Oct 12, 2023
Celiac disease (CD) is a common, inherited, chronic inflammatory condition of the small intestine triggered by gluten proteins found in wheat, barley and rye (Izzo, V. et al., 2011; Dubois, P. C. et al., 2010). Classic early childhood symptoms include chronic diarrhea, abdominal bloating, and failure to thrive, while patients diagnosed later in life experience anemia, fatigue, weight loss, diarrhea, and neurological symptoms. The only effective treatment available for celiac patients today is the absolute elimination of gluten from their diet. Celiac disease is a polygenic disease and human leukocyte antigen HLA is the most important genetic factor (Kim, Y. et al., 2004). Genetic predisposition to CD involves (HLA)-DQ2 and HLA-DQ8 heterodimers as major risk factors; these are estimated to explain approximately 40% of the heritability of the disease. The remaining 60% of genetic susceptibility to CD is shared among an unknown number of non-HLA genes, each predicted to contribute only a small risk (Romanos J. et al., 2009).
What is the LPP Gene?
LPP is highly expressed in the small intestinal mucosa and is thought to have a structural role at cell adhesion sites in maintaining cell shape and motility (Hunt, K. A. et al., 2008).
What is the HLA-DQ 2.5 Gene? What is the HLA-DQ 2.2 Gene? What is the HLA-DQ 4 Gene? What is the HLA-DQ 8 Gene?
Celiac Disease has a strong genetic association with human leukocyte antigen (HLA). Most CD patients (90–95%) express the heterodimer DQA1*05/DQB1*02. Among carriers of the DQA1*05/DQB1*02 heterodimer, the risk of disease is higher in individuals homozygous for DQB1*02 (Bourgey, M. et al., 2007).
What is LOC105371664 (RGS1) Gene?
RGS1 belongs to a family of RGS genes. RGS family genes act as GTPase-activating proteins, attenuating the signaling activity of G proteins. RGS1 functions to regulate chemokine receptor signaling and is known to play a role in B cell activation and proliferation. RGS1 is expressed in human small intestinal biopsies (Hunt, K. A. et al., 2008).
What is an Intergenic Gene?
It maps within a large cluster of chemokine receptor genes on 3p21, including CCR1, CCR2, CCRL2, CCR3, CCR5, and CCXCR1. rs6441961 is located 44kb 3' away from the closest gene (CCR3). Chemokines and their receptors are critical for the recruitment of effector immune cells to the site of inflammation (Hunt, K. A. et al., 2008).
What is the REL Gene?
REL is a subunit of the NF-kB complex and plays a role in T cell differentiation. It appears to be a key molecule regulating inflammation and the transition from tolerance to autoimmunity (Izzo, V. et al., 2011).
What is the IL 18RAP Gene?
The IL-18 pathway is highly important as mature IL-18 induces T cell synthesis of interferon-γ, an important cytokine involved in the mucosal inflammation of celiac disease. IL18RAP is strongly expressed in unstimulated T cells and NK cells and is expressed in small intestinal biopsies (Hunt, K. A. et al., 2008).
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GLUTEN SENSITIVITY |
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Genes |
rs |
Minor Allele |
Minor Allele Description |
Reference |
|
LPP |
rs1464510 |
A |
High relative risk for gluten sensitivity. |
|
|
HLA-DQ 2.5 |
rs2187668 |
A |
Increased relative risk for gluten sensitivity. |
|
|
HLA-DQ 2.2 |
rs2395182 |
T |
High relative risk for gluten sensitivity. |
|
|
LOC105371664 (RGS1) |
rs2816316 |
T |
Increased relative risk for gluten sensitivity. |
|
|
HLA-DQ 4 |
rs4713586 |
T |
High relative risk for gluten sensitivity. |
|
|
Intergenic |
rs6441961 |
T |
High relative risk for gluten sensitivity. |
|
|
HLA-DQ 8 |
rs7454108 |
C |
Increased relative risk for gluten sensitivity. |
|
|
HLA-DQ 2.2 |
rs7775228 |
C |
High relative risk for gluten sensitivity. |
|
|
REL |
rs842647 |
A |
High relative risk for gluten sensitivity. |
|
|
IL 18RAP |
rs917997 |
A |
Increased relative risk for gluten sensitivity. |
|
The table above includes genes and their polymorphisms that play a role in the development of celiac disease. HLA genes are located in the MHC region on chromosome 6p21.3. These genes play an important role in many autoimmune disorders such as celiac disease (CD), type 1 diabetes (T1D), rheumatoid arthritis, multiple sclerosis, psoriasis, and others (Monsuur, A. J., et. al., 2008). Around the HLA locus rs2187668- The A allele is the most common HLA-DQ2 haplotype associated with celiac disease (Franke, L. et al., 2007).
