Autoinflammatory & rare systemic diseases
IgG4-related disease in the Japanese population: a whole-genome sequencing study
Authors' conclusion
C4 copy number variation, in addition to HLA and FCGR2B, was found to be a distinct genetic factor associated with IgG4-related disease susceptibility, illustrating the complex polygenic nature of the disease.
Study context
- Population
- Patients with IgG4-RD and population controls, all of Hondo Japanese ancestry2 sets
- Participants
- 646 / 2,254 / 223 / 405
- Comparison
- IgG4-RD cases vs Japanese population controls
- Set 1 casesn = 646
- Set 1 controlsn = 2,254reference
- Set 2 casesn = 223
- Set 2 controlsn = 405reference
- Outcome
- Genetic susceptibility loci for IgG4-RD (SNPs, HLA amino acid residues, C4 copy number variation)
Methodological detailswhole-genome sequencing, case-control, two-set, subtype-stratified case-control, multicentre, WGS at depths of 15× or 30× (HiSeqX and NovaSeq, Illumina), C4 copy number variations typed with read-depth-based methods from short-read sequencing data
- Whole-genome sequencing, case-control
- Two-set
- Subtype-stratified case-control
- Multicentre
- WGS at depths of 15× or 30× (HiSeqX and NovaSeq, Illumina)
- C4 copy number variations typed with read-depth-based methods from short-read sequencing data
Main finding
As reported in the abstract
Susceptibility loci for IgG4-RD
- FCGR2B region validated as susceptibility locus
- p=9.8 × 10-11
- PTCH1, Mikulicz's disease-specific susceptibility locus
- p=3.8 × 10-8
- HLA amino acid residue DRB1-GB-7 association confirmed
- p=1.1 × 10-19
- HLA residue A-GA2-9 (additional)
- p=4.1 × 10-6
- HLA residue DQB1-GB-82 (additional)
- p=4.7 × 10-9
- C4A copy number, protective association (joint-association analysis)
- β=−0.127, p=7.9 × 10-3
- C4B copy number, increased risk (joint-association analysis)
- β=0.151, p=1.9 × 10-2
- Linkage disequilibrium between C4A/C4B alleles and identified HLA residues
- r2<0.15
Observational data: associations, not effects.
Further findings
Average, mg/dL
| Outcome | Set 1 controls | Set 2 controls |
|---|---|---|
| Serum IgG4 concentration at diagnosis (cases) | 653.1 (SD 596.3) | 543.5 (SD 603.5) |
Mikulicz's disease-specific susceptibility loci (subtype)
- PTCH1
- P = 3.8 × 10-8
- Long non-coding RNA LOC102724227 also a specific susceptibility locus
LD between C4A/C4B alleles and identified HLA amino acid residues
- Low LD in the main island Japanese population
- r2<0.15
Original publication
IgG4-related disease in the Japanese population: a whole-genome sequencing study. Lancet Rheumatol. Published 3 November 2025. doi:10.
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