An immune reaction to gluten that damages the small intestine. Nearly everyone who has it carries particular HLA types — and so do a third of people who do not, which is exactly why the genetics rules the disease out rather than in.
Solid lines are connections this site curates. Dashed lines mean the two ends share a research paper — worth knowing, and not a claim that one explains the other.
Celiac disease is an immune reaction to gluten, a protein in wheat, barley and rye. In people who have it, eating gluten damages the lining of the small intestine, which impairs absorption and can cause diarrhoea, weight loss, anaemia, fatigue, bone problems and, in children, poor growth. Many people have subtler symptoms or none at the time of diagnosis.
Almost everyone with celiac disease carries HLA-DQ2 or HLA-DQ8 — immune types that determine which fragments of gluten the immune system can be shown. Without one of them the disease is very unlikely.
But roughly a third of the general population carries them too and never develops it. So the test has a specific and limited use: it is good at ruling the disease out, and nearly useless for ruling it in. That asymmetry is the whole clinical value of celiac genetics, and it is why a consumer report saying "you carry DQ2" is not a diagnosis of anything.
rs17810546 sits near IL12A and comes from the wave of work that mapped the non-HLA part of the disease. That study genotyped 1,020 of the most strongly associated non-HLA markers in 1,643 further cases and 3,406 controls and, combined with its own earlier scan, identified seven previously unknown risk regions — most of them genes controlling immune responses, including CCR3, IL12A, IL18RAP, RGS1, SH2B3 and TAGAP.
These positions add small amounts of risk on top of HLA. None of them is diagnostic.
The same study noted that type 1 diabetes and celiac disease share risk regions: HLA-DQ, IL2-IL21, CCR3 and SH2B3. That is not a coincidence of statistics — the two diseases co-occur more often than chance, and people with type 1 diabetes are screened for celiac disease in many health systems for exactly this reason.
This is the practical warning worth carrying away. Diagnosis relies on antibodies produced in response to gluten, and often a biopsy showing the damage. If gluten has already been removed from the diet, both can normalise and the diagnosis becomes hard to make — sometimes requiring a deliberate return to eating gluten for weeks. If celiac disease is suspected, get tested first and change the diet afterwards.
HLA. Celiac disease requires HLA-DQ2 (DQA1*05/DQB1*02) or HLA-DQ8 (DQA1*03/DQB1*03:02) in nearly all cases; these molecules present deamidated gluten peptides to CD4+ T cells. Population carriage is high — on the order of a third in European-ancestry populations — so HLA typing has high negative predictive value and low positive predictive value, and is used clinically to exclude the diagnosis in ambiguous cases rather than to establish it.
Non-HLA loci. The 2008 follow-up genotyped 1,020 of the most strongly associated non-HLA markers from an earlier GWAS in 1,643 additional cases and 3,406 controls; joint analysis with the original scan (767 cases, 1,422 controls) identified seven previously unknown risk regions at P < 5 x 10-7, six harbouring immune-response genes: CCR3, IL12A, IL18RAP, RGS1, SH2B3 (non-synonymous rs3184504) and TAGAP. Whole-blood IL18RAP mRNA expression correlated with genotype. Shared risk regions with type 1 diabetes include HLA-DQ, IL2-IL21, CCR3 and SH2B3.
Diagnosis. Serology — tissue transglutaminase IgA with total IgA, or endomysial antibodies — is the entry point, with duodenal biopsy confirming villous atrophy in most adult pathways; some paediatric guidelines allow diagnosis on high-titre serology plus HLA without biopsy. All of this requires gluten in the diet at the time of testing. Management is a strict lifelong gluten-free diet with monitoring of adherence, nutritional status and antibody titres.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Celiac Disease comes down to these specific, well-studied positions — not a diagnosis.
Almost certainly not on that basis alone. About a third of people carry DQ2 or DQ8 and never develop it. The genetics is good at ruling the disease out and poor at ruling it in — which is precisely how clinicians use it.
No — this is the one practical warning on this page. The blood tests and the biopsy both depend on the immune reaction to gluten being active. Removing gluten first can make the diagnosis impossible to confirm without weeks of deliberately eating it again.
Because the two diseases share risk regions — HLA-DQ, IL2-IL21, CCR3 and SH2B3 — and occur together more often than chance. That is why people with type 1 diabetes are screened for celiac disease in many health systems.
Free to reuse. This page's text is original writing from freely-available research, licensed CC BY 4.0 — reuse it, including commercially, with attribution to MyGeneLog. It's general research-derived information, not medical advice or a diagnosis — see Terms of Use.