Newly identified genetic risk variants for celiac disease related to the immune response

Karen A Hunt; Alexandra Zhernakova; Graham Turner; Graham A R Heap; Lude Franke; Marcel Bruinenberg; Jihane Romanos; Lotte C Dinesen; Anthony W Ryan; Davinder Panesar; Rhian Gwilliam; Fumihiko Takeuchi; William M McLaren; Geoffrey K T Holmes; Peter D Howdle; Julian R F Walters; David S Sanders; Raymond J Playford; Gosia Trynka; Chris J J Mulder; M Luisa Mearin; Wieke H M Verbeek; Valerie Trimble; Fiona M Stevens; Colm O'Morain; Nicholas P Kennedy; Dermot Kelleher; Daniel J Pennington; David P Strachan; Wendy L McArdle; Charles A Mein; Martin C Wapenaar; Panos Deloukas; Ralph McGinnis; Ross McManus; Cisca Wijmenga; David A van Heel

doi:10.1038/ng.102

Newly identified genetic risk variants for celiac disease related to the immune response

Karen A Hunt, Alexandra Zhernakova, Graham Turner, Graham A R Heap, Lude Franke, Marcel Bruinenberg, Jihane Romanos, Lotte C Dinesen, Anthony W Ryan, Davinder Panesar, Rhian Gwilliam, Fumihiko Takeuchi, William M McLaren, Geoffrey K T Holmes, Peter D Howdle, Julian R F Walters, David S Sanders, Raymond J Playford, Gosia Trynka, Chris J J MulderM Luisa Mearin, Wieke H M Verbeek, Valerie Trimble, Fiona M Stevens, Colm O'Morain, Nicholas P Kennedy, Dermot Kelleher, Daniel J Pennington, David P Strachan, Wendy L McArdle, Charles A Mein, Martin C Wapenaar, Panos Deloukas, Ralph McGinnis, Ross McManus, Cisca Wijmenga, David A van Heel

Bristol Medical School (PHS)

Research output: Contribution to journal › Article (Academic Journal) › peer-review

480 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	395-402
Number of pages	8
Journal	Nature Genetics
Volume	40
Issue number	4
DOIs	https://doi.org/10.1038/ng.102
Publication status	Published - 2008

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Hunt, K. A., Zhernakova, A., Turner, G., Heap, G. A. R., Franke, L., Bruinenberg, M., Romanos, J., Dinesen, L. C., Ryan, A. W., Panesar, D., Gwilliam, R., Takeuchi, F., McLaren, W. M., Holmes, G. K. T., Howdle, P. D., Walters, J. R. F., Sanders, D. S., Playford, R. J., Trynka, G., ... van Heel, D. A. (2008). Newly identified genetic risk variants for celiac disease related to the immune response. Nature Genetics, 40(4), 395-402. https://doi.org/10.1038/ng.102

Hunt, Karen A ; Zhernakova, Alexandra ; Turner, Graham ; Heap, Graham A R ; Franke, Lude ; Bruinenberg, Marcel ; Romanos, Jihane ; Dinesen, Lotte C ; Ryan, Anthony W ; Panesar, Davinder ; Gwilliam, Rhian ; Takeuchi, Fumihiko ; McLaren, William M ; Holmes, Geoffrey K T ; Howdle, Peter D ; Walters, Julian R F ; Sanders, David S ; Playford, Raymond J ; Trynka, Gosia ; Mulder, Chris J J ; Mearin, M Luisa ; Verbeek, Wieke H M ; Trimble, Valerie ; Stevens, Fiona M ; O'Morain, Colm ; Kennedy, Nicholas P ; Kelleher, Dermot ; Pennington, Daniel J ; Strachan, David P ; McArdle, Wendy L ; Mein, Charles A ; Wapenaar, Martin C ; Deloukas, Panos ; McGinnis, Ralph ; McManus, Ross ; Wijmenga, Cisca ; van Heel, David A. / Newly identified genetic risk variants for celiac disease related to the immune response. In: Nature Genetics. 2008 ; Vol. 40, No. 4. pp. 395-402.

