Evidence for a polygenic contribution to androgenetic alopecia.

BACKGROUND: Male pattern baldness (androgenetic alopecia, AGA) is a highly heritable trait and the most common form of hair loss in humans. Eight genome-wide significant risk loci for AGA have been identified. OBJECTIVES: To determine whether a polygenic component contributes to the genetic risk for AGA. METHODS: This study used a German case-control sample for AGA, which comprised 581 severely affected patients and 617 controls, to determine the contribution of polygenic variance to AGA risk. The sample was divided evenly into discovery and test samples. An additive polygenic risk score was calculated from risk alleles with increasingly liberal P-values in the discovery dataset, which was then used to test for the enrichment of AGA risk score alleles in the independent test samples. RESULTS: The polygenic score analysis provided significant evidence for a polygenic contribution to AGA where the amount of variance explained was 1·4-4·5%. CONCLUSION: This study provides evidence for the specific contribution of a polygenic component to the overall heritable risk for AGA. To some degree, the polygenic architecture of AGA might reflect the complexity of the biological pathways involved. Further analyses and strategies that complement conventional genome-wide association studies are needed to identify these factors. These may include pathway-based analyses, the analysis of functional candidate genes and tests for epistatic effects with known loci.

Investigation of selected cytokine genes suggests that IL2RA and the TNF/LTA locus are risk factors for severe alopecia areata.

BACKGROUND: Alopecia areata (AA) is the second most common cause of hair loss in humans, and has a genetically complex inheritance. The hypothesis that AA is autoimmune in nature is supported by previous studies. These report an association with specific HLA alleles, as well as genetic variants of other genes implicated in autoimmunity, such as various cytokine genes. However, these cannot yet be considered proven susceptibility loci, as many of these association findings were derived from small patient samples. OBJECTIVES: To investigate the association between AA and selected cytokine genes using a sample of 768 patients with AA and 658 controls of Central European origin. METHODS: Eleven single-nucleotide polymorphisms (SNPs) from cytokine genes implicated in previous AA studies were genotyped. These genes were IL1B, IL1A, IL1RN, MIF, IFNG and the TNF/LTA gene region. We also genotyped 15 SNPs selected from cytokine genes that have shown significant association with other autoimmune diseases. These genes were IL10, IL36RN, IL12B, IL6, IL2, IL23, IL2RA and IL4R. RESULTS: Significant association was found for two variants within both IL2RA and TNF/LTA. In the overall sample, the most significant results were obtained for the IL2RA variant rs706778 (P = 0·00038) and the TNF/LTA locus variant rs1800629 (P = 0·0017). In subgroup analyses, according to severity, age at onset and family history these effects were stronger in the severely affected patients, with the lowest P-values being obtained for rs706778 (P = 3·8 × 10(-6) ). CONCLUSIONS: Our results point to the involvement of IL2RA and the TNF/LTA region in the aetiology of AA, in particular severe AA, and provide further support for the hypothesis that AA is autoimmune in nature.

Susceptibility variants on chromosome 7p21.1 suggest HDAC9 as a new candidate gene for male-pattern baldness.

BACKGROUND: Male-pattern baldness (androgenetic alopecia, AGA) is the most common form of hair loss among humans. Research has shown that it is caused by genetic factors. Numerous studies have unequivocally identified two major genetic risk loci for AGA: the X-chromosomal AR/EDA2R locus, and the PAX1/FOXA2 locus on chromosome 20. OBJECTIVES: To identify further candidate genes for AGA, and thus gain further insights into this phenotype. METHODS: A German sample of 581 severely affected cases and 617 controls was used to perform a genome-wide association study. The identified associated locus was further analysed by fine-mapping, and then independently replicated in an Australian sample. Expression and pathway analyses were performed to characterize the susceptibility gene identified. RESULTS: The most significant association signal was obtained for rs756853 (P = 1·64 × 10(-7) ), which is located intronically in the histone deacetylase 9 (HDAC9) gene. Fine-mapping and a family-based analysis revealed that rs756853 and the 6-kb distal rs2249817 were the most highly associated single nucleotide polymorphisms. The association finding was replicated in an independent Australian sample, when the analysis was restricted to severely affected cases and unaffected controls (P = 0·026). Analysis of rs2249817 in a combined sample of severely affected German and Australian cases and unaffected controls revealed a strong association signal (P = 9·09 × 10(-8) ). Tissue expression studies demonstrated HDAC9 expression in various tissues, including tissues of relevance to AGA. No strong genotypic effects were observed in genotype-specific expression or splice studies. Pathway analyses supported the hypothesis that HDAC9 plays a functional role in AGA via interaction with the AR gene. CONCLUSIONS: The present study suggests that HDAC9 is the third AGA susceptibility gene.

