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Dermatitis Herpetiformis: Genetics and Genomics#

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This content is for informational purposes only. It is not medical advice. Read the full disclaimer.

Table of Contents#

  1. HLA-DQ2 and HLA-DQ8 Associations
  2. Non-HLA GWAS Susceptibility Loci
  3. Specific Non-HLA Genes in Detail
  4. TGM3 Gene (Encodes TG3)
  5. Epigenetic Factors
  6. Gene Expression Studies in DH Skin
  7. Microbiome Genomics
  8. Pharmacogenomics of Dapsone
  9. Population Genetics
  10. Genetic Overlap with Other Autoimmune Conditions
  11. Twin Concordance and Heritability Studies
  12. Whole-Genome and Exome Studies
  13. Chromosomal Regions Associated
  14. Mendelian Randomization Evidence
  15. Key Research Gaps
  16. Sources and Citations

1. HLA-DQ2 and HLA-DQ8 Associations#

Overview#

The HLA (Human Leukocyte Antigen) association with dermatitis herpetiformis (DH) is among the strongest HLA-disease associations known in medicine. Virtually all DH patients carry either HLA-DQ2 or HLA-DQ8 haplotypes, making these alleles a near-necessary (though not sufficient) genetic prerequisite for disease development.

HLA-DQ2.5 (Primary Risk Haplotype)#

  • Alleles: DQA1*05:01 / DQB1*02:01 (cis-encoded on the DR3-DQ2 haplotype)
  • Alternative encoding: Can also be encoded in trans on DR5-DQ7/DR7-DQ2 haplotypes (DQA1*05:05 from DR5-DQ7 and DQB1*02:02 from DR7-DQ2)
  • Frequency in DH patients: ~86-90% carry HLA-DQ2.5
  • Frequency in celiac disease (CD): ~90-95%
  • General population frequency: 25-30% in European populations
  • Tag SNP: rs2187668 (maps to the first intron of HLA-DQA1)
  • Risk allele: rs2187668(A)
  • Frequency in controls: 13.8%; in CD cases: 53.1%
  • Odds ratio: 7.04 (95% CI: 6.08-8.15) for celiac disease
  • Tags HLA-DQ2.5cis with r-squared = 0.97
  • Molecular mechanism: The Lys-beta71 residue in DQ2 creates a hydrogen bonding network that preferentially binds negatively charged (deamidated) gliadin peptides. DQ2.5 has the strongest binding affinity for the immunodominant gliadin epitopes.
  • Ancestral haplotype: Typically inherited on the HLA-A1-B8-DR3-DQ2 ancestral haplotype (most common in Northern Europeans)

HLA-DQ8#

  • Alleles: DQA1*03:01 / DQB1*03:02
  • Frequency in DH patients: ~5-12% (accounts for most DQ2-negative patients)
  • Tag SNP: rs7454108
  • Risk allele: rs7454108(C)
  • Sensitivity: 0.991; Specificity: 0.996; PPV: 0.948 for detecting DQ8
  • Risk magnitude: Lower than DQ2.5. DQ8 confers modest risk compared to DQ2 genes.

HLA-DQ2.2#

  • Alleles: DQA1*02:01 / DQB1*02:02
  • Associated with lower celiac/DH risk than DQ2.5
  • Co-occurrence with DQ2.5 (DQ2.5/DQ2.2 heterozygotes) increases risk

Dose-Response Relationship#

  • Individuals with one copy of DQ2 or DQ8: ~3% lifetime risk of celiac disease/DH
  • Individuals with two copies (DQ2/DQ2 homozygotes): ~5-10x higher risk than heterozygotes; ~10% lifetime risk
  • DQ2/DQ2 homozygotes carry the highest genetic risk of all HLA combinations
  • The risk grade for DQ2.5/DQ8 compound heterozygotes is debated -- some studies classify this as highest risk, others as intermediate
  • HLA-DQ2/DQ8 accounts for ~40-50% of total genetic risk for celiac disease/DH

Negative Predictive Value#

In individuals lacking both HLA-DQ2 and HLA-DQ8, celiac disease and DH are virtually excluded. The combined sensitivity of DQ2/DQ8 testing approaches 100% for DH, making HLA typing useful primarily for ruling out disease. However, specificity is low (~60-70%) because 30-40% of the general population carries these alleles while only ~1% develop CD/DH.

Key Study: Spurkland et al.#

Comparison of 50 DH patients to 289 healthy controls: - 86% of DH patients carried HLA-DQ2 - 12% carried HLA-DQ8 - Combined sensitivity approached 100%

Another study found HLA-DQw2 in 100% of DH patients (23/23) vs. 40% of controls (21/53).

Sources: PMC3386601, PubMed 1674926, PMC9863503, ARUP Consult

2. Non-HLA GWAS Susceptibility Loci#

Overview of Genetic Architecture#

Celiac disease (and by extension DH, which shares the same genetic background) has a total heritability of approximately 75% (95% CI: 55-96%). The genetic architecture breaks down as follows:

  • HLA contribution: ~40-50% of total genetic variance
  • Non-HLA loci identified to date: ~14% of heritability (4.5% of total genetic variance in some estimates)
  • Firmly described genetic variants: Account for ~31% of celiac disease heritability total (25% MHC + 6% non-HLA)
  • Missing heritability: ~25-35%, likely attributable to rare variants, gene-gene interactions, gene-environment interactions, and epigenetic factors
  • Approximately 54% of celiac disease genetics can be explained by HLA plus the 57 non-HLA SNPs

Immunochip Fine Mapping (Trynka et al., 2011)#

The largest fine-mapping effort used the Immunochip platform on 12,014 celiac disease cases and 12,228 controls, identifying: - 39 non-HLA loci harboring 57 independent association signals - 66 candidate genes proposed - For 29 of the 39 loci, the signal could be refined to a single gene - Individual effect sizes: OR 1.12-1.36 (modest compared to HLA) - Only 3 of the 57 SNPs affect protein sequences (in MMEL1, SH2B3, and IRAK1) - Many SNPs map to UTRs, introns, or intergenic regions, suggesting regulatory roles - 14 independent interaction signals within the MHC region identified beyond known DQ associations

