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Evidence Based Guidance from Genetic Screening and Lifestyle Prevention Strategies of Coeliac Disease

Submitted:

31 July 2026

Posted:

03 August 2026

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Abstract
Background/Objectives: Coeliac disease (CD) is a highly heritable autoimmune disease. Given the high risk among first-degree relatives, early screening and prevention are essential, yet clinical guidelines vary. This review analyzed clinical practice guidelines issued by leading European, British, and North American organisations over a 12-year period (2014–2026) regarding genetic screening and lifestyle/dietary prevention strategies. Methods: A systematic search was conducted across official databases of prominent societies (ESSCD, UEG, ESPEN, NASPGHAN, AGA, ESPGHAN, WGO, BSG, ACG) for English-language guidelines and position papers. Extracted statements addressing genetic testing (HLA-DQ2/DQ8) and early-life risk-modifying strategies were coded into three thematic domains: 1) genetic predisposition, 2) lifestyle prevention or 3) both. Results: Eleven manuscripts yielded 399 statements, categorized into genetic predisposition (n=23, 5.8%), lifestyle prevention (n=30, 7.5%) and integrated approaches (n=2, 0.5%), with the remainder (n=344, 86.2%) addressing unrelated clinical topics. Universal consensus confirmed the high negative predictive value of HLA-DQ2/DQ8 testing to rule out CD, whereas dietary strategies (breastfeeding duration and timing of gluten introduction) showed no protective effect. ESPGHAN exclusively provided evidence regarding early-life high-risk genotypes and concluded that risk-stratified dietary guidance based on specific HLA profiles remains currently unsupported. Conclusions: Current CD guidelines demonstrate substantial international consensus regarding the role of genetic testing in disease exclusion and risk stratification. However, recommendations integrating genetic susceptibility with preventive lifestyle interventions remain scarce. Future research should focus on generating robust evidence to support precision prevention approaches and facilitate the harmonization of international guidelines.
Keywords: 
coeliac disease
;  
genetic predisposition
;  
lifestyle prevention
;  
guidelines
Subject: 
Medicine and Pharmacology  -   Dietetics and Nutrition

1. Introduction

Coeliac disease (CD) is a chronic immune-mediated disease triggered by the ingestion of gluten in genetically predisposed individuals. The global prevalence of CD has increased over time, with seroprevalence and biopsy-confirmed prevalence estimated at 1.4% and 0.7% respectively, leaving a substantial proportion of cases remaining undiagnosed [1].
Although CD stands out among autoimmune diseases in that its manifestation is entirely dependent upon gluten, it remains highly heritable [2]. This genetic susceptibility is primarily driven by specific human leukocyte antigen (HLA) allotypes of the major histocompatibility complex (MHC), specifically HLA-DQ2.5 - which is carried by more than 90% of patients and can be encoded in either cis or trans configurations - followed by HLA-DQ8 and the lower-risk HLA-DQ2.2 [3]. The genetic risk is further modulated by a gene-dosage effect, where homozygosity for these alleles significantly amplifies disease predisposition. Crucially, while developing CD in the absence of these three primary variants is extremely rare, some patients express the HLA-DQ7 haplotype (specifically carrying the DQA1*05 allele), demonstrating that complete negativity for HLA-DQ2/DQ8 cannot entirely exclude a diagnosis. This makes genetic testing a valuable tool to resolve borderline serological or histological cases [3,4].
Given this potent genetic component, screening high-risk populations remains crucial, particularly because familial clustering significantly influences diagnostic efficiency. First-degree relatives of affected individuals face a heavily elevated risk; for instance, the prevalence among offspring ranges drastically from 1.6% to 38% compared to the general population [5]. This risk is even more pronounced in multiplex families, where it reaches up to 26.3% for siblings and 12.9% for parents [6]. Identifying these at-risk individuals early is often challenging, as a substantial proportion of children, particularly older children and adolescents, present with atypical or silent forms of the disease without classic gastrointestinal symptoms, heavily contributing to global underdiagnosis [7].
While the HLA genes detailed above are a necessary requirement for familial risk, they are not sufficient on their own to cause the condition [8]. Indeed, while approximately 30–40% of the general population carries these predisposing HLA-DQ allotypes, only about 3% of these carriers ultimately develop CD, meaning that the vast majority of genetically susceptible individuals tolerate gluten without developing the condition [3]. Consequently, the onset and progression of CD relies heavily on a complex interplay of additional non-HLA genetic risk loci [9,10,11] and non-gluten environmental factors, among which alterations in the intestinal microbiota have recently emerged as a significant contributing element [12]. In this context, several early-life environmental exposures capable of shifting the gut microbiota’s composition are increasingly implicated in CD development, including birthing delivery mode, infant feeding practices, infections, and antibiotic use breastfeeding and the timing of gluten introduction [13,14,15,16,17,18].
Understanding how the environment triggers the immune response to gluten is essential because, currently, the only evidence-based treatment remains a strict, lifelong gluten-free diet (GFD) to induce symptom remission and mucosal healing [8,19]. The challenges of adhering to a GFD, combined with our growing knowledge of early-life risk factors, have prompted medical societies to explore preventive strategies. Over the past decade, several professional organisations—including European, British and North American gastroenterology and nutrition societies—have issued clinical guidelines and position papers on the diagnosis and management of CD [17,18,20,21,22,23,24,25,26,27,28]. These guidelines synthesize current evidence and provide recommendations for clinical practice, focusing on the diagnosis and management of CD. However, there has been no systematic effort to map and synthesize how these guidelines address genetic screening among at-risk populations and lifestyle prevention strategies.
Therefore, the aim of the present study is to systematically identify and analyse all guideline statements and recommendations issued by leading European, British, and American organisations regarding a) the use of genetic testing in individuals at risk of CD and b) lifestyle strategies, such as dietary practices, aimed at preventing or modifying the risk of CD development. By collating and analysing these recommendations, this review aims to clarify current clinical practice, identify consensus and discrepancies across organisations and highlight gaps for future research and guideline development in CD prevention and early detection. Ultimately, synthesizing this evidence will provide clinicians with a clearer framework for risk counseling and aid international societies in harmonizing future, evidence-based public health strategies for CD.

