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This study aims to investigate associations between observed clinical parameters and known genetic risk factors of psoriasis in a well-defined prospective cohort of paediatric patients with plaque psoriasis (n = 151). Significant associations were found for paediatric-onset psoriasis with ERAP1 (p = 0.002), IL23R (p = 0.01), LCE3C&#95;LCE3B-del (p = 0.00049) and HLA-C*06 (p = 3.15 × 10(-30)). Psoriasis severity was associated with the single nucleotide polymorphisms tagging IFIH1 and ERAP1 (p < 0.05). An onset before 10 years of age was associated with IL12B (p = 0.02). Nail psoriasis was more often seen in HLA-C*06-negative patients (p = 0.008). Remarkably, family history is clearly not associated with HLA-C*06 in this specific group. The large proportion of patients with a positive family history in HLA-C*06 negative patients (and the lack of correlation between the two) indicates that other genes, either alone or interaction between two or more genes, may have significant effects on heritability.

A single previous study has demonstrated significant association of psoriasis with copy number of β-defensin genes, using DNA from psoriasis cases and controls from Nijmegen and Erlangen. In this study, we attempted to replicate that finding in larger new cohorts from Erlangen (N=2,017) and Michigan (N=5,412), using improved methods for β-defensin copy number determination based on the paralog ratio test, and enhanced methods of analysis and association testing implemented in the CNVtools resource. We demonstrate that the association with psoriasis found in the discovery sample is maintained after applying improved typing and analysis methods (P=5.5 × 10(-4), odds ratio (OR)=1.25). We also find that the association is replicated in 2,616 cases and 2,526 controls from Michigan, although at reduced significance (P=0.014), but not in new samples from Erlangen (1,396 cases and 621 controls, P=0.38). Meta-analysis across all cohorts suggests a nominally significant association (P=6.6 × 10(-3)/2 × 10(-4)) with an effect size (OR=1.081) much lower than found in the discovery study (OR=1.32). This reduced effect size and significance on replication is consistent with a genuine but weak association.

Objective: Two recent studies, in a Spanish and a Chinese population, point to an association between rheumatoid arthritis (RA) risk and the deletion of the Late Cornified Envelope (LCE) 3B and 3C genes (LCE3C&#95;LCE3B-del), a known risk factor for psoriasis. We aimed to replicate these studies in a large Dutch cohort., Methods: 1039 RA cases and 759 controls were genotyped for LCE3C&#95;LCE3B-del. Association analysis was performed for the complete cohort and after stratification for the serologic markers anti-cyclic citrullinated peptide and rheumatoid factor. A meta-analysis was performed combining our data with the Spanish and Chinese datasets, resulting in an analysis including 2466 RA cases and 2438 controls., Results: In the Dutch cohort we did not observe a significant association of LCE3C&#95;LCE3B-del (p = 0.093) with RA risk. A stratified analysis for the serologic positive and negative group did not show an association between the genetic variant and disease risk, either. The meta-analysis, however, confirmed a significant association (p<0.0001, OR = 1.31, 95% confidence interval 1.16-1.47)., Conclusion: Our meta-analysis confirms the association of the LCE3 deletion with RA, suggesting that LCE3C&#95;LCE3B-del is a common risk factor for (auto)immune diseases.

There is evidence to suggest that genetic factors play an important role in the development of basal cell carcinomas (BCCs), and that skin neoplasms might be a sign for a genetic predisposition to cancer. We investigated whether the incidence of visceral and skin malignancies among first-degree relatives of BCC-patients was increased. Postal questionnaires were sent to 249 BCC-patients, who were divided into two groups (young = BCC under the age of 51 years and older = BCC over the age of 50 years), and asked them about cancer in their first-degree relatives. The reported numbers of cancer among the relatives were compared with the expected numbers based on sex and age-specific population-based incidence rates. The accuracy of the reported diagnoses was verified. A total of 157 BCC-patients reported 277 malignancies in 1,272 relatives. The incidence of the following cancers was higher than expected in relatives from young BCC-patients: bone and soft tissue (O/E = 3.91; 95% CI: 1.43-8.66), skin (O/E = 2.13; 95% CI: 1.30-3.29) and digestive tract (O/E = 1.59; 95% CI: 1.10-2.23). In relatives of older BCC-patients, only the incidence of digestive tract cancer was higher than expected (O/E = 1.44; 95% CI: 1.08-1.89). Diagnoses that were verified turned out to be accurate in 87% of the cases. This study suggests that the risk of certain cancers, particularly that of the digestive tract, in first-degree relatives of BCC-patients is increased. These findings may indicate a genetic predisposition to both skin and visceral malignancies in this patient group.