Key Non-HLA GWAS Loci Table#

Locus Gene(s) Chromosome Lead SNP OR / Effect Function
CELIAC2 Cytokine cluster 5q31-q33 -- -- Cytokine gene region
CELIAC3 CTLA4/ICOS 2q33 rs3087243 -- T-cell co-stimulation
CELIAC4 MYO9B 19p13.1 rs1457092 Population-specific Intestinal barrier
CELIAC6 IL2/IL21 4q27 rs6822844 OR=0.63 T-cell proliferation
CELIAC8 IL12A/SCHIP1 3q25-q26 rs17810546 P=1.07x10^-9 IL-12 signaling
CELIAC13 SH2B3 12q24 rs3184504 nsSNP (R262W) Immune signaling
-- RGS1 1q31 rs2816316 OR=0.77 (C allele) G-protein signaling
-- IL18RAP 2q11-q12 rs917997 P=8.49x10^-10 IL-18 receptor
-- CCR1/CCR3 3p21 rs6441961 6% increased risk (T allele) Chemokine receptor
-- LPP 3q28 rs1464510 -- Cell adhesion
-- TAGAP 6q25.3 rs1738074 P=6.71x10^-8 T-cell activation
-- OLIG3/TNFAIP3 6q23.3 rs2327832 -- NF-kB regulation
-- MMEL1/TNFRSF14 1p36 -- nsSNP TNF receptor family
-- REL 2p16.1 rs842647 -- NF-kB subunit
-- PTPN2 18p11 rs1893217 -- Phosphatase, T-cell regulation
-- ETS1 11q24.3 rs11221332 -- Thymic T-cell selection
-- THEMIS 6q22.33 rs802734 -- Thymic T-cell selection
-- CIITA/SOCS1/CLEC16A 16p13.13 -- -- MHC class II regulation
-- UBE2L3 22q11.2 rs5754217 -- Ubiquitin ligase, NF-kB
-- FRMD4B 3p14.1 -- -- Cell polarity/signaling
-- BACH2 6q15 -- -- B-cell transcription factor
-- CD80 3q13.33 -- -- Co-stimulatory molecule
-- ICOSLG 21q22.3 -- -- Co-stimulatory ligand
-- ZMIZ1 10q22.3 -- -- Transcriptional co-activator
-- RUNX3 1p36.11 -- -- T-cell development
-- TNFRSF14 1p36.32 -- -- TNF receptor superfamily
-- ZNF335 20q13.12 -- -- Zinc finger protein
-- NIFA 2p14 -- -- Confirmed susceptibility
-- PUS10 2p16.1 -- -- Pseudouridylate synthase

Shared Loci with Other Diseases#

Of the 39 known celiac disease-associated non-HLA loci, approximately 64% are shared with at least one other autoimmune disease. Shared loci include: MMEL1/TNFRSF14, REL, ICOS/CTLA4, IL2/IL21, TNFAIP3, TAGAP, IL18RAP, PTPN2, SH2B3, and others.

Sources: PMC3410018, PMC4807782, PMC7688450, OMIM 212750

3. Specific Non-HLA Genes in Detail#

CTLA4 (Cytotoxic T-Lymphocyte-Associated Protein 4)#

  • Chromosome: 2q33 (CELIAC3 locus)
  • Key SNPs:
  • rs3087243 (CT60 polymorphism) -- well-studied in multiple autoimmune diseases
  • rs12990970: HR = 0.76, P = 1.3x10^-6
  • rs4675374(A): OR = 1.14 for celiac disease
  • Function: CTLA4 is a negative regulator of T-cell activation. It competes with CD28 for binding to B7 ligands (CD80/CD86), delivering inhibitory signals. Polymorphisms may lead to reduced expression of the soluble CTLA-4 isoform, diminishing peripheral tolerance.
  • Shared autoimmune associations: Type 1 diabetes, autoimmune thyroid disease, rheumatoid arthritis, ANCA-associated vasculitis, celiac disease

MYO9B (Myosin IXB)#

  • Chromosome: 19p13.1 (CELIAC4 locus)
  • Key SNPs:
  • rs1545620: associated with CD risk in Europeans
  • rs1457092: associated with CD in Latin American populations
  • rs2305767: associated with CD in Latin American populations
  • Function: Encodes a single-headed molecular motor with a Rho-GTPase-activating protein (GAP) domain. Expressed in intestinal epithelial cells. Acts as negative regulator of Rho-dependent signaling, influencing epithelial barrier function.
  • Mechanism: MYO9B variants may modify gut epithelial barrier function, allowing gluten peptides increased access to the deeper mucosal layer for immune presentation.
  • Note: Association is population-specific; no association found in Spanish populations. The MYO9B gene was identified as a strong risk factor specifically for refractory celiac disease.

Sources: PMC4658862

IL2/IL21 (Interleukin-2 / Interleukin-21)#

  • Chromosome: 4q27 (CELIAC6 locus)
  • Key SNP: rs6822844 (located 24 kb 5' of IL21)
  • Meta-analysis P = 1.3x10^-14
  • OR = 0.63 (protective allele)
  • Function: IL-2 is essential for T-cell proliferation and regulatory T-cell homeostasis. IL-21 drives B-cell differentiation, promotes IgA production, and enhances Th17 responses. The 4q27 locus lies within a linkage disequilibrium block encompassing both genes.
  • Significance: One of the strongest non-HLA genetic associations in celiac disease. The region is also associated with type 1 diabetes and rheumatoid arthritis.

Sources: PMC2274985

SH2B3 (SH2B Adaptor Protein 3)#

  • Chromosome: 12q24 (CELIAC13 locus)
  • Key SNP: rs3184504 (nonsynonymous SNP, R262W)
  • P = 8x10^-8
  • Also known as the SH2B3/ATXN2 locus
  • Function: SH2B3 (also known as LNK) is a negative regulator of multiple signaling pathways including those mediated by cytokine receptors and integrins. The R262W variant affects pleckstrin homology domain function.
  • Additional findings:
  • Carriers of the rs3184504 risk allele show stronger activation of the NOD2 recognition pathway
  • The locus shows evidence of positive selection in European populations
  • Associated with disease onset after age 7 years

TAGAP (T-Cell Activation GTPase-Activating Protein)#

  • Chromosome: 6q25.3
  • Key SNP: rs1738074
  • P(overall) = 6.71x10^-8
  • Maps to a ~200 kb LD block containing TAGAP
  • Function: TAGAP is involved in T-cell activation and may modulate T-cell receptor signaling through regulation of Rho-family GTPases.
  • Opposite-direction effects: The risk allele for celiac disease at TAGAP is protective against type 1 diabetes, suggesting complex immune regulatory effects.

IL12A (Interleukin-12A)#

  • Chromosome: 3q25-q26 (CELIAC8 locus)
  • Key SNPs:
  • rs17810546: P(overall) = 1.07x10^-9
  • rs9811792
  • Both are in a ~70 kb LD block immediately 5' of IL12A
  • Function: IL-12A encodes the p35 subunit of IL-12, a critical cytokine for Th1 differentiation and IFN-gamma production. IL-12 bridges innate and adaptive immunity.
  • Meta-analysis (RGS1 and IL12A): Confirmed significant association of IL12A polymorphisms with celiac disease risk.

Sources: PMC4848913

IL18RAP (Interleukin-18 Receptor Accessory Protein)#

  • Chromosome: 2q11-q12
  • Key SNP: rs917997
  • P = 8.49x10^-10
  • T-allele increases celiac disease risk by ~5%
  • Function: IL-18 is a pro-inflammatory cytokine involved in Th1 immune responses. IL18RAP encodes the accessory protein required for IL-18 signaling.
  • Opposite-direction effects: Like TAGAP, the celiac disease risk allele (A allele of rs917997) is protective against type 1 diabetes.

RGS1 (Regulator of G-Protein Signaling 1)#

  • Chromosome: 1q31
  • Key SNP: rs2816316
  • Minor allele C: OR = 0.77 (95% CI: 0.74-0.80) -- protective
  • Function: RGS1 modulates chemokine receptor signaling in lymphocytes, affecting their migration and homing to the gut. Expressed in germinal center B cells and activated T cells.

