Genetics and celiac disease: the importance of screening

Abstract

The prevalence of celiac disease (CD) is increasing. Despite an increased awareness and an improvement in diagnostic testing, the majority of individuals with CD remain undiagnosed. Currently, genetic testing in screening for CD is used only to exclude a diagnosis or reinforce a strong clinical suspicion. In this paper, we review the most current literature regarding genetic testing in CD. In response to important data revealing that an individual’s HLA haplotype is one of the strongest known predictors of CD, we propose genetic screening for at-risk infants to stratify individuals based on genetic risk to ultimately create genetic specific screening algorithms.

Keywords:

• celiac disease
• genetic risk
• HLA
• screening

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The prevalence of celiac disease (CD) has doubled every 15 years in the past 50 years.

• Despite accurate serological testing, the majority of individuals with CD are undiagnosed due to presentation with atypical or non-existent symptoms and lack of targeted well-defined screening programs.

• The HLA locus contributes 40% of the genetic variance of CD, while the addition of known non-HLA genes explains up to 54% of the variability.

• Currently HLA testing is used to evaluate individuals in high-risk groups or otherwise complex patients to rule out the possibility of CD.

• Given the evidence that the specific HLA haplotype (DQ2) and the homozygosity status dramatically increase the risk of developing CD in at-risk infants within the first 5 years of age, HLA typing at birth in these infants should be considered as the standard of care in the near future.

• The use of non-HLA genetic testing is unlikely to be used clinically in the near future due to the high cost of non-HLA genetic testing combined with the small amount of additional predictability gained.

• Further clinically applicable contributions to understand what ultimately leads to the loss of tolerance to gluten in genetically at-risk individuals will likely come from careful studies evaluating the environmental factors leading to perturbations in the microbiome and metabolomes of infants at highest risk of CD.

Notes

CD: Celiac disease; GFD: Gluten free diet; T1DM: Type-1 diabetes mellitus; tTG: Tissue transglutaminase.