Collaborative Association Study of Psoriasis. Gonçalo Abecasis, Anne Bowcock, James Elder, Jerry Krueger

(1)

Collaborative Association

Study of Psoriasis

Gon

ç

alo Abecasis, Anne Bowcock,

James Elder, Jerry Krueger

(2)

Psoriasis

¾

Chronic, inflammatory skin condition

z

Characteristic lesions, can affect substantial proportion of bod

y surface

¾

Prevalence of 1

-

2% (U.S.), 0

-

3% (worldwide)

z

Peak age of onset ≈

Peak age of onset

≈

25 yrs old

¾

Inflammatory arthritis in 10

-

25% of patients

¾

Sex ratio

≈

1

1 ¾

¾

Environmental

“

trigger factors

”

z

Infections (esp. streptococcal pharyngitis

Infections (esp. streptococcal

pharyngitis)

)

z

Skin trauma (Koebner

Skin trauma (

Koebner

phenomenon)

z

Emotional stress

z

(3)

Cyclosporine A

(4)

Original Plan

¾

Case Control Association Study

z

1000 cases / 1000 controls (GAIN, first phase)

z

1000 cases / 1000 controls, follow-

1000 cases / 1000 controls, follow

-up

up

¾

Cases and controls drawn from 3 collections:

z

Anne Bowcock / Alan Menter

Anne Bowcock / Alan

Menter

(Wash U / Texas)

z

James Elder (Michigan)

z

Gerald Krueger (Utah)

¾

Objective

z

Identify genetic susceptibility factors, including modifiers of PSORS1

Identify genetic susceptibility factors, including modifiers of

PSORS1

¾

(5)

Case / Control Definitions

¾

Cases collected from Dermatology clinics

z

>90% participation rate in Utah, Michigan and Texas clinics

z

More severe disease spectrum

z

11% of body surface area affected, on average

¾

Controls collected to match geographic and ethnic origin

of cases

z

Free of psoriasis (Michigan, Texas)

z

To represent Utah Population (Mark

Leppert

, Utah)

¾

Initial round of genotyping will focus on individuals that

are

(6)

Information Provided to GAIN

¾

Age of Onset

¾

Presence of affected first degree relative

¾

Body surface area affected (%)

¾

Sites of involvement

z

Head, upper limbs, lower limbs, trunk, nails

¾

Psoriatic arthritis status

¾

Disease severity rating (scaling,

induration

,

erythema

)

¾

(7)

Familial Clustering of Psoriasis

(8)

Summary of Linkage Studies

15

16

17

18

19

20

21

22 Y

X

12

11

14

13

1

2

3

4

5

6

7

8

9

10

(9)

MHC Association

¾

Strongest genetic influence on psoriasis is in the MHC

z

First HLA association described in 1972 (Russell et al)

¾

Systematic comparisons, evaluation and

resequencing

of MHC haplotypes suggest HLA

-

Cw6 is responsible

z

In Caucasians, haplotypes without Cw6 but with risk alleles at

other nearby genes (e.g. CDSN) do not show association

(10)

PSOR2 (17q25)

¾

First mapped susceptibility locus (

Tohmforde

et al, 1994)

z

8 large pedigrees; segregates in

Mendelian

fashion

¾

Linkage widely replicated

z

(11)

Association Mapping within 17q25

¾

RUNX1 binding site, between SLC9A3R1 and NAT9

associated with psoriasis (Helms et al. 2003)

z

Association does not always replicate

¾

Given strength of linkage peak, other susceptibility

alleles likely exist in the region

(12)

Family History

yes

Family History

no

PsA

yes

Thin Plaques

PsA

no

Thick Plaques

Age at Onset

18-32

Age at Onset

>32

Age at Onset

<18

Infection Worse

yes

Infection Worse

no

Utah Psoriasis Initiative

Pooled Genotype Study

(13)

Utah Psoriasis Initiative

SNP Chr Mb P-value Trait Gene

rs1265053 6 31.19 1.8*10-14 Psoriasis Age of Onset C6orf15 rs713031 6 31.43 5.5*10-9 Family History HLA-C rs2271233 17 6.64 3.9*10-7 _{Psoriasis Age of Onset} _TEKT1 rs15574 6 31.79 5.5*10-7 _{Percent BSA at Worst} _LY6G6E rs9905086 17 3.16 2.7*10-6 _{Infection Worsens}

rs2857693 6 31.70 2.8*10-6 _{Percent BSA at Worst}

rs1003645 17 31.36 8.6*10-6 Psoriatic Arhtritis CCL23 rs437179 6 32.04 1.9*10-5 _{Percent BSA at Worst} _SKIV2L rs388685 19 49.11 2.0*10-5 _{Psoriasis Age of Onset} _ZNF45 rs981684 17 36.19 5.5*10-5 _{Family History} _KRT25C rs11944159 4 38.70 5.5*10-5 _{Psoriasis Age of Onset} _LOC92689 rs1475563 1 62.29 6.3*10-5 Family History

rs2853941 6 31.36 6.9*10-5 _{Family History} _HLA-C rs2523733 6 30.24 7.4*10-5 _{Psoriatic Arhtritis} _TRIM26 rs1800629 6 31.65 8.8*10-5 _{Family History}

rs2844749 6 30.42 1.2*10-4 _{Psoriatic Arhtritis} _RPP21 rs707936 6 31.84 1.5*10-4 Percent BSA at Worst C6orf27 rs2121133 19 8.93 1.7*10-4 _{Family History}