2. Results

2.1. Distribution of Total, Genetic Related and Lifestyle Prevention Statements per Organisation

The systematic search yielded a total of 11 relevant manuscripts published across nine European, British and North American organisations. Τhe distribution of these publications comprised three manuscripts issued by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) [17,18,20], two manuscripts by the European Society for Study of Coeliac Disease and the United European Gastroenterology (ESSCD/UEG) [21,22], while a single manuscript (n = 1) was identified for each of the remaining societies [the European Society for Clinical Nutrition and Metabolism (ESPEN), the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN), the American Gastroenterological Association (AGA), the World Gastroenterology Organization (WGO), the British Society of Gastroenterology (BSG) and the American College of Gastroenterology (ACG)] [23,24,25,26,27,28]. A detailed breakdown of these documents, organized by society and statement category, is presented in Table 1.
A total of 399 statements were extracted (Supplementary Table S1). Out of these, 23 statements (5.8%) focused exclusively on genetic predisposition and 30 (7.5%) addressed lifestyle prevention strategies, all of them focusing solely on dietary interventions. Notably, ESPGHAN demonstrated the highest integration of these themes, accounting for all 30 lifestyle prevention statements (56.6% of its total output) and serving as the sole organisation to feature integrated statements addressing both domains simultaneously (n = 2). Genetic recommendations were distributed across most societies, with the highest relative proportions observed in ESSCD/UEG (n = 5; 6.1%), NASPGHAN (n = 6; 10.2%) and WGO (n = 5; 10.2%), whereas no specific statements on either topic were identified in documents from ESPEN and ACG (Table 1).

2.2. Distribution of Total, Genetic Related and Lifestyle Prevention Statements per Publication Year

The analysis of the total number of extracted statements related to genetics and lifestyle prevention strategies from all nine organisations from 2014 to 2026 reveals a fluctuating pattern (see Table 2). While the 11 identified guidelines were distributed relatively evenly at one per year across the 12-year period (except for 2016, n = 2), the focus on genetics and prevention was highly concentrated. Genetic statements appeared throughout the decade, maintaining a relative frequency between 2.0% and 12.1% per publication year. The absence of genetic predisposition statements in 2022 and 2023 may reflect the lack of substantial new clinical evidence that would lead to the immediate update of existing consensus guidelines. Conversely, lifestyle prevention strategies were exclusively clustered in 2016 (n = 13; 17.6%) and 2024 (n = 17; 89.5%). Notably, 2024 was the only year with integrated statements addressing both genetic predisposition and lifestyle prevention concurrently (n = 2), highlighting a non-continuous pattern in guideline updates for these domains.

2.3. Qualitative Analysis of Statements on Genetic Predisposition of CD

The thematic synthesis of the 23 extracted statements regarding genetic predisposition revealed strong consensus across societies (Table 3). The recommendations were classified into three core themes:

2.3.1. Exclusion of Disease Diagnosis and Predictive Value

All reviewed medical societies agree that HLA-DQ2/DQ8 testing has a limited positive predictive value and therefore cannot confirm a diagnosis of CD. However, there is universal consensus regarding its exceptionally high negative predictive value, with the absence of both HLA-DQ2 and HLA-DQ8 effectively excluding the disease.

2.3.2. Diagnostic Utility of HLA Testing

There is a multi-society consensus that HLA genotyping has a limited role in routine diagnosis but is indicated in situations of diagnostic uncertainty. Regarding routine initial testing, NASPGHAN (2016), AGA (2019), ESPGHAN (2020) and ESSCD/UEG (2025) state that HLA typing should not be used as a first-line diagnostic tool for symptomatic individuals. ESPGHAN (2020) specifies that it adds no diagnostic certainty when standard serological criteria (TGA-IgA 10 ULN and EMA-IgA positivity) are met. However, in the presence of discordant findings, NASPGHAN (2016), WGO (2017) and AGA (2019) advocate for HLA testing when discrepancies arise between serology and histology, including cases of seronegative villous atrophy or potential CD (ESSCD/UEG, 2025). Finally, in case of pre-existing gluten-free diet (GFD), BSG (2014), NASPGHAN (2016), WGO (2017) and ESSCD/UEG (2025) recommend HLA typing for individuals already self-treated on a GFD prior to formal testing, where a negative result definitively excludes the disease.

