HLA-DQ2
Encyclopedia
HLA-DQ2 is a serotype
group within HLA-DQ
(DQ) serotyping system. The serotype is determined by the antibody recognition of β2 subset of DQ β-chains. The β-chain of DQ is encoded by HLA-DQB1
locus and DQ2 are encoded by the HLA-DQB1*02 allele group. This group currently contains two common alleles, DQB1*0201 and DQB1*0202. HLA-DQ2 and HLA-DQB1*02 are almost synonymous in meaning. DQ2 β-chains combine with α-chains, encoded by genetically linked HLA-DQA1
alleles, to form the cis-haplotype isoforms. These isoforms, nicknamed DQ2.2 and DQ2.5, are also encoded by the DQA1*0201 and DQA1*0501 genes, respectively.
DQ2 is most common in Western Europe
, North and West Africa
. Highest frequencies are observed in parts of Spain
and Ireland
; this distribution correlates with the frequency of two of the most prevalent autoimmune disease
s. There is also an increase in DQB1*0201 in Central Asia
, peaking in Kazakhstan
and declining slowly east to west into China
and finally Southeast Asia
. DQA1*0501 : DQB1*0201. DQ2.5 is one of the most predisposing factors for autoimmune disease.
DQ2.5 is encoded, often, by a haplotype associated with a large number of diseases. This haplotype, HLA A1-B8-DR3-DQ2
, is associated with diseases in which HLA-DQ2 has suspect involvement. Direct involvement of DQ2 is certain in coeliac disease
.
Serotyping efficiency. The serotyping efficiency of HLA-DQ2 is among the highest of the
antisera. DQ2 antibodies can be used to effectively type DQ2 bearing individuals, however antibody may detect DQB1*0303.
, with DRB1*03 it becomes part of the DR3-DQ2
(DR-DQ) serologically
defined haplotype. With DQA1*0501 the allele is most frequently found in coeliac disease
. With DR3 this DQ2 has the second strongest linkage to Type 1 diabetes, and when paired with HLA-DQ8
is the most abundant phenotype found in late onset, "Type1-Type2" diabetes mellitus type 1
. As the incidence of coeliac disease is about 1% this allele is associated with more autoimmune disease relative to any other DQ haplotype.
There are ambiguities regarding DQB1*0201 in the literature, some low resolution typing kits detect *0202 as *0201 and are presented as *0201 in the literature without distinction. DQB1*0201 in Europe is frequently found in the HLA A1-B8-DR3-DQ2
haplotype.
DQ2.5 haplotype is created by close genetic linkage of two alleles, written as a haplotype, DQA1*0501:DQB1*0201.
The haplotype encodes DQ2.5cis isoform, referring to the cis arrangement
of the DQA1*0501 and DQB1*0201 on the same variant of chromosome 6. The isoform can also be encoded trans-haplotype (between two sister chromosomes) forming the DQ2.5trans isoform. This isoform occurs when a person has the DQ7.5/DQ2.2 phenotype
.
DQ2.5 and the linked DR3 are associated with probably the greatest frequency of autoimmune occurrence relative to any other haplotypes. The haplotype is positively associated with coeliac disease
, dermatitis herpetiformis
, juvenile diabetes
, Lambert-Eaton myasthenic syndrome
(LEMS), Sjögren's syndrome
, and autoimmune hepatitis
(although significant proportion of the risk is secondary to coeliac disease). DR3 and/or DQ2.5 are linked to the following diseases: Moreen's ulceration, "bout onset" multiple sclerosis, Grave's disease and systemic lupus erythematosus
.
are associated with this haplotype, and some disease causing gliadins are presented by DQ2.2. The haplotype is found at high frequencies in the Mediterranean and West Africa
. The Eurasia
n geographic distribution of DQ2.2 is slightly greater than DQ2.5. Compared to DQ2.5, the freqeuncy in Sardinia
is low, but in Iberia
it is high reaching a maximum frequency of ~30% in Northern Iberia, and half that in the British Ilses. It extends along the Mediterranean and Africa at relatively high frequency and is found in high frequencies in some Central Asia
n, Mongolians
, and Han Chinese
. It does not appear to have an indigenous presence in the West Pacific Rim or the New World and DQ2.2 presence in Southeast Asia
and Indonesia
is likely the result of gene flow from India
and China
in post-neolithic
times. The haplotype shows considerable diversity in Africa and this has translated to Iberia with 2 addition haplotypes, DQA1*0303:DQB1*0202 and DR7:DQA1*0201:DQB1*0303. The expansion of DQ2.2 into Europe appears to have been slightly later or biased by some constriction between Iberia and the rest of the continent.
