Genetics and Hereditary Aspects of Celiac Disease

 In Autoimmune/Allergy Medicine, Gastrointestinal

Nadia Arora, ND

Celiac disease, also called celiac sprue, non-tropical sprue or gluten-sensitive enteropathy, is a condition characterized by chronic immune reaction in the intestines, precipitated by the ingestion of wheat, barley or rye in genetically susceptible individuals. Chronic immune reaction causes gradual destruction of the intestinal villi, leading to impaired absorption and assimilation of food. This, in turn, leads to multiple nutritional deficiencies. Classic celiac disease presents with intestinal symptoms within the first two years, soon after the introduction of gluten into the diet.

Celiac disease is characterized by a wide clinical heterogeneity. Diarrhea, anemia, weight loss and osteoporosis are considered typical symptoms of celiac disease; however, only half of the affected individuals present with such symptoms. A large portion of the patients with celiac disease have non-specific symptoms, such as infertility, muscle pain, depression and seizures; and some patients are asymptomatic. In many cases, onset of clinical symptoms occurs in the second, third or fourth decade of life, making diagnosis even more challenging.


General prevalence of celiac disease is 0.3-1% of the population in all countries and all ethnic groups where it has been investigated. Celiac disease is most frequently diagnosed in Europe, where it has been recognized since the early 1950s. It is reported to occur at the rate of 1 in 250 people in Italy, 1 in 300 in Ireland, and 1 in 100 people in Finland. In the U.S., prevalence of the disease is 1 in 133 people. Among individuals with affected first-degree relatives, celiac disease may be as frequent as 1 in 22 people (Fasano et al., 2003). Recent population studies from India, Pakistan, Israel, Cuba and South America demonstrated that rates of occurrence in those countries are similar to the European rates – 1 in 250-300 individuals (Malekzadeh, 2005; Goel, 2007; Eller, 2006; Pereira, 2006). Most studies report that males and females are equally affected, but some indicate that females are affected more often and present with more severe and rapidly progressing disease (Ciacci, 1995). A study from Turkey found that celiac disease, while previously not recognized in this population, occurs with the frequency similar to that of the European population, and the cumulative frequency of celiac disease was found to be higher in females than in males (Elsurer, 2005).

It appears that the incidence of celiac disease is increasing worldwide. In Finland, for example, the incidence of celiac disease among children is as high as 1 in 99 (Maki, 2003). A cross-population study from Italy found that celiac disease is more frequent in younger age groups: 5.7 per 1,000 children, compared with 4.9 per 1,000 adults (Volta, 2001). Some studies found a close association between the increased risk for celiac disease and early introduction of gluten-containing foods into the diet, with the risk being highest when gluten was introduced within the first four months of life (Norris, 2005).

Hereditary Nature

HLA-Related Factors

Heredity appears to have a major influence on the individual’s predisposition to celiac disease. Familial studies show that approximately 15% of the siblings of affected patients have celiac disease as well (Grover et al., 2007). Occurrence increases even further in twins – up to 60-70%. This hereditary predisposition has been strongly linked to the human leukocyte antigen (HLA) system, located on chromosome 6. In most studies, celiac disease was found to be strongly associated with particular variants of the HLA class II genes, located on the DQ locus. The exact mechanism that leads to gluten sensitivity in individuals with those variants has not been elucidated, but it has been proposed that certain sites on the HLA markers interact with gliadin and sensitize T-cells to gluten. Such a mechanism appears plausible considering that HLA class II genetic polymorphisms have been strongly linked to other autoimmune diseases, such as Type I diabetes, thyroiditis and rheumatoid arthritis.

Recent studies indicate that in affected individuals, the number of HLA-DQ alleles might play an important role in the clinical expression of celiac disease. A study from Italy looked at the levels of anti-transglutaminase autoantibodies in three groups of patients with clinical symptoms of celiac disease: homozygous for HLA DQB1*02 allele, heterozygous and negative for the allele (Nenna, 2008). The highest levels of autoantibodies as well as the most severe clinical expression were found in the homozygous group, indicating that the effect of HLA genes in the pathogenesis of celiac disease is dose-dependent.

