TY - JOUR
T1 - Immunochip meta-analysis in European and Argentinian populations identifies two novel genetic loci associated with celiac disease
AU - Consortium for the study of genetic associations of celiac disease in Latin-America
AU - Ricaño-Ponce, Isis
AU - Gutierrez-Achury, Javier
AU - Costa, Ana Florencia
AU - Deelen, Patrick
AU - Kurilshikov, Alexander
AU - Zorro, Maria Magdalena
AU - Platteel, Mathieu
AU - van der Graaf, Adriaan
AU - Sanna, Serena
AU - Daffra, Oscar
AU - Zhernakova, Alexandra
AU - Fu, Jingyuan
AU - Trynka, Gosia
AU - Smecuol, Edgardo
AU - Niveloni, Sonia Isabel
AU - Bai, Julio Cesar
AU - Kumar, Vinod
AU - Wijmenga, Cisca
PY - 2020/3/1
Y1 - 2020/3/1
N2 - Celiac disease (CeD) is a common immune-mediated disease of the small intestine that is triggered by exposure to dietary gluten. While the HLA locus plays a major role in disease susceptibility, 39 non-HLA loci were also identified in a study of 24,269 individuals. We now build on this earlier study by adding 4125 additional Caucasian samples including an Argentinian cohort. In doing so, we not only confirm the previous associations, we also identify two novel independent genome-wide significant associations at loci: 12p13.31 and 22q13.1. By applying a genomics approach and differential expression analysis in CeD intestinal biopsies, we prioritize potential causal genes at these novel loci, including LTBR, CYTH4, and RAC2. Nineteen prioritized causal genes are overlapping known drug targets. Pathway enrichment analysis and expression of these genes in CeD biopsies suggest that they have roles in regulating multiple pathways such as the tumor necrosis factor (TNF) mediated signaling pathway and positive regulation of I-κB kinase/NF-κB signaling.
AB - Celiac disease (CeD) is a common immune-mediated disease of the small intestine that is triggered by exposure to dietary gluten. While the HLA locus plays a major role in disease susceptibility, 39 non-HLA loci were also identified in a study of 24,269 individuals. We now build on this earlier study by adding 4125 additional Caucasian samples including an Argentinian cohort. In doing so, we not only confirm the previous associations, we also identify two novel independent genome-wide significant associations at loci: 12p13.31 and 22q13.1. By applying a genomics approach and differential expression analysis in CeD intestinal biopsies, we prioritize potential causal genes at these novel loci, including LTBR, CYTH4, and RAC2. Nineteen prioritized causal genes are overlapping known drug targets. Pathway enrichment analysis and expression of these genes in CeD biopsies suggest that they have roles in regulating multiple pathways such as the tumor necrosis factor (TNF) mediated signaling pathway and positive regulation of I-κB kinase/NF-κB signaling.
KW - GENOME-WIDE ASSOCIATION
KW - LYMPHOTOXIN-BETA-RECEPTOR
KW - NF-KAPPA-B
KW - SUSCEPTIBILITY LOCI
KW - RISK VARIANTS
KW - INTERFERON-GAMMA
KW - MULTIPLE COMMON
KW - EXPRESSION
KW - RAC2
KW - ACTIVATION
U2 - 10.1038/s41431-019-0520-4
DO - 10.1038/s41431-019-0520-4
M3 - Article
C2 - 31591516
SN - 1018-4813
VL - 28
SP - 313
EP - 323
JO - EJHG
JF - EJHG
IS - 3
ER -