haplotype. The isoform can also be produced by phenotypes were one haplotype is DQ4.3, DQ7.3, DQ8.1, DQ9.3 and the other haplotype is DQ2.2 or DQ2.5. Therefore the haplotype encoded receptor is a DQ2.3cis isoform which is genetically linked to DR7
By serology DR7-DQ2 cannot discriminate DQ2.2 from DQ2.3 haplotypes, and therefore DQA1 typing is required.
The relationship of DQ2 and coeliac disease, however, is complex because there are multiple DQ2 isoforms. The DQ α5β2 (DQ2.5) isoform is strongly associated with CD. This isoform is partially encoded by the DQB1*02 genes in HLA-DQ2 positive individuals. DQB1*0201 is genetically linked to DQA1*0501 forming the DQ2.5 haplotype that encodes both α5 and β2 subunits. The DQ2.5 haplotype confers the single highest genetic risk for disease, however comparable risk can also come from very similar alleles on different haplotypes.
The immunodominant site for DQ2.5 is on α2-gliadin. The site is a protease resistant 33mer that has 6 overlapping DQ2.5 restricted epitopes. This creates very strong binding of T-cells for DQ2.5-33mer complexes. DQ2.5 binds gliadin, but the binding is sensitive to deamidation caused by tissue transglutaminase
. In almost all case the highest affinity sites of gluten are derived by deamidation. The HLA DQB1*0202 and its linked DQA1* alleles (the DQ2.2 haplotype) do not produce the α5 subunit. While the DQ2.2 heterodimer cannot effectively present α-2 gliadin, it can present other gliadins. In at least 1% of coeliacs DQ2.2 confers adaptive immunity to gliadin permitting coeliac disease.
The highest risk for coeliac disease is in Western Ireland
and overlaps one of three global nodes of the DQ2.5 haplotype in Western Europe. The DQ2.5 haplotype is linked to DR3 and DR3 is not linked to DQ2.2. Therefore, using either serotyping or genotyping, DQ2.5 can be distinquished from DQ2.2 or DQ2.3. The refined studies of risk and immunology suggest that all DQ2 can mediate coeliac disease, but that DQ2.5 is the primary genetic risk factor. A genome wide survey of markers linked to CD, reveals that highest linkage is for a marker within the DQA1*0501 allele of the DQ2.5 haplotype. The association of DQB1*0201 is almost as high. Greatly elevating risk is the ability of the DQ2.5 haplotype encoded isoforms to increase abundance on the cell surface in DQ2.5 double homozygotes. While most people can form two or four different isoforms of DQ. Double homozygotes (of DQA1 and DQB1) can only form DQ2.5cis. This occurs when a person inherits a DQ2.5cis bearing chromosome from each parent. While the frequency of DQ2.5 haplotype is only 4 times higher than the general population, the number of DQ2.5 homozygotes is 10 to 20 times higher than the general population.
Multiple copies of the DQ2.5 haplotype do not cause apparent increases of severity, DQ2.5/DQ2 increases risk of life threatening complications and more severe histological findings. Of the approximately 90% of coeliacs that bear the DQ2.5 isoform only 4% produce DQ2.5 by pair alleles from different haplotypes, this isoform is called DQ2.5trans and differs slightly, one amino acid, from DQ2.5cis.
With the DQ2.2 isoform (DQ α2-β2), polar substitutions (amino acid
s such as asparagine
, glutamine
, glycine
, serine
, and threonine
) are not bound well to DQ2.2. The gliadin peptides that bind DQ2.5 are enriched in the amino acid glutamine. Since the β2 provides half the structural information for gluten presentation, other haplotypes might provide the rest. Such haplotypes are known to exist and these haplotypes confer different risk on DQ2.2. DQ2.2 however can present less pathogenic epitopes such as proteolytic peptides of gamma-gliadin. This appears to be the mediator of disease in 1% of coeliacs that are homozygotes for DQ2.2.
