C0634 - Somatic Mutations Within the Epitope-Binding Groove DNA Sequence of At-Risk HLA DQA1 and DQB1 Genes Are the Cause of Celiac Disease

Monday, October 24, 2022

3:00 PM – 5:00 PM ET

Location: Crown Ballroom

Has Audio

Presenting Author(s)

Piet C. De Groen, MD

University of Minnesota - Twin Cities Medical School
Rochester, MN

Piet C. De Groen, MD
University of Minnesota - Twin Cities Medical School, Rochester, MN

Introduction: Celiac disease (CD) is an inherited autoimmune disease (AID) that occurs after exposure to gluten, is associated with other AIDs and in many persons is associated with the presence of anti-gliadin and -transglutaminase antibodies (TGA). However, despite decades of research the disease mechanism is not understood. We proposed that the key mechanism of AID consists of a constant rate of somatic mutations within the epitope-binding groove of at-risk HLA genes, that are amplified by mutations in other genes identified by GWAS (DDW 2022). AIM: To investigate whether existing epidemiological and genetic data are compatible with somatic DNA mutations causing CD. We assume that one gene causes CD and any additional autoimmune diseases (AAID) in at-risk persons.

Methods: Published data were reviewed for the presence of disease patterns compatible with a constant rate of DNA mutations. HLA haplotypes DQA1*05:01/DQB1*02:01 (DQ2.5) and DQA1*03:01/DQB1*03:02 (DQ8) associated with increased risk for CD were evaluated for DNA sites prone to mutation. GWAS studies were analyzed for (1) HLA; (2) likely autoimmune target; (3) signal amplification factors.

Results: Three studies from northern Italy showed that the number of AID per person adhered to an exponential distribution supporting a constant rate of mutations (Fig 1A). The chance for an AAID was 0.8% per year per person (Fig 1B). Analysis of the DQ2.5 and DQ8 haplotypes shows presence of somatic diversification hypermutation hotspots (HH, Fig 1C-D), i.e., mutation-prone DNA loci, many involving amino acids at the base of the epitope-binding groove. GWAS studies show a strong signal for HLA and lesser signal for amplification factors, but do not show a likely autoimmune target as seen in type 1 diabetes (insulin), Graves’ disease (TSHR), and vitiligo (MC1R, OCA2). The Table shows a comparison of GWAS findings.

Discussion: Existing epidemiological and genetic data are compatible with a somatic DNA mutation mechanism as the cause of CD. The configuration and composition of the peptides causing CD within the mutated epitope-binding groove require a specific baseline configuration – hence only a few DQ alleles are associated with CD risk – and one or more mutations – hence inheritance with incomplete penetrance that depends on the number of HH and the number of mutations required to initiate disease. Transglutaminase is not an autoantigen causing CD but TGA are a result of the gluten-induced chronic inflammatory process of the small bowel mucosa.

Figure: Figure A-D

	Type 1 Diabetes	Graves' Disease	Celiac Disease
Main GWAS signal	HLA	HLA	HLA
Autoantigen GWAS signal	Insulin	TSHR	None?
Amplifier GWAS signal in FinnGen Release 7 (top 3) Cases / Controls	Insulin PTPN22 HIST1H2BA 7,337 / 255,551	TSHR PTPN22 CTLA4 1,421 / 231,654	LPP SH2B3 CCR3 2,953 / 296,917
Antibodies against GWAS signal	Yes	Yes	No
Germline mutations in autoantigen cause disease like AID	Yes	Yes	No
Symptom prevention	No	No	Gluten-free diet
Tissue affected by AID	Local cell destruction	Local cell activation	Inflammation small bowel mucosa
Contact with external antigen	No	No	Yes - small bowel
External antigen as cause of AID	No	No	Yes

Table: Our interpretation of a GWAS (FinnGen Release 7) for HLA-mediated AID is as follows. The key event is the interaction between HLA protein, content of the epitope-binding groove and the T-cell receptor; this event can be changed through mutations in one or more of each component. In HLA-mediated AID, the HLA signal will be dominant. If the key antigen causing AID is a self-antigen, any mutability of the self-antigen may result in a second signal in GWAS (Autoantigen GWAS signal: Type 1 diabetes and Graves' disease); germline mutations in these proteins may cause symptoms like those seen with AID. All other signals represent proteins that can amplify the main HLA signal. If the key antigen is a non-self-antigen as in CD, an obvious autoantigen will not be present on GWAS, and mutations in any of the proteins identified on GWAS do not cause symptoms like those seen in AID.

Disclosures:

Piet De Groen: EndoMetric – Intellectual Property/Patents.

Piet C. De Groen, MD. C0634 - Somatic Mutations Within the Epitope-Binding Groove DNA Sequence of At-Risk HLA DQA1 and DQB1 Genes Are the Cause of Celiac Disease, ACG 2022 Annual Scientific Meeting Abstracts. Charlotte, NC: American College of Gastroenterology.