Enhanced Contribution of HLA in Pediatric Onset Ulcerative Colitis

Suresh Venkateswaran; Jarod Prince; David J. Cutler; Urko M. Marigorta; David T. Okou; Sampath Prahalad; David Mack; Brendan Boyle; Thomas Walters; Anne Griffiths; Cary G. Sauer; Neal Leleiko; David Keljo; James Markowitz; Susan S. Baker; Joel Rosh; Marian Pfefferkorn; Melvin B. Heyman; Ashish Patel; Anthony Otley; Robert Baldassano; Joshua Noe; Paul Rufo; Maria Oliva-Hemker; Sonia Davis; Michael E. Zwick; Greg Gibson; Lee A. Denson; Jeffrey Hyams; Subra Kugathasan

doi:10.1093/ibd/izx084

Enhanced Contribution of HLA in Pediatric Onset Ulcerative Colitis

Suresh Venkateswaran, Jarod Prince, David J. Cutler, Urko M. Marigorta, David T. Okou, Sampath Prahalad, David Mack, Brendan Boyle, Thomas Walters, Anne Griffiths, Cary G. Sauer, Neal Leleiko, David Keljo, James Markowitz, Susan S. Baker, Joel Rosh, Marian Pfefferkorn, Melvin B. Heyman, Ashish Patel, Anthony OtleyRobert Baldassano, Joshua Noe, Paul Rufo, Maria Oliva-Hemker, Sonia Davis, Michael E. Zwick, Greg Gibson, Lee A. Denson, Jeffrey Hyams, Subra Kugathasan

School of Medicine

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Background The genetic contributions to pediatric onset ulcerative colitis (UC), characterized by severe disease and extensive colonic involvement, are largely unknown. In adult onset UC, Genome Wide Association Study (GWAS) has identified numerous loci, most of which have a modest susceptibility risk (OR 0.84-1.14), with the exception of the human leukocyte antigen (HLA) region on Chromosome 6 (OR 3.59). Method To study the genetic contribution to exclusive pediatric onset UC, a GWAS was performed on 466 cases with 2099 healthy controls using UK Biobank array. SNP2HLA was used to impute classical HLA alleles and their corresponding amino acids, and the results are compared with adult onset UC. Results HLA explained the almost entire association signal, dominated with 191 single nucleotide polymorphisms (SNPs) (p = 5 x 10 -8 to 5 x 10 -10). Although very small effects, established SNPs in adult onset UC loci had similar direction and magnitude in pediatric onset UC. SNP2HLA imputation identified HLA-DRB1∗0103 (odds ratio [OR] = 6.941, p = 1.92∗10 -13) as the most significant association for pediatric UC compared with adult onset UC (OR = 3.59). Further conditioning showed independent effects for HLA-DRB1∗1301 (OR = 2.25, p = 7.92∗10 -9) and another SNP rs17188113 (OR = 0.48, p = 7.56∗10 -9). Two HLA-DRB1 causal alleles are shared with adult onset UC, while at least 2 signals are unique to pediatric UC. Subsequent stratified analyses indicated that HLA-DRB1∗0103 has stronger association for extensive disease (E4: OR = 8.28, p = 4.66x10 -10) and female gender (OR = 8.85, p = 4.82x10 -13). Conclusion In pediatric onset UC, the HLA explains almost the entire genetic associations. In addition, the HLA association is approximately twice as strong in pediatric UC compared with adults, due to a combination of novel and shared effects. We speculate the paramount importance of antigenic stimulation either by infectious or noninfectious stimuli as a causal event in pediatric UC onset.

Original language	English (US)
Pages (from-to)	829-838
Number of pages	10
Journal	Inflammatory bowel diseases
Volume	24
Issue number	4
DOIs	https://doi.org/10.1093/ibd/izx084
State	Published - Mar 19 2018

Keywords

GWAS
HLA-DRB1
IBD
Inflammatory Bowel Disease
Pediatric UC
Ulcerative Colitis

ASJC Scopus subject areas

Immunology and Allergy
Gastroenterology

Access to Document

10.1093/ibd/izx084

Cite this

Venkateswaran, S., Prince, J., Cutler, D. J., Marigorta, U. M., Okou, D. T., Prahalad, S., Mack, D., Boyle, B., Walters, T., Griffiths, A., Sauer, C. G., Leleiko, N., Keljo, D., Markowitz, J., Baker, S. S., Rosh, J., Pfefferkorn, M., Heyman, M. B., Patel, A., ... Kugathasan, S. (2018). Enhanced Contribution of HLA in Pediatric Onset Ulcerative Colitis. Inflammatory bowel diseases, 24(4), 829-838. https://doi.org/10.1093/ibd/izx084