The DQ2.2/DQ7.5 phenotype. Also called DQ2.5trans in some publications. DQ7.5 haplotype is the DQA1*0505:DQB1*0301 haplotype. The DQA1*0505 allele is similar to the DQA1*0501 allele of the DQ2.5 haplotype. When DQA1*0505 or DQA1*0501 gene products are processed to the cell surface they become α5. The gene products of DQB1*0202 and DQB1*0201 are almost identical and function similarly. As a result one isoform produced by the phenotype of two haplotypes, DQ2.2/DQ7.5, is HLA DQ α5β2. A small percentage of coeliac disease patients have this haplotype. The other 3 isoforms are α2β2(DQ2.2), α2β7 (DQ7.2), and α5β7 (DQ7.5).
DQ2.2/DQ2.5. Random pairing of heterologous DQ alpha and beta isoforms produces 4 different isoforms at 1:1:1:1 ratios. The fraction of DQ2.5 can be 25%. In the case of this phenotype
, HLA DQB1*02 alleles are encoded by both chromosome 6 (maternal and paternal derived). Since DQB1*0201 and *0202 function similarly, only two types of isoforms can be produced and the ratio becomes 1:1. This increases the random number of isoforms from 25% to 50% that can cause disease, and as a result increases risk of celiac disease and probably increases risk of severe complications such as refractory celiac disease and lymphoma. These partial homozygotes in the Dutch CD population are approximately 20%, as compared to a randomly expected 3% indicating a sevenfold enrichment.
DQ2.2/DQ8. Among DQ8 positive celiacs without DQ2.5, 1/3 bear DQ2.2 haplotype, about 3 fold higher than random expectation.
DQ2.2/DQ2.2 DQ2.2 homozygotes represent about 1.1% of the celiac population, this is not high relative to controls, but it is very high with the DQ2.5(isoform)-,DQ8-,DQ2+ cohort at 30%. The random expectation is much lower. This fraction of coeliacs is important because they can only produce α2β2 and are useful for determining the role of DQ2.2 in coeliac disease.
(T1D) has a high association with DQ2.5 and there appears to be link between GSE and early onset male T1D. Anti-tTG antibodies are found elevated in a one-third of T1D patients and there are indicators that Triticeae may be involved but the gluten protein is a type of globulin (Glb1). Recent studies indicate a combination of DQ2.5 and DQ8 (both acid peptide presenters) greatly increase the risk of adult onset Type 1 Diabetes and ambiguous type I/II Diabetes. HLA-DR3
plays a prominent role in autoimmune diabetes. However, DQ2 presence with DR3 decreases the age of onset and the severity of the autoimmune disorder.
Serotype
Serotype or serovar refers to distinct variations within a subspecies of bacteria or viruses. These microorganisms, viruses, or cells are classified together based on their cell surface antigens...
group within HLA-DQ
HLA-DQ
HLA-DQ is a cell surface receptor type protein found on antigen presenting cells. DQ is an αβ heterodimer of the MHC Class II type. The α and β chains are encoded by HLA-DQA1 and HLA-DQB1, respectively. These two loci are adjacent to each other on chromosome 6p21.3. Both the α-chain and β-chain...
(DQ) serotyping system. The serotype is determined by the antibody recognition of β2 subset of DQ β-chains. The β-chain of DQ is encoded by HLA-DQB1
HLA-DQB1
Major histocompatibility complex, class II, DQ beta 1, also known as HLA-DQB1, is a human gene and also denotes the genetic locus that contains this gene...
locus and DQ2 are encoded by the HLA-DQB1*02 allele group. This group currently contains two common alleles, DQB1*0201 and DQB1*0202. HLA-DQ2 and HLA-DQB1*02 are almost synonymous in meaning. DQ2 β-chains combine with α-chains, encoded by genetically linked HLA-DQA1
HLA-DQA1
Major histocompatibility complex, class II, DQ alpha 1, also known as HLA-DQA1, is a human gene present on short arm of chromosome 6 and also denotes the genetic locus which contains this gene...
alleles, to form the cis-haplotype isoforms. These isoforms, nicknamed DQ2.2 and DQ2.5, are also encoded by the DQA1*0201 and DQA1*0501 genes, respectively.
