KIR Genes and Non-Celiac Wheat Sensitivity

Non-celiac Wheat Sensitivity Clinical Trial

Official title:

Contribution of KIR Genes on the Genetic Predisposition to Non-Celiac Wheat Sensitivity

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05469971
• Other study ID #: ACPM29
• Status: Completed
• Start date: November 1, 2022
• Est. completion date: September 30, 2023

Study information

• Verified date: November 2023
• Source: University of Palermo
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Non-celiac gluten sensitivity (NCGS) is a condition characterized by gastrointestinal and extraintestinal symptoms which are triggered by gluten ingestion in the absence of celiac disease (CD) and wheat allergy. In the last years studies suggested that wheat components other than gluten can be responsible of symptom's triggering, thus the term "non-celiac wheat sensitivity" (NCWS) has been proposed as a more appropriate label. To date, different pathogenetic mechanisms have been proposed, but no conclusive data have been reported; among these, some study groups a possible role of innate immunity and of Natural Killer (NK) cells. KIR (Killer Immunoglobulin-like Receptors) regulate the activation of NK cells through their interaction with Human Leucocyte Antigens (HLA). Both KIR and HLA loci are highly polymorphic, and, in the case of KIR, two main haplotypes have been identified: A and B. Haplotype A is the simplest and correlates mainly with NK inhibition, while haplotype B has a variable number of genes, most of which activate NK cells. The investigators hypothesis is that the genetic variants of KIR, which define the haplotype "inhibitor" or "activator", can affect the development and the course of NCWS too. Thus, the researchers aimed to:1. Identify putative KIR genetic variants in NCWS patients (50 subjects) respect to celiac disease patients (50 subjects) and blood donors (50 subjects); 2. Evaluate the possible association of KIR genetic variants with specific clinical manifestations of patients with NCWS.

Description:

Non-celiac gluten sensitivity (NCGS) is a condition characterized by gastrointestinal and extraintestinal symptoms which are triggered by gluten ingestion in the absence of celiac disease (CD) and wheat allergy. Despite the great interest in NCGS, much remains unknown about its pathogenesis. Some studies seem to suggest that wheat components other than gluten (i.e. amylase/trypsin inhibitors, ATIs) can be responsible of symptom's triggering, and therefore the term "non-celiac wheat sensitivity" (NCWS) has been proposed as a more appropriate label. NCWS pathogenesis has been attributed to very different mechanisms: innate or adaptive immunity, incomplete digestion and/or absorption of fermentable oligosaccharides and disaccharides, monosaccharides, and polyols, and, finally, psychological effect. Although NCWS might be considered in its clinical features like CD, to date, no data are available about genes that confer a higher genetic predisposition to the disease. It is known that, in contrast to CD, patients with NCWS do not have a characteristic Human Leucocyte Antigens (HLA) genotype/phenotype, even if HLA DQ2/DQ8 alleles are present in 40-50% of these patients, a value higher than that of the general population (30%). Many studies ascertained the importance of innate immunity and of Natural Killer (NK) cells in the pathogenesis of NCWS. KIRs (Killer Immunoglobulin-like Receptors) regulate the activation of NK cells through their interaction with HLA. Both KIR and HLA loci are highly polymorphic, and, in the case of KIR, two main haplotypes have been identified: A and B. Haplotype A is the simplest and correlates mainly with NK inhibition, while haplotype B has a variable number of genes, most of which activate NK cells. More in general, several studies have shown that haplotypes containing predominantly activator genes confer protection against viral infections and susceptibility to the development of autoimmune and neoplastic diseases. In the context of CD, NK cells are one of the main components of innate immunity and are involved in the destruction of epithelial cells and their cytotoxic activity is closely related to the function of KIRs. The investigators hypothesis is that the genetic variants of KIR, which define the haplotype "inhibitor" or "activator", can affect the development and the course of NCWS too. Thus, the researchers aimed to: 1. Identify putative KIR genetic variants in NCWS patients (50 subjects) respect to celiac disease patients (50 subjects) and blood donors (50 subjects); 2. Evaluate the possible association of KIR genetic variants with specific clinical manifestations of patients with NCWS.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 170
• Est. completion date: September 30, 2023
• Est. primary completion date: June 30, 2023
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