2.3.3. Screening and Risk Stratification in Asymptomatic Populations

Societies present harmonized strategies regarding the use of HLA testing to optimize screening in high-risk populations. For first-degree relatives, BSG (2014), NASPGHAN (2016), and WGO (2017) recommend HLA testing as an early screening tool to rule out CD and eliminate the need for repetitive serological monitoring in negative individuals. Regarding pediatric-specific protocols, ESSCD/UEG (2026) recommends HLA genotyping as the initial screening step specifically for children of CD patients, while recommending periodic antibody follow-up (every 4–5 years) only for those who carry the risk alleles. In alignment with this risk stratification, ESPGHAN (2016) reports that the very early development of Coeliac Disease Autoimmunity (CDA) and CD (at less than 3–5 years of age) preferentially affects children carrying high-risk homozygous HLA-DQ2.5 alleles; this specific genotype is found in only 1% to 2% of the general population but rises significantly to 10% to 15% among children with affected first-degree relatives. Finally, in relation to non-celiac gluten sensitivity (NCGS), NASPGHAN (2016) notes that while HLA haplotypes may be slightly more prevalent in NCGS patients than healthy controls, genetic testing cannot be used to screen for or diagnose this condition.

2.4. Qualitative Analysis of Statements on Lifestyle Prevention Strategies Regarding CD

The thematic synthesis of the 30 lifestyle prevention statements, which focused specifically on dietary strategies and were issued exclusively by ESPGHAN (2016, 2024) (Table 4), resulted in four clinical themes:

2.4.1. Breastfeeding Practices

Both the 2016 and 2024 guidelines agree that any or exclusive breastfeeding up to 6 months does not reduce CD risk or delay its onset. Furthermore, breastfeeding at the time of gluten introduction offers no protective benefit compared to post-weaning introduction. Consequently, ESPGHAN states that infant breastfeeding recommendations must not be altered based on CD genetic risk.

2.4.2. Timing of Gluten Introduction

Consensus across the 12-year period confirms that the exact age of introducing gluten does not influence the cumulative incidence of CDA or CD. The recommended safe window for gluten introduction remains between completed 4 and 12 months of age. For high-risk children, introduction at 6 versus 12 months does not change cumulative incidence but prompts earlier clinical manifestation (2016).

2.4.3. Type and Volume of Gluten Consumed

The clinical impact of the volume and type of gluten consumed during early life represents a key focus of evolving evidence. Regarding gluten volume, ESPGHAN (2016) initially linked high-volume gluten intake during weaning to an increased risk of disease development. The 2024 update reinforced this association, stating that a higher, dose-dependent daily gluten intake during the first 2 to 5 years of life increases the risk of both CDA and CD in genetically predisposed children. In terms of clinical guidance, while the 2016 guideline conditionally suggested discouraging large amounts of gluten at weaning, the 2024 position paper concludes that safe consumption thresholds cannot be established based on current data. Consequently, no formal recommendation regarding gluten volume up to 3 years of age can presently be made for infants of either known or unknown risk, leaving definitive guidance pending the results of ongoing intervention trials. Finally, concerning gluten type, both documents consistently agree that the specific source or type of gluten-containing food utilized during dietary introduction does not modify the absolute risk of developing CD.

2.4.4. Maternal Dietary Interventions

Introduced in 2024, ESPGHAN notes that evidence regarding maternal gluten intake during pregnancy is inconclusive and completely lacking for the lactation period. Therefore, no specific dietary recommendations can be formulated for maternal gluten consumption to prevent CD in the offspring.

2.5. Integrated Statements on Genetic Predisposition and Lifestyle Prevention Interactions

A specific subset of statements (n = 2, exclusively from ESPGHAN 2024) evaluated the direct interaction between genetic HLA profiles and dietary preventive strategies. Focusing on the interplay between HLA profiles and gluten volume, it is noted that evidence from observational, cohort and case-control studies does not demonstrate that the impact of high gluten intake on CD and CDA development varies across different HLA risk types. Consequently, the ESPGHAN (2024) position paper concludes that current evidence is insufficient to support or justify differentiated, risk-stratified recommendations for gluten consumption based on an individual’s specific HLA risk profile.
Table 5. Extracted statements on genetic predisposition and lifestyle prevention.
Table 5. Extracted statements on genetic predisposition and lifestyle prevention.
Organisation, Year Integrated statements on genetic predisposition and lifestyle prevention strategies
ESPGHAN,
2024		 Observational studies, including cohort and case-control studies, do not provide evidence that the effect of high gluten intake on CD and CDA development is related to different HLA risk types [18].
ESPGHAN,
2024		 There is not enough evidence to give differentiated recommendations on gluten consumption for various HLA risk types [18].
strategies from guideline documents (n=2).

