Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population

Hirota, Tomomitsu; Takahashi, Atsushi; Kubo, Michiaki; Tsunoda, Tatsuhiko; Tomita, Kaori; Sakashita, Masafumi; Yamada, Tetsuji; Fujieda, Shigeharu; Tanaka, Shota; Doi, Satoru; Miyatake, Akihiko; Enomoto, Tadao; Nishiyama, Chiharu; Nakano, Nobuhiro; Maeda, Keiko; Okumura, Ko; Ogawa, Hideoki; Ikeda, Shigaku; Noguchi, Emiko; Sakamoto, Tohru; Hizawa, Nobuyuki; Ebe, Koji; Saeki, Hidehisa; Sasaki, Takashi; Ebihara, Tamotsu; Amagai, Masayuki; Takeuchi, Satoshi; Furue, Masutaka; Nakamura, Yusuke; Tamari, Mayumi

doi:10.1038/ng.2438

Cited by 315 publications

(247 citation statements)

References 37 publications

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“…In a genome-wide association study of patients with atopic dermatitis, Nlrp10, which is highly expressed in the skin, was identified as one of eight susceptibility loci (33). Further suggesting NLRP10 is important to the immune response in the skin, Lautz et al demonstrated that NLRP10 plays a crucial role in regulating dermal fibroblast immunity to Shigella flexneri by acting as a positive regulator of the NOD1 inflammasome (5).…”

Section: C3h/hejmentioning

confidence: 99%

Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration

Krishnaswamy¹,

Singh²,

Gowthaman³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Dendritic cells (DCs) are the primary leukocytes responsible for priming T cells. To find and activate naïve T cells, DCs must migrate to lymph nodes, yet the cellular programs responsible for this key step remain unclear. DC migration to lymph nodes and the subsequent T-cell response are disrupted in a mouse we recently described lacking the NOD-like receptor NLRP10 (NLR family, pyrin domain containing 10); however, the mechanism by which this pattern recognition receptor governs DC migration remained unknown. Using a proteomic approach, we discovered that DCs from Nlrp10 knockout mice lack the guanine nucleotide exchange factor DOCK8 (dedicator of cytokinesis 8), which regulates cytoskeleton dynamics in multiple leukocyte populations; in humans, loss-of-function mutations in Dock8 result in severe immunodeficiency. Surprisingly, Nlrp10 knockout mice crossed to other backgrounds had normal DOCK8 expression. This suggested that the original Nlrp10 knockout strain harbored an unexpected mutation in Dock8, which was confirmed using whole-exome sequencing. Consistent with our original report, NLRP3 inflammasome activation remained unaltered in NLRP10-deficient DCs even after restoring DOCK8 function; however, these DCs recovered the ability to migrate. Isolated loss of DOCK8 via targeted deletion confirmed its absolute requirement for DC migration. Because mutations in Dock genes have been discovered in other mouse lines, we analyzed the diversity of Dock8 across different murine strains and found that C3H/HeJ mice also harbor a Dock8 mutation that partially impairs DC migration. We conclude that DOCK8 is an important regulator of DC migration during an immune response and is prone to mutations that disrupt its crucial function.D endritic cells (DCs) are crucial for the initiation of an adaptive immune response. Upon acquiring antigens in the periphery, DCs undergo a maturation process that includes antigen processing, cytokine production, and up-regulation of costimulatory molecules. A mature DC must then migrate from peripheral tissues to draining lymph nodes (LNs) to fulfill its role as an antigen-presenting cell that primes naïve T cells (1). Although the signals that induce this maturation process are now well-established (1), relatively little is understood about DC migration aside from the primary chemotactic cue provided by CCR7 that guides DCs to the LN (2, 3).We recently described a genetically modified NLRP10 (NLR family, pyrin domain containing 10) knockout strain in which this migration step was disrupted while leaving the remainder of the DC maturation program, including CCR7 expression, intact (4).NLRP10 is the only NOD-like receptor (NLR) without a leucine-rich repeat domain, the putative pathogen-associated molecular pattern (PAMP)-binding domain. It has been proposed to both positively and negatively regulate other NLRs, such as NOD1 and NLRP3, respectively (5, 6). Although we found that NLRP3 inflammasome activation was unaltered in the absence of NLRP10, we discovered that Nlrp10 −/− mice could ...