[Galli-Galli disease. Clinical and histopathological investigation using a case series of 18 patients]. / Morbus Galli-Galli. Klinische und histopathologische Untersuchung anhand einer Fallserie von 18 Patienten.

Galli-Galli disease, a rare genodermatosis belonging to the spectrum of reticulate pigment dermatoses, is classified as an acantholytic variant of Dowling-Degos disease on the basis of its characteristic clinical and histological findings. In the context of this case series, Galli-Galli disease is characterized in detail based on the clinical and histopathological evaluation of 18 patients. The disease pattern is discussed in view of the current literature. In addition, a classification into two clinical subtypes is made and a genotype/phenotype correlation with mutations in the keratin 5 (KRT5) gene is established.

Systematic mutation screening of KRT5 supports the hypothesis that Galli-Galli disease is a variant of Dowling-Degos disease.

BACKGROUND: Galli-Galli disease (GGD) is a rare genodermatosis. Its clinical presentation is identical to that of Dowling-Degos disease (DDD), but the presence of the histopathological feature of acantholysis in GGD is thought to distinguish the two disorders. Mutations in the keratin 5 gene (KRT5) have been identified in the majority of patients with DDD and in a small number of patients with GGD. OBJECTIVES: To provide further support for the hypothesis that GGD is merely a variant of DDD, and to examine whether acantholysis is genuinely rare in DDD or rather a common but under-reported histological feature of DDD. METHODS: We conducted the first systematic mutational investigation of patients with GGD and re-examined the histopathology of patients previously assigned a diagnosis of DDD. For the mutational investigation, KRT5 was sequenced in seven unrelated patients with clinically and histopathologically confirmed GGD. In addition, the histopathological findings of six patients with DDD were re-evaluated. RESULTS: The mutation c.418dupA was found in five patients with GGD. The typical histopathological features of GGD were identified in six patients who had previously been assigned a diagnosis of DDD. CONCLUSIONS: We found further evidence to suggest that GGD is indeed a variant of DDD and not a distinct disease entity. Two facts in particular support this conclusion: the same KRT5 mutation was found in patients with GGD and in patients with DDD, and acantholysis seems to be present in a large number of patients who had previously been assigned a diagnosis of DDD.

The TRAF1/C5 locus confers risk for familial and severe alopecia areata.

BACKGROUND: Alopecia areata (AA) is a common hair loss disorder with a complex mode of inheritance. Autoimmune mechanisms are presumed to be crucial aetiologically. It is plausible that a number of autoimmune disorders may share a common genetic background. This phenomenon has been demonstrated in previous studies, which have shown an overlap of susceptibility alleles between AA and other autoimmune disorders. Recent studies have shown that genetic variants on the TRAF1/C5 (tumor necrosis factor receptor-associated factor 1, complement component 5) locus confer susceptibility to rheumatoid arthritis (RA). OBJECTIVES: To examine the role of the TRAF1/C5 locus in the development of AA using a large sample of 1,195 patients with AA and 1280 controls. METHODS: We genotyped the two most significant single nucleotide polymorphisms (SNPs) (rs10818488, rs2416808) from a former RA candidate gene study. After having obtained evidence for association, we performed a fine-mapping study and genotyped the locus with an additional 27 SNPs. RESULTS: While no significant result was obtained for the overall sample, rs2416808 showed significant associations in the analysis of the subgroups with severe AA and with a positive family history. The most significant P-value for rs2416808 was in familial cases (P = 0.004, P(corr) = 0.026). The fine mapping revealed significant associations for four additional SNPs in the analysis of subgroups, with rs2416808 remaining the most significant marker. CONCLUSIONS: Our results point to the involvement of the TRAF1/C5 locus in the aetiology of familial and severe AA, and provide further support for a shared aetiology between AA and other autoimmune disorders.

