Chromosome
Locus
Population
Reference
11q13.5
C11ORF30/LRRC32 (GARP)
European
[5]
1p21.3
FLG
Chinese Han
[6]
5q22.1
TMEM232/SLC25A46
20q13.33
TNFRSF6B/ZGPAT
11q13.1
OVOL1
European
[9]
19p13.2
ACTL9
5q31.1
KIF3A/RAD50/IL13
2q12
IL1RL1/IL18R1/IL18RAP
Japanese
[10]
3p21.33
GLB1
3q13.2
CCDC80
6p21.3
The MHC region
7p22
CARD11
10q21.2
ZNF365
11p15.4
OR10A3/NLRP10
20q13
CYP24A1/PFDN4
4q27
IL2/IL21
European
[26]
11p13
PRR5L
16p13.13
CLEC16A/DEXI
17q21.32
ZNF652
1q21.3
IL6R
European
[29]
13q21.31
PCDH9
Korean
[30]
2q24.3
XIRP2
European
[31]
9p21.3
DMRTA1
14q13.2
PPP2R3C
Multi-ancestrya
[32]
11q24.3
−/ETS1
1q21.2
C1orf51/MRPS21
8q21.13
MIR5708/ZBTB10
10p15.1
IL15RA/IL2RA
5p13.2
IL7R/CAPSL
2p25.1
LINC00299/−
2p16.1
PUS10
17q21.2
STAT3
3p21.1
SFMBT1/RFT1
2p13.3
CD207/VAX2
) and have improved our understanding of its pathogenesis.
5.2 Genome-Wide Association Studies of Atopic Dermatitis in European and Chinese Populations
The first GWAS for AD was reported in 2009. The study analyzed 939 cases and 975 controls as well as 270 complete nuclear families with two affected siblings [5]. Genetic variants that showed associations with AD in both discovery set were examined in two independent replication populations totaling 2637 cases and 3957 controls. The GWAS found that rs7927894 located 38 kb downstream of C11orf30 (11q13.5) was associated with AD (P = 7.6 × 10−10). The locus had been reported to be a susceptibility locus for Crohn’s disease, which shares many pathophysiological features with AD such as recurrent inflammation of the epithelium, defective barrier function, and dysfunction of innate immune responses against infections.
In a Chinese Han population, a GWAS of AD was conducted using 1012 cases and 1362 controls followed by a replication set of 3624 cases and 12,197 controls [6]. It also conducted a replication study using 1806 cases and 3256 controls from Germany. The GWAS identified novel two loci, TMEM232/SLC25A46 (5q22.1) and TNFRSF6B/ZGPAT (20q13.33), and found an association of a common variant, rs3126085 in the FLG locus, with AD at genome-wide significance levels. The association at the TNFRSF6B/ZGPAT locus was replicated in the German sample. TNFRSF6B (also called DCR3) encodes a TNF receptor superfamily gene that plays a suppressive role in FasL- and LIGHT-mediated cell death. Interestingly, LIGHT is a target for airway remodeling in asthma [14] and binds the herpes virus entry mediator (TNFRSF14) [15].
A genome-wide association meta-analysis using 5606 cases and 20,565 controls from 16 population-based studies was reported in 2011 [7]. The study was followed by one with 5419 cases and 19,833 controls from 14 studies that finally identified a total of three novel loci that reached genome-wide significance, OVOL1 (11q13.1), ACTL9 (19p13.2), and KIF3A (5q31.1). Interestingly OVOL1 and ACTL9 are implicated in epidermal proliferation and differentiation, and KIF3A is located in the cytokine cluster region at 5q31.1 containing IL13.
5.3 Genome-Wide Association Studies of Atopic Dermatitis in the Japanese Population
In 2012, a GWAS of AD in the Japanese population using a total of 1472 cases and 7971 controls was published, followed by a replication study with an additional 1856 cases and 7021 controls [8]. The study investigated 606,164 SNP loci and identified a total of 8 novel susceptibility loci for AD: IL1RL1/IL18R1/IL18RAP (2q12), the HLA region (6p21.3), OR10A3/NLRP10 (11p15.4), GLB1 (3p21.33), CCDC80 (3q13.2), CARD11 (7p22), ZNF365 (10q21.2), and CYP24A1/PFDN4 (20q13) (Fig. 5.1). The study also replicated the associations of the FLG, C11orf30, OVOL1, TNFRSF6B/ZGPAT, TMEM232/SLC25A46, ACTL9, and KIF3A/IL13 loci in prior GWASs for AD. All cases were recruited from hospitals in Japan, and the mean ages of the cases in the discovery and replication study were 28.6 and 33.0, respectively. Candidate genes identified by the GWAS suggested important roles for skin barrier functions, adaptive immune responses, IL-1 family signaling, regulatory T cells, and the vitamin D pathway in the pathogenesis of AD.