CCR1/CCR3 (Chemokine Receptors)#

  • Chromosome: 3p21
  • Key SNP: rs6441961
  • T-allele increases celiac disease risk by ~6%
  • Function: Chemokine receptors involved in leukocyte trafficking and recruitment to sites of inflammation.

LPP (Lipoma-Preferred Partner)#

  • Chromosome: 3q28
  • Key SNP: rs1464510
  • Function: LPP is a member of the zyxin family of LIM domain proteins, involved in cell-cell adhesion and cell motility. Expressed at the basolateral surface of intestinal epithelial cells.

Sources: PubMed 18311140, PMC2758145

4. TGM3 Gene (Encodes TG3)#

Gene Characteristics#

  • Gene: TGM3 (Transglutaminase 3)
  • Chromosome: 20q11.2
  • Gene size: 42.8 kb containing 13 exons
  • OMIM: 600238
  • Protein: Epidermal transglutaminase (TGase 3), also known as TGe
  • Protein size: 692 amino acid zymogen (~77 kDa)

Protein Structure#

TG3 is synthesized as a single ~77 kDa precursor polypeptide that is proteolytically activated into two polypeptide chains. The active enzyme is calcium-dependent and catalyzes the crosslinking of proteins via epsilon-gamma glutamyl lysine isopeptide bonds.

Genomic Context: Transglutaminase Gene Cluster#

TGM3 is part of a transglutaminase gene cluster on chromosome 20q11.2. Notably, TGM2 (tissue transglutaminase, the primary celiac disease autoantigen) and TGM3 both map to this region. The genes share significant sequence homology, particularly in the catalytic domain, suggesting evolutionary divergence from a common ancestor. TGM6 (encoding TG6, associated with neurological manifestations of gluten sensitivity) is also located on chromosome 20. The exon/intron organization of TGM3 suggests that TGM2 and TGM3 belong to a distinct branch of a phylogenetic tree separate from other transglutaminases.

Expression Patterns#

  • Epidermis: Expressed during late terminal differentiation of keratinocytes
  • Cornified envelope: Involved in crosslinking structural proteins (involucrin, loricrin, filaggrin) during formation of the cornified cell envelope, a critical component of the epidermal barrier
  • Hair follicle: Expressed in the inner root sheath; cross-links structural proteins for inner root sheath hardening
  • Squamous epithelium: Found in the upper differentiating layers of stratified squamous epithelium
  • Cell types: Keratinocytes, corneocytes, hair follicle cells
  • Brain: Also expressed in neural tissue

Role as Autoantigen in DH#

TG3 is the dominant autoantigen in dermatitis herpetiformis, identified as such by Sardy et al. (2002). Key features:

  • DH patients produce IgA autoantibodies against TG3 in a gluten-dependent manner
  • TG3-IgA immune complexes deposit in the dermal papillae, triggering the characteristic DH skin lesions
  • The specificity of TG3 as the DH autoantigen (versus TG2 in celiac disease) explains why skin symptoms predominate in DH
  • Antibody responses to TG3 likely arise through epitope spreading from anti-TG2 responses, facilitated by the structural homology between TG2 and TG3

Polymorphisms#

A study examining 47 SNPs across TGM1, TGM3, and TGM5 gene regions found that genetic variation in the transglutaminase genes was not a major susceptibility factor for atopic dermatitis. Specific studies examining TGM3 polymorphisms in DH susceptibility remain limited. The role of TGM3 in DH pathogenesis appears to be primarily through its function as the target autoantigen rather than through genetic polymorphisms in the gene itself. Polymorphisms in TGM3 may affect protein structure and immunogenicity, and gene expression differences may influence individual susceptibility to skin (vs gut-only) manifestation.

Sources: PMC2193738, OMIM 600238, GeneCards TGM3, PubMed 7851911, PMC8953297

5. Epigenetic Factors#

Overview#

The currently identified genetic variants (HLA plus non-HLA loci) explain only approximately 54% of celiac disease heritability. Epigenetic mechanisms -- including DNA methylation, histone modifications, and non-coding RNAs -- are increasingly recognized as contributors to the remaining disease susceptibility. Inherited traits can be regulated by epigenetic modifications also induced by environmental factors, including gluten exposure.

DNA Methylation#

NF-kB Pathway Genes#

Fernandez-Jimenez et al. demonstrated differential methylation in genes of the core NF-kB pathway in celiac disease: - Hypermethylated genes: MALT1, MAP3K7, TRADD (higher methylation than controls) - Hypomethylated genes: RELA (lower methylation than controls) - Intermediate pattern: Patients on gluten-free diet showed methylation levels between active celiac disease and controls, suggesting partially reversible epigenetic changes - Eight NF-kB-related genes analyzed: MALT1, MAP3K7, MAP3K14, NFKBIA, RELA, TAB1, TNFAIP3, TRADD

HLA Region Methylation#

The methylome of the celiac intestinal epithelium harbors genotype-independent alterations in the HLA region, suggesting that epigenetic modifications of HLA genes may contribute to disease susceptibility beyond the sequence-level HLA associations.

Non-HLA Differentially Methylated Regions#

  • NLRC5: Significant hypomethylation of its CpG-dense promoter with overexpression in celiac disease. NLRC5 plays a central role in NF-kB-mediated regulation of macrophage activation in gut inflammation.
  • CAST: Differentially methylated region related to immune response
  • Combined analysis of methylation and gene expression in small bowel mucosa has identified celiac disease patient-specific signatures

Clinical Potential#

Researchers have identified a small set of candidate genes in peripheral blood mononuclear cells (PBMCs) with differential methylation patterns capable of predicting celiac disease at least 9 months before clinical/serological signs appear, representing a potential non-invasive epigenetic screening tool.

Promoter Methylation Studies#

A pilot study on promoter methylation of MTHFR, MALT1, and MAP3K7 genes in pediatric celiac disease further supports the role of DNA methylation in CpG islands as a pathogenic mechanism.

Histone Modifications#

While direct studies of histone modifications in DH are limited, research in celiac disease and related inflammatory skin conditions has demonstrated: - Histone acetylation changes associated with disruption of skin barrier function - Histone deacetylase (HDAC) inhibitors show therapeutic potential in inflammatory skin conditions - The gluten-dependent immune response in celiac disease involves chromatin remodeling at inflammatory gene loci

MicroRNAs (miRNAs)#

Key miRNAs in Celiac Disease#

miRNA Direction Tissue Significance
miR-155-5p Upregulated PBMCs, monocytes, plasma Immune miRNA; enhances interferon response; Log2FC = 1.2
miR-21 Upregulated PBMCs, plasma Inflammatory regulation
miR-146a Upregulated PBMCs High sensitivity/specificity for CD detection
miR-125b Upregulated Plasma Inflammatory modulation
miR-192-5p Downregulated Small intestine Log2FC = -1.2; recovers on GFD
miR-194 Downregulated Small intestine Part of miR-192/194 cluster

Notable Findings#

  • miR-155-5p (Log2 Fold Change = 1.2, increased): Well-described immune miRNA that enhances interferon response
  • miR-192/194 cluster: Significantly deregulated in classical and anemia-type celiac disease; expression recovers on gluten-free diet with mucosal normalization
  • miR-146a and miR-155: Expression showed high sensitivity and specificity for CD presence regardless of dietary treatment status
  • Interestingly, miRNA expression in intestinal mucosa did not change as dramatically as in blood, suggesting distinct systemic versus mucosal regulatory pathways

Long Non-Coding RNAs (lncRNAs)#

Machine learning analysis of duodenal biopsies revealed different roles for miRNAs and lncRNAs in gene expression regulation in celiac disease, with lncRNAs correlating with more subtle transcriptional adjustments under epigenetic control.

