TY - JOUR
T1 - Independent and cumulative coeliac disease-susceptibility loci are associated with distinct disease phenotypes
AU - Cerqueira, Juliana X.M.
AU - Saavalainen, Päivi
AU - Kurppa, Kalle
AU - Laurikka, Pilvi
AU - Huhtala, Heini
AU - Nykter, Matti
AU - L. E. Koskinen, Lotta
AU - Yohannes, Dawit A.
AU - Kilpeläinen, Elina
AU - Shcherban, Anastasia
AU - Palotie, Aarno
AU - Kaukinen, Katri
AU - Lindfors, Katri
N1 - Funding Information:
Acknowledgements This study was supported by grants from the Academy of Finland, the Sigrid Juselius Foundation, the Foundation for Pediatric Research and the Competitive State Research Financing of the Expert Area of Tampere University Hospital. The funding sources had no role in the design of the study, the collection, analysis, or interpretation of the data; the preparation or review of the manuscript; or the decision to submit the manuscript for publication.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/1
Y1 - 2021/1
N2 - The phenotype of coeliac disease varies considerably for incompletely understood reasons. We investigated whether established coeliac disease susceptibility variants (SNPs) are individually or cumulatively associated with distinct phenotypes. We also tested whether a polygenic risk score (PRS) based on genome-wide associated (GWA) data could explain the phenotypic variation. The phenotypic association of 39 non-HLA coeliac disease SNPs was tested in 625 thoroughly phenotyped coeliac disease patients and 1817 controls. To assess their cumulative effects a weighted genetic risk score (wGRS39) was built, and stratified by tertiles. In our PRS model in cases, we took the summary statistics from the largest GWA study in coeliac disease and tested their association at eight P value thresholds (PT) with phenotypes. Altogether ten SNPs were associated with distinct phenotypes after correction for multiple testing (PEMP2 ≤ 0.05). The TLR7/TLR8 locus was associated with disease onset before and the SH2B3/ATXN2, ITGA4/UBE2E3 and IL2/IL21 loci after 7 years of age. The latter three loci were associated with a more severe small bowel mucosal damage and SH2B3/ATXN2 with type 1 diabetes. Patients at the highest wGRS39 tertiles had OR > 1.62 for having coeliac disease-related symptoms during childhood, a more severe small bowel mucosal damage, malabsorption and anaemia. PRS was associated only with dermatitis herpetiformis (PT = 0.2, PEMP2 = 0.02). Independent coeliac disease-susceptibility loci are associated with distinct phenotypes, suggesting that genetic factors play a role in determining the disease presentation. Moreover, the increased number of coeliac disease susceptibility SNPs might predispose to a more severe disease course.
AB - The phenotype of coeliac disease varies considerably for incompletely understood reasons. We investigated whether established coeliac disease susceptibility variants (SNPs) are individually or cumulatively associated with distinct phenotypes. We also tested whether a polygenic risk score (PRS) based on genome-wide associated (GWA) data could explain the phenotypic variation. The phenotypic association of 39 non-HLA coeliac disease SNPs was tested in 625 thoroughly phenotyped coeliac disease patients and 1817 controls. To assess their cumulative effects a weighted genetic risk score (wGRS39) was built, and stratified by tertiles. In our PRS model in cases, we took the summary statistics from the largest GWA study in coeliac disease and tested their association at eight P value thresholds (PT) with phenotypes. Altogether ten SNPs were associated with distinct phenotypes after correction for multiple testing (PEMP2 ≤ 0.05). The TLR7/TLR8 locus was associated with disease onset before and the SH2B3/ATXN2, ITGA4/UBE2E3 and IL2/IL21 loci after 7 years of age. The latter three loci were associated with a more severe small bowel mucosal damage and SH2B3/ATXN2 with type 1 diabetes. Patients at the highest wGRS39 tertiles had OR > 1.62 for having coeliac disease-related symptoms during childhood, a more severe small bowel mucosal damage, malabsorption and anaemia. PRS was associated only with dermatitis herpetiformis (PT = 0.2, PEMP2 = 0.02). Independent coeliac disease-susceptibility loci are associated with distinct phenotypes, suggesting that genetic factors play a role in determining the disease presentation. Moreover, the increased number of coeliac disease susceptibility SNPs might predispose to a more severe disease course.
U2 - 10.1038/s10038-020-00888-5
DO - 10.1038/s10038-020-00888-5
M3 - Article
C2 - 33446885
AN - SCOPUS:85100001559
SN - 1434-5161
VL - 66
SP - 613
EP - 623
JO - JOURNAL OF HUMAN GENETICS
JF - JOURNAL OF HUMAN GENETICS
ER -
