Genetics of celiac disease, fructose and lactose intolerance

What’s measured

Coeliac disease or gluten intolerance

Coeliac disease is a systemic condition characterised by an immune system response occurring in genetically predisposed individuals. It results in a lasting intolerance of the immune system to gluten, a protein present in various grains such as wheat, rye, and barley.  The disease is caused by an abnormal activation of the immune system, leading to damage in the small intestine.

Genetic testing has demonstrated that genes from the major histocompatibility complex (MHC II) region primarily contribute to genetic predisposition. It's estimated that this complex accounts for up to 40% of the genetic susceptibility to coeliac disease. However, the presence of these genes does not mean that coeliac disease will develop. Around 25–30% of the population carries this genetic makeup, yet only 1% of them are likely to develop the disease. Given that the vast majority of individuals with confirmed coeliac disease (99%) possess one of the DQ2/DQ8 alleles of the HLA system, this test proves valuable for ruling out a predisposition to coeliac disease. A negative test result means that it is virtually impossible for you to develop coeliac disease in your lifetime. [1].

Lactose intolerance

Lactose is one of the fundamental carbohydrates found in milk. Lactose intolerance, also known as hypolactasia, occurs due to a reduction in the activity of the enzyme lactase, responsible for breaking down lactose in the small intestine. In the European population, lactose intolerance is linked to two polymorphisms on the gene responsible for the lactase enzyme. Intolerance to lactose-containing foods is common [2]. Symptoms of lactose intolerance include abdominal pain, flatulence, nausea, bloating, and diarrhoea following the consumption of milk or milk-containing products. These symptoms may be associated with lactose malabsorption, which is the result of low levels of small intestinal lactase.

Genetic testing specifically identifies primary lactase deficiency and is applicable only to certain populations. This test is applicable in populations where the -13910 T/C polymorphism has been linked to lactase persistence [3,4].

Fructose intolerance

Fructose, also known as fruit sugar, occurs naturally in fruits, honey, and certain vegetables. A synthetic version of fructose is also utilised as a sweetener in food products. Hereditary fructose intolerance stems from a mutation in the gene responsible for the enzyme aldolase B, which metabolises the fruit sugar fructose. Congenital fructose intolerance arises from mutations in the ALDOB gene, leading to decreased activity of the enzyme aldolase B and consequently impairing the body's capacity to metabolise fructose. A deficiency in the enzyme aldolase B results in the buildup of fructose 1-phosphate within liver cells, leading to their severe damage.

Genetic testing for fructose intolerance reveals it to be an autosomal recessive condition, wherein the patient carries two mutant alleles of the ALDOB gene [5].

What does the examination include?

The test monitors for the presence of genes associated with coeliac disease:

• HLA-DQ2 and HLA-DQ8
• for lactose intolerance, it examines two polymorphisms on the lactase gene (-13910 T > C and -22018 A > G) 
• for fructose intolerance, it detects four mutations in the aldolase B gene (del4E4, A149P, A174D, and N334K).
  

Instructions before collection

The result of the genetic test is not affected by adherence to lactose-free, gluten-free and fructose-free diets. Peripheral blood sampling does not need to be performed fasting and can be performed at any time of the day. The result of the test is not affected by the use of any medications, diets or smoking.

Sources

[1]Kaukinen K, Partanen J, Mäki M, Collin P. HLA-DQ typing in the diagnosis of celiac disease. Am J Gastroenterol 2002; 97:695.

[2]Suchy FJ, Brannon PM, Carpenter TO, et al. National Institutes of Health Consensus Development Conference: lactose intolerance and health. Ann Intern Med 2010; 152:792.

[3]Baffour-Awuah NY, Fleet S, Montgomery RK, et al. Functional significance of single nucleotide polymorphisms in the lactase gene in diverse US patients and evidence for a novel lactase persistence allele at -13909 in those of European ancestry. J Pediatr Gastroenterol Nutr 2015; 60:182.

[4]Marton A, Xue X, Szilagyi A. Meta-analysis: the diagnostic accuracy of lactose breath hydrogen or lactose tolerance tests for predicting the North European lactase polymorphism C/T-13910. Aliment Pharmacol Ther 2012; 35:429.

[5]Ali M, Rellos P, Cox TM. Hereditary fructose intolerance. J Med Genet 1998; 35:353. Kim AY, Hughes JJ, Pipitone Dempsey A, et al. Pitfalls in the Diagnosis of Hereditary Fructose Intolerance. Pediatrics 2020; 146.