Fig. 5.1
Manhattan plot showing the P values from the GWAS of AD in the Japanese population
5.3.1 IL1RL1/IL18R1/IL18RAP
The 2q12 locus contains genes IL1RL1, IL18R1, and IL18RAP, which encode the receptors of IL-1 family cytokines that play crucial roles in the skin. IL1RL1, a component of the IL-33 receptor, is highly expressed in Th2 cells and mast cells. The levels of IL-33 expression are increased in inflamed skin tissue of subjects with AD, and it has been suggested that IL-33 produced in the damaged tissues of AD induces Th2-type inflammation [16].
5.3.2 The HLA Region
The HLA region contains hundreds of immune system genes, and the locus often shows the strongest association for most autoimmune diseases. Generally, seropositive diseases are associated with HLA class II, and seronegative diseases are associated with HLA class I [17]. The most significant association with AD in the GWAS was observed at rs176095 in the HLA class III region (P = 8.38 × 10−20). After logistic regression analysis of the HLA region, there were two independent association signals in the HLA class I and III regions. The HLA region shows significant associations with asthma [18] and peanuts allergy [19]. Recent studies have reported the involvement of autoimmunity in the pathophysiology of AD, and IgE antibodies against keratinocytes and endothelial cells have been identified in severe AD. However, further studies are necessary to elucidate the involvement of autoimmunity in chronic inflammation in subjects with AD.
5.3.3 OR10A3/NLRP10
The region at 11p15.4 contains two genes, NLRP10 and OR10A3. OR10A3 encodes an olfactory receptor family gene. NALP proteins sense both microbial and danger signals, and NLRP10 encodes a NALP family protein that lacks the leucine-rich repeat region. NLRP10 is highly expressed in the skin and plays a role in immune responses against invasive bacteria. A recent study using a mouse model of contact hypersensitivity has shown that NLRP10 is involved in T cell-mediated skin inflammation and plays a role in epidermal keratinocytes [20].
5.3.4 GLB1
GLB1 encodes β-galactosidase-1, but the involvement of the enzyme in allergic inflammation remains unclear. The 3p21.33 locus is located adjacent to the CCR4 gene, which encodes a chemokine receptor for CCL22 and CCL17 (also called TARC). Interestingly, TSLP derived from keratinocytes induces dendritic cells to produce TARC, and skin-specific recruitment of T cells during inflammation is mediated by CCR4. TARC is produced by endothelial cells, keratinocytes, and fibroblasts and plays an important role in AD, bullous pemphigoid, and mycosis fungoides [21]. Serum TARC levels are associated with the disease activity of AD [21].
5.3.5 CCDC80
The 3q13.2 locus includes CCDC80, which encodes a protein associated with the induction of peroxisome proliferator-activated receptor γ (PPARγ) and C/EBPα. A recent study has shown that PPARγ agonists suppress the maturation and migration of dendritic cells and decrease TSLP expression in the skin in a mouse model of AD [22]. C/EBPα is expressed in basal keratinocytes and upregulated in terminal differentiation of keratinocytes [23].
5.3.6 CARD11
The 3p21.33 locus contains CARD11, which encodes CARMA1. CARMA1 regulates T cell receptor/NF-kB signaling and controls completion of Th17 differentiation [24]. Interestingly, mice homozygous for the CARMA1 mutation develop AD with high levels of serum IgE. Sézary syndrome is an erythrodermic form of cutaneous T cell lymphoma characterized by scaling and itching [25]. Sézary cells, circulating atypical T lymphocytes, show a Th2 cytokine profile, activating CCR4 and CARD11 mutations in nearly one-third of patients. Overlap of the target genes would be helpful to unveil details of shared etiologies.
