HLA-DQA1
major histocompatibility complex, class II, DQ alpha 1
The HLA-DQA1 gene provides instructions for making a protein that plays a critical role in the immune system. The HLA-DQA1 gene is part of a family of genes called the human leukocyte antigen (HLA) complex. The HLA complex helps the immune system distinguish the body's own proteins from proteins made by foreign invaders such as viruses and bacteria.
The HLA complex is the human version of the major histocompatibility complex (MHC), a gene family that occurs in many species. The HLA-DQA1 gene belongs to a group of MHC genes called MHC class II. MHC class II genes provide instructions for making proteins that are present on the surface of certain immune system cells. These proteins attach to protein fragments (peptides) outside the cell. MHC class II proteins display these peptides to the immune system. If the immune system recognizes the peptides as foreign (such as viral or bacterial peptides), it triggers a response to attack the invading viruses or bacteria.
The protein produced from the HLA-DQA1 gene attaches (binds) to the protein produced from another MHC class II gene, HLA-DQB1. Together, they form a functional protein complex called an antigen-binding DQαβ heterodimer. This complex displays foreign peptides to the immune system to trigger the body's immune response.
Each MHC class II gene has many possible variations, allowing the immune system to react to a wide range of foreign invaders. Researchers have identified hundreds of different versions (alleles) of the HLA-DQA1 gene, each of which is given a particular number (such as HLA-DQA1*05:01).
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At least two specific combinations of HLA gene variants (HLA haplotypes) have been found to increase the risk of developing celiac disease, a disorder in which inflammation damages the intestinal tract and other organs and tissues. One of these haplotypes, known as DQ2, is composed of the protein produced from HLA-DQA1 gene variants known as HLA-DQA1*05:01 or HLA-DQA1*05:05 bound to the protein produced from HLA-DQB1 gene variants known as HLA-DQB1*02:01 or HLA-DQB1*02:02. The other haplotype, known as DQ8, is composed of the protein produced from HLA-DQA1 gene variants known as HLA-DQA1*03:01 or HLA-DQA1*03:02 bound to the protein produced from the HLA-DQB1 gene variant known as HLA-DQB1*03:02.
The DQ2 and DQ8 haplotypes, which may occur separately or together, seem to increase the risk of an inappropriate immune response to the protein gluten, which is found in wheat, rye, and barley. This immune system malfunction results in the damage to the body's organs and tissues that occurs in celiac disease. However, the DQ2 and DQ8 haplotypes are also found in 30 percent of the general population, and only 3 percent of individuals with these haplotypes develop celiac disease.
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Combinations of variations in the HLA-DQA1 gene and other HLA genes affect the risk of type 1 diabetes. Type 1 diabetes is characterized by high blood sugar levels resulting from a shortage of the hormone insulin and is caused by autoimmune damage to insulin-producing cells in the pancreas.
Type 1 diabetes risk is most increased by two HLA haplotypes involving variations of the HLA-DQA1 and HLA-DQB1 genes and another HLA gene called HLA-DRB1. One haplotype, written as DRB1*03:01-DQA1*05:01-DQB1*02, is called DR3. The other haplotype, written as DRB1*04:01/02/04/05/08-DQA1*03:01-DQB1*02, is called DR4. People at highest risk of developing type 1 diabetes have one copy of the DR3 haplotype and one copy of the DR4 haplotype in each cell. Other HLA haplotypes only mildly increase the risk of type 1 diabetes, while some haplotypes seem to protect against developing this condition. Variations in other genes and environmental factors are also thought to affect the risk of this complex disorder.
Certain normal variations of the HLA-DQA1 gene have been associated with increased risk of autoimmune disorders, which occur when the immune system malfunctions and attacks the body's own tissues and organs. It is unclear how different versions of the HLA-DQA1 gene influence the risk of developing autoimmune disorders. These conditions are thought to result from a combination of multiple environmental and genetic factors. Changes in other HLA and non-HLA genes, some of which remain unknown, also likely contribute to the risk of developing these complex conditions.
Normal variations in the HLA-DQA1 gene can affect the body's ability to recognize and react to foreign invaders (pathogens). For example, variations of this gene have been shown to increase or decrease a person's chance of getting infections such as hepatitis B and leprosy or may affect the severity of illness if infection occurs.
A particular variant of the HLA-DQA1 gene known as HLA-DQA1*02:01 increases the risk of liver damage in women with advanced breast cancer treated with a drug called lapatinib. Researchers suggest that the variant may increase immune system sensitivity to the drug, resulting in inflammation that damages the liver.
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Cytogenetic Location: 6p21.3, which is the short (p) arm of chromosome 6 at position 21.3
Molecular Location: base pairs 32,637,396 to 32,654,774 on chromosome 6 (Homo sapiens Annotation Release 107, GRCh38.p2) (NCBI)
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- Abadie V, Sollid LM, Barreiro LB, Jabri B. Integration of genetic and immunological insights into a model of celiac disease pathogenesis. Annu Rev Immunol. 2011;29:493-525. doi: 10.1146/annurev-immunol-040210-092915. Review.
- Gene Review: Gene Review: Celiac Disease
- Lipton RB, Drum M, Greeley SA, Danielson KK, Bell GI, Hagopian WA. HLA-DQ haplotypes differ by ethnicity in patients with childhood-onset diabetes. Pediatr Diabetes. 2011 Jun;12(4 Pt 2):388-95. doi: 10.1111/j.1399-5448.2010.00712.x. Epub 2011 Mar 21.
- OMIM: MAJOR HISTOCOMPATIBILITY COMPLEX, CLASS II, DQ ALPHA-1
- Noble JA, Valdes AM. Genetics of the HLA region in the prediction of type 1 diabetes. Curr Diab Rep. 2011 Dec;11(6):533-42. doi: 10.1007/s11892-011-0223-x. Review.
- Spraggs CF, Budde LR, Briley LP, Bing N, Cox CJ, King KS, Whittaker JC, Mooser VE, Preston AJ, Stein SH, Cardon LR. HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. J Clin Oncol. 2011 Feb 20;29(6):667-73. doi: 10.1200/JCO.2010.31.3197. Epub 2011 Jan 18.
- Tjon JM, van Bergen J, Koning F. Celiac disease: how complicated can it get? Immunogenetics. 2010 Oct;62(10):641-51. doi: 10.1007/s00251-010-0465-9. Epub 2010 Jul 27. Review.
- Uibo R, Tian Z, Gershwin ME. Celiac disease: a model disease for gene-environment interaction. Cell Mol Immunol. 2011 Mar;8(2):93-5. doi: 10.1038/cmi.2010.62. Epub 2011 Feb 14. Review.
- Xun YH, Guo JC, Shi WZ, Shi JP, Liu CL. [Association between HLA-DQA1 gene polymorphism and the outcomes of hepatitis B virus infection]. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi. 2009 Dec;23(6):430-3. Chinese.
- da Silva SA, Mazini PS, Reis PG, Sell AM, Tsuneto LT, Peixoto PR, Visentainer JE. HLA-DR and HLA-DQ alleles in patients from the south of Brazil: markers for leprosy susceptibility and resistance. BMC Infect Dis. 2009 Aug 22;9:134. doi: 10.1186/1471-2334-9-134.