Venkateswaran, S, Prince, J, Cutler, DJ, Marigorta, UM, Okou, DT, Prahalad, S, Mack, D, Boyle, B, Walters, T, Griffiths, A, Sauer, CG, Leleiko, N, Keljo, D, Markowitz, J, Baker, SS, Rosh, J, Pfefferkorn, M, Heyman, MB, Patel, A, Otley, A, Baldassano, R, Noe, J, Rufo, P, Oliva-Hemker, M, Davis, S, Zwick, ME, Gibson, G, Denson, LA, Hyams, J & Kugathasan, S 2018, 'Enhanced Contribution of HLA in Pediatric Onset Ulcerative Colitis', Inflammatory bowel diseases, vol. 24, no. 4, pp. 829-838. https://doi.org/10.1093/ibd/izx084

@article{c83ae01771a74c67a9b80c96f2aecc06,

title = "Enhanced Contribution of HLA in Pediatric Onset Ulcerative Colitis",

abstract = "Background The genetic contributions to pediatric onset ulcerative colitis (UC), characterized by severe disease and extensive colonic involvement, are largely unknown. In adult onset UC, Genome Wide Association Study (GWAS) has identified numerous loci, most of which have a modest susceptibility risk (OR 0.84-1.14), with the exception of the human leukocyte antigen (HLA) region on Chromosome 6 (OR 3.59). Method To study the genetic contribution to exclusive pediatric onset UC, a GWAS was performed on 466 cases with 2099 healthy controls using UK Biobank array. SNP2HLA was used to impute classical HLA alleles and their corresponding amino acids, and the results are compared with adult onset UC. Results HLA explained the almost entire association signal, dominated with 191 single nucleotide polymorphisms (SNPs) (p = 5 x 10 -8 to 5 x 10 -10). Although very small effects, established SNPs in adult onset UC loci had similar direction and magnitude in pediatric onset UC. SNP2HLA imputation identified HLA-DRB1∗0103 (odds ratio [OR] = 6.941, p = 1.92∗10 -13) as the most significant association for pediatric UC compared with adult onset UC (OR = 3.59). Further conditioning showed independent effects for HLA-DRB1∗1301 (OR = 2.25, p = 7.92∗10 -9) and another SNP rs17188113 (OR = 0.48, p = 7.56∗10 -9). Two HLA-DRB1 causal alleles are shared with adult onset UC, while at least 2 signals are unique to pediatric UC. Subsequent stratified analyses indicated that HLA-DRB1∗0103 has stronger association for extensive disease (E4: OR = 8.28, p = 4.66x10 -10) and female gender (OR = 8.85, p = 4.82x10 -13). Conclusion In pediatric onset UC, the HLA explains almost the entire genetic associations. In addition, the HLA association is approximately twice as strong in pediatric UC compared with adults, due to a combination of novel and shared effects. We speculate the paramount importance of antigenic stimulation either by infectious or noninfectious stimuli as a causal event in pediatric UC onset.",

keywords = "GWAS, HLA-DRB1, IBD, Inflammatory Bowel Disease, Pediatric UC, Ulcerative Colitis",

author = "Suresh Venkateswaran and Jarod Prince and Cutler, {David J.} and Marigorta, {Urko M.} and Okou, {David T.} and Sampath Prahalad and David Mack and Brendan Boyle and Thomas Walters and Anne Griffiths and Sauer, {Cary G.} and Neal Leleiko and David Keljo and James Markowitz and Baker, {Susan S.} and Joel Rosh and Marian Pfefferkorn and Heyman, {Melvin B.} and Ashish Patel and Anthony Otley and Robert Baldassano and Joshua Noe and Paul Rufo and Maria Oliva-Hemker and Sonia Davis and Zwick, {Michael E.} and Greg Gibson and Denson, {Lee A.} and Jeffrey Hyams and Subra Kugathasan",

note = "Publisher Copyright: {\textcopyright} 2018 Crohn's & Colitis Foundation. Published by Oxford University Press on behalf of Crohn's & Colitis Foundation.",

year = "2018",

month = mar,

day = "19",

doi = "10.1093/ibd/izx084",

language = "English (US)",

volume = "24",

pages = "829--838",

journal = "Inflammatory bowel diseases",

issn = "1078-0998",

publisher = "John Wiley and Sons Inc.",

number = "4",

}

TY - JOUR

T1 - Enhanced Contribution of HLA in Pediatric Onset Ulcerative Colitis

AU - Venkateswaran, Suresh

AU - Prince, Jarod

AU - Cutler, David J.

AU - Marigorta, Urko M.

AU - Okou, David T.

AU - Prahalad, Sampath

AU - Mack, David

AU - Boyle, Brendan

AU - Walters, Thomas

AU - Griffiths, Anne

AU - Sauer, Cary G.

AU - Leleiko, Neal

AU - Keljo, David

AU - Markowitz, James

AU - Baker, Susan S.

AU - Rosh, Joel

AU - Pfefferkorn, Marian

AU - Heyman, Melvin B.

AU - Patel, Ashish

AU - Otley, Anthony

AU - Baldassano, Robert

AU - Noe, Joshua

AU - Rufo, Paul

AU - Oliva-Hemker, Maria

AU - Davis, Sonia

AU - Zwick, Michael E.