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title = "Newly identified genetic risk variants for celiac disease related to the immune response",

abstract = "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.",

author = "Hunt, {Karen A} and Alexandra Zhernakova and Graham Turner and Heap, {Graham A R} and Lude Franke and Marcel Bruinenberg and Jihane Romanos and Dinesen, {Lotte C} and Ryan, {Anthony W} and Davinder Panesar and Rhian Gwilliam and Fumihiko Takeuchi and McLaren, {William M} and Holmes, {Geoffrey K T} and Howdle, {Peter D} and Walters, {Julian R F} and Sanders, {David S} and Playford, {Raymond J} and Gosia Trynka and Mulder, {Chris J J} and Mearin, {M Luisa} and Verbeek, {Wieke H M} and Valerie Trimble and Stevens, {Fiona M} and Colm O'Morain and Kennedy, {Nicholas P} and Dermot Kelleher and Pennington, {Daniel J} and Strachan, {David P} and McArdle, {Wendy L} and Mein, {Charles A} and Wapenaar, {Martin C} and Panos Deloukas and Ralph McGinnis and Ross McManus and Cisca Wijmenga and {van Heel}, {David A}",

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doi = "10.1038/ng.102",

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pages = "395--402",

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Hunt, KA, Zhernakova, A, Turner, G, Heap, GAR, Franke, L, Bruinenberg, M, Romanos, J, Dinesen, LC, Ryan, AW, Panesar, D, Gwilliam, R, Takeuchi, F, McLaren, WM, Holmes, GKT, Howdle, PD, Walters, JRF, Sanders, DS, Playford, RJ, Trynka, G, Mulder, CJJ, Mearin, ML, Verbeek, WHM, Trimble, V, Stevens, FM, O'Morain, C, Kennedy, NP, Kelleher, D, Pennington, DJ, Strachan, DP, McArdle, WL, Mein, CA, Wapenaar, MC, Deloukas, P, McGinnis, R, McManus, R, Wijmenga, C & van Heel, DA 2008, 'Newly identified genetic risk variants for celiac disease related to the immune response', Nature Genetics, vol. 40, no. 4, pp. 395-402. https://doi.org/10.1038/ng.102

Newly identified genetic risk variants for celiac disease related to the immune response. / Hunt, Karen A; Zhernakova, Alexandra; Turner, Graham; Heap, Graham A R; Franke, Lude; Bruinenberg, Marcel; Romanos, Jihane; Dinesen, Lotte C; Ryan, Anthony W; Panesar, Davinder; Gwilliam, Rhian; Takeuchi, Fumihiko; McLaren, William M; Holmes, Geoffrey K T; Howdle, Peter D; Walters, Julian R F; Sanders, David S; Playford, Raymond J; Trynka, Gosia; Mulder, Chris J J; Mearin, M Luisa; Verbeek, Wieke H M; Trimble, Valerie; Stevens, Fiona M; O'Morain, Colm; Kennedy, Nicholas P; Kelleher, Dermot; Pennington, Daniel J; Strachan, David P; McArdle, Wendy L; Mein, Charles A; Wapenaar, Martin C; Deloukas, Panos; McGinnis, Ralph; McManus, Ross; Wijmenga, Cisca; van Heel, David A.

In: Nature Genetics, Vol. 40, No. 4, 2008, p. 395-402.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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AU - Hunt, Karen A

AU - Zhernakova, Alexandra

AU - Turner, Graham

AU - Heap, Graham A R

AU - Franke, Lude

AU - Bruinenberg, Marcel

AU - Romanos, Jihane

AU - Dinesen, Lotte C

AU - Ryan, Anthony W

AU - Panesar, Davinder

AU - Gwilliam, Rhian

AU - Takeuchi, Fumihiko

AU - McLaren, William M

AU - Holmes, Geoffrey K T

AU - Howdle, Peter D

AU - Walters, Julian R F

AU - Sanders, David S

AU - Playford, Raymond J

AU - Trynka, Gosia

AU - Mulder, Chris J J

AU - Mearin, M Luisa

AU - Verbeek, Wieke H M

AU - Trimble, Valerie

AU - Stevens, Fiona M

AU - O'Morain, Colm

AU - Kennedy, Nicholas P

AU - Kelleher, Dermot

AU - Pennington, Daniel J

AU - Strachan, David P

AU - McArdle, Wendy L

AU - Mein, Charles A

AU - Wapenaar, Martin C

AU - Deloukas, Panos

AU - McGinnis, Ralph

AU - McManus, Ross

AU - Wijmenga, Cisca

AU - van Heel, David A

PY - 2008

Y1 - 2008

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AB - 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.

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DO - 10.1038/ng.102

M3 - Article (Academic Journal)

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EP - 402

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

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