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Mutations in the HLA Genes

Increased risk of developing Celiac Disease

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Production of HLA Protein

The HLA genes are located on chromosome 6, and produce the HLA protein. The HLA protein is a heterodimer composed of two chains: HLA-DQA1 (the HLA alpha chain) and HLA-DQB1 (the HLA beta chain). Two mutations in the HLA alpha chain (HLA-DQA1*0501 or *0505) in combination with two mutations in the HLA beta chain (HLA-DQB1*0201 or *0202) are present in 90-95% of patients with Celiac Disease. The heterodimer formed with two of these four mutations is called HLA-DQ2. Another mutation in the HLA beta chain (HLA-DQB1*0302) is associated with 5-10% of Celiac Disease cases. The heterodimer formed with this mutation is HLA-DQ8.

HLA-DQA1*0501

This allele, in combination with HLA-DQB1*0201, is the most common HLA-DQ2 haplotype. This haplotype (referred to as HLA-DQ2.5) is detected in the majority of Celiac Disease patients.

HLA-DQA1*0505

This allele is most often associated with HLA-DQB1*0301, a beta chain allele not associated with Celiac Disease (referred to as HLA-DQ7.5). However, HLA-DQA1*0505 is very similar to HLA-DQA1*0501. Therefore, if an individual also has the HLA-DQB1*0202 allele on their other HLA chromosome (haplotype HLA-DQ2.2), they will be at an increased risk of developing Celiac Disease.

HLA-DQB1*0201

This allele, in combination with HLA-DQA1*0501, is the most common HLA-DQ2 haplotype (haplotype DQ2.5). If an individual is homozygous for this allele, and also has either the HLA-DQA1*0501 or *0505 mutation, they have a five-fold greater risk of developing Celiac Disease than a person with a heterozygous beta chain. These individuals are also at an increased risk of experiencing severe complications of Celiac Disease and increased mucosa damage. An individual with only this mutation is rarely observed within Celiac Disease patients; therefore, possession of only this mutation is indicative of only a slightly increased risk of developing Celiac Disease.

HLA-DQB1*0202

The haplotype with the HLA-DQB1*0202 allele is referred to as DQ2.2. About 25% of Celiac Disease patients are homozygous for HLA-DQB1*0201 or *0202. If these individuals do not also have HLA-DQA1*0501 or *0505, they will most likely be homozygous for HLA-DQB1*0202; this occurs in approximately 1.1% of Celiac Disease patients. Patients that are homozygous for HLA-DQB1*0201 or *0202 and also have HLA-DQA1*0501 or *0505 tend to be at greatest risk for severe complications arising from Celiac Disease (these individuals have haplotype DQ2.5 and DQ2.2). An individual with only this mutation is rarely observed within Celiac Disease patients; therefore, possession of only this mutation is indicative of only a slightly increased risk of developing Celiac Disease.

HLA-DQB1*0302

This mutation is inherited in an autosomal dominant manner, and is always inherited with other HLA-DQA1*03 alleles due to linkage disequilibrium (usually HLA-DQA1*0301; this is haplotype DQ8). This means that an individual that inherits this mutation from only one of their parents is at an increased risk of developing Celiac Disease, but the risk is lower than individuals that have the DQ2 genotype. This mutation accounts for up to 10% of Celiac Disease cases, and is most frequent in Native Americans of Central America and tribes of Eastern America.