A genome-wide meta-analysis of palmoplantar pustulosis implicates T_H2 responses and cigarette smoking in disease pathogenesis

Background Palmoplantar pustulosis (PPP) is an inflammatory skin disorder that mostly affects smokers and manifests with painful pustular eruptions on the palms and soles. Although the disease can present with concurrent plaque psoriasis, TNF and IL-17/IL-23 inhibitors show limited efficacy. There is therefore a pressing need to uncover PPP disease drivers and therapeutic targets. Objectives We sought to identify genetic determinants of PPP and investigate whether cigarette smoking contributes to disease pathogenesis. Methods We performed a genome-wide association meta-analysis of 3 North-European cohorts (n = 1,456 PPP cases and 402,050 controls). We then used the scGWAS program to investigate the cell-type specificity of the association signals. We also undertook genetic correlation analyses to examine the similarities between PPP and other immune-mediated diseases. Finally, we applied Mendelian randomization to analyze the causal relationship between cigarette smoking and PPP. Results We found that PPP is not associated with the main genetic determinants of plaque psoriasis. Conversely, we identified genome-wide significant associations with the FCGR3A/FCGR3B and CCHCR1 loci. We also observed 13 suggestive (P &lt; 5 × 10−6) susceptibility regions, including the IL4/IL13 interval. Accordingly, we demonstrated a significant genetic correlation between PPP and TH2-mediated diseases such as atopic dermatitis and ulcerative colitis. We also found that genes mapping to PPP-associated intervals were preferentially expressed in dendritic cells and often implicated in T-cell activation pathways. Finally, we undertook a Mendelian randomization analysis, which supported a causal role of cigarette smoking in PPP. ConclusionsThe first genome-wide association study of PPP points to a pathogenic role for deregulated TH2 responses and cigarette smoking.</p

The Genetic and Environmental Determinants of Benign Melanocytic Naevi

Abstract for thesis entitled 'The genetic and environmental determinants ofbenign melanocytic naevi' submitted by Dr Rachel Caroline Wachsmuth for the degree of Doctor of Medicine 2006. The work covered in this thesis contributes to our understanding ofthe relationships between genes, sun exposure, benign melanocytic naevi and melanoma. Rare families with multiple cases of melanoma have been found to possess mutations in a limited number of genes, the first of which to be identified being CDKN2A (on chromosome 9p) that codes for the cell cycle regulating protein: p16. Epidemiological studies have shown that melanoma is a disease primarily of Caucasians who are at even greater risk with increased sun exposure. Furthermore, individuals with numerous benign melanocytic naevi are at increased risk ofmelanoma both in melanoma families and the general population. A combination of sun exposure and genes defining general and naevus phenotype is therefore key to the development of melanoma. In the first part of this thesis I examine the relationships between CDKN2A mutation status, --- --- ---:-----nae\ilisphe-riotype -ana presence of melanom-a,-inastuCly of 5-UK-iriehirioma-families. -I----- demonstrate a naevogenic role for CDKN2A, but a lack of absolute correlation between general naevus phenotype and CDKN2A genotype. I also estimate the penetrance ofCDKN2A mutation for melanoma within these families. I conClude that the practice oftargeting individuals with many naevi as potential gene carriers is untenable for melanoma screening purposes. In the second and main part of this thesis I examine the role ofgenes and sun exposure on the development of benign naevi in a twin study of221 UK twin pairs. In agreement with published literature, naevi were more common in males, persons with fairer skintypes or blue eyes, and in continuously sun exposed body sites compared to intermittently or non-exposed sites. Heritability analysis assessed genetic and environmental effects on naevus development and estimated that 26% of the variation in naevus counts between individuals was due to environmental effects (one third of which is hot holiday sun exposure), 3% to age and sex, 6% to measurement error and 65% due to genetic effects. Variation in naevus number is thus predominantly genetically inherited with a further breakdown ofthis 65% into 7% associated with eye colour, 6% with hair colour, I% with skintype and 51% with as yet unidentified 'naevus genes'. Such naevus genes may represent more common but lower penetrant melanoma genes than those identified to date. The previously mentioned CDKN2A gene was studied as a possible naevus gene by linkage analysis, but found not to associate with naevus counts. Further gene studies are therefore required to identify these naevus genes.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

A to F Think MF! A Memory Aid for the Early Recognition of Mycosis Fungoides/Sézary syndrome.

Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of rare non-Hodgkin lymphomas that account for approximately 75% of all cutaneous lymphomas. Classic mycosis fungoides (MF), its variants, and Sézary syndrome (SS) are the most common types of CTCL, with an estimated annual incidence of 0.3–0.9/100 000 population and 0.1/1 000 000 population, respectively, in Europe. Patients with early-stage MF (stage IA–IIA) have predominantly skin-limited disease with patches and/or plaques with or without nonlymphomatous lymphadenopathy (typically due to dermatopathic changes or early nodal involvement without effacement of architecture) and no or minimal blood involvement. Early-stage MF is associated with a favourable 10-year overall survival rate. Late-stage MF/SS is characterized by any tumour (IIB), erythroderma, lymph node effacement, blood involvement (meeting criteria for SS) or visceral disease. In contrast to early-stage disease, survival is poor (10-year overall survival 15–53%) for late-stage MF/SS. The risk of progression from early- to late-stage disease has been estimated to be 10–30%.1,2 Across all stages, severe itch is one of the most distressing symptoms for patients, leading not only to impaired quality of life, but also to a significant emotional burden. When compounded by a delayed diagnosis, this psychological toll is further amplified, underscoring the importance of timely recognition

