Guido H. Dolmans

Wnt Signaling and Dupuytren's Disease

BACKGROUND Dupuytrens disease is a benign fibromatosis of the hands and fingers that leads to flexion contractures. We hypothesized that multiple genetic and environmental factors influence susceptibility to this disease and sought to identify susceptibility genes to better understand its pathogenesis. METHODS We conducted a genomewide association study of 960 Dutch persons with Dupuytrens disease and 3117 controls (the discovery set) to test for association between the disease and genetic markers. We tested the 35 single-nucleotide polymorphisms (SNPs) most strongly associated with Dupuytrens disease (P<1×10(-4)) in the discovery set in three additional, independent case series comprising a total of 1365 affected persons and 8445 controls from Germany, the United Kingdom, and The Netherlands. RESULTS Initially, we observed a significant genomewide association between Dupuytrens disease and 8 SNPs at three loci. Tests of replication and joint analysis of all data from 2325 patients with Dupuytrens disease and 11,562 controls yielded an association with 11 SNPs from nine different loci (P<5.0×10(-8)). Six of these loci contain genes known to be involved in the Wnt-signaling pathway: WNT4 (rs7524102) (P=2.8×10(-9); odds ratio, 1.28), SFRP4 (rs16879765) (P=5.6×10(-39); odds ratio, 1.98), WNT2 (rs4730775) (P=3.0×10(-8); odds ratio, 0.83), RSPO2 (rs611744) (P=7.9×10(-15); odds ratio, 0.75), SULF1 (rs2912522) (P=2.0×10(-13); odds ratio, 0.72), and WNT7B (rs6519955) (P=3.2×10(-33); odds ratio, 1.54). CONCLUSIONS This study implicates nine different loci involved in genetic susceptibility to Dupuytrens disease. The fact that six of these nine loci harbor genes encoding proteins in the Wnt-signaling pathway suggests that aberrations in this pathway are key to the process of fibromatosis in Dupuytrens disease.

Dupuytren diathesis and genetic risk

PURPOSE Dupuytren disease (DD) is a benign fibrosing disorder of the hand and fingers. Recently, we identified 9 single nucleotide polymorphisms (SNPs) associated with DD in a genome-wide association study. These SNPs can be used to calculate a genetic risk score for DD. The aim of this study was to test whether certain clinical characteristics (including the DD diathesis features) of patients with DD are associated with a high genetic risk score. METHODS Between 2007 and 2010, we prospectively invited all DD patients (1,120 in total) to participate. Clinical characteristics were noted using patient- and doctor-completed questionnaires, and blood was obtained for DNA analysis. We analyzed a total of 933 subjects with genetic and clinical data. The 9 previously identified DD SNPs were used to calculate a weighted genetic risk score. Patients were categorized into high and low genetic risk score groups, according to their weighted genetic risk score. Logistic regression was performed to study the association of clinical characteristics with a high genetic risk score. RESULTS In a univariate regression model, patients with an age of onset of DD younger than 50 years, a family history positive for DD, knuckle pads, and Ledderhose disease were statistically significantly associated with a high genetic risk score. In an additional analysis using high and low genetic risk groups that deviate further from the median, Ledderhose disease was no longer significantly associated with DD. CONCLUSIONS Patients with DD who present with these diathesis features, and predominantly patients with knuckle pads, are more likely to carry more risk alleles for the discovered DD SNPs than patients without these diathesis features. CLINICAL RELEVANCE These markers may prove useful in predicting disease progression or recurrence.

WNT2 Locus Is Involved in Genetic Susceptibility of Peyronie's Disease

INTRODUCTION Peyronies disease (PD) is a fibromatosis of the penis, with a pathology very similar to what is seen in the hand (palmar fascia) in Dupuytrens disease (DD). Recently, we performed a genome-wide association study and identified nine genetic loci containing common variants associated with DD. Seven of these loci mapped within or near genes of the canonical WNT pathway and each locus yielded relatively large odds ratios (ORs) for DD disease status. AIM Given the clinical overlap between PD and DD, we examined whether the nine DD susceptibility loci are also involved in PD. METHODS An association study was performed using a case/control design. From 2007 to 2010, we prospectively included 111 men who had been clinically diagnosed with PD. Control subjects (N = 490 males) were randomly drawn from a population-based cohort from the same region of the Netherlands. Allele frequencies in the 111 PD cases and 490 controls were compared using a 1-degree-of-freedom basic chi-square test. A P value < 0.05 after Bonferroni correction for the nine tested single nucleotide polymorphisms (SNPs) was considered statistically significant (i.e., P < 0.0056). MAIN OUTCOME MEASURE Association of genetic markers (SNPs) with PD. RESULTS We observed significant association with SNP rs4730775 at the wingless-type MMTV integration site family member 2 (WNT2) locus on chromosome 7 (P = 0.0015, OR 0.61), but found no evidence for the other eight loci being involved with PD despite the large effect size seen for some of these variants in DD. The WNT2 association was even more significant after we removed 15 patients with comorbid DD. CONCLUSIONS WNT2 is a susceptibility locus for PD and our finding provides evidence for a partly shared genetic susceptibility between PD and DD.

Meta-Analysis of Genome-Wide Association Studies and Network Analysis-Based Integration with Gene Expression Data Identify New Suggestive Loci and Unravel a Wnt-Centric Network Associated with Dupuytren's Disease

Dupuytren´s disease, a fibromatosis of the connective tissue in the palm, is a common complex disease with a strong genetic component. Up to date nine genetic loci have been found to be associated with the disease. Six of these loci contain genes that code for Wnt signalling proteins. In spite of this striking first insight into the genetic factors in Dupuytren´s disease, much of the inherited risk in Dupuytren´s disease still needs to be discovered. The already identified loci jointly explain ~1% of the heritability in this disease. To further elucidate the genetic basis of Dupuytren´s disease, we performed a genome-wide meta-analysis combining three genome-wide association study (GWAS) data sets, comprising 1,580 cases and 4,480 controls. We corroborated all nine previously identified loci, six of these with genome-wide significance (p-value < 5x10-8). In addition, we identified 14 new suggestive loci (p-value < 10−5). Intriguingly, several of these new loci contain genes associated with Wnt signalling and therefore represent excellent candidates for replication. Next, we compared whole-transcriptome data between patient- and control-derived tissue samples and found the Wnt/β-catenin pathway to be the top deregulated pathway in patient samples. We then conducted network and pathway analyses in order to identify protein networks that are enriched for genes highlighted in the GWAS meta-analysis and expression data sets. We found further evidence that the Wnt signalling pathways in conjunction with other pathways may play a critical role in Dupuytren´s disease.

A Clinical Genetic Study of Familial Dupuytren’s Disease in the Netherlands

Although several studies on the genetic origin of Dupuytren’s disease have been performed, the mode of inheritance is still not clear. We describe 11 pedigrees with familial Dupuytren’s disease from the Netherlands.