KIR Genes and Non-Celiac Wheat Sensitivity

NCT05469971 | Completed

• 1 other identifier: ACPM29
• Study Type: observational
• Target: 170
• Locations: 1 country
• Sites: 4

Brief 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.

Conditions

Non-celiac Wheat Sensitivity

Outcome Measures

Primary Outcomes (6)

• 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

• 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

• 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

• 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

• 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

• 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

Study Arms (3)

NCWS patients

The researchers will enrol NCWS, presenting with IBS and/or dyspepsia-like symptoms, according to the Rome IV criteria (20). These patients were diagnosed by DBPC wheat challenge between January 2010 and June 2022 in three tertiary centers for "gluten-related disorders" (Department of Internal Medicine, University Hospital of Palermo, Italy; Department of Internal Medicine, "Cervello" Hospital of Palermo, Italy, and Department of Internal Medicine, Hospital of Sciacca, Agrigento, Italy.

Genetic: KIR genotyping

Celiac disease

The researchers will enrol CD patients diagnosed between January 2010 and June 2022 in three tertiary centers for "gluten-related disorders" (Department of Internal Medicine, University Hospital of Palermo, Italy; Department of Internal Medicine, "Cervello" Hospital of Palermo, Italy, and Department of Internal Medicine, Hospital of Sciacca, Agrigento, Italy.

Genetic: KIR genotyping

Blood donors

The researchers will enroll blood donors from the Transfusion Centre of the University Hospital of Palermo, Italy.

Genetic: KIR genotyping

Interventions

KIR genotyping GENETIC

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

Blood donors; Celiac disease; NCWS patients

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

50 NCWS patients, 50 CD patients, and 50 healthy blood donors.

You may qualify if:

• 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.

You may not qualify if:

• age \<18 and \>65 years
• alcohol and/or drug abuse
• 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.
• 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).
• 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

Sponsors & Collaborators

• University of Palermo: lead

Study Sites (4)

Department of Internal Medicine, Giovanni Paolo II Hospital of Sciacca

Sciacca, Agrigento, 92019, Italy

Location

Internal Medicine Division of the "Cervello-Villa Sofia" Hospital

Palermo, PA, 90146, Italy

Location

Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Clinical Laboratory Medicine, University of Palermo

Palermo, 90127, Italy

Location

Department of Internal Medicine, University Hospital of Palermo

Palermo, 90129, Italy

Location

Related Publications (8)

• 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-Celiac Wheat Sensitivity. Nutrients. 2021 Jun 8;13(6):1971. doi: 10.3390/nu13061971.

  PMID: 34201313 RESULT

• 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 of adaptive immunity. Am J Physiol Gastrointest Liver Physiol. 2020 Sep 1;319(3):G281-G288. doi: 10.1152/ajpgi.00104.2020. Epub 2020 Jul 13.

  PMID: 32658621 RESULT

• 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.

  PMID: 24533607 RESULT

• 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. Am J Gastroenterol. 2012 Dec;107(12):1898-906; quiz 1907. doi: 10.1038/ajg.2012.236. Epub 2012 Jul 24.

  PMID: 22825366 RESULT

• 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 Jan 11.

  PMID: 17215859 RESULT

• 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.2011.04.008. Epub 2011 May 13.

  PMID: 21616111 RESULT

• 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.

  PMID: 22180175 RESULT

• 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 mellitus. Rev Esp Enferm Dig. 2015 Sep;107(9):547-53. doi: 10.17235/reed.2015.3817/2015.

  PMID: 26334461 RESULT

Biospecimen

Retention: SAMPLES WITH DNA

A venous blood sample will be taken for each patient (1 dry tube and 1 EDTA tube). Blood samples will be stored at -80°C and subsequently used for DNA extraction and KIR genotyping by KIR SSO Genotyping Test (One Lambda, Thermo Fisher, Monza, Italy).

Study Officials

• Antonio Carroccio, MD

  Department of Internal Medicine, "Cervello" Hospital of Palermo, Italy

  STUDY CHAIR

• Marcello Ciaccio, MD

  Institute of Clinical Biochemistry, University of Palermo, Italy

  STUDY DIRECTOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: July 11, 2022
• First Posted: July 22, 2022
• Study Start: November 1, 2022
• Primary Completion: June 30, 2023
• Study Completion: September 30, 2023
• Last Updated: November 28, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

IT (4)