DQ2 is most common in Western Europe
Western Europe
Western Europe is a loose term for the collection of countries in the western most region of the European continents, though this definition is context-dependent and carries cultural and political connotations. One definition describes Western Europe as a geographic entity—the region lying in the...
, North and West Africa
West Africa
West Africa or Western Africa is the westernmost region of the African continent. Geopolitically, the UN definition of Western Africa includes the following 16 countries and an area of approximately 5 million square km:-Flags of West Africa:...
. Highest frequencies are observed in parts of Spain
Spain
Spain , officially the Kingdom of Spain languages]] under the European Charter for Regional or Minority Languages. In each of these, Spain's official name is as follows:;;;;;;), is a country and member state of the European Union located in southwestern Europe on the Iberian Peninsula...
and Ireland
Ireland
Ireland is an island to the northwest of continental Europe. It is the third-largest island in Europe and the twentieth-largest island on Earth...
; this distribution correlates with the frequency of two of the most prevalent autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
s. There is also an increase in DQB1*0201 in Central Asia
Central Asia
Central Asia is a core region of the Asian continent from the Caspian Sea in the west, China in the east, Afghanistan in the south, and Russia in the north...
, peaking in Kazakhstan
Kazakhstan
Kazakhstan , officially the Republic of Kazakhstan, is a transcontinental country in Central Asia and Eastern Europe. Ranked as the ninth largest country in the world, it is also the world's largest landlocked country; its territory of is greater than Western Europe...
and declining slowly east to west into China
China
Chinese civilization may refer to:* China for more general discussion of the country.* Chinese culture* Greater China, the transnational community of ethnic Chinese.* History of China* Sinosphere, the area historically affected by Chinese culture...
and finally Southeast Asia
Southeast Asia
Southeast Asia, South-East Asia, South East Asia or Southeastern Asia is a subregion of Asia, consisting of the countries that are geographically south of China, east of India, west of New Guinea and north of Australia. The region lies on the intersection of geological plates, with heavy seismic...
. DQA1*0501 : DQB1*0201. DQ2.5 is one of the most predisposing factors for autoimmune disease.
DQ2.5 is encoded, often, by a haplotype associated with a large number of diseases. This haplotype, HLA A1-B8-DR3-DQ2
HLA A1-B8-DR3-DQ2
HLA A1-B8-DR3-DQ2 haplotype is a multigene haplotype that covers a majority of the human major histocompatibility complex on chromosome 6...
, is associated with diseases in which HLA-DQ2 has suspect involvement. Direct involvement of DQ2 is certain in coeliac disease
Coeliac disease
Coeliac disease , is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward...
.
Serology
| DQB1* | DQ2 | Sample |
| allele | % | size (N) |
| 98 | 9175 | |
| 87 | 656 | |
| DQ | DQ | DQ | Freq | |||||
|---|---|---|---|---|---|---|---|---|
| Serotype | cis-isoform | Subtype | A1 | B1 | % | rank | ||
| DQ2 | α5-β2 | 2.5 | 0501♣ | 0201 | 13. | 16 | 2nd | |
| α2-β2 | 2.2 | 0201 | 0202 | 11. | 08 | 3rd | ||
| α3-β2 | 2.3 | 0302♠ | 0202 | 0. | 08 | |||
| ♠DQA1*0302 & *0303 not reolved; ♣DQB1*0501 & *0505 , and some *0303 are resolvable by haplotype |
||||||||
Serotyping efficiency. The serotyping efficiency of HLA-DQ2 is among the highest of the
antisera. DQ2 antibodies can be used to effectively type DQ2 bearing individuals, however antibody may detect DQB1*0303.
DQB1*0201
The DQB1*0201 allele is genetically linked to DQA1*0501 and DRB1*03. With DQA1*0501 it forms the DQ2.5cis encoding haplotypeHaplotype
A haplotype in genetics is a combination of alleles at adjacent locations on the chromosome that are transmitted together...
, with DRB1*03 it becomes part of the DR3-DQ2
HLA DR3-DQ2
HLA DR3-DQ2 is double serotype that specifically recognizes cells from individuals who carry a multigene HLA DR, DQ haplotype.Certain HLA DR and DQ genes have known involvementin autoimmune diseases. DR3-DQ2, a multigene...
