Newly identified genetic risk variants for celiac disease related to the immune response.
Our genome-wide association study of celiac disease previously identified risk variants in the IL2-IL21 region. To identify additional risk variants, we genotyped 1,020 of the most strongly associated non-HLA markers in an additional 1,643 cases and 3,406 controls. Through joint analysis including the genome-wide association study data (767 cases, 1,422 controls), we identified seven previously unknown risk regions (P < 5 x 10(-7)). Six regions harbor genes controlling immune responses, including CCR3, IL12A, IL18RAP, RGS1, SH2B3 (nsSNP rs3184504) and TAGAP. Whole-blood IL18RAP mRNA expression correlated with IL18RAP genotype. Type 1 diabetes and celiac disease share HLA-DQ, IL2-IL21, CCR3 and SH2B3 risk regions. Thus, this extensive genome-wide association follow-up study has identified additional celiac disease risk variants in relevant biological pathways.
Hunt
Karen A
KA
Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, UK.
Zhernakova
Alexandra
A
Turner
Graham
G
Heap
Graham A R
GA
Franke
Lude
L
Bruinenberg
Marcel
M
Romanos
Jihane
J
Dinesen
Lotte C
LC
Ryan
Anthony W
AW
Panesar
Davinder
D
Gwilliam
Rhian
R
Takeuchi
Fumihiko
F
McLaren
William M
WM
Holmes
Geoffrey K T
GK
Howdle
Peter D
PD
Walters
Julian R F
JR
Sanders
David S
DS
Playford
Raymond J
RJ
Trynka
Gosia
G
Mulder
Chris J J
CJ
Mearin
M Luisa
ML
Verbeek
Wieke H M
WH
Trimble
Valerie
V
Stevens
Fiona M
FM
O'Morain
Colm
C
Kennedy
Nicholas P
NP
Kelleher
Dermot
D
Pennington
Daniel J
DJ
Strachan
David P
DP
McArdle
Wendy L
WL
Mein
Charles A
CA
Wapenaar
Martin C
MC
Deloukas
Panos
P
McGinnis
Ralph
R
McManus
Ross
R
Wijmenga
Cisca
C
van Heel
David A
DA
D000818:Animals; D015415:Biomarkers; D016022:Case-Control Studies; D002446:Celiac Disease / Q000235:genetics* / Q000276:immunology; D002874:Chromosome Mapping; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D005260:Female; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006683:HLA-DQ Antigens / Q000378:metabolism; D006801:Humans; D053765:Interleukin-12 Subunit p35 / Q000235:genetics; D053728:Interleukin-18 Receptor beta Subunit / Q000097:blood / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D051379:Mice; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D020710:RGS Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054397:Receptors, CCR3 / Q000235:genetics; D012307:Risk Factors; D014018:Tissue Distribution
D015415:Biomarkers; D005819:Genetic Markers; D006683:HLA-DQ Antigens; C508858:IL12A protein, human; C115629:IL18RAP protein, human; D053765:Interleukin-12 Subunit p35; D053728:Interleukin-18 Receptor beta Subunit; D020710:RGS Proteins; C080831:RGS1 protein, human; D012333:RNA, Messenger; D054397:Receptors, CCR3