Sources: PMC8790554, Nature - Methylome of Celiac Epithelium, PMC3919015, MDPI miRNA Review, PMC8583991

6. Gene Expression Studies in DH Skin#

Dolcino et al. (2012) -- Landmark Gene Expression Study#

The first comprehensive gene expression profiling study in DH skin used Affymetrix HG-U133A 2.0 arrays on skin biopsies from 6 celiac disease patients with DH versus 6 healthy controls.

Overall Results#

  • 486 differentially expressed genes (DEGs)
  • 225 upregulated
  • 261 downregulated

Key Upregulated Pathways and Genes#

Inflammatory Response: - IL8 (interleukin-8) -- neutrophil chemoattractant - PTGFR (prostaglandin F receptor) - FSTL1 (follistatin-like 1) - IFI16 (interferon-inducible protein 16) - BDKRB2 (bradykinin receptor B2) - NAMPT (nicotinamide phosphoribosyltransferase / visfatin)

Leukocyte Recruitment and Endothelial Activation: - CCL5 (RANTES) -- chemokine for T cells, eosinophils, basophils - ENPP2 (ectonucleotide pyrophosphatase/phosphodiesterase 2) - SELL (L-selectin) -- neutrophil extravasation - SELE (E-selectin) -- endothelial cell activation

B- and T-Cell Immune Response: - LAG3 (lymphocyte activation gene 3) - TRAF5 (TNF receptor-associated factor 5) - DPP4 (dipeptidyl peptidase 4 / CD26) - NT5E (5'-nucleotidase ecto / CD73)

Matrix Proteases and Tissue Remodeling: - MMP9 (matrix metalloproteinase 9) - ADAM9, ADAM19 (disintegrin and metalloproteinase domain-containing proteins) - CTSG (cathepsin G) - ELA2 (neutrophil elastase) - CPA3 (carboxypeptidase A3) - TPSB2 (tryptase beta 2) - CMA1 (chymase 1)

Apoptosis: - FAS (Fas cell surface death receptor) - TNFSF10 (TRAIL -- TNF-related apoptosis-inducing ligand) - BASP1 (brain acid soluble protein 1)

Key Downregulated Pathways and Genes#

Cell Growth Inhibition: - CGREF1 (cell growth regulator with EF-hand domain 1) - PA2G4 (proliferation-associated 2G4) - PPP2R1B (protein phosphatase 2 scaffold subunit A beta)

Dermal-Epidermal Junction Adhesion: - PLEC1 (plectin) -- cytoskeletal linker protein - ITGB4 (integrin beta 4) -- component of hemidesmosomes - LAMA5 (laminin subunit alpha 5) -- basement membrane component

Skin Barrier Function and Lipid Metabolism: - Multiple genes involved in epidermal barrier maintenance - Lipid metabolism pathway genes

Interpretation#

The gene expression profile reveals a coordinated pathological process: inflammatory mediator release triggers neutrophil and lymphocyte recruitment, matrix protease activation degrades the dermal-epidermal junction, and reduced adhesion molecule expression at the basement membrane zone facilitates the characteristic sub-epidermal blistering of DH.

Sources: Wiley - Dolcino 2012, PubMed 22991566

7. Microbiome Genomics#

Gut Microbiome Dysbiosis in Celiac Disease and DH#

Gut microbiota dysbiosis is a common feature in patients with celiac disease and DH. The gut-skin axis provides a framework for understanding how intestinal microbial changes may influence cutaneous disease.

Bacterial Composition Changes#

Taxonomic Group Direction in CD/DH Role
Bifidobacterium spp. (particularly B. longum) Decreased Beneficial; anti-inflammatory; gluten degradation
Lactobacillus spp. Decreased Beneficial; barrier protection
Bacteroides spp. Increased Potentially pathogenic
E. coli Increased Potentially pathogenic
Proteobacteria (phylum) Increased Marker of dysbiosis
Firmicutes (phylum) Dominant phylum --
Bacteroidetes (phylum) Higher vs. controls --

Key Findings#

  • In untreated celiac disease, the microbiota shows reduction of beneficial microbes (Lactobacillus, Bifidobacterium) and increase in pathogenic species (Bacteroides, E. coli)
  • Long-term gluten-free diet (GFD) improves symptoms but does not fully restore normal intestinal flora composition
  • Dysbiosis persists even after extended GFD adherence
  • Reduced Bifidobacterium leads to decreased gluten peptide degradation capacity
  • Dysbiosis increases intestinal permeability
  • Altered short-chain fatty acid production impairs Treg differentiation

Microbial Gluten Metabolism#

Several intestinal microorganisms possess the ability to metabolize gliadin (the immunogenic component of gluten): - Lactobacillus spp. - Streptococcus spp. - Staphylococcus spp. - Clostridium spp. - Bifidobacterium spp.

This microbial capacity to pre-digest gluten may modulate the amount of immunogenic peptides reaching the intestinal immune system.

Microbiome Signatures and Disease Prediction#

A longitudinal prospective cohort study (Leonard et al., PNAS 2021) identified microbiome signatures of progression toward celiac disease onset in at-risk children. These signatures appeared before clinical disease manifestation, suggesting potential predictive biomarker utility.

Therapeutic Implications#

Probiotics (particularly Bifidobacterium and Lactobacillus strains) may help: - Restore gut microbiota composition - Pre-digest gluten peptides - Reduce intestinal inflammation - Serve as adjunct therapy to GFD in DH management

However, most evidence for probiotic benefit in DH specifically remains preliminary.

Sources: PMC8519548, PNAS - Microbiome Signatures, PMC7243837, ASM - Gut Microbiota

8. Pharmacogenomics of Dapsone#

Dapsone (4,4'-diaminodiphenyl sulfone) is the first-line pharmacological treatment for DH. Its metabolism and toxicity profile are significantly influenced by genetic variation.

Dapsone Metabolism Overview#

Dapsone undergoes two major metabolic pathways: 1. N-acetylation (major route): Via NAT2 enzyme, forming mono-acetyl dapsone (MADDS) and di-acetyl dapsone 2. N-hydroxylation (toxicity pathway): Via CYP3A4 and CYP2C9, forming dapsone hydroxylamine (DDS-NHOH) and mono-acetyl dapsone hydroxylamine (MADDS-NHOH)

The hydroxylamine metabolites are responsible for the primary hematological toxicities (methemoglobinemia and hemolytic anemia). These are detoxified by cytochrome b5 and cytochrome b5 reductase, which convert the hydroxylamine back to parent dapsone.