3. Discussion

This systematic review mapped recommendations from major European, British and North American medical societies over a 12-year period and demonstrated that genetic screening and lifestyle prevention remain relatively underrepresented topics within CD guidelines. Although nearly 400 statements were identified, only a small proportion addressed genetic predisposition (5.8%) or lifestyle prevention strategies (7.5%), while recommendations integrating both domains were exceptionally scarce (0.5%). These findings highlight an important gap between the growing scientific understanding of CD pathogenesis and its translation into preventive clinical guidance.
A finding of this review is the remarkable consistency across organisations regarding the clinical utility of HLA testing. All societies agreed that the absence of HLA-DQ2 and HLA-DQ8 virtually excludes CD, supporting the use of genetic testing as a valuable tool for ruling out the disease, particularly in diagnostically challenging situations and among high-risk relatives. The limited positive predictive value of HLA positivity was also consistently acknowledged, emphasizing that genetic predisposition alone is insufficient for disease development [17,18,20,21,22,24,25,26,27]. This approach is thoroughly aligned with clinical literature, which serves as a practical guide for clinicians on the appropriate use and interpretation of HLA-typing, ensuring it is used efficiently to clarify ambiguous cases rather than as a tool for routine diagnosis [29,30,31].
The genetic architecture of CD is highly complex, driven by a unique combination of genetic variants in each individual that collectively dictate overall disease susceptibility [11,32]. The major histocompatibility complex (MHC) class II molecules HLA-DQ2 and HLA-DQ8 remain the most critical predisposing factors [32,33], and their role in disease pathogenesis is well established [34]. However, because these HLA molecules are necessary but not sufficient for clinical onset, fine-mapping and genome-wide association studies (GWAS) have identified additional independent loci within the MHC region, alongside over 40 non-HLA susceptibility loci that exert minor, yet cumulative, effects on CD development [8,9,10,11]. While the individual contribution of these non-HLA loci is small, they help explain the wide variation in disease penetrance among HLA-susceptible individuals [33]. Furthermore, recent studies suggest that combining HLA information with these additional genetic variants through genomic risk scores (GRS) can significantly improve the identification of individuals at the highest risk of developing CD [35,36,37,38]. Concurrently, refined approaches capture high-resolution, non-additive HLA interactions through a minimal panel of tag SNPs, offering a highly translatable, low-cost pathway for immediate clinical screening and risk stratification [37,38]. While such approaches illustrate the evolving potential of HLA screening as a tool not only for disease exclusion but also for more personalized risk prediction [32], these advances have not yet been incorporated into current clinical guidelines, due to the current lack of strong, high-level clinical evidence regarding the long-term utility of these genomic models. This observation is consistent with findings from our group’s recent review, which evaluated the intersection of genetics and nutrition in gastroenterology. According to our findings, although the statements focusing exclusively on nutrition were numerous, those statements incorporating genetic predisposition were far fewer, underscoring the limited integration of genomics into current dietary recommendations [39].
Regarding the recommendations on lifestyle prevention strategies, these originated exclusively from ESPGHAN [17,18] and focused solely on breastfeeding and gluten introduction. This finding might be explained by the fact that prevention strategies for CD include early-life dietary exposures and infant feeding patterns and, thus, this domain might be better addressed by pediatric organizations, rather than adult gastroenterology societies. The available evidence consistently indicated that breastfeeding practices, timing of gluten introduction and the type of gluten-containing foods do not significantly modify the long-term risk of CD. This result is in agreement with large prospective studies demonstrating that breastfeeding has limited influence on the risk of developing CD [40,41,42] despite previous hypotheses suggesting a potential protective effect [43]. Similarly, evidence from prospective cohort studies has shown that the timing of gluten introduction is not associated with the risk of developing CDA or overt CD. Neither early nor delayed introduction of gluten beyond six months of age appears to significantly alter disease risk among genetically susceptible children [41,44,45]. Furthermore, studies evaluating dietary gluten exposure during early childhood have reported that gluten consumption patterns and the amount of gluten consumed between 11 and 36 months of age do not substantially influence CD development across most HLA risk genotypes [46].
Notably, the only dietary factor for which some evidence of risk modification exists is the quantity of gluten consumed during early childhood [18]. ESPGHAN acknowledged evidence suggesting a dose-dependent relationship between higher gluten intake and increased risk of CDA and CD among genetically susceptible children. This position is supported by prospective birth cohort studies, including children at increased genetic risk, which have consistently reported associations between greater gluten consumption during the first years of life and subsequent development of CDA or overt CD [47,48,49,50]. Nevertheless, the current evidence remains insufficient to establish safe intake thresholds or formulate quantitative dietary recommendations.
Emerging evidence also suggests that the relationship between diet and CD risk may extend beyond individual nutritional factors, such as breastfeeding or the timing of gluten introduction, toward broader dietary patterns during early life. Recent prospective cohort studies have reported associations between overall dietary compositions and the subsequent development of CDA and CD in genetically susceptible children, independent of absolute gluten intake. Infant dietary patterns characterized by a higher consumption of wheat-based products and vegetable fats have been associated with increased disease risk, whereas more prudent, balanced dietary patterns have been linked to a lower risk of autoimmunity [51,52]. A primary biological mechanism hypothesized to mediate this relationship is the gut microbiome, which represents a critical area of ongoing research [53]. Distinct dietary patterns are known to actively shape the composition and metabolic activity of the infant microbiota; a state of early-life dysbiosis can compromise intestinal barrier integrity and modulate immune tolerance, thereby acting as a secondary environmental trigger in genetically predisposed individuals [54,55].
Beyond diet, other early-life environmental exposures have been investigated for their potential to disrupt the microbiome and influence CD risk. These include perinatal factors (such as the mode of delivery, infections, or antibiotics during pregnancy), early childhood infections (particularly gastrointestinal viral infections like rotavirus), vaccination patterns, and early exposure to antibiotics [56]. While these factors have been epidemiologically linked to alterations in gut permeability and immune maturation, the available data remain highly heterogeneous, with conflicting results across prospective cohorts [56]. Consequently, the current evidence remains insufficient to support specific, actionable dietary, lifestyle, or clinical recommendations, which fully explains the absence of non-dietary environmental guidelines (such as mode of delivery or antibiotic use) in our review.
One of the most significant observations of this review is the near absence of recommendations integrating genetic susceptibility with lifestyle prevention strategies. Despite CD being one of the most strongly HLA-associated autoimmune disorders, only two statements explicitly addressed the interaction between HLA risk profiles and preventive dietary measures [18]. These statements concluded that available evidence does not support differential dietary recommendations according to specific HLA genotypes. Thus, although genetic testing can identify individuals at increased risk, it currently provides limited guidance regarding personalized preventive interventions. However, findings by Crespo-Escobar et al. (2017) demonstrated that although mean daily gluten intake from 10 months of age was not generally associated with CD development up to 3 years of age, a significant association did emerge uniquely for children carrying the specific HLA-DQ2.2/-DQ7 genotype [46]. This exception underscores that while broad, multi-allele guidelines remain currently unfeasible, future precision prevention frameworks may ultimately rely on identifying such highly specific, sub-phenotypic genetic-dietary interactions.
Taken together, the findings of this review suggest that the limited integration of genetic predisposition and lifestyle prevention within current guidelines does not reflect a lack of scientific progress, but rather the complexity of the available evidence. Contemporary research increasingly supports a multifactorial model of CD pathogenesis involving interactions between HLA and non-HLA genetic susceptibility, dietary exposures, immune regulation and the intestinal microbiome [8,52,55]. However, these factors rarely act independently, and their effects appear to vary according to age, genetic background, environmental context and study population. As a result, despite the rapid expansion of knowledge in genomics, nutrition, and microbiome science, the evidence remains insufficiently consistent to support specific, universally applicable preventive recommendations [52]. This complexity may explain the absence of more comprehensive prevention-focused guidelines by international societies.
Several limitations of the present systematic review should be acknowledged. First, the synthesis of lifestyle prevention and integrated genetic-dietary strategies is heavily dominated by a single organisation (ESPGHAN). This concentration reflects a broader deficit in the literature, as other major North American and adult-focused European societies have not issued updated or explicit preventative mandates regarding early-life environmental modifiers within our 12-year search window. Second, this review focused on the content and frequency of recommendations rather than on the methodological quality of the underlying evidence supporting each statement. Finally, our study was restricted to English-language guidelines issued by prominent, pre-selected international societies and so potentially relevant consensus statements from national registries or smaller regional networks published in other languages were not captured.
Future research should prioritize prospective, longitudinal studies capable of integrating genetic susceptibility, dietary exposures, microbiome composition and immune biomarkers within unified predictive models. In particular, the development and validation of standardized GRS may enable more precise identification of individuals at greatest risk of disease development. Equally important will be determining whether preventive interventions can be tailored according to genetic or microbial risk profiles. Such evidence is essential before precision prevention strategies can be incorporated into future clinical guidelines. In the future, international medical organizations could collaborate and harmonize their frameworks, ensuring that as precision prevention data emerge, they can be seamlessly integrated into unified, cross-continental clinical practice guidelines.

