A fibro-inflammatory disease that can affect almost any organ, tied to a specific immune cell type and antibody. A Chinese study found 16 general susceptibility loci, mostly in immune-signalling regions; a separate Japanese study using whole-genome sequencing then found that one clinical subtype — Mikulicz's disease, which affects the salivary and lacrimal glands — has its own distinct genetics on top of the general ones.
IgG4-related disease (IgG4-RD) is an immune-mediated condition in which tissue becomes infiltrated with IgG4-positive plasma cells and a distinctive pattern of scarring (storiform fibrosis), usually alongside high blood levels of the IgG4 antibody. It can affect almost any organ — the pancreas, bile ducts, salivary and lacrimal glands, kidneys, and others — and was only recognized as a single, unified disease in the 2000s, having previously been diagnosed separately by whichever organ it happened to affect.
The first genome-wide association study of IgG4-RD in a Chinese Han population analysed 1,115 patients and 10,154 controls across two cohorts, using a Han-specific reference panel to resolve the HLA region in detail. It found 22 genome-wide-significant variants defining 16 distinct loci, replicated consistently across both cohorts. The strongest signal sits in the extended MHC region on chromosome 6 — the same broad region that carries much of human immune-response genetics — and a separate signal on chromosome 1 involves the Fc-gamma receptor gene family, receptors that bind antibodies like IgG4 directly and help decide how the immune system responds to them. Fine-mapping identified 6 independent HLA alleles, 2 amino-acid changes, and rs3888777 as signals independent of each other. The same variants were also linked to clinical features — serum IgG4 level, which organs were involved, clinical subtype, and risk of relapse — extending the finding past who develops the disease into what it looks like once someone has it.
A separate whole-genome-sequencing study in a Japanese population took a different technical approach: rather than array-based genotyping and imputation, it sequenced the whole genome directly, specifically because the HLA and complement regions are too structurally complex for arrays to resolve well. Across two case-control sets (646 and 223 patients; 2,254 and 405 controls), it validated FCGR2B and three HLA amino-acid residues as susceptibility factors, and found that copy number of complement component 4 is itself a distinct risk factor — more copies of C4A were protective, more copies of C4B increased risk.
The finding that matters most for this page: two loci, near PTCH1 and a long non-coding RNA (LOC102724227, tagged here by the nearby CAPZA3 region), were specific to Mikulicz's disease — a named clinical subtype of IgG4-RD involving chronic, painless swelling of the salivary and lacrimal glands — and were not shared with IgG4-RD generally. The authors read this as evidence that the clinical diversity of IgG4-RD, which organs it ends up affecting in a given person, has a real genetic basis rather than being one disease wearing different faces at random.
IgG4-related disease is diagnosed by biopsy, blood IgG4 levels and imaging, not by genotype. It is also frequently misdiagnosed at first, since it mimics cancer and other conditions in the organs it affects — none of the variants on this page change that diagnostic process, and none predict which organs a given person's disease will involve.
Both studies behind this page were conducted in East Asian populations (Chinese Han and Japanese) — a meaningful strength for a disease first characterized in Japan and more commonly studied there, but a real limit on how far these specific loci are known to generalize to other ancestries, which has not yet been directly tested.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about IgG4-Related Disease comes down to these specific, well-studied positions — not a diagnosis.
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IgG4-Related Disease. MyGeneLog™. https://www.mygenelog.com/conditions/igg4-related-disease
An immune-mediated condition in which tissue becomes infiltrated with IgG4-positive plasma cells and a distinctive pattern of scarring, usually alongside high blood levels of the IgG4 antibody. It can affect almost any organ and was only recognized as one unified disease in the 2000s.
Analysing 1,115 patients and 10,154 controls, it found 22 genome-wide-significant variants defining 16 loci, the strongest in the HLA/MHC region on chromosome 6, with a separate signal in the Fc-gamma receptor gene family on chromosome 1.
Yes. A Japanese whole-genome-sequencing study found that Mikulicz's disease — chronic swelling of the salivary and lacrimal glands — carries two loci, near PTCH1 and a long non-coding RNA, that are not shared with IgG4-related disease generally.
No. Diagnosis relies on biopsy, blood IgG4 levels and imaging — the disease is also frequently mistaken for cancer at first because of where it occurs. No variant on this page predicts which organs a given person's disease will involve.
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