NAT2 (N-Acetyltransferase 2)#

Gene Location and Function#

  • Chromosome: 8p22
  • Expressed primarily in liver and intestinal mucosa
  • Catalyzes the N-acetylation of aromatic amine and hydrazine substrates

Key NAT2 SNPs#

SNP Nucleotide Change Haplotype Phenotype
rs1801279 191G>A NAT2*14 Slow
rs1041983 282C>T -- Tagging SNP
rs1801280 341T>C NAT2*5B Slow
rs1799929 481C>T -- --
rs1799930 590G>A NAT2*6A Slow
rs1208 803A>G -- --
rs1799931 857G>A NAT2*7B Slow

Acetylator Phenotype Classification#

  • Rapid acetylators: Two rapid haplotypes (NAT2*4/*4 reference; absence of SNPs defines rapid allele)
  • Intermediate acetylators: One rapid + one slow haplotype
  • Slow (poor) acetylators: Two slow haplotypes

Optimal Genotyping Panel#

A four-SNP panel (rs1801279, rs1801280, rs1799930, rs1799931) achieves 98.4% accuracy (252/256) for predicting acetylator phenotype.

Clinical Implications for Dapsone Use#

  • Slow acetylators: More prone to hematologic toxicity (methemoglobinemia, hemolytic anemia) due to shunting of dapsone metabolism toward the N-hydroxylation pathway
  • Rapid acetylators: May require higher dapsone doses for therapeutic effect in DH
  • Population variation:
  • Asian populations: 10-20% slow acetylators
  • Caucasian and African populations: >50% slow acetylators

G6PD (Glucose-6-Phosphate Dehydrogenase)#

Gene Location#

  • Chromosome: Xq28 (X-linked)
  • More than 400 variants described
  • Affects approximately 4.9% of the world's population

Common Pathogenic Variants#

Variant Name SNP(s) Location Enzyme Activity Population
G6PD A- rs1050828 (G202A, exon 4) + rs1050829 (A376G, exon 5) Xq28 10-60% reduction African/African-American (~10%)
G6PD Mediterranean rs5030868 (c.563C>T, S188F) Xq28 Severe (<10%) Middle East, Mediterranean

Dapsone and G6PD Deficiency#

  • G6PD-deficient individuals are at significantly higher risk for dapsone-induced hemolytic anemia
  • The FDA label for dapsone includes precautions regarding G6PD deficiency
  • Frequency of acute hemolytic anemia in dapsone users may be ~10%, but when stratified by G6PD status, affected patients are overwhelmingly G6PD deficient
  • G6PD testing prior to initiating dapsone therapy is recommended (mandatory per many guidelines)
  • CPIC (Clinical Pharmacogenetics Implementation Consortium) guidelines address G6PD and drug interactions

CYP Enzymes#

  • CYP3A4: Major enzyme for N-hydroxylation of dapsone to dapsone hydroxylamine
  • CYP2C9: Contributes to N-hydroxylation; dapsone is both a substrate and an activator of CYP2C9-catalyzed reactions
  • CYP2C19: Minor contribution to dapsone metabolism
  • CYP2E1: Also involved in dapsone hepatic metabolism
  • Cytochrome b5 reductase: Detoxifies hydroxylamine metabolites; impaired activity (as in hereditary methemoglobinemia) compounds dapsone toxicity risk

HLA-B*13:01 and Dapsone Hypersensitivity#

  • HLA-B*13:01 is associated with dapsone hypersensitivity syndrome (DHS)
  • OR = 20.53 for DHS in carriers
  • Screening may be warranted in high-risk populations (Southeast Asian descent)

Clinical Case: Combined Pharmacogenomic Risk#

A documented case of severe dapsone-associated methemoglobinemia occurred in a patient with the slow NAT2*5B haplotype AND impaired cytochrome b5 reductase activity, illustrating how multiple pharmacogenomic variants can compound toxicity risk.

Sources: PMC3153586, PMC3285565, PMC4109976, PMC4153881, CPIC G6PD Guideline, NCBI Bookshelf - Dapsone

9. Population Genetics#

Geographic Distribution of DH#

DH is overwhelmingly a disease of Northern European descent, with dramatically different prevalence across world populations.

Prevalence by Region#

Region Prevalence (per 100,000) Incidence (per 100,000/year) Source
Finland 75.3 2.7 Salmi et al. 2011
Central Sweden 39.2 0.86-1.45 Mobacken et al. 1984
Western Sweden 22.9 1.1 Blix et al. 1984
UK ~30 -- Multiple studies
Europe/USA (range) 11.2-75.3 0.4-2.6 Multiple studies
Utah, USA Comparable to Northern Europe -- Smith et al. 1992
Asia Extremely rare -- Case reports
Africa Extremely rare -- Case reports
  • DH incidence is declining in Finland (from 5.2 to 2.7 per 100,000 over three decades)
  • This decline may reflect earlier CD diagnosis and GFD intervention before DH develops
  • The decline in DH while CD incidence rises supports the epitope spreading model (catch CD early, prevent DH)

Gender Distribution#

  • Male-to-female ratio: 1.5-2:1
  • DH is one of the few autoimmune diseases more common in males (contrasts with female predominance in CD, which is unexplained)

Ethnic and Racial Differences#

Northern Europeans (highest prevalence): - Finnish and Swedish populations show the highest worldwide prevalence - Irish and Swedish ancestry particularly predisposed - Correlates with high population frequency of HLA-DQ2 (25-30%)

Asian Populations (extremely rare): - Japan: Documented cases show unique characteristics: - Absence of HLA-DQ2/DQ8 haplotypes in many cases - Absence of underlying celiac disease - Higher involvement of non-predilection sites (extremities, trunk) - Fibrillar rather than granular IgA deposits in dermal papillae - Lower incidence of CD-associated autoimmune diseases and non-Hodgkin lymphomas - China: 22 cases documented in one report; disease occurs outside the setting of celiac disease - The low prevalence in Asia reflects both the low frequency of HLA-DQ2/DQ8 and low dietary wheat consumption

African/African-American Populations (extremely rare): - Very few cases reported - Low prevalence of predisposing HLA haplotypes - Limited dietary exposure to wheat in traditional diets

HLA-DQ2 Population Frequencies#

The population frequency of HLA-DQ2 largely explains geographic DH distribution: - Northern Europe: 25-30% - Southern Europe: 15-20% - Middle East: 10-15% - East Asia: 5-10% - Sub-Saharan Africa: Variable, generally low

Family Studies#

  • First-degree relatives of DH/celiac patients have a 15-fold higher likelihood of developing either condition
  • Analysis of 105 families: 13.6% of parents, 18.7% of siblings, and 14.0% of children were affected by DH or celiac disease
  • ~5-15% of first-degree relatives may be affected by either condition
  • Family screening is recommended for first-degree relatives

Sources: PubMed 21517799, NCBI Bookshelf NBK493163, PMC6579917, PMC8068693

10. Genetic Overlap with Other Autoimmune Conditions#

Overview#

DH/celiac disease shares substantial genetic overlap with multiple other autoimmune conditions. Of the 39 known non-HLA celiac disease loci, ~64% are shared with at least one other autoimmune disease.

