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Mol Bio Syst 6: 1579–82 Genetic Variation in the Inflammasome and Atopic Dermatitis Susceptibility Journal of Investigative Dermatology (2013) 133, 2486–2489; doi:10.1038/jid.2013.168; published online 16 May 2013 TO THE EDITOR Atopic dermatitis (AD) is a common chronic inflammatory skin disease. The pathophysiological factors include genetic predisposition to skin-barrier defects, dysregulated immunity, and hypersensitive allergen response (Novak and Simon, 2011). The high levels of proinflammatory cytokines in AD initiate and maintain the inflam- mation (Bieber, 2008) and mediate cross-talk between innate and adaptive immune systems. The recently described cytosolic receptors of the nucleotide- binding domain and leucine-rich repeat (NLR)–containing family have been shown to have a key role in innate immune regulation. The NLR family pyrin domain–containing pro- teins (NLRPs) are recognized for forming a multiprotein complex referred to as the ‘‘inflammasome’’, which activates the proinflammatory cytokines, interleu- kin (IL)-1b, -18, and -33 (Li et al., 2008). The above ILs are important in innate immune functions and in the regulation of adaptive immunity. Single-nucleotide polymorphisms (SNPs) in NLRP1 have been associated with vitiligo and related autoimmune conditions (Jin et al., 2007a,b), whereas SNPs in NLRP3 have been associated with food anaphy- laxis and allergic asthma (Hitomi et al., 2009), rheumatoid arthritis (Kastbom et al., 2008), Crohn’s disease (Schoultz et al., 2009; Villani et al., 2009), and malignant melanoma (Verma et al., 2012). As atopic manifestations, e.g., food allergies, asthma, allergic rhinitis, and allergic conjunctivitis, are common, we investigate the significance of seven SNPs located in three different inflammasome genes (NLRP1, NLRP3, and CARD8) in the susceptibility of AD. All of the studied SNPs except those in NLRP1 are demonstrated to be of functional significance. A Swedish AD family material (Bradley et al., 2000) including 1,708 individuals (1,260 affected) from 494 families with at least two affected siblings were included in the analysis. Measurements of total serum-IgE con- centrations and IgE-specific antibodies for food and inhalant allergens were performed (Bradley et al., 2000). A Swedish control population without eczema comprising 732 healthy indivi- duals was analyzed as the reference population. We performed TaqMan genotyping for variants of NLRP1 (rs6502867 and rs12150220), NLRP3 (rs35829419, rs10733113, rs10754558, and rs4612666), and CARD8 (rs2043211) using an ABI Prism 7500 Sequence Detection System, with the SDS 2.3 software for allelic discri- mination (Applied Biosystems, Foster City, CA). None of the SNPs were in linkage disequilibrium (r 2 p0.3). A pedigree disequilibrium test (PDT) was carried out to investigate evidence for the association between the genetic variants and AD. Data for the family- based association analysis, including odds ratio (OR), 95% confidence interval, and correction for multiple testing (10.000 permutations), were cal- culated using the UNPHASED program (v.3.1.4, http://unphased.sourceforge.net). All SNPs were shown to be in Hardy– Weinberg equilibrium in the control population. No statistical associations between variants and AD were found either overall or after stratification for different phenotypes (Supplementary Table S1a online). As gender-specific associations have previously been reported for NLRP3 SNPs (Schoultz et al., 2009), we further stratified for gender. The results showed a signifi- cant association between NLRP3 Accepted article preview online 5 April 2013; published online 16 May 2013 Abbreviations: AD, atopic dermatitis; CI, confidence interval; IL, interleukin; NLR, nucleotide-binding domain and leucine-rich repeat; NLRP, NLR family pyrin domain–containing protein; OR, odds ratio; PDT, pedigree disequilibrium test; SNP, single-nucleotide polymorphism C Bivik et al. Inflammasome SNPs in Atopic Dermatitis 2486 Journal of Investigative Dermatology (2013), Volume 133