(DR-DQ) serologically
Serology
Serology is the scientific study of blood serum and other bodily fluids. In practice, the term usually refers to the diagnostic identification of antibodies in the serum...
defined haplotype. With DQA1*0501 the allele is most frequently found in coeliac disease
Coeliac disease
Coeliac disease , is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward...
. With DR3 this DQ2 has the second strongest linkage to Type 1 diabetes, and when paired with HLA-DQ8
HLA-DQ8
HLA-DQ8 is a human leukocyte antigen serotype within the HLA-DQ serotype group. DQ8 is a split antigen of the DQ3 broad antigen. DQ8 is determined by the antibody recognition of β8 and this generally detects the gene product of DQB1*0302....
is the most abundant phenotype found in late onset, "Type1-Type2" diabetes mellitus type 1
Diabetes mellitus type 1
Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...
. As the incidence of coeliac disease is about 1% this allele is associated with more autoimmune disease relative to any other DQ haplotype.
There are ambiguities regarding DQB1*0201 in the literature, some low resolution typing kits detect *0202 as *0201 and are presented as *0201 in the literature without distinction. DQB1*0201 in Europe is frequently found in the HLA A1-B8-DR3-DQ2
HLA A1-B8-DR3-DQ2
HLA A1-B8-DR3-DQ2 haplotype is a multigene haplotype that covers a majority of the human major histocompatibility complex on chromosome 6...
haplotype.
DQB1*0202
This allele is linked to several DQA1* alleles, the linkage with DQA1*0201 forms the DQ2.2 haplotype and linkage with DQA1*0303 forms the DQ2.3 haplotype. In Africa the DQA1*0501 haplotype is also linked rarely to DQB1*0202 and may represent that ancestral form of the DQ2.5 haplotype.DQ2 isoforms and DQ2 haplotypes
EWLINE
|
DQ2.5
DQ2.5 refers to either a protein isoform and a genetic (chromosomal) haplotype. DQ2.5 isoform or heterodimer is shorthand for the cell surface receptor HLA-DQ α5β2. Frequently called 'the DQ2 heterodimer', the DQ2.5 isoform is actually one of two common DQ heterodimers, the other being DQ2.2.DQ2.5 haplotype is created by close genetic linkage of two alleles, written as a haplotype, DQA1*0501:DQB1*0201.
The haplotype encodes DQ2.5cis isoform, referring to the cis arrangement
of the DQA1*0501 and DQB1*0201 on the same variant of chromosome 6. The isoform can also be encoded trans-haplotype (between two sister chromosomes) forming the DQ2.5trans isoform. This isoform occurs when a person has the DQ7.5/DQ2.2 phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
.
DQ2.5 and the linked DR3 are associated with probably the greatest frequency of autoimmune occurrence relative to any other haplotypes. The haplotype is positively associated with coeliac disease
Coeliac disease
Coeliac disease , is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward...
, dermatitis herpetiformis
Dermatitis herpetiformis
Dermatitis herpetiformis , or Duhring's disease,Freedberg, et al. . Fitzpatrick's Dermatology in General Medicine. . McGraw-Hill. ISBN 0-07-138076-0. is a chronic blistering skin condition, characterised by blisters filled with a watery fluid...
, juvenile diabetes
Diabetes mellitus type 1
Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...
, Lambert-Eaton myasthenic syndrome
Lambert-Eaton myasthenic syndrome
Lambert–Eaton myasthenic syndrome is a rare autoimmune disorder that is characterised by muscle weakness of the limbs...
(LEMS), Sjögren's syndrome
Sjögren's syndrome
Sjögren's syndrome , also known as "Mikulicz disease" and "Sicca syndrome", is a systemic autoimmune disease in which immune cells attack and destroy the exocrine glands that produce tears and saliva....
, and autoimmune hepatitis
Autoimmune hepatitis
Autoimmune Hepatitis is a disease of the liver that occurs when the body's immune system attacks cells of the liver. Anomalous presentation of human leukocyte antigen class II on the surface of hepatocytes, possibly due to genetic predisposition or acute liver infection, causes a cell-mediated...
(although significant proportion of the risk is secondary to coeliac disease). DR3 and/or DQ2.5 are linked to the following diseases: Moreen's ulceration, "bout onset" multiple sclerosis, Grave's disease and systemic lupus erythematosus
Systemic lupus erythematosus
Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
.