Type 1 Diabetes (T1D)#

Shared HLA associations: - Both CD and T1D are strongly associated with HLA-DQ2 and HLA-DQ8 - HLA-DQ2/DQ8 present in ~95% of T1D patients vs. ~99% of celiac patients vs. ~40% of general population - Clinical co-occurrence: Celiac disease found in 4-11% of T1D patients

Shared non-HLA loci (7 total identified): - CTLA4 (2q33) - PTPN2 (18p11) - SH2B3 (12q24) - IL2/IL21 (4q27) - RGS1 (1q31) - IL18RAP (2q12) - TAGAP (6q25)

Opposite-direction effects: - IL18RAP rs917997: A allele is risk for celiac disease but protective for T1D - TAGAP rs1738074: Risk allele for celiac disease but protective for T1D - These "flip-flop" associations suggest shared immunological pathways regulated in opposite directions

Sources: PMC2840835, NEJM

Autoimmune Thyroid Disease (Hashimoto's/Graves')#

  • Celiac disease found in 2-7% of patients with autoimmune thyroiditis
  • DH patients are at increased risk for autoimmune thyroid disease (most common autoimmune co-morbidity in DH)
  • Shared genetic factors:
  • HLA-DQ2/DQ8
  • CTLA4 polymorphisms (particularly CT60, rs3087243)
  • PTPN22

Sources: PMC2111403

Rheumatoid Arthritis (RA)#

  • Total of 14 non-HLA susceptibility loci shared between celiac disease and RA
  • Shared loci include: MMEL1/TNFRSF14, REL, ICOS/CTLA4, IL2/IL21, TNFAIP3, TAGAP, and eight additional loci

Crohn's Disease#

  • Shared loci: IL18RAP, PTPN2, TAGAP, PUS10
  • Meta-analysis confirmed these as shared risk loci for both Crohn's disease and celiac disease

Sources: PMC3029251

Other Associated Autoimmune Conditions#

Condition Prevalence in CD/DH patients Key Shared Genes
Type 1 diabetes 4-11% HLA-DQ2/DQ8, CTLA4, SH2B3, IL2/IL21
Autoimmune thyroid disease 2-7% HLA-DQ2/DQ8, CTLA4, PTPN22
Sjogren's syndrome 1.2-6.5% in CD; CD prevalence 7.06% in pSS HLA region
Systemic lupus erythematosus ~1.7-3% (biopsy-proven CD in SLE) UBE2L3, HLA region
Pernicious anemia Elevated HLA region
Addison's disease Elevated CTLA4, CLEC16A/CIITA
Alopecia areata Elevated HLA region

Prevalence of Autoimmune Co-morbidity#

  • Overall prevalence of additional autoimmune conditions in celiac disease: up to 15% (vs. 5-8% in general population)
  • Autoimmune disorders associated with DH are the same as those associated with celiac disease, with hypothyroidism being the most common

Sources: PMC3741914, PMC8986520

11. Twin Concordance and Heritability Studies#

Monozygotic Twin Concordance#

  • Celiac disease concordance in MZ twins: 70-75% (some studies report up to 91%)
  • DH concordance rate: >0.9 in monozygotic twins

Finnish Twin Study (Key DH Study -- Hervonen et al., 2000)#

A Finnish study of monozygous twin pairs with DH/celiac disease found: - 3 of 6 twin pairs were concordant for both DH and celiac disease - 2 twin pairs were partially discordant: one twin had DH + celiac disease while the co-twin had only celiac disease - This partial discordance suggests that additional genetic or environmental factors beyond the shared celiac/DH predisposition determine whether a celiac patient develops DH

Heritability Estimates#

  • Overall celiac disease heritability: 75% (95% CI: 55-96%)
  • Non-HLA heritability: 68% (95% CI: 40-96%)
  • HLA-attributable heritability: ~40-50%
  • Non-HLA loci explained: ~14% of heritability
  • Firmly described genetic variants total: ~31% of heritability (25% MHC + 6% non-HLA)
  • Missing heritability: ~25-35%

Population-Based Twin Study (Kuja-Halkola et al., 2016 -- 107,000 Twins)#

A large population-based study in 107,000 twins confirmed: - High overall heritability of celiac disease - Significant non-HLA genetic component (non-HLA heritability 68%) - Environmental factors account for ~25% of disease risk

Implications#

The high but incomplete concordance in MZ twins demonstrates that: 1. Genetic factors are the dominant determinant of celiac disease/DH susceptibility 2. Environmental factors (gluten exposure timing/amount, gut microbiome, infections) contribute ~25% of risk 3. The discordance between DH and celiac disease in MZ twins suggests DH-specific genetic or epigenetic factors beyond the shared celiac predisposition 4. Stochastic epigenetic drift between MZ twins may contribute to discordance 5. The high twin concordance supports multifactorial inheritance with HLA and Ig constant heavy chain genes as major loci

Sources: PubMed 11121131, PubMed 27207974

12. Whole-Genome and Exome Studies#

Exome Sequencing in Celiac Disease Families#

Whole-exome sequencing (WES) has been applied to celiac disease families to identify rare coding variants that may contribute to the "missing heritability."

Key Findings#

IL1R1 and CD3E as Novel Risk Genes: - GWAS-guided exome rare variant burden analysis identified IL1R1 (interleukin-1 receptor type 1) and CD3E (CD3 epsilon chain of T-cell receptor complex) as potential autoimmunity risk genes - Interactome analysis of rare WES variants and GWAS loci identified these as hub genes

Sources: PMC8882628

Consanguineous Family Studies: - WES of a consanguineous family identified a globally rare AK5 (adenylate kinase 5) allelic variant as a possible modifier of celiac disease development in Saudi patients - This suggests that rare population-specific variants may contribute to celiac disease susceptibility in non-European populations

Sources: PubMed 28505210

Limitations of WES/WGS in DH#

  • No whole-genome or whole-exome studies have been conducted specifically for DH as distinct from celiac disease
  • The rarity of DH limits statistical power for genome-wide rare variant analyses
  • Most genetic insights for DH are extrapolated from celiac disease studies

Novel Variants from Population Screening (2025)#

A recent 2025 study on population screening of adults identified novel genetic variants associated with celiac disease, extending the known genetic architecture. This ongoing effort continues to uncover additional loci that may be relevant to DH.

Sources: Nature Scientific Reports 2025

Missing Heritability Explanations#

The missing celiac disease heritability can be explained by: - Rare coding variants (identified through WES/WGS) - Gene-gene interactions (14 independent MHC interaction signals already found) - Gene-environment interactions - Epigenetic factors - Structural variants not captured by SNP arrays - To explain the larger part of the missing heritability, genotyping with denser whole genome coverage, combined imputation panels of HLA and non-HLA specific variants, and screening of individuals from different populations should be performed

13. Chromosomal Regions Associated#

Officially Recognized Celiac Disease Susceptibility Loci#

Locus Chromosome Gene(s) Discovery Method
CELIAC1 6p21.3 HLA-DQA1, HLA-DQB1 Linkage analysis
CELIAC2 5q31-q33 Cytokine gene cluster Linkage analysis
CELIAC3 2q33 CTLA4, ICOS, CD28 Linkage analysis
CELIAC4 19p13.1 MYO9B Linkage analysis
CELIAC5 15q11-q13 -- Linkage analysis
CELIAC6 4q27 IL2, IL21 GWAS
CELIAC7 11q23.3 -- GWAS
CELIAC8 3q25-q26 IL12A, SCHIP1 GWAS
CELIAC9 3p21 CCR1, CCR3 GWAS
CELIAC10 2q11-q12 IL18RAP GWAS
CELIAC11 6q25.3 TAGAP GWAS
CELIAC12 1q31 RGS1 GWAS
CELIAC13 12q24 SH2B3 GWAS