rs9267532 6 31.75 1.9*10-4 _{Percent BSA at Worst} _LY6G5B rs9911226 17 3.16 1.9*10-4 _{Infection Worsens} _OR3A2 rs2074890 17 15.50 2.1*10-4 _{Infection Worsens}

rs3744108 17 53.94 2.5*10-4 Psoriasis Age of Onset MTMR4 rs707936 6 31.84 2.5*10-4 Infection Worsens C6orf27 rs11655759 17 76.82 2.6*10-4 _{Family History} _FLJ44861 rs9386620 6 107.61 2.7*10-4 _{Psoriatic Arhtritis} _C6orf210 rs2318789 17 46.71 2.8*10-4 _{Percent BSA at Worst} _CGI-48 rs713031 6 31.43 2.8*10-4 Family History HLA-C rs2782641 1 43.68 2.9*10-4 Thick Plaques

(14)

Utah Psoriasis Initiative

SNP Chr Mb P-value Trait Gene

rs1265053 6 31.19 1.8*10-14 Psoriasis Age of Onset C6orf15 rs713031 6 31.43 5.5*10-9 Family History HLA-C rs2271233 17 6.64 3.9*10-7 _{Psoriasis Age of Onset} _TEKT1 rs15574 6 31.79 5.5*10-7 _{Percent BSA at Worst} _LY6G6E rs9905086 17 3.16 2.7*10-6 _{Infection Worsens}

rs2857693 6 31.70 2.8*10-6 _{Percent BSA at Worst}

rs1003645 17 31.36 8.6*10-6 Psoriatic Arhtritis CCL23 rs437179 6 32.04 1.9*10-5 _{Percent BSA at Worst} _SKIV2L rs388685 19 49.11 2.0*10-5 _{Psoriasis Age of Onset} _ZNF45 rs981684 17 36.19 5.5*10-5 _{Family History} _KRT25C rs11944159 4 38.70 5.5*10-5 _{Psoriasis Age of Onset} _LOC92689 rs1475563 1 62.29 6.3*10-5 Family History

rs2853941 6 31.36 6.9*10-5 _{Family History} _HLA-C rs2523733 6 30.24 7.4*10-5 _{Psoriatic Arhtritis} _TRIM26 rs1800629 6 31.65 8.8*10-5 _{Family History}

rs2844749 6 30.42 1.2*10-4 _{Psoriatic Arhtritis} _RPP21 rs707936 6 31.84 1.5*10-4 Percent BSA at Worst C6orf27 rs2121133 19 8.93 1.7*10-4 _{Family History}

rs9267532 6 31.75 1.9*10-4 _{Percent BSA at Worst} _LY6G5B rs9911226 17 3.16 1.9*10-4 _{Infection Worsens} _OR3A2 rs2074890 17 15.50 2.1*10-4 _{Infection Worsens}

rs3744108 17 53.94 2.5*10-4 Psoriasis Age of Onset MTMR4 rs707936 6 31.84 2.5*10-4 Infection Worsens C6orf27 rs11655759 17 76.82 2.6*10-4 _{Family History} _FLJ44861 rs9386620 6 107.61 2.7*10-4 _{Psoriatic Arhtritis} _C6orf210 rs2318789 17 46.71 2.8*10-4 _{Percent BSA at Worst} _CGI-48 rs713031 6 31.43 2.8*10-4 Family History HLA-C rs2782641 1 43.68 2.9*10-4 Thick Plaques

(15)

Additional Phenotype Information

¾

Evaluation of gene expression for ~50,000 transcripts

z

Affymetrix

U133 Plus 2.0 Arrays

¾

Skin biopsies

z

40 control biopsies (buttock)

z

40 biopsies of unaffected skin from cases (buttock)

z

40 biopsies of affected skin from cases (plaque)

¾

Early assessment of the impact of any associated

variants we identify

z

Comparison of control and unaffected skin biopsies particularly

interesting

(16)

Overall Analysis Plan

¾

Primary interest is to identify risk alleles for psoriasis

z

Compare genotypes in cases and controls

¾

Things on our mind:

z

Correlating genes with

subphenotypes

•

• Can we predict disease manifestations based on genes?

Can we predict disease manifestations based on genes?

z

Allowing for known MHC effect

•

• Can we increase power to map secondary or interacting alleles?

Can we increase power to map secondary or interacting alleles?

z

Ensuring matching of cases and controls

•

• Can we expand our control pool? Would it help?

Can we expand our control pool? Would it help?

z

Evaluating the effects of unobserved alleles

•

• Can we use HapMap information effectively to do this?

Can we use HapMap information effectively to do this?

z

Incorporating family information into analysis

•

(17)

Restrictions on Data Use

¾

Data can be used to study psoriasis and other

genetic diseases

¾

Proviso:

z

Original consent (Washington U

-

St. Louis) states

that data will be used to study psoriasis and other

auto

-

immune diseases

z

IRB has approved use of de

-

identified samples (such

as provided to GAIN) to study other diseases

(18)

Credits

¾

University of Utah

z

Gerald Krueger

z

Kristina

Callis

z

David

Goldgar

¾

University of Michigan

z

JT Elder

z

Rajan

Nair

z

Phil Stuart

z

Johann

Gudjonsson

z

John Voorhees

¾

Washington University

z

Anne Bowcock

z

Alan

Menter

z

Justin

Paschall

z

Cindy Helms

z

Gon

ç

alo Abecasis

z