Non-HLA Genetic Factors

Since the concordance of the disease is higher in twins than in HLA-identical siblings (70% vs. 30%), it is clear that HLA class II genetic inheritance does not fully account for the susceptibility to celiac disease and that other, non-HLA genetic factors, must be involved. In one study a genome-wide search for non-HLA markers identified regions of susceptibility on chromosomes 5 and 19 (Amundsen, 2007). Fine mapping of chromosome 19 revealed that gene MYO9b, which codes for myosin, might be strongly involved in the pathogenesis of celiac disease (Cirillo, 2007). Myosin is involved in the barrier function of the lining of the small intestine; therefore, any genetic mutations that disrupt the function of this protein could result in defective function of the intestinal barrier. Another gene associated with celiac disease is the gene that codes for CTLA4, a molecule that down regulates the immune response. A study from the Netherlands found an association between polymorphism in the CTLA4 gene and early-onset celiac disease (Van Belzen, 2004). Among other genes that might be implicated in celiac disease is the tumor necrosis factor (TNF) gene. Certain polymorphisms in this gene result in increased production of tumor necrosis factor-alpha, which leads to chronic inflammatory response, particularly in the intestines (Woolley et al., 2005).

The non-HLA genes associated with celiac disease are often co-inherited and contribute stronger than HLA genes to the pathogenesis of the disease. Recent data suggest that both types of genes – those that regulate the structural integrity of the intestinal lining and those involved in the immune system function – are involved.

The level of gene expression and gene modification even in the absence of genetic mutations might also contribute to the development of celiac disease. A study from Ireland revealed altered gene expression in the enterocytes of patients with active celiac disease (Bracken, 2008). Out of some 3,800 entero-genes studied, 102 had a significantly altered expression. Authors concluded that such changes could have led to multiple pathological processes of celiac disease, including changes in cell proliferation, differentiation, survival, structure and transport.

Associated Hereditary Conditions

Other genetic and chromosomal disorders are frequently associated with celiac disease. For example, individuals with Down syndrome have prevalence of celiac disease ranging from 5% to 12%. In the European population, these rates increase to almost 16%. The exact reasons for such co-morbidity are not well understood, but it has been observed that patients with Down syndrome generally have a higher incidence of autoimmune disease. Increased rates of celiac disease have been reported for patients with Turner syndrome and hereditary IgA deficiency. In addition, a high incidence of celiac disease has been reported for patients with lactase deficiency (Oiettia, 2005). In these patients, lactose intolerance is often the only manifestation of celiac disease.

Genetic Testing – Applications and Limitations

Diagnosis of celiac disease is typically made on the basis of laboratory testing and clinical response to a gluten-free diet. The role of genetic testing is confirmatory. Approximately 90% of patients with confirmed celiac disease have polymorphisms in HLA class II genes, which lead to the development of tests that aim to identify these specific HLA markers. Genetic testing for HLA DQ alleles has high sensitivity (90-95%), but due to the fact that only about 30% of the patients without celiac disease carry these alleles, the specificity of this test is low. The negative test automatically excludes the diagnosis of celiac disease, while the positive test alone does not have such a diagnostic value.

Multiple studies show that celiac disease-like symptoms, laboratory findings and positive HLA DQ2, HLA DQ8 markers may be found in approximately one-third of patients with other autoimmune conditions, such as diabetes, thyroiditis and rheumatoid arthritis (Bao, 1999). Generally, genetic testing is recommended only after all clinical testing has been completed, including biopsy of the small intestine. A study from Hungary found that clinical tests and even biopsy are not always reliable for the definitive diagnosis of celiac disease (Kapitani, 2006). They found that subjects previously diagnosed with celiac disease based on blood tests and biopsy and who tested negative for the HLA DQ2, HLA DQ8 markers did not improve with the gluten-free diet. On the other hand, patients with biopsy-diagnosed celiac disease who tested positive for HLA DQ2 and HLA DQ8 genetic markers responded favorably to the gluten-free diet and experienced severe relapse upon discontinuation of the diet. The authors of the study concluded that negative HLA DQ markers firmly indicate the absence of celiac disease. Therefore, they recommend genetic testing for all patients with diagnosed celiac disease to identify those individuals in whom clinical diagnosis needs to be revised. Despite their high value in exclusion of the diagnosis of celiac disease, current genetic tests have limited value in their ability to identify individuals with the disease due to their low specificity. Similarly, the low specificity of the tests reduces their value in the screening of family members of affected individuals. New tests that include multiple genetic markers are necessary to improve the diagnostic potential of genetic testing for celiac disease.

