Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
Psoriasis is a common immune-mediated disorder that affects the skin, nails and joints. To identify psoriasis susceptibility loci, we genotyped 438,670 SNPs in 1,409 psoriasis cases and 1,436 controls of European ancestry. We followed up 21 promising SNPs in 5,048 psoriasis cases and 5,041 controls. Our results provide strong support for the association of at least seven genetic loci and psoriasis (each with combined P < 5 x 10(-8)). Loci with confirmed association include HLA-C, three genes involved in IL-23 signaling (IL23A, IL23R, IL12B), two genes that act downstream of TNF-alpha and regulate NF-kappaB signaling (TNIP1, TNFAIP3) and two genes involved in the modulation of Th2 immune responses (IL4, IL13). Although the proteins encoded in these loci are known to interact biologically, we found no evidence for epistasis between associated SNPs. Our results expand the catalog of genetic loci implicated in psoriasis susceptibility and suggest priority targets for study in other auto-immune disorders.
Nair
Rajan P
RP
Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Duffin
Kristina Callis
KC
Helms
Cynthia
C
Ding
Jun
J
Stuart
Philip E
PE
Goldgar
David
D
Gudjonsson
Johann E
JE
Li
Yun
Y
Tejasvi
Trilokraj
T
Feng
Bing-Jian
BJ
Ruether
Andreas
A
Schreiber
Stefan
S
Weichenthal
Michael
M
Gladman
Dafna
D
Rahman
Proton
P
Schrodi
Steven J
SJ
Prahalad
Sampath
S
Guthery
Stephen L
SL
Fischer
Judith
J
Liao
Wilson
W
Kwok
Pui-Yan
PY
Menter
Alan
A
Lathrop
G Mark
GM
Wise
Carol A
CA
Begovich
Ann B
AB
Voorhees
John J
JJ
Elder
James T
JT
Krueger
Gerald G
GG
Bowcock
Anne M
AM
Abecasis
Gonçalo R
GR
D000328:Adult; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D015236:HLA-C Antigens / Q000235:genetics; D006801:Humans; D053762:Interleukin-12 Subunit p40 / Q000235:genetics; D018793:Interleukin-13 / Q000235:genetics; D053759:Interleukin-23 / Q000235:genetics*; D015847:Interleukin-4 / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011565:Psoriasis / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D055815:Young Adult
D004268:DNA-Binding Proteins; D015236:HLA-C Antigens; C500879:IL12B protein, human; C508598:IL4 protein, human; D053762:Interleukin-12 Subunit p40; D018793:Interleukin-13; D053759:Interleukin-23; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; C117046:TNIP1 protein, human; D015847:Interleukin-4; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3