Genetic Association Analysis Reveals Differences in the Contribution of NOD2 Variants to the Clinical Phenotypes of Orofacial Granulomatosis.
Orofacial granulomatosis (OFG) is a rare, inflammatory disorder of the mouth, in which some patients also have intestinal Crohn's disease (CD). The etiology remains largely unknown, although there is a high prevalence of atopy, and oral granulomas are also seen in other immune disorders particularly CD and sarcoidosis. We investigated whether genetic variants associated with an increased risk of CD, sarcoidosis, or atopy were also associated with susceptibility to OFG.



Patients were stratified clinically as isolated oral manifestations (OFG only) or concurrent intestinal CD (OFG+CD). We genotyped 201 patients and 1023 healthy controls for risk variants in NOD2, IRGM, IL23R, ATG16L1 (CD), BTNL2 (sarcoidosis), and FLG (atopy). The coding regions of the NOD2 gene were screened for rare, potentially pathogenic variants in OFG.



A combined analysis of 3 CD-risk variants in NOD2 showed no association with any OFG subgroup. NOD2 p.L1007insC was associated with OFG+CD (P = 0.023) and IL23R p.R381Q with all OFG (P = 0.031). The sarcoidosis risk variant rs2076530 in BTNL2 was associated with all OFG (P = 0.013). We identified 7 rare missense NOD2 alleles in 8 individuals with OFG, 4 OFG-only patients and 4 patients with OFG+CD. There was a significant enrichment of NOD2 variants in the OFG+CD group compared to the OFG-only group (P = 0.008, common variants; P = 0.04, all common and rare variants).



Our findings suggest that genetic variants in NOD2 are only associated with OFG in patients with concurrent intestinal disease. A genome-wide association scan is needed to fully define the genetic architecture of OFG.
*Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust and King's College London, London, United Kingdom; †Department of Medical and Molecular Genetics, Faculty of Life Science and Medicine, King's College London, Guy's Hospital, London, United Kingdom; ‡Oral Medicine, Guy's and St. Thomas' NHS Foundation Trust and King's College London, London, United Kingdom; §Diabetes and Nutritional Sciences Division, King's College London, London, United Kingdom; ‖Faculty of Health and Environmental Sciences, AUT University, Auckland, New Zealand; ¶Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom; and **Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of Witwatersrand, South Africa.
Alexander
A
Mentzer
Shalini
S
Nayee
Yasmin
Y
Omar
Esther
E
Hullah
Kirstin
K
Taylor
Rishi
R
Goel
Hannah
H
Bye
Tarik
T
Shembesh
Timothy R
TR
Elliott
Helen
H
Campbell
Pritash
P
Patel
Anita
A
Nolan
John
J
Mansfield
Stephen
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Challacombe
Michael
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Escudier
Christopher G
CG
Mathew
Jeremy D
JD
Sanderson
Natalie J
NJ
Prescott
D000071183:Autophagy-Related Proteins / Q000235:genetics; D000071797:Butyrophilins / Q000235:genetics; D016022:Case-Control Studies; D003424:Crohn Disease / Q000150:complications / Q000235:genetics*; D000091344:Filaggrin Proteins; D019204:GTP-Binding Proteins / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D051261:Granulomatosis, Orofacial / Q000150:complications / Q000235:genetics*; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics; D007381:Intermediate Filament Proteins / Q000235:genetics; D020125:Mutation, Missense; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D010641:Phenotype; D018123:Receptors, Interleukin / Q000235:genetics; D012507:Sarcoidosis / Q000235:genetics
C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; C408263:BTNL2 protein, human; D000071797:Butyrophilins; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; C515500:IL23R protein, human; D007381:Intermediate Filament Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D018123:Receptors, Interleukin; D019204:GTP-Binding Proteins; C513539:IRGM protein, human