[Omalizumab for therapy-resistant chronic urticaria with angioedema]. / Omalizumab bei therapierefraktärer chronischer Urtikaria mit Angioödem.

A 29-old man presented with severe chronic urticaria and angioedema. Routine evaluation including history, laboratory parameters and imaging procedures did not reveal any pathologic findings. We tried combined therapy regimes including high-dose systemic corticosteroids and antihistamines, leukotriene antagonist, cyclosporine and antibiotics. Because of a poor response and dramatic escalation of symptoms, we initiated therapy with omalizumab resulting in the complete remission of the chronic urticaria after two weeks.

[Incontinentia pigmenti (Bloch-Sulzberger syndrome)]. / Incontinentia pigmenti (Bloch-Sulzberger-Syndrom).

A female infant, aged two weeks, presented with linear erythematous crusted papules, plaques and blisters on the right leg which had occurred two days after birth. Histological examination revealed typical features of incontinentia pigmenti in the inflammatory stage. Incontinentia pigmenti is a rare X-linked dominant genodermatosis caused by mutations in the NEMO gene located at Xq28 affecting the skin, different organ systems, the central nervous system, eyes, teeth and skeleton with variable expression. We summarize important clinical and diagnostic aspects of incontinentia pigmenti as well as its genetic and molecular basis.

[Infantile hemangioma. Successful treatment with propranolol]. / Infantiles Hämangiom. Erfolgreiche Behandlung mit Propranolol.

We report on an infant, aged four months, suffering from a severe hemangioma of the left labium majus. We induced systemic treatment with propranolol in off-label-use over a period of 5 1/2 months. A few weeks after onset of the treatment, the size and color of hemangioma was obviously reduced; finally there was an almost complete regression. This result underlines the role of propranolol in treatment of problematic hemangioma.

The R620W polymorphism in PTPN22 confers general susceptibility for the development of alopecia areata.

BACKGROUND: The functional R620W (c.1858C>T) variant of the protein tyrosine phosphatase nonreceptor 22 gene (PTPN22) has been associated with a variety of autoimmune disorders. A recent study has suggested that R620W also contributes to the severe form of alopecia areata (AA). OBJECTIVES: We sought to replicate the finding of an association between PTPN22 and severe AA. In addition, we wanted to study the effect of PTPN22 on the general risk to develop AA and on other subtypes of AA (mild AA, early/late age at onset, positive/negative family history). METHODS: The R620W variant was genotyped in a large case-control sample of Belgian-German origin with 435 patients and 628 controls. RESULTS: Significant results were obtained for the overall collective of patients with AA (P=0.007). Subdividing the sample according to severity of AA, family history and age at onset, we detected lowest P-values for patients with the severe form of AA (Pcorr=0.036), with a positive family history (Pcorr=0.042) and with an age at onset

Investigation of the functional variant c.-169T > C of the Fc receptor-like 3 (FCRL3) gene in alopecia areata.

A functional variant in the Fc receptor-like 3 (FCRL3) gene has been implicated in susceptibility to autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and autoimmune thyroid disease. Investigating a large case-control sample of patients with alopecia areata (AA), we found no evidence for the involvement of FCRL3 in susceptibility to AA.

Investigation of the p.Ser278Arg polymorphism of the autoimmune regulator (AIRE) gene in alopecia areata.

A recent study has suggested that the g.961C >G (p.Ser278Arg) variant of the autoimmune regulator (AIRE) gene contributes to susceptibility to alopecia areata (AA). We attempted to replicate this finding using a case-control sample of Belgian-German origin (273 patients and 283 controls). Despite adequate power, our study results do not support a significant association of the risk allele in our AA patient sample. This remained the case when we stratified our sample according to severity and family history of disease. Our study results do not support the hypothesis that the g.961C >G (p.Ser278Arg) polymorphism of the AIRE gene is associated with an increased risk for AA.