Editing Coeliac disease (section)

===Genetics===
[[File:DQa2b5 da gliadin.JPG|thumb|DQ α<sup>5</sup>-β<sup>2</sup> -binding cleft with a deamidated gliadin peptide (yellow), modified from {{PDB|1S9V}}<ref>{{Cite journal |vauthors=Kim C, Quarsten H, Bergseng E, Khosla C, Sollid L |title=Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease |journal=Proc Natl Acad Sci USA |volume=101 |issue=12 |pages=4175–9 |year=2004 |pmid=15020763 |doi=10.1073/pnas.0306885101 |pmc=384714 |bibcode=2004PNAS..101.4175K |doi-access=free}}</ref>]]
The vast majority of people with coeliac have one of two types (out of seven) of the [[HLA-DQ]] protein.<ref name="pmid17785484">{{cite journal |vauthors=Hadithi M, von Blomberg BM, Crusius JB, Bloemena E, Kostense PJ, Meijer JW, Mulder CJ, Stehouwer CD, Peña AS |title=Accuracy of serologic tests and HLA-DQ typing for diagnosing celiac disease |journal=Ann. Intern. Med. |volume=147 |issue=5 |pages=294–302 |year=2007 |pmid=17785484 |doi=10.7326/0003-4819-147-5-200709040-00003 }}</ref> HLA-DQ is part of the [[Major histocompatibility complex|MHC class II antigen-presenting receptor]] (also called the [[human leukocyte antigen]]) system and distinguishes cells between self and non-self for the purposes of the [[immune system]]. The two subunits of the HLA-DQ protein are encoded by the HLA-DQA1 and HLA-DQB1 genes, located on the short arm of [[chromosome 6]].<ref>{{Cite journal |last1=Morar |first1=R. |last2=Duarte |first2=R. |last3=Wadee |first3=A. A. |last4=Feldman |first4=C. |date=2022-12-01 |title=HLA class I and class II antigens in sarcoidosis |url=https://pubmed.ncbi.nlm.nih.gov/36472318 |journal=South African Medical Journal = Suid-Afrikaanse Tydskrif vir Geneeskunde |volume=112 |issue=12 |pages=904–910 |doi=10.7196/SAMJ.2022.v112i12.16586 |doi-broken-date=7 May 2025 |issn=2078-5135 |pmid=36472318}}</ref>

There are seven HLA-DQ variants (DQ2 and DQ4–DQ9). Over 95% of people with coeliac have the isoform of DQ2 or DQ8, which is inherited in families. The reason these genes produce an increase in the risk of coeliac disease is that the receptors formed by these genes bind to gliadin peptides more tightly than other forms of the antigen-presenting receptor. Therefore, these forms of the receptor are more likely to activate [[T cell|T lymphocytes]] and initiate the autoimmune process.<ref name=VanHeelWest/>

[[File:HLA.svg|upright=0.9|thumb|HLA region of chromosome 6]]
Most people with coeliac bear a two-gene HLA-DQ2 [[haplotype]] referred to as [[HLA-DQ2#DQ2.5|DQ2.5 haplotype]]. This haplotype is composed of two adjacent gene [[allele]]s, DQA1*0501 and [[HLA-DQ2#DQB1*0201|DQB1*0201]], which encode the two subunits, DQ α<sup>5</sup> and DQ β<sup>2</sup>. In most individuals, this DQ2.5 isoform is encoded by one of two chromosomes 6 inherited from parents (DQ2.5cis). Most coeliacs inherit only one copy of this DQ2.5 haplotype, while some inherit it from ''both'' parents; the latter are especially at risk for coeliac disease as well as being more susceptible to severe complications.<ref name="pmid17190762">{{cite journal |vauthors=Jores RD, Frau F, Cucca F, Grazia Clemente M, Orrù S, Rais M, De Virgiliis S, Congia M |title=HLA-DQB1*0201 homozygosis predisposes to severe intestinal damage in celiac disease |journal=Scand. J. Gastroenterol. |volume=42 |issue=1 |pages=48–53 |year=2007 |pmid=17190762 |doi=10.1080/00365520600789859}}</ref>

Some individuals inherit DQ2.5 from one parent and an additional portion of the haplotype (either DQB1*02 or DQA1*05) from the other parent, increasing risk. Less commonly, some individuals inherit the DQA1*05 allele from one parent and the DQB1*02 from the other parent (DQ2.5trans) (called a trans-haplotype association), and these individuals are at similar risk for coeliac disease as those with a single DQ2.5-bearing chromosome 6, but in this instance, the disease tends not to be familial. Among the 6% of European coeliacs that do not have DQ2.5 (cis or trans) or DQ8 (encoded by the haplotype DQA1*03:DQB1*0302), 4% have the [[HLA-DQ2#DQ2.2 and gluten|DQ2.2]] isoform, and the remaining 2% lack DQ2 or DQ8.<ref name="pmid12651074">{{cite journal |vauthors=Karell K, Louka AS, Moodie SJ, Ascher H, Clot F, Greco L, Ciclitira PJ, Sollid LM, Partanen J |title=HLA types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer: results from the European Genetics Cluster on Celiac Disease |journal=Hum. Immunol. |volume=64 |issue=4 |pages=469–77 |year=2003 |pmid=12651074 |doi=10.1016/S0198-8859(03)00027-2}}</ref>