1. Inclusion Criteria for NCWS patients

• age >18 and <65 years
• subjects with gluten/wheat-dependent symptoms, both intestinal and extra-intestinal
• negativity of anti-deamidated gliadin protein (DGP) immunoglobulins (Ig) class A (IgA) and IgG, anti-tissue transglutaminase (tTG) IgA and IgG, Endomysium antibody (EMA)
• absence of villous atrophy at the duodenal level, documented in all patients with HLA DQ2 and/or DQ8 (therefore, regardless of the negativity of CD-specific serum antibodies), evaluated when patients had a minimum intake of 100 grams of pasta and/or bread a day, for at least 45 days
• absence of wheat allergy (negative prick-test and/or specific serum IgE assay for wheat, gluten and gliadin)
• resolution of symptoms with a strict standard elimination diet, i.e., "oligoantigenic" (without wheat, cow's milk, egg, tomato and chocolate, and other foods self-reported by the patient as causing symptoms), for at least 4 weeks, followed by the reappearance of the same after a Double-Blind Placebo-Controlled Challenge (DBPCC) with gluten/wheat
• complete medical records
• duration of follow-up greater than 12 months after initial diagnosis and at least 2 outpatient visits during the follow-up period.

2. Exclusion Criteria for NCWS patients

• age <18 and >65 years
• alcohol and/or drug abuse
• self-exclusion of gluten/wheat from the diet and refusal to reintroduce it, for diagnostic purposes, before entering the study
• treatment with steroids and/or non-steroidal anti-inflammatory drugs (NSAIDs) in the 2 weeks prior to performing duodenal biopsies
• positivity of EMA in the culture medium of duodenal biopsies, even in the presence of a normal villus/crypt ratio in the duodenal mucosa
• incomplete medical records
• lack of clinical follow-up of at least 12 months from diagnosis
• pregnancy
• diagnosis of chronic inflammatory bowel disease or other organic pathology affecting the digestive system, diseases of the nervous system, major psychiatric disorders, infectious diseases, immunological deficits, and impairments that limit physical activity.

3. Criteria for inclusion of patients with CD

• age >18 and <65 years
• subjects with gluten/wheat-dependent symptoms, both intestinal and extraintestinal, who meet the diagnostic criteria of CD reported in the current guidelines ("four out of five rule"): 1) typical intestinal and extraintestinal signs and symptoms of CD; 2) antibody positivity (both immunoglobulin (Ig) A class anti-tTG and EMA in IgA-sufficient or IgG class anti-tTG and EMA in IgA-deficient subjects); 3) HLA-DQ2 and/or -DQ8 positivity; 4) intestinal damage (demonstrated by histology on duodenal biopsies according to the Marsh classification); 5) clinical response to gluten-free diet (GFD) (e.g., resolution of intestinal and/or extra-intestinal symptoms).

4. Exclusion criteria for patients with CD

• age <18 and >65 years
• alcohol and/or drug abuse
• incomplete medical records
• lack of clinical follow-up of at least 12 months from diagnosis
• pregnancy
• diagnosis of chronic inflammatory bowel disease or other organic pathology affecting the digestive system, diseases of the nervous system, major psychiatric disorders, infectious diseases, immunological deficits and impairments that limit physical activity.

Related Conditions & MeSH terms

• Hypersensitivity
• Non-celiac Wheat Sensitivity

Intervention

Genetic:
• KIR genotyping
DNA extraction and KIR genotyping by KIR SSO Genotyping Test (One Lambda, Thermo Fisher, Monza, Italy).