The Effect of Sun Exposure in Determining Nevus Density in UK Adolescent Twins

We report a study of 221 teenage twin pairs to examine the genetic and environmental determinants of nevi representing the most potent phenotypic risk factor for melanoma. Our published heritability analysis estimated that nevi are mainly genetically determined. In this paper we examine the role of sun exposure. We report a correlation between nevus density and sun exposure, particularly that acquired in hotter countries than in the UK (mean nevus density 41 per m2 in those in the highest quartile of exposure vs 24 per m2 in those with no exposure, p<0.0001). We were not able to demonstrate a protective effect for either sun protection cream or shirt wearing. By including phenotypic variables and reported sun exposure into the heritability analysis, we conclude that 66% of the total variance of nevus count is attributable to genetic effects: 7% associated to eye color, 6% to hair color, and 1% to reported skin type, which leaves 52% as to yet unidentified genetic factors. Of the 25% of variation attributable to environmental influences, one-third is estimated to be because of sun exposure on hot holidays

Jazz The Known: Artistic Experiments on Women of the ’20s

Jazz The Known: Artistic Experiments on Women of the ’20s. Co-organised with the Goethe-Institut, Ines Weizman, the Royal College of Art and Belmacz gallery. An evening of conversations on the occasion of Belmacz's group exhibition Women of the ’20s, at the Goethe-Institut London, including artists, curators, historians and theorists of art and architecture. Through a series of dynamic relays, this expanded conversation aimed to reflect on artistic practices that ‘jazz’ the known, in order to make sensible occluded ways of being

Genotype/Phenotype and Penetrance Studies in Melanoma Families with Germline CDKN2A Mutations

Patients with a family history of melanoma are at increased risk of this tumor. Those family members who also have the atypical mole syndrome are commonly targeted for screening in the belief that they are more likely to be mutant gene carriers. We have correlated the atypical mole syndrome phenotype and gene carrier status in five families with germline CDKN2A mutations and shown that family members with the atypical mole syndrome were three times more likely to be mutant gene carriers than their relatives who did not have the atypical mole syndrome (odds ratio 3.4; confidence interval 1.0–11.1), supporting the view that CDKN2A is nevogenic. Individual characteristics which best predicted mutant gene carrier status were: nevi on the buttocks (odds ratio 4.4; confidence interval 1.6–12.4), nevi on the feet (odds ratio 4.2; confidence interval 1.4–12.5), total nevus number being at least 100 (nevi ≥ 2 mm in diameter) (odds ratio 3.4; confidence interval 1.0–11.1) and two or more clinically atypical nevi (odds ratio 3.1; confidence interval 1.1–9.0). Gene carriers were also significantly more likely to have noticeable freckling and possibly also Fitzpatrick skin types 1–3. The overlap between gene carriers and nongene carriers was, however, marked: the atypical mole syndrome did not clearly differentiate mutant gene carriers from those with a normal gene. This study is of significance to clinicians as the clinical practice of using the atypical mole syndrome to identify particular family members for surveillance is shown to be inappropriate. Until formal gene testing is available, all members of families with an excessive number of melanoma cases should be treated as potential mutation carriers at increased risk of melanoma

Heritability and Gene–Environment Interactions for Melanocytic Nevus Density Examined in a U.K. Adolescent Twin Study

Risk factors for melanoma include environmental (particularly ultraviolet exposure) and genetic factors. In rare families, susceptibility to melanoma is determined by high penetrance mutations in the genes CDKN2A or CDK4, with more common, less penetrant genes also postulated. A further, potent risk factor for melanoma is the presence of large numbers of melanocytic nevi so that genes controlling nevus phenotype could be such melanoma susceptibility genes. A large Australian study involving twins aged 12 y of predominantly U.K. ancestry showed strong evidence for genetic influence on nevus number and density. We carried out essentially the same study in the U.K. to gain insight into gene–environment interactions for nevi. One hundred and three monozygous (MZ) and 118 dizygous (DZ) twin pairs aged 10–18 y were examined in Yorkshire and Surrey, U.K. Nevus counts were, on average, higher in boys (mean = 98.6) than girls (83.8) (p =0.009) and higher in Australia (110.4) than in the U.K. (79.2, adjusted to age 12 y, p <0.0001), and nevus densities were higher on sun-exposed sites (92 per m2) than sun-protected sites (58 per m2) (p <0.0001). Correlations in sex and age adjusted nevus density were higher in MZ pairs (0.94, 95%CI 0.92–0.96) than in DZ pairs (0.61, 95%CI 0.49–0.72), were notably similar to those of the Australian study (MZ = 0.94, DZ = 0.60), and were consistent with high heritability (65% in the U.K., 68% in Australia). We conclude that emergence of nevi in adolescents is under strong genetic control, whereas environmental exposures affect the mean number of nevi