The frequency of these genes varies geographically. DQ2.5 has high frequency in peoples of North and Western Europe ([[Basque Country (greater region)|Basque Country]] and Ireland<ref>{{cite journal |vauthors=Michalski JP, McCombs CC, Arai T, Elston RC, Cao T, McCarthy CF, Stevens FM |title=HLA-DR, DQ genotypes of celiac disease patients and healthy subjects from the West of Ireland |journal=Tissue Antigens |volume=47 |issue=2 |pages=127–33 |year=1996 |pmid=8851726 |doi=10.1111/j.1399-0039.1996.tb02525.x}}</ref> with highest frequencies) and portions of Africa and is associated with disease in India,<ref>{{cite journal |vauthors=Kaur G, Sarkar N, Bhatnagar S, Kumar S, Rapthap CC, Bhan MK, Mehra NK |title=Pediatric celiac disease in India is associated with multiple DR3-DQ2 haplotypes |journal=Hum. Immunol. |volume=63 |issue=8 |pages=677–82 |year=2002 |pmid=12121676 |doi=10.1016/S0198-8859(02)00413-5}}</ref> but it is not found along portions of the West Pacific rim. DQ8 has a wider global distribution than DQ2.5 and is particularly common in South and Central America; up to 90% of individuals in certain Amerindian populations carry DQ8 and thus may display the coeliac [[phenotype]].<ref>{{cite journal |vauthors=Layrisse Z, Guedez Y, Domínguez E, Paz N, Montagnani S, Matos M, Herrera F, Ogando V, Balbas O, Rodríguez-Larralde A |title=Extended HLA haplotypes in a Carib Amerindian population: the Yucpa of the Perija Range |journal=Hum Immunol |volume=62 |issue=9 |pages=992–1000 |year=2001 |pmid=11543901 |doi=10.1016/S0198-8859(01)00297-X}}</ref>

Other genetic factors have been repeatedly reported in coeliac disease; however, involvement in disease has variable geographic recognition. Only the HLA-DQ loci show a consistent involvement over the global population.<ref name="Dubois2010">{{cite journal |vauthors=Dubois PC, Trynka G, Franke L, Hunt KA, Romanos J, Curtotti A, Zhernakova A, Heap GA, Adány R, Aromaa A, Bardella MT, van den Berg LH, Bockett NA, de la Concha EG, Dema B, Fehrmann RS, Fernández-Arquero M, Fiatal S, Grandone E, Green PM, Groen HJ, Gwilliam R, Houwen RH, Hunt SE, Kaukinen K, Kelleher D, Korponay-Szabo I, Kurppa K, MacMathuna P, Mäki M, Mazzilli MC, McCann OT, Mearin ML, Mein CA, Mirza MM, Mistry V, Mora B, Morley KI, Mulder CJ, Murray JA, Núñez C, Oosterom E, Ophoff RA, Polanco I, Peltonen L, Platteel M, Rybak A, Salomaa V, Schweizer JJ, Sperandeo MP, Tack GJ, Turner G, Veldink JH, Verbeek WH, Weersma RK, Wolters VM, Urcelay E, Cukrowska B, Greco L, Neuhausen SL, McManus R, Barisani D, Deloukas P, Barrett JC, Saavalainen P, Wijmenga C, van Heel DA |title=Multiple common variants for celiac disease influencing immune gene expression |journal=Nature Genetics |volume=42 |issue=4 |pages=295–302 |year=2010 |pmid=20190752 |pmc=2847618 |doi=10.1038/ng.543}}</ref> Many of the loci detected have been found in association with other autoimmune diseases. One locus, the [[LPP (gene)|LPP]] or lipoma-preferred partner gene, is involved in the adhesion of extracellular matrix to the cell surface, and a minor variant ([[Single nucleotide polymorphism|SNP]]=rs1464510) increases the risk of disease by approximately 30%. This gene strongly associates with coeliac disease ([[Probability#Relation to randomness|p]] < 10<sup>−39</sup>) in samples taken from a broad area of Europe and the US.<ref name="Dubois2010"/>

The prevalence of coeliac disease genotypes in the modern population is not completely understood. Given the characteristics of the disease and its apparent strong heritability, it would normally be expected that the genotypes would undergo negative selection and to be absent in societies where agriculture has been practised the longest (compare with a similar condition, [[lactose intolerance]], which has been negatively selected so strongly that its prevalence went from ~100% in ancestral populations to less than 5% in some European countries). This expectation was first proposed by Simoons (1981).<ref>{{cite book |title=Food, nutrition, and evolution: food as an environmental factor in the genesis of human variability | vauthors = Walcher DN, Kretchmer N |pages=179–199 |publisher=Papers presented at the International Congress of the International Organization for the Study of Human Development, Masson Pub. USA |year=1981 |isbn=978-0-89352-158-5}}</ref> By now, however, it is apparent that this is not the case; on the contrary, there is evidence of ''positive'' selection in coeliac disease genotypes. It is suspected that some of them may have been beneficial by providing protection against bacterial infections.<ref>{{cite journal |title=Where Is Celiac Disease Coming From and Why? |vauthors=Catassi C |journal=[[Journal of Pediatric Gastroenterology & Nutrition]] |year=2005 |doi=10.1097/01.MPG.0000151650.03929.D5 |pmid=15735480 |volume=40 |issue=3 |pages=279–282|doi-access=free }}</ref><ref name="pmid20560212">{{cite journal |vauthors=Zhernakova A, Elbers CC, Ferwerda B, Romanos J, Trynka G, Dubois PC, de Kovel CG, Franke L, Oosting M, Barisani D, Bardella MT, Joosten LA, Saavalainen P, van Heel DA, Catassi C, Netea MG, Wijmenga C |title=Evolutionary and functional analysis of celiac risk loci reveals SH2B3 as a protective factor against bacterial infection |journal=[[American Journal of Human Genetics]] |volume=86 |issue=6 |pages=970–7 |year=2010 |pmid=20560212 |pmc=3032060 |doi=10.1016/j.ajhg.2010.05.004}}</ref>