Locations

Country	Name	City	State
Italy	Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Clinical Laboratory Medicine, University of Palermo	Palermo
Italy	Department of Internal Medicine, University Hospital of Palermo	Palermo
Italy	Internal Medicine Division of the "Cervello-Villa Sofia" Hospital	Palermo	PA
Italy	Department of Internal Medicine, Giovanni Paolo II Hospital of Sciacca	Sciacca	Agrigento

Sponsors (1)

Lead Sponsor	Collaborator
University of Palermo

Country where clinical trial is conducted

Italy, 

References & Publications (8)

Akar HH, Patiroglu T, Sevinc E, Aslan D, Okdemir D, Kurtoglu S. Contribution of KIR genes, HLA class I ligands, and KIR/HLA class I ligand combinations on the genetic predisposition to celiac disease and coexisting celiac disease and type 1 diabetes melli — View Citation

Caggiari L, Toffoli G, De Re V, Orzes N, Spina M, De Zorzi M, Maiero S, Cannizzaro R, Canzonieri V. KIR/HLA combination associated with the risk of complications in celiac disease. Int J Biol Markers. 2011 Oct-Dec;26(4):221-8. doi: 10.5301/JBM.2011.8903. — View Citation

Carroccio A, Mansueto P, Iacono G, Soresi M, D'Alcamo A, Cavataio F, Brusca I, Florena AM, Ambrosiano G, Seidita A, Pirrone G, Rini GB. Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. A — View Citation

Carroccio A, Soresi M, Chiavetta M, La Blasca F, Compagnoni S, Giuliano A, Fayer F, Mandreucci F, Castellucci D, Seidita A, Affronti A, Florena AM, Mansueto P. Frequency and Clinical Aspects of Neurological and Psychiatric Symptoms in Patients with Non-Ce — View Citation

Fernandez-Jimenez N, Santin I, Irastorza I, Plaza-Izurieta L, Castellanos-Rubio A, Vitoria JC, Bilbao JR. Upregulation of KIR3DL1 gene expression in intestinal mucosa in active celiac disease. Hum Immunol. 2011 Aug;72(8):617-20. doi: 10.1016/j.humimm.2011 — View Citation

Mansueto P, Di Liberto D, Fayer F, Soresi M, Geraci G, Giannone AG, Seidita A, D'Alcamo A, La Blasca F, Lo Pizzo M, Florena AM, Dieli F, Carroccio A. TNF-alpha, IL-17, and IL-22 production in the rectal mucosa of nonceliac wheat sensitivity patients: role — View Citation

Mansueto P, Seidita A, D'Alcamo A, Carroccio A. Non-celiac gluten sensitivity: literature review. J Am Coll Nutr. 2014;33(1):39-54. doi: 10.1080/07315724.2014.869996. — View Citation

Santin I, Castellanos-Rubio A, Perez de Nanclares G, Vitoria JC, Castano L, Bilbao JR. Association of KIR2DL5B gene with celiac disease supports the susceptibility locus on 19q13.4. Genes Immun. 2007 Mar;8(2):171-6. doi: 10.1038/sj.gene.6364367. Epub 2007 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	KIR genetic variants in NCWS patients respect to CD patients and blood donors	Evaluation of the presence and prevalence of KIR genetic variants (haplotype A or B) in NCWS patients respect to CD patients and blood donors.	Through study completion, an average of 1 year
Primary	Association between KIR genetic variants and clinical manifestation of NCWS patients	Association between KIR genetic variants and the clinical symptoms (irritable bowel syndrome-like, functional dyspepsia-like, and extraintestinal) of NCWS patients.	Through study completion, an average of 1 year
Primary	Association between KIR genetic variants and associated autoimmune diseases of NCWS patients	Association between KIR genetic variants and the associated autoimmune diseases (e.g., autoimmune thyroiditis) of NCWS patients.	Through study completion, an average of 1 year
Primary	Association between KIR genetic variants and coexistent other food allergies/intolerances of NCWS patients	Association between KIR genetic variants and the coexistent other food allergies/intolerances (e.g., self-reported milk intolerance) of NCWS patients.	Through study completion, an average of 1 year
Primary	Association between KIR genetic variants and HLA DQ2-DQ8 genotypes of NCWS patients.	Association between KIR genetic variants and the HLA DQ2-DQ8 genotypes of NCWS patients.	Through study completion, an average of 1 year
Primary	Association between KIR genetic variants and duodenal histology of NCWS patients.	Association between KIR genetic variants and the duodenal histology (i.e., Marsh-Oberuber classification) of NCWS patients.	Through study completion, an average of 1 year