DQ2.2
DQ2.2 is shorthand for the DQ α2β2 heterodimeric isoform. The isoform is encoded almost exclusively by the DQA1*0201:DQB1*0202 haplotype. The haplotype is linked to DR7. A small percentage of coeliac diseaseCoeliac disease
Coeliac disease , is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward...
are associated with this haplotype, and some disease causing gliadins are presented by DQ2.2. The haplotype is found at high frequencies in the Mediterranean and West Africa
West Africa
West Africa or Western Africa is the westernmost region of the African continent. Geopolitically, the UN definition of Western Africa includes the following 16 countries and an area of approximately 5 million square km:-Flags of West Africa:...
. The Eurasia
Eurasia
Eurasia is a continent or supercontinent comprising the traditional continents of Europe and Asia ; covering about 52,990,000 km2 or about 10.6% of the Earth's surface located primarily in the eastern and northern hemispheres...
n geographic distribution of DQ2.2 is slightly greater than DQ2.5. Compared to DQ2.5, the freqeuncy in Sardinia
Sardinia
Sardinia is the second-largest island in the Mediterranean Sea . It is an autonomous region of Italy, and the nearest land masses are the French island of Corsica, the Italian Peninsula, Sicily, Tunisia and the Spanish Balearic Islands.The name Sardinia is from the pre-Roman noun *sard[],...
is low, but in Iberia
Iberian Peninsula
The Iberian Peninsula , sometimes called Iberia, is located in the extreme southwest of Europe and includes the modern-day sovereign states of Spain, Portugal and Andorra, as well as the British Overseas Territory of Gibraltar...
it is high reaching a maximum frequency of ~30% in Northern Iberia, and half that in the British Ilses. It extends along the Mediterranean and Africa at relatively high frequency and is found in high frequencies in some Central Asia
Central Asia
Central Asia is a core region of the Asian continent from the Caspian Sea in the west, China in the east, Afghanistan in the south, and Russia in the north...
n, Mongolians
Mongols
Mongols ) are a Central-East Asian ethnic group that lives mainly in the countries of Mongolia, China, and Russia. In China, ethnic Mongols can be found mainly in the central north region of China such as Inner Mongolia...
, and Han Chinese
Han Chinese
Han Chinese are an ethnic group native to China and are the largest single ethnic group in the world.Han Chinese constitute about 92% of the population of the People's Republic of China , 98% of the population of the Republic of China , 78% of the population of Singapore, and about 20% of the...
. It does not appear to have an indigenous presence in the West Pacific Rim or the New World and DQ2.2 presence in Southeast Asia
Southeast Asia
Southeast Asia, South-East Asia, South East Asia or Southeastern Asia is a subregion of Asia, consisting of the countries that are geographically south of China, east of India, west of New Guinea and north of Australia. The region lies on the intersection of geological plates, with heavy seismic...
and Indonesia
Indonesia
Indonesia , officially the Republic of Indonesia , is a country in Southeast Asia and Oceania. Indonesia is an archipelago comprising approximately 13,000 islands. It has 33 provinces with over 238 million people, and is the world's fourth most populous country. Indonesia is a republic, with an...
is likely the result of gene flow from India
India
India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...
and China
China
Chinese civilization may refer to:* China for more general discussion of the country.* Chinese culture* Greater China, the transnational community of ethnic Chinese.* History of China* Sinosphere, the area historically affected by Chinese culture...
in post-neolithic
Neolithic
The Neolithic Age, Era, or Period, or New Stone Age, was a period in the development of human technology, beginning about 9500 BC in some parts of the Middle East, and later in other parts of the world. It is traditionally considered as the last part of the Stone Age...
times. The haplotype shows considerable diversity in Africa and this has translated to Iberia with 2 addition haplotypes, DQA1*0303:DQB1*0202 and DR7:DQA1*0201:DQB1*0303. The expansion of DQ2.2 into Europe appears to have been slightly later or biased by some constriction between Iberia and the rest of the continent.
DQ2.3
DQ2.3 is shorthand for the DQ α3β2 heterodimeric isoform. The isoform is encoded by DQA1*0303:DQB1*0202haplotype. The isoform can also be produced by phenotypes were one haplotype is DQ4.3, DQ7.3, DQ8.1, DQ9.3 and the other haplotype is DQ2.2 or DQ2.5. Therefore the haplotype encoded receptor is a DQ2.3cis isoform which is genetically linked to DR7
By serology DR7-DQ2 cannot discriminate DQ2.2 from DQ2.3 haplotypes, and therefore DQA1 typing is required.
