 %
2 9.3 %
3 0.3 %
t ot al
cont rols
2 953
1 607
1 346
1 9.4 %
1 0.3 %
3 0.2 %
1 .7 8
3 .6 3
1 .0 0
PsA
Cw7
Cw7
Cw7
Al l
Japanese
Ot hers
3 39
28
3 11
90
12
78
2 6.5 %
4 2.9 %
2 5.1 %
7 92
1 20
6 72
1 62
22
1 40
2 0.5 %
1 8.3 %
2 0.8 %
1 .4 1
3 .3 4
1 .2 7
PsV
B38/ 39
B38/ 39
B38/ 39
Al l
Japanese
Ot hers
4 41
1 92
2 49
79
41
38
1 7.9 %
2 1.4 %
1 5.3 %
1 300
5 72
7 28
66
41
25
5 .1 %
7 .2 %
3 .4 %
4 .0 8
3 .5 2
4 .8 1
PsA
B38/ 39
B38/ 39
B38/ 39
Al la
B38
B39
7 06
6 06
7 06
1 38
96
42
1 9.5 %
1 7.7 %
5 .9 %
2 046
1 724
2 046
69
42
27
3 .4 %
2 .4 %
1 .3 %
6 .9 6
7 .5 4
4 .7 3
PsA
Cw6
Cw6
Cw6
Al l
Japanese
Ot hers
6 49
62
5 87
2 28
3
2 25
3 5.1 %
4 .8 %
3 8.3 %
1 201
1 20
1 081
1 71
1
1 70
1 4.2 %
0 .8 %
1 5.7 %
3 .2 6
6 .0 5
3 .3 3
PsV b
Cw6
Caucasians
1 097
5 57
5 4.4%
4 010
4 24
1 0.6%
a
t here were no publicati ons deta iling t he prevalence of B38/ 39 in Japanese subject s wit h PsA
b
f rom Mallon et al, JID 1 13 :69 3, 1 99 9
8 .7 2
PsV
%
Haplotype Frequencies (HLA 1991)
a
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•
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Haplot yp e
Japan
Canada
Spain
French
USA
B39 -Cw7
4 .2
0 .0
0 .0
1 .2
0 .9
B8-C w7
0 .0
9 .2
6 .0
5 .4
6 .5
B7-C w7
4 .9
1 0.4
6 .7
6 .2
7 .5
B38 -CBLa
0 .0
1 .5
2 .0
2 .8
3 .2
B39 -CBLa
0 .0
1 .4
0 .0
1 .2
0 .0
CBL indicat es t hat t he serologic t est s used t o obt ain t hese dat a yielded no
result ; Cw1 2 cannot be t yped serologically
Note high prevalence of Cw7-B39 haplotype in Japan, low prevalence
in Caucasian populations
Cw7 associations generally limited to Japan/Orient
Primary association may be with B38/B39, rather than Cw7
Psoriasis Genes: 2003
• Evidence for PSORS1 very strong, but cannot
account for all genetic effects in psoriasis (s = 510, s,MHC = 1.6)
• Coding variants of all RH2 genes except CDSN
have been ruled out
• B46-Cw1 haplotype genetically and functionally
distinct--further study needed
• HLA-B38/B39 may confer risk for PsA--better
ascertainment of PsA needed
• Association studies on large case-control cohorts
and linkage studies on large (>10 affected)
pedigrees will be needed to identify multiple nonMHC genes
Collaborators
• Ann Arbor
– Rajan Nair
– Phil Stuart
– John Voorhees
• Detroit
– Henry Lim (HFH)
• Psoriasis Genetics
Consortium
• Kiel
–
–
–
–
Michael Wiechenthal
Stefan Jenisch
Tilo Henseler
Enno Christophers
• San Diego
– Nik Schork
– Caroline Nievergelt
• Cluster 17 Collaboration
– Jonathan Barker (London)
– Richard Trembath (Leicester)
• International Psoriasis
– Anne Bowcock (Wash Univ)
Genetics Committee
Supported by NIAMS and NPF
How Might Specific HLA Class I
Alleles Cause Disease?
• Clonal TCR rearrangements suggest response to
specific antigen(s)
• Class I molecules should be presenting
intracellular proteins of the APC
• They may be very good a presenting certain selfantigens
• They may be very poor at presenting certain selfantigens, leading to failure of thymic elimination
of anti-self T-cells
• Alternatively, they may mis-regulate NK cells,
leading to overproduction of IFN-g
Finding the Non-MHC Genes
• Genome-wide association studies
– Haplotype block mapping
– Coding sequence variation
– Case-control design OK
• Identifying heterogeneous loci
– Large families essential for initial identification
– Create dense marker maps, build haplotypes
– Search for these haplotypes in case-control or
TDT studies
• Incorporate MHC data into analyses