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Genetic tests in at-risk children can reveal more than the presence or absence of celiac disease genes

November 3, 2022

Researchers develop a model for predicting risk, linking it to a system that gives individual screening recommendations

By Amy Ratner, director of scientific affairs

Genetic tests can reveal more than a simple “yes” or “no” regarding whether an at-risk child has the genes associated with celiac disease, and the results can be used for individualized follow-up testing, a new international study finds.

The level of risk for children in families with celiac disease depends on gender, age, type of celiac-disease-related genes and the number of relatives with celiac disease, according to the study, published in the journal Gastroenterology.

When combined, these factors provide a predictive score that estimates cumulative risk over years and can be used to determine how often an at-risk child who does not have symptoms should be tested for celiac disease, making the timetable for screening more individualized, says the study by Caroline R. Meijer, MD, of the Leiden University Medical Center in the Netherlands, and colleagues.

The study found that children with first degree relatives often develop celiac disease early in life and that the risk for celiac disease was significantly higher in girls who have two copies of HLA DQ2, one of the genes commonly associated with celiac disease. When someone has two copies of a gene, they are called homozygous.

Additionally, the results show that children who have a first degree relative have a significantly greater risk of developing celiac disease during their first 10 years than has previously been thought, the study says.

“Until recently, the lifetime risk of celiac disease for first degree relatives of [those with celiac disease] was considered to be 5 to 10 percent, yet our data show that at the age of 8 years this is as high as 17 percent,” the authors wrote, noting this finding emphasizes the importance of “sound advice” for early screening.

Value of positive and negative results

Genetic testing is mainly used to determine who is unlikely to get celiac disease because a negative result for HLA DQ2 and DQ8 genes largely rules out the possibility of developing celiac disease. Meanwhile, a positive test is less conclusive because 40 percent of the general population carries the genes, but only about 1 percent has celiac disease. That means a positive genetic test alone is insufficient to diagnose celiac disease, and further blood tests and a biopsy are needed.

HLA DQ2 and DQ8 are sometimes called the celiac disease genes because almost everyone who has celiac disease has these genes. Children who have a parent or sibling diagnosed with celiac disease and who have the genes are at increased risk of developing the condition even when they have no symptoms, so regular blood testing is recommended.

“However, the frequency with which to test has not been established,” says an editorial about the international study also published in Gastroenterology. “It is within this context of uncertainty that the study… sheds important light.” The editorial was written by Benjamin Lebwohl, MD, director of clinical research at the Celiac Disease Center at Columbia University, and Luigi Greco, MD, of the European Laboratory for Food Induced Diseases at the University of Naples, who were not involved in the study.

“It appears we should be paying attention to the details of HLA results beyond its negative predictive value,” the editorial says, noting that previous studies have also shown that the specific HLA haplotype matters. A haplotype is a physical grouping of genomic variants that tend to be inherited together, according to the National Human Genome Institute.

Longest follow-up

The study is based on analysis of 10 years of follow-up data from previous research involving nearly 950 children who had both the genes for celiac disease and a first degree relative who had been diagnosed. Of these, 135 children developed celiac disease. About 60 percent were girls and about 40 percent boys.

Children included in the study were enrolled at birth between 2007 and 2010 in Croatia, Germany, Hungary, Israel, Italy, the Netherlands, Poland and Spain. They were followed up for an average of 10 years, which gave researchers a “unique opportunity to study the natural development of celiac disease in children from high-risk families,” the study says.

It is based on the longest follow-up data from birth of a group of genetically predisposed children with a first degree relative with celiac disease, the authors note.

All the children in the study were assessed regularly, including seven times before they were three years old and afterwards either annually or at least once between 2016 and 2019. Monitoring included parents’ reports on gluten consumption and blood tests for tissue transglutaminase IgA (TTG-IgA). Celiac disease diagnosis was confirmed with a biopsy except for five children who were diagnosed following European guidelines that allow for diagnosis without a biopsy if certain celiac disease blood test results are high enough.

Age at diagnosis

Four years was the average age of diagnosis. Of those who developed celiac disease, the cumulative incidence was about 8 percent at age 3, 17 percent at age 8 and 18 percent at age 10.  Overall, at the age of 10, girls had a nearly 8 percent higher cumulative incidence than boys, about 22 percent compared to 14 percent.

The authors note that while the increased risk of celiac disease in children with two copies of HLA-DQ2 and the predominance of celiac disease in girls have been known, their study is the first to report the significant additional effect of the interaction between these two factors, in certain types of HLA-DQ2 homozygosity in particular.

“This different effect of gender appears very early in life, and it persists and increases during the first 10 years of age,” the study says.

Risk calculator

In addition to describing risk factors, researchers developed a web-based prediction calculator that takes a child’s age, sex, HLA type and number of affected relatives into account to determine absolute risk and provides recommendations for how often follow-up celiac disease testing should be done.

The calculator is based on prediction models of celiac disease developed as part of the study. The calculator can be used for individualized screening advice. The basis for the advice uses the current standard of care at celiac disease centers, which calls for yearly screening of children with a first-degree relative. The authors call for initial screening of all children with a first-degree relative through TTG-IgA and total IgA blood tests and genetic tests, including typing of HLA-DQ2 and DQ8 which reveals more detailed information.

If the TTG blood tests are negative, the risk of developing celiac disease can be assessed through the prediction calculator. If the prediction of risk is greater than 10 percent in the next two years, researchers advise repeat screening after six months. If the risk is between 5 and 10 percent, they advise repeat screening after one year and if it is less than 5 percent, screening should be repeated after two years.

“As a result of the risk calculator developed in the present study, we can now use the details of our patients’ HLA haplotype to develop a rational testing strategy and think beyond the dichotomy of ‘positive’ or ‘negative’ genetic testing in celiac disease,” Lebwohl and Greco wrote in their editorial.

They note that the risk calculator provides “a path and a schedule,” for parents and physicians in screening at-risk children who have no symptoms of celiac disease. “They have developed an easy-to-use web-based calculator that provides useful data for families and healthcare providers, including absolute risks and recommendations regarding testing frequency based on an individual patient’s risk profile,” the editorial says.

Parents can work with their child’s physician by accessing the prediction calculator here. Details on HLA typing are needed to determine the HLA risk group.

Although researchers followed study participants until the age of 10, the prediction calculator applies until the age of 8 because all study participants were at least 8 when the data was frozen for analysis.

The authors note that screening advice was developed for children from families with celiac disease and should not be applied to children in the general population until that use has been validated. Additionally, they call for evaluation of the prediction models in clinical settings.

Original study

The follow-up data used in the study came from the Prevent CD trial, which found that neither early introduction of a small amount of gluten nor breast feeding reduced the risk of celiac disease at three years of age among children with a first-degree relative.

The new analysis found that that the quantity of gluten at-risk children eat at early age, rather than the timing of gluten introduction, is associated with a higher risk of celiac disease development, the authors note. The study says this result agrees with findings from other studies that suggest the quantity of gluten consumed may be a preventative factor. The amount of gluten intake, however, is not included in the prediction of risk models in the study, because this information if generally unknown in a standard clinical setting, the study says.

You can read more about the study here.

Beyond Celiac Town Hall

Watch the recording of our November 2022 Town Hall where Dr. Lebwohl discussed the role of genetic testing for celiac disease and the potential future of genetic risk stratification based on recent research. 


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