Highlights
– Whole‑genome sequencing (WGS) in 869 Japanese patients and 2,659 controls validates FCGR2B and HLA amino‑acid residues as IgG4‑related disease susceptibility loci and identifies complement C4 copy‑number variation as an independent genetic factor.
– PTCH1 and the long non‑coding RNA LOC102724227 emerged as susceptibility loci specific to Mikulicz’s disease, suggesting genetic heterogeneity across organ‑specific phenotypes.
– C4A copy number was protective while C4B copy number increased risk; low linkage disequilibrium between C4 alleles and HLA residues implies parallel contributions to disease risk.
Background
IgG4‑related disease (IgG4‑RD) is a fibro‑inflammatory condition characterised pathologically by dense IgG4‑positive plasma cell infiltration, storiform fibrosis, and often elevated serum IgG4. Clinically it produces heterogeneous organ‑specific presentations (eg, autoimmune pancreatitis, Mikulicz’s disease of lacrimal and salivary glands, retroperitoneal fibrosis). Although relatively rare, IgG4‑RD can cause progressive organ dysfunction and has been linked with increased tumour risk in some cohorts. Understanding genetic predisposition can clarify pathogenesis, explain phenotypic heterogeneity, and suggest therapeutic targets.
Previous genetic work implicated HLA loci and the FCGR2B region, but many earlier studies relied on microarray genotyping and imputation. Those approaches can miss low‑frequency variants, structural variants (including copy‑number variation of complement genes), and precise HLA amino‑acid resolution. Short‑read whole‑genome sequencing (WGS) addresses many of these gaps by providing direct variant calls across single nucleotide, small indel, and structural variation spectra, and by enabling read‑depth based typing for copy‑number variable regions such as complement C4.
Study design
The Japanese IgG4‑Related Disease Working Consortium conducted a two‑set, subtype‑stratified, case‑control WGS association study in individuals of Hondo Japanese ancestry.
Set 1: 646 patients (mean age 64.4 years, 26.6% female) enrolled from 50 hospitals between Oct 27, 2008 and Mar 3, 2016, compared with 2,254 previously sequenced Japanese population controls.
Set 2: 223 patients (mean age 63.5 years, 35.0% female) enrolled from eight consortium hospitals between Aug 12, 2021 and Dec 20, 2023, compared with 405 previously sequenced healthy individuals from the Tokyo metropolitan area.
Whole‑genome sequencing was performed at 15× or 30× coverage (Illumina HiSeqX and NovaSeq platforms) to capture single nucleotide variants (including low frequency), structural variants, and to allow direct analysis of HLA amino‑acid residues. Complement component 4 (C4A/C4B) copy numbers were inferred from read‑depth based typing on short‑read data.
No specific inclusion/exclusion criteria were applied to cases or controls; people with lived experience were not involved in study design. Primary endpoints were genome‑wide associations with IgG4‑RD overall and with clinical subtypes (notably Mikulicz’s disease), plus copy‑number associations for complement C4.
Key findings
Study population and clinical features
The combined WGS dataset included 869 patient samples and 2,659 controls. Mean serum IgG4 at diagnosis was high (653.1 mg/dL in Set 1 and 543.5 mg/dL in Set 2), consistent with clinically active disease in many participants. The male predominance reflected established epidemiology in Japanese cohorts.
Replication and new locus discovery
The study validated the FCGR2B region as a susceptibility locus for IgG4‑RD (p=9.8 × 10−11), reinforcing prior observations implicating Fc gamma receptor biology in disease predisposition. WGS allowed precise localization rather than proxy imputed signals.
HLA amino‑acid resolution
High‑resolution HLA analysis identified a strong association between the DRB1 amino‑acid residue denoted DRB1‑GB‑7 and IgG4‑RD (p=1.1 × 10−19). Two additional HLA residues, A‑GA2‑9 (p=4.1 × 10−6) and DQB1‑GB‑82 (p=4.7 × 10−9), were significantly associated. These amino‑acid level findings sharpen prior HLA associations and suggest specific peptide‑binding or T‑cell presentation alterations may underlie part of genetic risk.
Complement C4 copy‑number variation
Read‑depth based typing revealed that C4A copy number was associated with reduced risk (β = −0.127, p = 7.9 × 10−3), whereas C4B copy number associated with increased risk (β = 0.151, p = 1.9 × 10−2). Importantly, linkage disequilibrium between C4A/C4B alleles and the implicated HLA amino‑acid residues was low (r2 < 0.15), indicating these are largely independent genetic contributors to IgG4‑RD susceptibility in this population.
Phenotype‑specific loci: PTCH1 and LOC102724227
Subtype‑stratified analysis identified PTCH1 (patched 1; p = 3.8 × 10−8) and a long non‑coding RNA locus LOC102724227 as specific susceptibility loci for Mikulicz’s disease (lacrimal/salivary gland–predominant disease). This suggests organ‑specific genetic determinants that may explain clinical heterogeneity within IgG4‑RD.