Celiac disease is a chronic inflammatory condition triggered by ingestion of gluten in genetically susceptible individuals. In the last decade, significant progress has been made in the understanding of genetic and environmental factors that contribute to the development of this disease. Understanding the genetic mechanisms that underlie pathogenesis of celiac disease allows for early detection of the disease and identification of individuals with hereditary predisposition. This, in turn, could lead to prevention of complications of celiac disease and help with finding better treatment options and alternatives to the gluten-free diet.

AroraNadia Arora, ND is a graduate of Bastyr University. She practices naturopathic family medicine in Washington, DC. Her special interests in genetics and heredity have led her to become a medical writer for Kromosoft, a genetics research company. Dr. Arora is also a faculty member at the Potomac Massage Training Institute in Washington, DC, where she teaches courses on basic anatomy and physiology, and nutrition.



Fasano et al: Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study, Arch Intern Med Feb 10;163(3):286-92, 2003.

Malekzadeh R: Coeliac disease in developing countries: Middle East, India and North Africa, Best Pract Res Clin Gastroenterol 19(3):351-358, 2005.

Goel GK: Prevalence of celiac disease in first-degree siblings of celiac disease patients, Indian J Gastroenterol 26(1):46, 2007.

Eller E: Celiac disease and HLA in a Bedouin kindred, Hum Immunol 67(11):940-50, 2006.

Pereira MA: Prevalence of celiac disease in an urban area of Brazil with predominantly European ancestry, World J Gastroentrol 12(40):6546-50, 2006.

Ciacci C: Gender and clinical presentation in adult celiac disease, Scand J Gastroenterol 30(11):1077-81, 1995.

Elsurer R: Celiac disease in the Turkish population, Dig Dis Sci 50(1):136-42, 2005.

Maki M: Prevalence of celiac disease among children in Finland, N Engl J Med 348(25):2517-2524, 2003.

Volta U: High prevalence of celiac disease in Italian general population, Dig Dis Sci 46(7):1500-5, 2001.

Norris JM: Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease, JAMA 293:2343-2351, 2005.

Grover et al: Familial prevalence among first-degree relatives of celiac disease in North India, Dig Liver Dis Oct;39(10):903-7, 2007.

Nenna R: HLA-DQB1*02 dose effect on RIA anti-tissue transglutaminase autoantibody levels and clinicopathological expressivity of celiac disease, J Pediatr Gastroenterol Nutr 47(3):288-92, 2008.

Amundsen SS: A comprehensive screen for SNP associations on chromosome region 5q31-33 in Swedish/Norwegian celiac disease families, Eur J Hum Genet 15(9):980-987, 2007.

Cirillo G: Do MYO9B variants predispose to celiac disease? An association study in a cohort of South Italian children, Dig Liver Dis 39(3):228-31, 2007.

Van Belzen MJ: CTLA4 +49 A/G and CT60 polymorphisms in Dutch celiac disease patients, Eur J Hum Genet 12(9):782-85, 2004.

Woolley N et al: Cytokine gene polymorphisms and genetic association with coeliac disease in the Finnish population, Scand J Immunol Jan;61(1):51-6, 2005.

Bracken S: Altered gene expression in highly purified enterocytes from the patients with active coeliac disease, BMC Genomics 8; 9:377, 2008.

Oiettia V: High prevalence of celiac disease in patients with lactose intolerance, Digestion 71(2):97-103, 2005.

Bao F: One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease-associated transglutaminase antibodies, J Autoimmune 13(1):143-8, 1999.

Kapitani A: Diagnostic significance of HLA-DQ typing in patients with previous celiac disease diagnosis based on histology alone, Aliment Pharmacol Ther 24(9):1395-402, 2006.

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