Will Shaw

Dupuytren's disease & drug repurposing

How the disease works

How Dupuytren's starts and gets worse, what's happening in the cells, and what the genetics tell us.

Why it’s usefulIt explains why timing matters: a drug would most likely need to be given early, before a finger is stuck in a bend.

~80%
heritability, from 30,330 Danish twin pairs PMID 24835475
12 · 21 · 29%
modelled prevalence at ages 55, 65 and 75 in Western populations PMID 24263394
3–4 : 1
male-to-female ratio; bilateral in about half of cases PMID 34225446
11–16%
of hands stable or regressing over five years without treatment PMID 35404338

Nodule → cord → contracture Interactive

Schematic side view of a hand and finger A schematic showing the palm and one finger from the side. The current stage is described in the text beside the diagram.

Schematic, not to scale. Digits 4 and 5 are most commonly affected; flexor tendons and muscle are not involved PMID 34225446.

The cells a drug would target are busiest early, in the nodule. By the time a finger is fixed in a bend, many of them have gone. So a drug would most likely need to be given early PMID 19910144.

How a fibroblast becomes a myofibroblast Animated

Fibroblast to myofibroblast transition An animated schematic of a palm fibroblast receiving signals, becoming a contractile myofibroblast, and leaving behind a cell-poor collagen cord. Each step is described in the text beside it.

The genetics

Manhattan plot of about 200 genome-wide significant Dupuytren's variants across chromosomes 1 to 22. Wnt-pathway genes are highlighted in red. WNT7B on chromosome 22 reaches about 509 on the minus log10 p scale, SFRP4 on chromosome 7 about 180, with LINC01592, DUXA, RSPO2 and MMP14 also labelled. A dashed line marks genome-wide significance at p = 5 × 10⁻⁸.
How to read this chart: each dot is a genetic variant linked to Dupuytren's. Height shows how confident the studies are about the link, not how much the variant raises risk. It pools p-values from studies ranging from 73 to about 651,000 participants, so the biggest studies produce the tallest points. The axis is broken: WNT7B reaches −log10 p ≈ 509.
Genome-wide significant variants from the GWAS Catalog (11 studies, 255 curated associations), GRCh38 coordinates. Download the associations (CSV).

The genetics point most strongly at Wnt signalling, a set of proteins that control how cells grow. The first large study found nine loci; six contained Wnt-pathway genes, including the two largest effects in the literature, SFRP4 (OR 1.98) and WNT7B (OR 1.54) PMID 21732829. WNT7B has since replicated in a North American cohort PMID 39570219.

One gene has a clear explanation. A common MMP14 variant leaves the enzyme with 17% of its normal collagen-cutting activity. That means the body is worse at clearing collagen away, which is a different problem from making too much of it. About 30% of people worldwide carry at least one copy PMID 33592276.

The popular idea that Dupuytren's is a "Viking disease" doesn't hold up: tests for extra Norse ancestry found none PMID 31663799. Three of 61 risk regions do carry DNA inherited from Neandertals, including the second and third strongest PMID 37315093.

None of the strongest genetic targets has a drug yet. SFRP4, WNT7B, EPDR1 and MMP14 have no approved drug, and studies disagree about which way SFRP4 pushes the disease PMID 28886342 PMID 36719100.

Which risk factors actually cause it?

Observational studies show what goes along with Dupuytren's. Mendelian randomisation uses genetics to test whether a risk factor actually causes it. The two don't always agree.

ExposureObservational studiesMendelian randomisationSources
Long-term high blood sugarAssociated (diabetes)Supports causation OR 1.17 per 10 mmol/mol HbA1cPMID 32970002PMID 38205890
AlcoholDose–response associationSupports causation in two studiesPMID 37679690PMID 42608758
SmokingOR ≈ 1.5, very high heterogeneityNot supported in two studiesPMID 41092106PMID 37679690
Higher body-mass index-Inverse, unexplained OR 0.94 per 5 kg/m²PMID 38205890PMID 34906131
Manual work and vibrationConsistent dose–response (GRADE moderate for vibration)Cannot be tested not genetically instrumentablePMID 39317441PMID 36635095