4. Materials and Methods

4.1. Guideline Identification

A comprehensive systematic search was conducted to identify clinical practice guidelines, consensus statements, position papers and evidence-based recommendations on CD published between January 2014 and April 2026. This specific timeframe was selected to capture the modern era of CD guidelines, which was initiated by the publication of data from prospective observational studies regarding the role of breastfeeding and the timing of initial gluten introduction [57].
The search included publications from leading European, British, and North American organisations, including: European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) [17,18,20], European Society for Study of Coeliac Disease (ESSCD) [21,22], United European Gastroenterology (UEG) [21,22], European Society for Clinical Nutrition and Metabolism (ESPEN) [23], North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) [24], American Gastroenterological Association (AGA) [25], World Gastroenterology Organization (WGO) [26], British Society of Gastroenterology (BSG) [27] and American College of Gastroenterology (ACG) [28]. Two guidelines were developed by ESSCD and officially published by Wiley Periodicals LLC on behalf of United European Gastroenterology (UEG) [21,22]. The search was restricted to major European and North American guidelines as these societies represent the regions with high prevalence of CD [1] and offer highly accessible clinical guidelines.
A structured search was performed in the official websites or guideline repositories of each organisation. Manual searches were conducted within each organisation’s guideline database to ensure completeness.

4.2. Eligibility Criteria

Publications were eligible for inclusion if they were clinical guidelines, consensus statements, or position papers issued or endorsed by the above organisations, addressed CD in any population (paediatric or adult), included recommendations on diagnosis, screening, genetic testing, prevention, or risk reduction, were published in English between January 2014 and April 2026. Narrative reviews, editorials, conference abstracts and non-evidence-based opinion papers were excluded, because they lack multi-disciplinary grading of evidence and high quality clinical consensus. Publications focusing exclusively on surgical management, oncology, or unrelated gastrointestinal conditions were excluded.

4.3. Data Extraction and Review Process

All recommendations, statements, and consensus points from eligible publications were systematically extracted into a structured database. Two independent reviewers (V.S A.T) screened all extracted content using a predefined set of key terms. For the genetic predisposition domain statements were identified using keywords such as: “HLA-DQ2”, “HLA-DQ8”, “genetic susceptibility”, “genetic predisposition””haplotype”, “at-risk populations”, “first-degree relatives”, “discordant serology”. For the lifestyle prevention strategies domain reviewers targeted terms including: “infant feeding”, “breastfeeding”, “gluten introduction”, “nutrition”, “dietary patterns”, “infections”, “microbiome”, “antibiotics”, “type of birth” and “environmental modifiers”.Using this targeted approach, extracted statements were coded into three distinct categories, (a) genetic predisposition related statements, addressing the utility of HLA testing (b) lifestyle prevention related statements, focusing on early-life risk-modifying exposures and (c) integrated statements. Disagreements between reviewers were resolved by consensus or consultation with a third investigator (D.E.S).

4.4. Data Synthesis

Quantitative summaries were generated to report the number of total statements per organisation and the proportion addressing genetic predisposition or/and prevention strategies.
Temporal trends were analysed across the 12-year period. Extracted statements were presented in tabular form, organised by (a) organisation, (b) year of publication and (c) thematic domain (genetics vs prevention). A narrative synthesis was conducted to describe the scope, consistency and strength of recommendations across organisations, highlighting areas of consensus, divergence and evidence gaps in the use of genetic screening and prevention strategies in CD.

