TY - JOUR
T1 - Variants of thymic stromal lymphopoietin and its receptor associate with eosinophilic esophagitis
AU - Sherrill, Joseph D.
AU - Gao, Pei Song
AU - Stucke, Emily M.
AU - Blanchard, Carine
AU - Collins, Margaret H.
AU - Putnam, Phil E.
AU - Franciosi, James P.
AU - Kushner, Jonathan P.
AU - Abonia, J. Pablo
AU - Assa'ad, Amal H.
AU - Kovacic, Melinda Butsch
AU - Biagini Myers, Jocelyn M.
AU - Bochner, Bruce S.
AU - He, Hua
AU - Hershey, Gurjit Khurana
AU - Martin, Lisa J.
AU - Rothenberg, Marc E.
N1 - Funding Information:
Supported in part by National Institutes of Health grant U19 AI070235 , National Institutes of Health grant R01 DK076893 , Public Health Service grant P30 DK0789392 , the Department of Defense, the Food Allergy Project, the Buckeye Foundation, and the Campaign Urging Research for Eosinophilic Disorders (CURED) Foundation . J.D.S. is supported by a T32 National Institutes of Health training grant ( HL091805 ). P.G., B.S.B., and M.E.R. were supported by a Dana Foundation Human Immunology Consortium Grant .
Funding Information:
Disclosure of potential conflict of interest: M. H. Collins has consultant and reviewer arrangements with GlaxoSmithKline, Ception Therapeutics, and Meritage Pharma. J. P. Abonia receives research support from the National Institutes of Health, Ception Therapeutics, and the Children's Digestive Health and Nutrition Foundation . A. H. Assa'ad receives research support from GlaxoSmithKline and is a volunteer member of the medical board of directors for the American Partnership for Eosinophilic Disorders. L. J. Martin receives research support from the National Institutes of Health . M. E. Rothenberg is on the speakers' bureau for Merck; has consultant arrangements with Merck, Centocor, Ception Therapeutics, Nycomed, Array Biopharma, Biocrystal Pharmaceuticals, Endo Pharmaceuticals, and Pieres AG; receives research support from the National Institutes of Health, the Food Allergy and Anaphylaxis Network, and the Dana Foundation ; is on the Medical Advisory Board for American Partnership for Eosinophilic Disorders; and is on the Executive Council for the International Eosinophil Society. The rest of the authors have declared that they have no conflict of interest.
PY - 2010/7
Y1 - 2010/7
N2 - Background: The genetic cause of eosinophilic esophagitis (EE) has been largely unexplored until a recent genome-wide association study identified a disease susceptibility locus on 5q22, a region that harbors the thymic stromal lymphopoietin (TSLP) gene. However, it is unclear whether the observed genetic associations with EE are disease-specific or confounded by the high rate of allergy in patients with EE. In addition, the genetic contributions of other allergy-associated genes to EE risk have not been explored. Objective: We aimed to delineate single nucleotide polymorphisms (SNPs) that associated with EE apart from allergy. Methods: We used a custom array containing 738 SNPs in 53 genes implicated in allergic responses, immune responses, or both to genotype 220 allergic or 246 nonallergic control subjects and a discovery cohort of 170 patients with EE. We replicated a statistically significant SNP association in an independent case-control cohort and examined the induction of the candidate gene in primary esophageal epithelial cells. Results: A single SNP residing in the TSLP gene reached Bonferroni linkage disequilibrium-adjusted significance but only when patients with EE were compared with allergic control subjects (rs10062929; P = 4.11 × 10-5; odds ratio, 0.35). A nonsynonymous polymorphism in the thymic stromal lymphopoietin receptor (TSLPR) gene on Xp22.3 and Yp11.3 was significantly associated with disease only in male patients with EE. Primary esophageal epithelial cells expressed TSLP mRNA after Toll-like receptor 3 stimulation. Conclusion: These data collectively identify TSLP as a candidate gene critically involved in EE susceptibility beyond its role in promoting TH2 responses.
AB - Background: The genetic cause of eosinophilic esophagitis (EE) has been largely unexplored until a recent genome-wide association study identified a disease susceptibility locus on 5q22, a region that harbors the thymic stromal lymphopoietin (TSLP) gene. However, it is unclear whether the observed genetic associations with EE are disease-specific or confounded by the high rate of allergy in patients with EE. In addition, the genetic contributions of other allergy-associated genes to EE risk have not been explored. Objective: We aimed to delineate single nucleotide polymorphisms (SNPs) that associated with EE apart from allergy. Methods: We used a custom array containing 738 SNPs in 53 genes implicated in allergic responses, immune responses, or both to genotype 220 allergic or 246 nonallergic control subjects and a discovery cohort of 170 patients with EE. We replicated a statistically significant SNP association in an independent case-control cohort and examined the induction of the candidate gene in primary esophageal epithelial cells. Results: A single SNP residing in the TSLP gene reached Bonferroni linkage disequilibrium-adjusted significance but only when patients with EE were compared with allergic control subjects (rs10062929; P = 4.11 × 10-5; odds ratio, 0.35). A nonsynonymous polymorphism in the thymic stromal lymphopoietin receptor (TSLPR) gene on Xp22.3 and Yp11.3 was significantly associated with disease only in male patients with EE. Primary esophageal epithelial cells expressed TSLP mRNA after Toll-like receptor 3 stimulation. Conclusion: These data collectively identify TSLP as a candidate gene critically involved in EE susceptibility beyond its role in promoting TH2 responses.
KW - Eosinophilic esophagitis
KW - Toll-like receptor 3
KW - allergy
KW - cytokine receptor-like factor 2
KW - single nucleotide polymorphism
KW - thymic stromal lymphopoietin
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U2 - 10.1016/j.jaci.2010.04.037
DO - 10.1016/j.jaci.2010.04.037
M3 - Article
C2 - 20620568
AN - SCOPUS:77954082579
SN - 0091-6749
VL - 126
SP - 160-165.e3
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 1
ER -