Other isoforms
DQ2 beta chains can pair with trans to other alpha chain. However there is no precedance in cis isoforms for DQ2,4,7,8, or 9 binding DQ1 (DQA1*01) alpha chains. DQA1*03, *05 chains process to near identical alpha chains. The *04 chain can potentially complex with DQ2 forming DQ2.4. In East Asia there is the possibility of DQ2.6 resulting from pairing with DQA1*0601.In coeliac disease
DQ2 represents the second highest risk factor for coeliac disease, the highest risk is a close family member with disease. Due to its link to coeliac disease, DQ2 has the highest association of any HLA serotype with autoimmune disease, close to 95% of all coeliacs have DQ2, of that 30% have 2 copies of DQ2. Of the DQ2 homozygotes who eat wheat, life long risk is between 20 and 40% for coeliac disease.The relationship of DQ2 and coeliac disease, however, is complex because there are multiple DQ2 isoforms. The DQ α5β2 (DQ2.5) isoform is strongly associated with CD. This isoform is partially encoded by the DQB1*02 genes in HLA-DQ2 positive individuals. DQB1*0201 is genetically linked to DQA1*0501 forming the DQ2.5 haplotype that encodes both α5 and β2 subunits. The DQ2.5 haplotype confers the single highest genetic risk for disease, however comparable risk can also come from very similar alleles on different haplotypes.
Tissue transglutaminase
Tissue transglutaminase is an enzyme of the transglutaminase family. Like other transglutaminases, it crosslinks proteins between an ε-amino group of a lysine residue and a γ-carboxamide group of glutamine residue, creating an inter- or intramolecular bond that is highly resistant to proteolysis...
. In almost all case the highest affinity sites of gluten are derived by deamidation. The HLA DQB1*0202 and its linked DQA1* alleles (the DQ2.2 haplotype) do not produce the α5 subunit. While the DQ2.2 heterodimer cannot effectively present α-2 gliadin, it can present other gliadins. In at least 1% of coeliacs DQ2.2 confers adaptive immunity to gliadin permitting coeliac disease.
DQ2.5 and gluten
As mentioned the DQA1*0501:DQB1*0201 haplotype produces DQ2.5cis which by frequency and efficiency in alpha-gliadin presentation is the major factor in adaptive immunity. The isoform, referred to frequently as the DQ2 heterodimer or DQ2 (DQA1*05:DQB1*02) and more recently DQ2.5 can be differentiated from responses from other DQ isoforms, including other DQ2. Specifically, that this DQ2 heterodimer is responsible for presenting the α2-gliadin that most effectively stimulates pathogenic T-cells.The highest risk for coeliac disease is in Western Ireland
Ireland
Ireland is an island to the northwest of continental Europe. It is the third-largest island in Europe and the twentieth-largest island on Earth...
and overlaps one of three global nodes of the DQ2.5 haplotype in Western Europe. The DQ2.5 haplotype is linked to DR3 and DR3 is not linked to DQ2.2. Therefore, using either serotyping or genotyping, DQ2.5 can be distinquished from DQ2.2 or DQ2.3. The refined studies of risk and immunology suggest that all DQ2 can mediate coeliac disease, but that DQ2.5 is the primary genetic risk factor. A genome wide survey of markers linked to CD, reveals that highest linkage is for a marker within the DQA1*0501 allele of the DQ2.5 haplotype. The association of DQB1*0201 is almost as high. Greatly elevating risk is the ability of the DQ2.5 haplotype encoded isoforms to increase abundance on the cell surface in DQ2.5 double homozygotes. While most people can form two or four different isoforms of DQ. Double homozygotes (of DQA1 and DQB1) can only form DQ2.5cis. This occurs when a person inherits a DQ2.5cis bearing chromosome from each parent. While the frequency of DQ2.5 haplotype is only 4 times higher than the general population, the number of DQ2.5 homozygotes is 10 to 20 times higher than the general population.