5. Conclusions

This systematic review highlights a substantial gap in current clinical guidelines for CD, where genetic predisposition and lifestyle prevention strategies remain significantly underrepresented. While international consensus is robust regarding the utility of HLA typing for ruling out the disease, newer GRS and personalized risk prediction frameworks have yet to be adopted. Furthermore, current evidence confirms that breastfeeding practices and the timing of gluten introduction do not modify CD risk, whereas early-life gluten quantity, broader dietary patterns, and gut dysbiosis emerge as critical but complex environmental triggers. Future research must utilize longitudinal models that integrate genomics, nutrition and microbiome data in order to develop effective precision prevention strategies, providing organisations with the necessary evidence to harmonize future clinical guidelines.

Supplementary Materials

The following supporting information can be downloaded at the website of this paper posted on Preprints.org, Table S1: Extracted statements mentioned within UEG, ESPGHAN, ESSCD, ESPEN, BSG, ACG, NASPGHAN, AGA, WGO manuscripts between 2014-2026.

Author Contributions

Conceptualization, V.S. D.E.S. O.A.; methodology, V.S. A.T.; formal analysis, A.T. M.D. A.M.P.; data curation, A.T. M.D. A.M.P. D.E.S.; writing—original draft preparation, V.S. A.T.; writing—review and editing, V.S. A.T. M.D. A.M.P. D.E.S. M.M. E.G.; supervision, V.S. O.A.; project administration, A.T. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

All data created for the purposes of the current study are included within the supporting Table S1.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
ACG American College of Gastroenterology
AGA American Gastroenterological Association
BF Breastfeeding
BSG British Society of Gastroenterology
CD Coeliac Disease
CDA Coeliac Disease Autoimmunity
EMA Endomysial antibodies
ESPEN European Society for Clinical Nutrition and Metabolism
ESPGHAN European Society for Paediatric Gastroenterology, Hepatology and Nutrition
ESSCD European Society for Study of Coeliac Disease
GFD Gluten free diet
GRS Genomic Risk Score
HLA Human Leukocyte Antigen
MHC Major Histocompatibility Complex
NASPGHAN North American Society for Pediatric Gastroenterology, Hepatology and
Nutrition
NCGS Non-celiac Gluten Sensitivity
TGA Tissue Transglutaminase Antibodies
UEG United European Gastroenterology
WGO World Gastroenterology Organization