AU - Gibson, Greg

AU - Denson, Lee A.

AU - Hyams, Jeffrey

AU - Kugathasan, Subra

PY - 2018/3/19

Y1 - 2018/3/19

N2 - Background The genetic contributions to pediatric onset ulcerative colitis (UC), characterized by severe disease and extensive colonic involvement, are largely unknown. In adult onset UC, Genome Wide Association Study (GWAS) has identified numerous loci, most of which have a modest susceptibility risk (OR 0.84-1.14), with the exception of the human leukocyte antigen (HLA) region on Chromosome 6 (OR 3.59). Method To study the genetic contribution to exclusive pediatric onset UC, a GWAS was performed on 466 cases with 2099 healthy controls using UK Biobank array. SNP2HLA was used to impute classical HLA alleles and their corresponding amino acids, and the results are compared with adult onset UC. Results HLA explained the almost entire association signal, dominated with 191 single nucleotide polymorphisms (SNPs) (p = 5 x 10 -8 to 5 x 10 -10). Although very small effects, established SNPs in adult onset UC loci had similar direction and magnitude in pediatric onset UC. SNP2HLA imputation identified HLA-DRB1∗0103 (odds ratio [OR] = 6.941, p = 1.92∗10 -13) as the most significant association for pediatric UC compared with adult onset UC (OR = 3.59). Further conditioning showed independent effects for HLA-DRB1∗1301 (OR = 2.25, p = 7.92∗10 -9) and another SNP rs17188113 (OR = 0.48, p = 7.56∗10 -9). Two HLA-DRB1 causal alleles are shared with adult onset UC, while at least 2 signals are unique to pediatric UC. Subsequent stratified analyses indicated that HLA-DRB1∗0103 has stronger association for extensive disease (E4: OR = 8.28, p = 4.66x10 -10) and female gender (OR = 8.85, p = 4.82x10 -13). Conclusion In pediatric onset UC, the HLA explains almost the entire genetic associations. In addition, the HLA association is approximately twice as strong in pediatric UC compared with adults, due to a combination of novel and shared effects. We speculate the paramount importance of antigenic stimulation either by infectious or noninfectious stimuli as a causal event in pediatric UC onset.

AB - Background The genetic contributions to pediatric onset ulcerative colitis (UC), characterized by severe disease and extensive colonic involvement, are largely unknown. In adult onset UC, Genome Wide Association Study (GWAS) has identified numerous loci, most of which have a modest susceptibility risk (OR 0.84-1.14), with the exception of the human leukocyte antigen (HLA) region on Chromosome 6 (OR 3.59). Method To study the genetic contribution to exclusive pediatric onset UC, a GWAS was performed on 466 cases with 2099 healthy controls using UK Biobank array. SNP2HLA was used to impute classical HLA alleles and their corresponding amino acids, and the results are compared with adult onset UC. Results HLA explained the almost entire association signal, dominated with 191 single nucleotide polymorphisms (SNPs) (p = 5 x 10 -8 to 5 x 10 -10). Although very small effects, established SNPs in adult onset UC loci had similar direction and magnitude in pediatric onset UC. SNP2HLA imputation identified HLA-DRB1∗0103 (odds ratio [OR] = 6.941, p = 1.92∗10 -13) as the most significant association for pediatric UC compared with adult onset UC (OR = 3.59). Further conditioning showed independent effects for HLA-DRB1∗1301 (OR = 2.25, p = 7.92∗10 -9) and another SNP rs17188113 (OR = 0.48, p = 7.56∗10 -9). Two HLA-DRB1 causal alleles are shared with adult onset UC, while at least 2 signals are unique to pediatric UC. Subsequent stratified analyses indicated that HLA-DRB1∗0103 has stronger association for extensive disease (E4: OR = 8.28, p = 4.66x10 -10) and female gender (OR = 8.85, p = 4.82x10 -13). Conclusion In pediatric onset UC, the HLA explains almost the entire genetic associations. In addition, the HLA association is approximately twice as strong in pediatric UC compared with adults, due to a combination of novel and shared effects. We speculate the paramount importance of antigenic stimulation either by infectious or noninfectious stimuli as a causal event in pediatric UC onset.

KW - GWAS

KW - HLA-DRB1

KW - IBD

KW - Inflammatory Bowel Disease

KW - Pediatric UC

KW - Ulcerative Colitis

UR - http://www.scopus.com/inward/record.url?scp=85044446552&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85044446552&partnerID=8YFLogxK

U2 - 10.1093/ibd/izx084

DO - 10.1093/ibd/izx084

M3 - Article

C2 - 29562276

AN - SCOPUS:85044446552

SN - 1078-0998

VL - 24

SP - 829

EP - 838

JO - Inflammatory bowel diseases

JF - Inflammatory bowel diseases

IS - 4

ER -

Enhanced Contribution of HLA in Pediatric Onset Ulcerative Colitis

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this