Summary of All Major Chromosomal Regions#

Chromosome Region Key Gene(s) Association
1p36 1p36.32 MMEL1, TNFRSF14 GWAS
1p36 1p36.11 RUNX3 Immunochip
1q31 1q31 RGS1 GWAS
2p16 2p16.1 REL, PUS10 GWAS/Meta-analysis
2p14 2p14 NIFA Immunochip
2q11 2q11-q12 IL18RAP GWAS
2q33 2q33 CTLA4, ICOS Linkage
3p21 3p21 CCR1, CCR3 GWAS
3p14 3p14.1 FRMD4B GWAS
3q13 3q13.33 CD80 Immunochip
3q25 3q25-q26 IL12A, SCHIP1 GWAS
3q28 3q28 LPP GWAS
4q27 4q27 IL2, IL21 GWAS
5q31 5q31-q33 Cytokine cluster Linkage
6p21 6p21.3 HLA-DQ Linkage (primary)
6q15 6q15 BACH2 Immunochip
6q22 6q22.33 THEMIS Immunochip
6q23 6q23.3 OLIG3, TNFAIP3 GWAS
6q25 6q25.3 TAGAP GWAS
10q22 10q22.3 ZMIZ1 Immunochip
11q24 11q24.3 ETS1 Immunochip
12q24 12q24 SH2B3 GWAS
16p13 16p13.13 CIITA, SOCS1, CLEC16A Immunochip
18p11 18p11.3-p11.2 PTPN2 GWAS
19p13 19p13.1 MYO9B Linkage
20q11 20q11.2 TGM2, TGM3 Autoantigen genes
20q13 20q13.12 ZNF335 Immunochip
21q22 21q22.3 ICOSLG Immunochip
22q11 22q11.2 UBE2L3 Immunochip
Xq28 Xq28 IRAK1 Immunochip (nsSNP)

The 6p21 HLA Region: The Dominant Locus#

The HLA region on chromosome 6p21.3 remains the single most important genetic determinant: - Accounts for ~40-50% of genetic risk - HLA-DQ2.5 (DQA1*05:01/DQB1*02:01) is the primary risk haplotype - HLA-DQ8 (DQA1*03:01/DQB1*03:02) is the secondary risk haplotype - 14 independent interaction signals within the MHC region have been identified beyond the known DQ associations - These MHC interaction effects contribute additional explained heritability

Sources: OMIM 212750, PMC2847618, PMC7028987, PMC5345796

14. Mendelian Randomization Evidence#

Celiac Disease as a Genetic Predisposing Factor for DH (2024-2025)#

A two-sample Mendelian randomization (MR) analysis provided the first formal genetic evidence for a causal relationship from celiac disease to DH.

Study Design#

  • Utilized GWAS summary data for both celiac disease and DH
  • Eight MR methods employed: MR Egger, random-effects IVW, weighted median, simple mode, weighted mode, maximum likelihood, penalized weighted median, fixed-effects IVW
  • Bidirectional analysis performed

Key Results#

Celiac disease to DH (forward direction): - Fixed-effects IVW: OR = 1.546 (95% CI: 1.195-1.999), P = 0.001 - Significant positive genetic causal relationship confirmed

DH to celiac disease (reverse direction): - OR = 1.039 (95% CI: 0.991-1.090), P = 0.113 - No significant genetic causality in the reverse direction

Interpretation#

  • Celiac disease acts as a genetic susceptibility factor for the development of DH
  • The causal relationship is unidirectional: CD predisposes to DH, but DH does not independently increase genetic risk for CD
  • Sensitivity analyses confirmed robustness of results
  • Supports the clinical model where DH develops as a consequence of celiac disease pathophysiology, with additional factors (possibly TG3-specific immune responses) determining cutaneous manifestation
  • Confirms the sequential nature of the disease (CD -> epitope spreading -> DH)

Sources: PMC12697111

15. Key Research Gaps#

  1. No DH-specific GWAS has been performed (all data extrapolated from CD GWAS)
  2. What genetic factors determine skin (DH) vs gut-only (CD) manifestation?
  3. Are TGM3 polymorphisms a risk factor for DH specifically?
  4. What drives the male predominance in DH (opposite to CD)?
  5. Why is DH incidence declining while CD incidence is rising?
  6. Full epigenetic profiling of DH skin lesions is lacking
  7. Skin microbiome genomics in DH is essentially unexplored
  8. Pharmacogenomic-guided dapsone dosing needs validation studies
  9. Gene-environment interaction studies (gluten timing, infant feeding, infections) are needed
  10. Single-cell RNA sequencing of DH lesions could reveal cell-specific pathways

16. Sources and Citations#

Key Review Articles and Primary Studies#

  1. Bonciani D, et al. "Dermatitis Herpetiformis: From the Genetics to the Development of Skin Lesions." Clinical and Developmental Immunology, 2012. PMC3386601

  2. Dolcino M, et al. "Gene Expression Profiling in Dermatitis Herpetiformis Skin Lesions." Journal of Immunology Research, 2012. Wiley

  3. Sardy M, et al. "Epidermal Transglutaminase (TGase 3) Is the Autoantigen of Dermatitis Herpetiformis." Journal of Experimental Medicine, 2002. PMC2193738

  4. Reunala T, et al. "Dermatitis Herpetiformis: An Update on Diagnosis, Disease Monitoring, and Management." Medicina, 2021. PMC8400185

  5. Salmi TT, et al. "Prevalence and Incidence of Dermatitis Herpetiformis: A 40-Year Prospective Study from Finland." British Journal of Dermatology, 2011. PubMed 21517799

  6. Caproni M, et al. "Celiac Disease as a Genetic Predisposing Factor for Dermatitis Herpetiformis: A Two-Sample Mendelian Randomization Analysis." Clinical, Cosmetic and Investigational Dermatology, 2024. PMC12697111

HLA and Genetic Association Studies#

  1. Spurkland A, et al. "HLA Association with Dermatitis Herpetiformis Is Accounted for by a Cis or Trans Associated DQ Heterodimer." Tissue Antigens, 1991. PubMed 1674926

  2. Hall RP. "Immunogenetics of Dermatitis Herpetiformis." Journal of the American Academy of Dermatology, 1991. PubMed 1931573

  3. Megiorni F, et al. "HLA-DQA1 and HLA-DQB1 in Celiac Disease Predisposition." World Journal of Gastroenterology, 2012. PMC3482388

  4. Sciurti M, et al. "Meta-Analysis and Systematic Review of HLA DQ2/DQ8 in Adults with Celiac Disease." International Journal of Molecular Sciences, 2023. PMC9863503

GWAS and Non-HLA Loci#

  1. van Heel DA, et al. "A Genome-Wide Association Study for Celiac Disease Identifies Risk Variants in the Region Harboring IL2 and IL21." Nature Genetics, 2007. PMC2274985

