Summary To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of three genome-wide association studies (GWAS) and two independent datasets genotyped on the Immunochip, involving 10,588 cases and 22,806 controls in total. We identified 15 new disease susceptibility regions, increasing the number of psoriasis-associated loci to 36 for Caucasians. Conditional analyses identified five independent signals within previously known loci. The newly identified shared disease regions encompassed a number of genes whose products regulate T-cell function (e.g. RUNX3, TAGAP and STAT3). The new psoriasis-specific regions were notable for candidate genes whose products are involved in innate host defense, encoding proteins with roles in interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C), and NF-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.

Atopic dermatitis (AD) is a multifactorial, heterogenous disease that arises as a result of the interaction between both environmental and genetic factors. Changes in at least three groups of genes encoding structural proteins, epidermal proteases, and protease inhibitors predispose to a defective epidermal barrier and increase the risk of developing AD. Loss-of-function mutations found within the FLG gene encoding the structural protein, filaggrin, represent the most significant genetic factor predisposing to AD identified to date. Enhanced protease activity and decreased synthesis of the lipid lamellae lead to exacerbated breakdown of the epidermal barrier. Environmental factors, including the use of soap and detergents, exacerbate epidermal barrier breakdown, attributed to the elevation of stratum corneum pH. A sustained increase in pH enhances the activity of degradatory proteases and decreases the activity of the lipid synthesis enzymes. The strong association between both genetic barrier defects and environmental insults to the barrier with AD suggests that epidermal barrier dysfunction is a primary event in the development of this disease. Our understanding of gene-environment interactions should lead to a better use of some topical products, avoidance of others, and the increased use and development of products that can repair the skin barrier.

To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 × 10⁻⁸ and two loci with a combined P < 5 × 10⁻⁷). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 × 10⁻⁶). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis

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The frequency of alopecia areata and observed patterns of heritability are in keeping with a polygenic inheritance model but the genetics of alopecia areata is still poorly understood. The role of environmental factors in triggering disease initiation or exacerbation remains almost entirely speculative. Using the candidate gene approach, three susceptibility/severity factors have been identified. HLA alleles were the first to show a strong association with alopecia areata and some DQB and DR alleles have been demonstrated to confer a high risk for disease by both case-control and family-based studies. Interleukin (IL)-1 cluster genes, mainly the IL-1 receptor antagonist, show a strong association with disease severity in alopecia areata and a number of other autoimmune and inflammatory diseases. Finally, the association of alopecia areata with Down's syndrome, the high frequency of alopecia areata in autoimmune polyglandular syndrome type I due to mutations of the autoimmune regulator (AIRE) gene on chromosome 21q22.3 and the finding of association with MX1, another gene in the Down's syndrome region of chromosome 21 indicate this area of the genome as a promising target for future-family based investigations. The role of individual genes of the MHC, IL-1 cluster or chromosome 21q22.3 is difficult to establish and further genetic and functional investigations are needed to confirm their involvement in the pathogenesis of alopecia areata.

Atopic dermatitis is a disease with an impaired skin barrier that affects 15%-20% of children. In the normal epidermis, the stratum corneum chymotryptic enzyme (SCCE) thought to play a central role in desquamation by cleaving proteins of the stratum corneum (e.g., corneodesmosin and plakoglobin). Genetic variations within the SCCE gene could be associated with dysregulation of SCCE activity leading to an abnormal skin barrier. We screened the SCCE gene for variations and performed a case-control study on 103 atopic dermatitis patients and 261 matched controls. 16 synonymous single nucleotide polymorphisms (SNPs) have been identified and a 4 bp (AACC) insertion has been found in the 3'UTR. We performed an association study of the SCCE AACC insertion in the 3'UTR, and found a significant trend between the AACC allele with the two insertions and disease in the overall data set [odds ratio (OR)=2.31; p=0.0007]. The AACC insertion in the SCCE gene may result in a change to SCCE activity within the skin barrier. These findings suggest that SCCE could have an important role in the development of atopic dermatitis.

Alopecia areata is characterized by a reversible form of patchy or complete hair loss associated with T-cell infiltration of hair follicles. The lifetime disease risk of approximately 1.4% in the general population is increased to more than 30% in autoimmune polyendocrinopathy candidiasis ectodermal dysplasia syndrome (APECED), a recessive condition resulting from a mutation of the autoimmune regulator (AIRE) gene on chromosome 21q22.3. Aire protein is thought to have transcriptional regulatory activity but its role is not well defined at present. In this study, we have examined the possible involvement of AIRE in the pathogenesis of alopecia areata. On screening the AIRE coding sequence, we identified 20 variants. Two of these at positions, G961C and T1029C, give rise to amino acid changes, S278R and V301A, located in the DNA-binding segment (SAND) and PHD1 zinc finger motif, respectively. We found no difference in the frequency of the AIRE T1029C polymorphism between the control and patient groups. We genotyped 202 alopecia areata patients and 175 matched Caucasian controls for the AIRE G961C alleles. The frequency of the rare allele (961G) was 0.08 in the controls and there was a significant increase to 0.13 in alopecia areata overall and 0.20 in severe disease (alopecia universalis). We found no association between the AIRE G961G variant and mild (patchy) alopecia areata or alopecia totalis. However, the AIRE 961G allele is a potent risk factor (> 3) for the severest form of alopecia areata, and for disease of early age at onset (at 30 years). The change from serine to arginine in the SAND domain of AIRE protein may have a significant effect on AIRE DNA-binding activity. Moreover, our results could provide a rational explanation of the unusually high frequency of AA in APECED patients, supporting the concept of AA as an autoimmune disease.

Ten genome-wide scans have been conducted over the past few years in the search for psoriasis susceptibility genes, but only one potential susceptibility region has been consistently replicated. A meta-analysis using the genome-search meta-analysis method was undertaken combining the results of six of these psoriasis genome-wide studies. The results of this analysis revealed linkage to the major histocompatibility complex on chromosome 6p21 that includes the PSORS1 locus. In addition, linkage was also recorded to a region on chromosome 4q28-q31 previously identified only in a Chinese Hans population. Both these regions were statistically significant even after correction for multiple testing. A possible reason for the erratic replication of findings could be the large effect of the PSORS1 locus (6p21) masking the effect of other loci involved in psoriasis. To overcome this problem, we suggest that future studies condition on the effect of the PSORS1 locus.