Variants of thymic stromal lymphopoietin and its receptor associate with eosinophilic esophagitis.
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 x 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.


CONCLUSIONS
These data collectively identify TSLP as a candidate gene critically involved in EE susceptibility beyond its role in promoting T(H)2 responses.
Sherrill
Joseph D
JD
Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229, USA.
Gao
Pei-Song
PS
Stucke
Emily M
EM
Blanchard
Carine
C
Collins
Margaret H
MH
Putnam
Phil E
PE
Franciosi
James P
JP
Kushner
Jonathan P
JP
Abonia
J Pablo
JP
Assa'ad
Amal H
AH
Kovacic
Melinda Butsch
MB
Biagini Myers
Jocelyn M
JM
Bochner
Bruce S
BS
He
Hua
H
Hershey
Gurjit Khurana
GK
Martin
Lisa J
LJ
Rothenberg
Marc E
ME
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000235:genetics* / Q000502:physiology; D004802:Eosinophilia / Q000209:etiology / Q000235:genetics*; D004941:Esophagitis / Q000209:etiology / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D020641:Polymorphism, Single Nucleotide; D018121:Receptors, Cytokine / Q000235:genetics; D000094632:Thymic Stromal Lymphopoietin
C498762:CRLF2 protein, human; D016207:Cytokines; D018121:Receptors, Cytokine; D000094632:Thymic Stromal Lymphopoietin