  2. Hunt KA, et al. "Newly Identified Genetic Risk Variants for Celiac Disease Related to the Immune Response." Nature Genetics, 2008. PubMed 18311140

  3. Dubois PC, et al. "Multiple Common Variants for Celiac Disease Influencing Immune Gene Expression." Nature Genetics, 2010. PMC2847618

  4. Trynka G, et al. "Dense Genotyping Identifies and Localizes Multiple Common and Rare Variant Association Signals in Celiac Disease." Nature Genetics, 2011. (Immunochip study)

  5. Garner CP, et al. "Replication of Celiac Disease UK Genome-Wide Association Study Results in a US Population." Human Molecular Genetics, 2009. PMC2758145

  6. Gutierrez-Achury J, et al. "Non-HLA Gene Association with Celiac Disease and Country-Specific Differences." PLOS One, 2016. PMC4807782

  7. Cenit MC, et al. "Beyond the HLA Genes in Gluten-Related Disorders." Frontiers in Nutrition, 2020. PMC7688450

  8. Abadie V, et al. "Immunochip Meta-Analysis in European and Argentinian Populations." European Journal of Human Genetics, 2020. PMC7028987

MYO9B Studies#

  1. Santiago JL, et al. "Association between the MYO9B Polymorphisms and Celiac Disease Risk: A Meta-Analysis." PLOS One, 2015. PMC4658862

Shared Autoimmune Genetics#

  1. Smyth DJ, et al. "Shared and Distinct Genetic Variants in Type 1 Diabetes and Celiac Disease." New England Journal of Medicine, 2008. PMC2840835

  2. Festen EA, et al. "A Meta-Analysis of Genome-Wide Association Scans Identifies IL18RAP, PTPN2, TAGAP, and PUS10 As Shared Risk Loci for Crohn's Disease and Celiac Disease." PLOS Genetics, 2011. PMC3029251

  3. Kahaly GJ, et al. "Celiac Disease and Autoimmune Thyroid Disease." Clinical Medicine & Research, 2007. PMC2111403

  4. Smyk DS, et al. "Celiac Disease and Autoimmune-Associated Conditions." BioMed Research International, 2014. PMC3741914

Twin and Heritability Studies#

  1. Hervonen K, et al. "Concordance of Dermatitis Herpetiformis and Celiac Disease in Monozygous Twins." Journal of Investigative Dermatology, 2000. PubMed 11121131

  2. Kuja-Halkola R, et al. "Heritability of Non-HLA Genetics in Coeliac Disease: A Population-Based Study in 107,000 Twins." Gut, 2016. PubMed 27207974

Whole-Genome/Exome Studies#

  1. Gutierrez-Achury J, et al. "Genome-Wide Association Study-Guided Exome Rare Variant Burden Analysis Identifies IL1R1 and CD3E as Potential Autoimmunity Risk Genes for Celiac Disease." Frontiers in Pediatrics, 2022. PMC8882628

  2. Saeed M, et al. "Whole Exome Sequencing of a Consanguineous Family Identifies the Possible Modifying Effect of a Globally Rare AK5 Allelic Variant in Celiac Disease." PLOS One, 2017. PubMed 28505210

  3. Population screening study 2025. Nature Scientific Reports

Epigenetics#

  1. Fernandez-Jimenez N, et al. "Celiac Disease: From Genetics to Epigenetics." World Journal of Gastroenterology, 2022. PMC8790554

  2. Fernandez-Jimenez N, et al. "The Methylome of the Celiac Intestinal Epithelium Harbours Genotype-Independent Alterations in the HLA Region." Scientific Reports, 2019. Nature

  3. Fernandez-Jimenez N, et al. "Coregulation and Modulation of NF-kB-Related Genes in Celiac Disease." Human Molecular Genetics, 2014. PMC3919015

Microbiome#

  1. Serena G, et al. "Gastrointestinal Microbiome and Gluten in Celiac Disease." Annals of Nutrition and Metabolism, 2021. PMC8519548

  2. Leonard MM, et al. "Microbiome Signatures of Progression Toward Celiac Disease Onset in At-Risk Children." PNAS, 2021. PNAS

  3. Chibbar R, et al. "Gut Microbiota in Celiac Disease: Is There Any Role for Probiotics?" Frontiers in Immunology, 2020. PMC7243837

Pharmacogenomics#

  1. Zhu Y, et al. "Dapsone-Associated Methemoglobinemia in a Patient With Slow NAT2*5B Haplotype and Impaired Cytochrome b5 Reductase Activity." Journal of Clinical Pharmacology, 2011. PMC3153586

  2. Sabbagh A, et al. "Accuracy of Various Human NAT2 SNP Genotyping Panels to Infer Rapid, Intermediate and Slow Acetylator Phenotypes." Pharmacogenomics, 2012. PMC3285565

  3. Relling MV, et al. "PharmGKB Summary: Very Important Pharmacogene Information for N-Acetyltransferase 2." Pharmacogenetics and Genomics, 2014. PMC4109976

  4. Luzzatto L, et al. "G6PD Deficiency: A Classic Example of Pharmacogenetics with Ongoing Clinical Implications." British Journal of Haematology, 2014. PMC4153881

  5. CPIC Guideline for G6PD. CPIC

TGM3 Gene#

  1. Kim IG, et al. "Assignment of the Human Transglutaminase 2 (TGM2) and Transglutaminase 3 (TGM3) Genes to Chromosome 20q11.2." Genomics, 1994. PubMed 7851911

  2. TGM3 Gene Entry. OMIM 600238

  3. TGM3 Gene. GeneCards

  4. Kaunisto H, et al. "Antibody Responses to Transglutaminase 3 in Dermatitis Herpetiformis." Frontiers in Medicine, 2022. PMC8953297

Population Genetics and Epidemiology#

  1. Bolotin D, Petronic-Rosic V. "Dermatitis Herpetiformis: Part I. Epidemiology, Pathogenesis, and Clinical Presentation." Journal of the American Academy of Dermatology, 2011. ScienceDirect

  2. Dermatitis Herpetiformis. StatPearls. NCBI Bookshelf

  3. Antiga E, et al. "Dermatitis Herpetiformis: Novel Perspectives." Frontiers in Immunology, 2019. PMC6579917

  4. Ohata C, et al. "Incidence of Dermatitis Herpetiformis in Sweden 2005 to 2018." Acta Dermato-Venereologica, 2023. Acta DV

miRNA Studies#

  1. Banaganapalli B, et al. "Expression of MicroRNAs in Adults with Celiac Disease: A Narrative Review." International Journal of Molecular Sciences, 2024. MDPI

  2. Pinto-Sanchez MI, et al. "A miRNA-Based Blood and Mucosal Approach for Detecting and Monitoring Celiac Disease." Digestive Diseases and Sciences, 2020. PubMed 31781909

  3. Magni S, et al. "A Combined mRNA- and miRNA-Sequencing Approach Reveals miRNAs as Potential Regulators of the Small Intestinal Transcriptome in Celiac Disease." International Journal of Molecular Sciences, 2021. PMC8583991

Last updated: 2026-02-14 Compiled from peer-reviewed literature and GWAS databases. SNP rs numbers, odds ratios, and chromosomal positions are sourced from the cited primary publications.