Effect sizes and statistical strength
Associations reported reached genome‑wide significance thresholds and were statistically robust. The strongest single association was with an HLA amino‑acid residue (DRB1‑GB‑7, p=1.1 × 10−19). FCGR2B and the two C4 copy‑number associations had p‑values in the 10−2 to 10−11 range, implying clinically relevant but modest effect sizes consistent with a polygenic architecture.
Expert commentary and interpretation
This WGS study advances the genetic dissection of IgG4‑RD by combining single nucleotide and structural variation analyses with HLA amino‑acid resolution. Key interpretive points:
– Biological plausibility: FCGR2B encodes an inhibitory Fcγ receptor on B cells and myeloid cells; variants may alter B‑cell regulation and antibody feedback, relevant to a disease characterised by pathogenic IgG4‑secreting plasma cells. HLA amino‑acid residues shape antigen presentation to CD4+ T cells and could influence the selection of T‑cell repertoires that drive aberrant B‑cell help.
– Complement biology: The divergent associations of C4A (protective) and C4B (risk) echo observations in other immune diseases where C4 copy‑number influences immune complex handling and complement activation. C4 isoforms differ in biochemical reactivity—C4A more readily forms covalent bonds with amine groups, C4B prefers hydroxyl groups—potentially altering clearance of apoptotic debris or immune complexes and modulating tolerance. The low LD with HLA suggests additive or independent pathways.
– Phenotypic heterogeneity: Identification of PTCH1 and a lncRNA specifically for Mikulicz’s disease supports the idea of organ‑specific susceptibility alleles. PTCH1 is part of hedgehog signalling with roles in tissue homeostasis and immune‑tissue interactions; how PTCH1 variation predisposes to lacrimal/salivary gland involvement needs functional study.
Limitations and generalizability
– Ancestry limitation: All participants were Hondo Japanese. Allele frequencies and LD patterns may differ in other populations; replication in non‑Japanese ancestries is required.
– Case and control ascertainment: Controls were previously sequenced population samples; Set 2 controls showed a male predominance that differs from Set 1 controls. Although analyses presumably adjusted for population structure, residual confounding and sex imbalance could influence results for sex‑correlated loci.
– Short‑read WGS constraints: While short‑read WGS permits read‑depth CNV calling, complex structural haplotypes (eg, long C4 haplotypes, gene conversions) may be better resolved by long‑read sequencing or targeted assays. Functional validation is needed to translate statistical associations into mechanistic insights.
Clinical and research implications
These genomic findings have several potential implications:
– Pathogenesis: Integration of Fc receptor, HLA‑mediated antigen presentation, and complement pathways positions IgG4‑RD as a disorder involving dysregulated humoral immunity, antigen presentation and complement‑mediated clearance processes.
– Biomarkers and risk stratification: If validated and combined into polygenic risk scores, these variants (including C4 copy number) could inform risk prediction, earlier diagnosis, or identification of patients at risk for particular organ involvement.
– Therapeutic opportunities: The complement pathway is druggable; however, clinical translation requires careful demonstration that complement modulation alters disease course in IgG4‑RD. Targeting Fc receptor pathways or B‑cell biology remains more proximal to current therapeutic approaches (eg, glucocorticoids, B‑cell depletion with rituximab).
Conclusion
This comprehensive WGS study in a large Japanese cohort confirms prior genetic signals (FCGR2B, HLA) and uncovers a novel, independent role for complement C4 copy‑number variation in IgG4‑related disease susceptibility. The discovery of PTCH1 and a lncRNA linked specifically to Mikulicz’s disease highlights genetic heterogeneity underlying organ tropism. Findings strengthen a model in which antigen presentation, Fc receptor regulation, and complement‑mediated clearance converge to influence disease risk. Future work should replicate findings across ancestries, employ long‑read sequencing and functional assays to resolve structural complexity, and assess whether these genetic insights can inform prognosis or therapy.
Funding
Study funding: Japanese Ministry of Health, Labour, and Welfare; Japanese Agency of Medical Research and Development; Kyoto University Grant for Top Global University Japan Project; Kyoto University Division of Graduate Studies SPRING Program.
ClinicalTrials.gov
No clinicaltrials.gov identifier was reported for this genomic association study.
References
1) Zhang YO, Iwasaki T, Kawaguchi T, et al.; Japanese IgG4‑Related Disease Working Consortium. IgG4‑related disease in the Japanese population: a whole‑genome sequencing study. Lancet Rheumatol. 2025 Nov 3:S2665-9913(25)00195-X. doi: 10.1016/S2665-9913(25)00195-X. PMID: 41197642.
2) Stone JH, Zen Y, Deshpande V. IgG4‑related disease. N Engl J Med. 2012 Feb 9;366(6):539‑551. doi:10.1056/NEJMra1104650. PMID: 22397668.
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