Individuals homozygous for the minor rs917997 A allele expressed the lowest levels of IL18RAP mRNA and homozygotes for the G allele expressed the highest levels (Hunt, K. A. et al., 2008).
The rs1464510 polymorphism in the LPP gene, the RGS1 rs2816316 polymorphism, and the rs842647 polymorphism in the REL gene were found to be significantly associated with celiac disease (Izzo, V. et al., 2011).
In the rs6441961 ( CCR1/CCR3/CCR2 ) polymorphism, it has been observed that the T genotype increases the risk of celiac disease, while the C genotype reduces this risk to the same extent (Amundsen, S. S. et al., 2009).
REFERENCES
Amundsen, S. S., Rundberg, J., Adamovic, S., Gudjónsdóttir, A. H., Ascher, H., Ek, J., Nilsson, S., Lie, B. A., Naluai, Å. T., & Sollid, L. M. (2009). Four novel coeliac disease regions replicated in an association study of a Swedish–Norwegian family cohort. Genes & Immunity, 11(1), 79-86. https://doi.org/10.1038/gene.2009.67
Bourgey, M., Calcagno, G., Tinto, N., Gennarelli, D., Greco, L., Limongelli, M. G., Esposito, O., Marano, C., Troncone, R., Spampanato, A., & Sacchetti, L. (2007). HLA related genetic risk for coeliac disease. Gut, 56(8), 1054-1059. https://doi.org/10.1136/gut.2006.108530
Dubois, P. C., Trynka, G., Franke, L., Hunt, K. A., Romanos, J., Curtotti, A., Zhernakova, A., Heap, G. A., Ádány, R., Aromaa, A., Bardella, M. T., Bockett, N. A., Dema, B., Fehrmann, R. S., Fernández-Arquero, M., Fiatal, S., Grandone, E., Green, P. M., Groen, H. J., . . . Wijmenga, C. (2010). Multiple common variants for celiac disease influencing immune gene expression. Nature Genetics, 42(4), 295. https://doi.org/10.1038/ng.543
Franke, L., Hunt, K. A., Gwilliam, R., Zhernakova, A., Inouye, M., Wapenaar, M. C., Barnardo, M. C., Bethel, G., Holmes, G. K., Feighery, C., Jewell, D., Kelleher, D., Kumar, P., Travis, S., Walters, J. R., Sanders, D. S., Howdle, P., Swift, J., Playford, R. J., . . . Wijmenga, C. (2007). A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nature Genetics, 39(7), 827. https://doi.org/10.1038/ng2058
Hunt, K. A., Zhernakova, A., Turner, G., Heap, A. R., Franke, L., Bruinenberg, M., Romanos, J., Dinesen, L. C., Ryan, A. W., Panesar, D., Gwilliam, R., Takeuchi, F., McLaren, W. M., Holmes, G. K., Howdle, P. D., Walters, J. R., Sanders, D. S., Playford, R. J., Trynka, G., . . . Wijmenga, C. (2008). Novel celiac disease genetic determinants related to the immune response. Nature Genetics, 40(4), 395. https://doi.org/10.1038/ng.102
Izzo, V., Pinelli, M., Tinto, N., Esposito, M. V., Cola, A., Sperandeo, M. P., Tucci, F., Cocozza, S., Greco, L., & Sacchetti, L. (2011). Improving the Estimation of Celiac Disease Sibling Risk by Non-HLA Genes. PLoS ONE, 6(11). https://doi.org/10.1371/journal.pone.0026920
Kim, Y., Quarsten, H., Bergseng, E., Khosla, C., & Sollid, L. M. (2004). Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease. Proceedings of the National Academy of Sciences of the United States of America, 101(12), 4175-4179. https://doi.org/10.1073/pnas.0306885101
Monsuur, A. J., de Bakker, P. I., Zhernakova, A., Pinto, D., Verduijn, W., Romanos, J., Auricchio, R., Lopez, A., van Heel, D. A., Crusius, J. B., & Wijmenga, C. (2008). Effective detection of human leukocyte antigen risk alleles in celiac disease using tag single nucleotide polymorphisms. PloS one, 3(5), e2270. https://doi.org/10.1371/journal.pone.0002270
Romanos J, van Diemen CC, Nolte IM, Trynka G, Zhernakova A, Fu J, Bardella MT, Barisani D, McManus R, van Heel DA, Wijmenga C. Analysis of HLA and non-HLA alleles can identify individuals at high risk for celiac disease. Gastroenterology. 2009 Sep;137(3):834-40, 840.e1-3. doi: 10.1053/j.gastro.2009.05.040. Epub 2009 May 18. PMID: 19454285. https://pubmed.ncbi.nlm.nih.gov/19454285/