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Table 1. Distribution of extracted statements on genetic predisposition and lifestyle.
Table 1. Distribution of extracted statements on genetic predisposition and lifestyle.
Name of Organisation Manuscripts identified, n Total statements, n Genetic statements, n (%)1 Lifestyle prevention statements, n (%)1 Genetic and lifestyle prevention statements, n (%)1
ESSCD/UEG 2 82 5 (6.1%) 0 (0%) 0 (0%)
ESPEN 1 100 0 (0%) 0 (0%) 0 (0%)
NASPGHAN 1 59 6 (10.2%) 0 (0%) 0 (0%)
AGA 1 12 1 (8.3%) 0 (0%) 0 (0%)
ESPGHAN 3 53 3 (5.7%) 30 (56.6%) 2 (3.8%)
WGO 1 49 5 (10.2%) 0 (0%) 0 (0%)
BSG 1 33 3 (9.1%) 0 (0%) 0 (0%)
ACG 1 11 0 (0%) 0 (0%) 0 (0%)
Total 11 399 23 (5.8%) 30 (7.5%) 2 (0.5%)
prevention in total papers by organisation. 1n = number; % = percentage.
Table 2. Number (%) of extracted statements related to genetic predisposition and/or lifestyle prevention per year of publication.
Table 2. Number (%) of extracted statements related to genetic predisposition and/or lifestyle prevention per year of publication.
Year Manuscripts identified, n Total statements, n Genetic,
n (%)1 		Lifestyle prevention,
n (%)1 		Genetic and lifestyle prevention,
n (%)1
2014 1 33 3 (9.1%) 0 (0%) 0 (0%)
2016 2 74 7 (9.5%) 13 (17.6%) 0 (0%)
2017 1 49 5 (10.2%) 0 (0%) 0 (0%)
2019 1 12 1 (8.3%) 0 (0%) 0 (0%)
2020 1 19 2 (10.5%) 0 (0%) 0 (0%)
2022 1 11 0 (0%) 0 (0%) 0 (0%)
2023 1 100 0 (0%) 0 (0%) 0 (0%)
2024 1 19 0 (0%) 17 (89.5%) 2 (10.5%)
2025 1 33 4 (12.1%) 0 (0%) 0 (0%)
2026* 1 49 1 (2.0%) 0 (0%) 0 (0%)
Total 11 399 23 30 2
1n = number; % = percentage; * = search conducted till April 2026.
Table 3. Extracted statements on genetic predisposition from guideline documents (n=23).
Table 3. Extracted statements on genetic predisposition from guideline documents (n=23).
Organisation, Year Statements on genetic predisposition
ESSCD/UEG, 2025 In adults with persistently positive IgA anti-TG2 serology but architecturally normal duodenal histology (Marsh 0–I), a definitive diagnosis of CeD cannot be established. However, if these individuals carry the HLA-DQ2 and/or DQ8 haplotype, they may be classified as having potential CD [21].
ESSCD/UEG, 2025 After excluding other causes of seronegative villous atrophy, diagnosis of CeD should rely on the clinical and histological response to a GFD in individuals with HLA-DQ2 or HLA-DQ8 haplotypes [21].
ESSCD/UEG, 2025 HLA testing has a poor positive predictive value (PPV) but a high negative predictive value (NPV) for CeD; therefore, the guideline panel recommends that HLA-DQ2/8 testing should not be used routinely in the initial diagnosis of CeD. It is indicated when there is uncertainty about the diagnosis and in the screening of certain risk groups for developing CeD [21].
ESSCD/UEG, 2025 Confirm HLA-DQ2/DQ8 before starting a gluten challenge, as a negative result rules out CeD [21].
ESSCD/UEG, 2026 HLA-DQ2/8 genotyping is recommended as the initial screening step primarily in children of patients with CeD —where it can prevent repeated testing—while anti-TG2 serology remains the most cost-effective and widely available initial test for adults and lower-risk relatives. 2. Follow-up: For first-degree relatives who are seronegative at initial assessment, periodic antibody follow-up (e.g., every 4–5 years) may be considered based on individual risk factors and new symptoms [22].
NASPGHAN, 2016 HLA testing should not be used as an initial diagnostic test for CD [24].
NASPGHAN, 2016 Testing for HLA-DQ2/8 is best reserved for patients in whom there is a diagnostic dilemma, such as when there is a discrepancy between the serological and histologic findings or when a GFD has been started before any testing. In such patients, if neither HLA-DQ2 nor DQ8 is present, CD is highly unlikely, and an alternative diagnosis should be sought [24].
NASPGHAN, 2016 It has been recommended that the HLA test should be used as a first test when screening asymptomatic people at increased risk for CD such as family members of an index case [24].
NASPGHAN, 2016 In those who are negative for both DQ2 and DQ8 alleles, no further testing for CD is needed, whereas in all other patients testing for tTG/EMA antibodies is needed to identify those who require intestinal biopsies to confirm the diagnosis [24].
NASPGHAN, 2016 There is a suggestion that those with NCGS are more likely to have an elevated AGA test or have the HLA DQ2 or DQ8 haplotype than healthy controls, but neither of these tests can be used to screen for NCGS with any degree of confidence [24].
NASPGHAN, 2016 Other autoimmune conditions and inflammatory bowel disease should be considered because these can have transient elevations of CD-associated antibodies. HLA typing may be helpful in these patients as if negative for both the HLA DQ2 and DQ8 risk alleles, CD is highly unlikely [24].
AGA, 2019 Determination of HLA-DQ2/DQ8 has a limited role in the diagnosis of CD. Its value is largely related to its negative predictive value to rule out CD in patients who are seronegative in the face of histologic changes, in patients who did not have serologic confirmation at the time of diagnosis, and in those patients with a historic diagnosis of celiac disease; especially as very young children prior to the introduction of celiac-specific serology [25].
ESPGHAN,
2016		 The very early development of CDA and CD (<3–5 years of age) seems to affect preferentially children carrying the very high risk of CD alleles (HLA-DQ2.5 homozygous), which are found in only 1% to 2% of the general population but in 10% to 15% of children with first degree relatives having CD [17].
ESPGHAN, 2020 HLA- typing does not add to the certainty of the diagnosis if the other criteria for CD diagnosis are fulfilled. Testing for HLA DQ2 and DQ8 may be useful in other circumstances. If no risk alleles are found, CD is unlikely [20].
ESPGHAN, 2020 We recommend that HLA typing is not required in patients with positive TGA-IgA, if they qualify for CD diagnosis with biopsies or if they have high serum TGA-IgA (10 ULN) and EMA-IgA positivity. If a patient tests negative for HLA DQ2 and DQ8, the risk of CD is very low, while a positive result does not confirm the diagnosis [20].
WGO, 2017 HLA-DQ2/DQ8 genotyping may be important to exclude celiac disease in patients with enteropathy but negative serology, and to exclude celiac disease before embarking on a formal gluten challenge [26].
WGO, 2017 A negative HLA test is helpful for excluding the possibility of celiac disease [26].
WGO, 2017 In individuals with an uncertain diagnosis of celiac disease with negative serology, but with histology suggestive of celiac disease. HLA testing is helpful here only if it is negative. HLA testing will most likely be positive if the serology is positive and the histologic findings are negative [26].
WGO, 2017 To distinguish between first-degree relatives of celiac disease patients or those with associated genetic diseases (who can be reassured that it is unlikely that they will develop celiac disease) and those who need to be monitored for development of the disease [26].
