KIR Genes and Non-Celiac Wheat Sensitivity

November 27, 2023 updated by: Pasquale Mansueto, University of Palermo

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

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

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Detailed 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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
170

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • Italy
      • Palermo, Italy, 90129
        • Department of Internal Medicine, University Hospital of Palermo
      • Palermo, Italy, 90127
        • Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Clinical Laboratory Medicine, University of Palermo
    • Agrigento
      • Sciacca, Agrigento, Italy, 92019
        • Department of Internal Medicine, Giovanni Paolo II Hospital of Sciacca
    • PA
      • Palermo, PA, Italy, 90146
        • Internal Medicine Division of the "Cervello-Villa Sofia" Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Probability Sample

Study Population

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

Description

  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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Control
  • Time Perspectives: Retrospective

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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
DNA extraction and KIR genotyping by KIR SSO Genotyping Test (One Lambda, Thermo Fisher, Monza, Italy).
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
DNA extraction and KIR genotyping by KIR SSO Genotyping Test (One Lambda, Thermo Fisher, Monza, Italy).
Blood donors
The researchers will enroll blood donors from the Transfusion Centre of the University Hospital of Palermo, Italy.
Genetic: KIR genotyping
DNA extraction and KIR genotyping by KIR SSO Genotyping Test (One Lambda, Thermo Fisher, Monza, Italy).

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
KIR genetic variants in NCWS patients respect to CD patients and blood donors
Time Frame: Through study completion, an average of 1 year
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
Time Frame: Through study completion, an average of 1 year
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
Time Frame: Through study completion, an average of 1 year
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
Time Frame: Through study completion, an average of 1 year
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.
Time Frame: Through study completion, an average of 1 year
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.
Time Frame: Through study completion, an average of 1 year
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Palermo

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Chair: Antonio Carroccio, MD, Department of Internal Medicine, "Cervello" Hospital of Palermo, Italy
  • Study Director: Marcello Ciaccio, MD, Institute of Clinical Biochemistry, University of Palermo, Italy

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
November 1, 2022

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 30, 2023

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
September 30, 2023

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 11, 2022

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 19, 2022

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 22, 2022

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
November 28, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 27, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
November 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • ACPM29

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

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