Multiple copies of the DQ2.5 haplotype do not cause apparent increases of severity, DQ2.5/DQ2 increases risk of life threatening complications and more severe histological findings. Of the approximately 90% of coeliacs that bear the DQ2.5 isoform only 4% produce DQ2.5 by pair alleles from different haplotypes, this isoform is called DQ2.5trans and differs slightly, one amino acid, from DQ2.5cis.
DQ2.2 and gluten
DQ2.2 does not produce all the necessary subunits to efficiently present the most pathogenic gluten proteins to the immune system.With the DQ2.2 isoform (DQ α2-β2), polar substitutions (amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s such as asparagine
Asparagine
Asparagine is one of the 20 most common natural amino acids on Earth. It has carboxamide as the side-chain's functional group. It is not an essential amino acid...
, glutamine
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
, glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
, serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
, and threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
) are not bound well to DQ2.2. The gliadin peptides that bind DQ2.5 are enriched in the amino acid glutamine. Since the β2 provides half the structural information for gluten presentation, other haplotypes might provide the rest. Such haplotypes are known to exist and these haplotypes confer different risk on DQ2.2. DQ2.2 however can present less pathogenic epitopes such as proteolytic peptides of gamma-gliadin. This appears to be the mediator of disease in 1% of coeliacs that are homozygotes for DQ2.2.
The DQ2.2/DQ7.5 phenotype. Also called DQ2.5trans in some publications. DQ7.5 haplotype is the DQA1*0505:DQB1*0301 haplotype. The DQA1*0505 allele is similar to the DQA1*0501 allele of the DQ2.5 haplotype. When DQA1*0505 or DQA1*0501 gene products are processed to the cell surface they become α5. The gene products of DQB1*0202 and DQB1*0201 are almost identical and function similarly. As a result one isoform produced by the phenotype of two haplotypes, DQ2.2/DQ7.5, is HLA DQ α5β2. A small percentage of coeliac disease patients have this haplotype. The other 3 isoforms are α2β2(DQ2.2), α2β7 (DQ7.2), and α5β7 (DQ7.5).
DQ2.2/DQ2.5. Random pairing of heterologous DQ alpha and beta isoforms produces 4 different isoforms at 1:1:1:1 ratios. The fraction of DQ2.5 can be 25%. In the case of this phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
, HLA DQB1*02 alleles are encoded by both chromosome 6 (maternal and paternal derived). Since DQB1*0201 and *0202 function similarly, only two types of isoforms can be produced and the ratio becomes 1:1. This increases the random number of isoforms from 25% to 50% that can cause disease, and as a result increases risk of celiac disease and probably increases risk of severe complications such as refractory celiac disease and lymphoma. These partial homozygotes in the Dutch CD population are approximately 20%, as compared to a randomly expected 3% indicating a sevenfold enrichment.
DQ2.2/DQ8. Among DQ8 positive celiacs without DQ2.5, 1/3 bear DQ2.2 haplotype, about 3 fold higher than random expectation.
DQ2.2/DQ2.2 DQ2.2 homozygotes represent about 1.1% of the celiac population, this is not high relative to controls, but it is very high with the DQ2.5(isoform)-,DQ8-,DQ2+ cohort at 30%. The random expectation is much lower. This fraction of coeliacs is important because they can only produce α2β2 and are useful for determining the role of DQ2.2 in coeliac disease.
Juvenile diabetes association
Juvenile diabetesDiabetes mellitus type 1
Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...
(T1D) has a high association with DQ2.5 and there appears to be link between GSE and early onset male T1D. Anti-tTG antibodies are found elevated in a one-third of T1D patients and there are indicators that Triticeae may be involved but the gluten protein is a type of globulin (Glb1). Recent studies indicate a combination of DQ2.5 and DQ8 (both acid peptide presenters) greatly increase the risk of adult onset Type 1 Diabetes and ambiguous type I/II Diabetes. HLA-DR3
HLA-DR3
HLA-DR3 is composed to the HLA-DR17 and HLA-DR18 split 'antigens' serotypes. DR3 is a component gene-allele of the AH8.1 haplotype in Northern and Western Europeans. Genes between B8 and DR3 on this haplotype are frequently associated with autoimmune disease....
plays a prominent role in autoimmune diabetes. However, DQ2 presence with DR3 decreases the age of onset and the severity of the autoimmune disorder.