WGO, 2017 In individuals with other autoimmune diseases and some genetic disorders, who should be investigated for celiac disease (eg, autoimmune thyroiditis) [26].
BSG, 2014 HLA typing should be used to rule out CD. A positive DQ2.5 or DQ8 can never confirm the diagnosis [25].
BSG, 2014 HLA typing should be used in individuals who are self-treated on a GFD and never had appropriate testing for CD before changing their diet [27].
BSG, 2014 HLA typing can be used to rule out CD, and minimise future testing, in high-risk individuals with CD, for example, first-degree relatives [27].
Table 4. Extracted statements on lifestyle prevention strategies from guideline documents (n=30).
Table 4. Extracted statements on lifestyle prevention strategies from guideline documents (n=30).
Organisation, Year Statements on lifestyle prevention strategies
ESPGHAN, 2016 Breastfeeding (BF) compared with no BF has not been shown to reduce the risk of developing CD during childhood [17].
ESPGHAN, 2016 Recommendations on BF should not be modified because of considerations regarding prevention of CD (conditional recommendation; low quality of evidence) [17].
ESPGHAN, 2016 BF at the time of gluten introduction, as compared to gluten introduction after weaning (ie, cessation of BF), has not been shown to reduce the risk of developing CD during childhood [17].
ESPGHAN, 2016 Introducing gluten while the infant is being breast-fed cannot be recommended as a means of reducing the risk of developing CD (conditional recommendation; low quality of evidence) [17].
ESPGHAN, 2016 Gluten introduction at 4 to 6 months compared with gluten introduction at >6 months of age does not reduce the cumulative incidence of CDA or CD during childhood [17].
ESPGHAN, 2016 In children at high risk for CD, gluten introduction at 6 months compared with gluten introduction at 12 months of age does not reduce the cumulative incidence of CDA or CD, but it leads to an earlier manifestation of CD [17].
ESPGHAN, 2016 It remains unclear whether gluten introduction at <3 to 4 months compared with gluten introduction at 4 to 6 months of age has an effect on the risk of developing CDA or CD [17].
ESPGHAN, 2016 It remains unclear whether gluten introduction at <3 to 4 months compared with gluten introduction at >6 months of age has an effect on the risk of developing CDA or CD [17].
ESPGHAN, 2016 It remains unclear whether gluten introduction at <6 months compared with gluten introduction at >6 months of age has an effect on the risk of developing CDA [17].
ESPGHAN, 2016 Gluten can be introduced into the infant’s diet between the ages of 4 and 12 completed months. The age of gluten introduction in infants in this age range does not seem to influence the absolute risk of developing CDA or CD during childhood (conditional recommendation; depending on the age, quality of evidence varies from very low to high quality of evidence). 4 completed months ¼ 17 weeks of age [17].
ESPGHAN, 2016 The type of gluten at introduction was not shown to modify the risk of developing CD [17].
ESPGHAN, 2016 Introduction of 200 mg of vital wheat gluten (equivalent to 100 mg of immunologically active gluten) per day at 4 to 6 months of age compared to avoidance of gluten did not modify the risk of developing CDA or CD at 3 years of age. Data from observational studies indicate that consumption of large amounts of gluten at weaning and during the first 2 years of life may increase the risk of CD during childhood [17].
ESPGHAN, 2016 Neither the optimal amounts of gluten to be introduced at weaning nor the effects of different wheat preparations on the risks of developing CD and CDA have been established. Despite the limited evidence regarding the exact amounts and with no RCTs to support it, ESPGHAN suggests that consumption of large amounts of gluten should be discouraged during the first months after gluten introduction (conditional recommendation; very low quality of evidence) [17].
ESPGHAN, 2024 Any BF compared with no BF has not been shown to reduce the risk of developing CD during childhood or to delay the development of CD [18].
ESPGHAN, 2024 Exclusive BF up to age 6 months compared to a shorter duration has not been shown to reduce the risk of CD during childhood [18].
ESPGHAN, 2024 Recommendations on BF for infants with known or unknown genetic risk should not be modified due to considerations regarding prevention of CD [18].
ESPGHAN, 2024 Breastfeeding at the time of gluten introduction, as compared to gluten introduction after weaning from BF, has not been shown to reduce the risk of developing CD during childhood [18].
ESPGHAN, 2024 Introducing gluten while the infant is being breastfed cannot be recommended as a means of reducing the risk of developing CD [18].
ESPGHAN, 2024 The age of gluten introduction between completed 4 months (≥17 weeks) and 12 months of age does not seem to influence the absolute risk of developing CDA or CD during childhood [18].
ESPGHAN, 2024 Gluten can be introduced into the infant’s diet at any time between completed 4 months (≥17 weeks) and 12 months of age without affecting the cumulative risk of CDA or CD development during childhood [18].
ESPGHAN, 2024 Observational and case-control studies suggest that the consumption of a higher amount of gluten at weaning and/or thereafter may increase the risk of CDA and CD in genetically at-risk children [18].
ESPGHAN, 2024 In birth cohort studies, a higher and dose-dependent daily gluten intake during the first years of life (specifically the first 2 to 3 years, and even 5 years in some studies) was found to increase the risk of CDA and CD. However, the daily gluten amounts varied significantly across studies, reflecting different feeding patterns and dietary habits among countries, as well as various dietary assessment methods used [18].
ESPGHAN, 2024 The optimal amounts of gluten for introduction at weaning and throughout childhood to reduce the risk for CDA and CD cannot be established from the current data [18].
ESPGHAN, 2024 There is no evidence that a safe amount of gluten intake exists that can prevent CDA and CD development with a high degree of certainty [18].
ESPGHAN, 2024 No recommendation can be made regarding the amount of gluten intake at weaning and up to 2-3 years of age for infants of unknown risk for CD [18].
ESPGHAN, 2024 Similarly, for infants with a known CD risk, no recommendation can be made. We recommend awaiting the results of ongoing intervention studies before any guidance can be given on the consumption of gluten amounts during the first 2 or 3 years of life [18].
ESPGHAN, 2024 The type of gluten at introduction was not shown to modify the risk for developing CD [18].
ESPGHAN, 2024 No recommendation can be made regarding the source and type of gluten-containing food to be used at food introduction or after weaning [18].
ESPGHAN, 2024 There is inconclusive evidence on the link between maternal gluten intake during pregnancy and the risk of CD in the offspring, and no evidence regarding the impact of maternal gluten intake during lactation [18].
ESPGHAN, 2024 There is no evidence to give specific recommendations on gluten intake by the mother during pregnancy and lactation [18].
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