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Section: C3h/hejmentioning

confidence: 99%

Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration

Krishnaswamy¹,

Singh²,

Gowthaman³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…This is especially significant because a large proportion of infants developing AD progress to other systemic atopic and allergic disorders, in a process termed "the atopic march" (21). Notably, of the immune genes identified in genome-wide association studies, the IL1RL1-IL18R1-IL18RAP genetic locus was strongly associated with AD in a cohort of Japanese patients (22).…”

mentioning

confidence: 99%

The Inflammatory Caspases-1 and -11 Mediate the Pathogenesis of Dermatitis in Sharpin-Deficient Mice

Douglas

Champagne

Morizot

et al. 2015

The Journal of Immunology

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Chronic proliferative dermatitis in mice (cpdm) is a spontaneous multiorgan inflammatory disorder with pathological hallmarks similar to atopic dermatitis and psoriasis in humans. Cpdm mice lack expression of SHANK-associated RH domain–interacting protein, an adaptor of the linear ubiquitin assembly complex, which acts in the NF-κB pathway to promote inflammation and protect from apoptosis and necroptosis. Although skin inflammation in cpdm mice is driven by TNF- and RIPK1-induced cell death, the contribution of initiating innate immunity sensors and additional inflammatory pathways remains poorly characterized. In this article, we show that inflammasome signaling, including the expression and activation of the inflammatory caspase-1 and -11 and IL-1 family cytokines, was highly upregulated in the skin of cpdm mice prior to overt disease onset. Genetic ablation of caspase-1 and -11 from cpdm mice significantly reduced skin inflammation and delayed disease onset, whereas systemic immunological disease persisted. Loss of Nlrp3 also attenuated skin disease, albeit more variably. Strikingly, induction of apoptosis and necroptosis effectors was sharply decreased in the absence of caspase-1 and -11. These results position the inflammasome as an important initiating signal in skin disease pathogenesis and provide novel insights about inflammasome and cell death effector cross-talk in the context of inflammatory diseases.

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“…GWA studies have identified a strong relationship between the common SNP rs4722404 in CARD11 and AD (Hirota et al, 2012;Weidinger et al, 2013). Genetic evidence has demonstrated a higher level of genomic similarities between AD and psoriasis (Weidinger et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, SNPs in CARD11 may have significant effects on heritability. A previous study reported a significant association between the genotype of SNP rs4722404 and the risk of atopic dermatitis in the Japanese population (Hirota et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Genome-wide association (GWA) studies have also demonstrated a high degree of genetic overlap between these two common skin disorders (Baurecht et al, 2015). GWA studies have identified an association between the single nucleotide polymorphism (SNP) rs4722404, in the caspase recruitment domain family member 11 gene (CARD11) on chromosome 7, and AD (Hirota et al, 2012;Weidinger et al, 2013). The identification of shared genetic components highlights the key molecular pathways involved in chronic inflammatory skin diseases; therefore, we further explored the association between the SNP rs4722404 and psoriasis vulgaris (PsV) in a Chinese Cohort.…”

Section: Introductionmentioning

confidence: 99%

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Association between atopic dermatitis-related single nucleotide polymorphisms rs4722404 and psoriasis vulgaris in a southern Chinese cohort

Shi

et al. 2016

Genet. Mol. Res.

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Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population

Cited by 315 publications

References 37 publications

Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration

Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration

The Inflammatory Caspases-1 and -11 Mediate the Pathogenesis of Dermatitis in Sharpin-Deficient Mice

Association between atopic dermatitis-related single nucleotide polymorphisms rs4722404 and psoriasis vulgaris in a southern Chinese cohort

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