5.3.7 ZNF365
The 10q21.2 locus includes three genes, ZNF365, ADO, and EGR2. The most associated variant, rs10995251, is located within ZNF365. Although the region shows a suggestive association with AD in the Chinese population (P = 1.1 × 10−7), it is associated with AD at the genome-wide significance level in the Japanese population (P = 5.9 × 10−20). The locus is also associated with Vogt-Koyanagi-Harada syndrome, which is a multisystem autoimmune disorder affecting pigmented tissues in the ocular, integumentary, auditory, and central nervous systems [26]. Regulatory T cells control the maintenance of immune tolerance and protect the body from harmful immune responses to antigens. It is recognized that dysregulation of Tregs is responsible for the development of a number of immune-mediated diseases. A recent study has shown that induced Tregs characteristically express both LAG3 and EGR2 [27], and EGR2 is involved in the negative regulation of T cell proliferation and inflammation [28].
5.3.8 CYP24A1/PFDN4
The 20q13 locus contains CYP24A1 and PFDN4. PFDN4 encodes a subunit of a molecular chaperone complex, prefoldin. CYP24A1 encodes 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) 24-hydroxylase, a mitochondrial cytochrome P450 superfamily enzyme that initiates the degradation of the physiologically active form of vitamin D3 by hydroxylation of the side chain [29]. The active form of vitamin D3, 1,25(OH)2D3 is synthesized in the skin systemically after its exposure to sunlight. Since local 1,25(OH)2D3 synthesis activates innate immune responses, sun exposure is an important environmental factor in immune function. A recent study has shown an association between vitamin D deficiency and the severity of AD [30].
5.4 Immunochip Analysis for Atopic Dermatitis
The Immunochip array is an Illumina Infinium SNP array that was designed by researchers investigating 11 distinct inflammatory and autoimmune diseases in 2009. The chip covers a total of 195,806 SNPs and 718 small insertion-deletions, and the top 2000 associated variants for each disease are included. High-density genotyping study using the Immunochip array identified a total of four novel susceptibility loci for AD in 2013: IL2/IL21 (4q27), PRR5L (11p13), CLEC16A/DEXI (16p13.13), and ZNF652 (17q21.32) [9]. A total of 2425 German subjects with AD and 5449 controls were assessed, and a validation study with 7196 cases and 15,480 controls was conducted using populations from Germany, Ireland, Japan, and China. The IL2 locus is located near the IL21 gene. IL-2 is required for T cell activation and proliferation and regulates the proliferation and survival of regulatory T cells. Cyclosporin A is an inhibitor of calcineurin, which suppresses IL-2 production [31]. Interestingly, recent studies have shown associations of IL2RA and IL21 with immune-mediated diseases [17]. CLEC16A encodes a member of the C-type lectin domain containing family, and CLEC16A variants are associated with multiple immune-mediated diseases such as celiac disease, Crohn’s disease, and alopecia areata [32]. A recent study has shown that CLEC16A modulates thymic epithelial cell autophagy and alters T cell selection and reactivity [32]. In the Japanese population, a total of three loci, PRR5L, CLEC16A/DEXI, and ZNF652, were replicated.
5.5 Recent Genome-Wide Association Studies of Atopic Dermatitis in Other Populations
A recent study focused on a total of 318 markers associated with any inflammatory trait obtained from a public GWAS database and assessed associations with AD in a three-step approach using 7130 AD cases and 9253 controls [10]. A functional nonsynonymous variant in IL6R (rs2228145, Asp358Ala), which determines the balance between the membrane bound (IL-6R) and soluble forms (sIL-6R), was significantly associated with AD. Interestingly the study also identified increased serum levels of sIL-6R and their influence on the prognosis and persistence of AD.
A GWAS of recalcitrant AD, which is defined as moderate-to-severe AD with allergic sensitization, in Korean children was reported in 2015 [11]. Genetic variants on 13q21.31 were associated with recalcitrant AD at genome-wide significance levels. The closest gene, protocadherin 9 (PCDH9), is located more than 1 Mb from those related variants. In the GWAS, four loci, NBAS (2p24.3), THEMIS (6q22.33), GATA3 (10p14), and SCAPER (15q24.3), showed P values <1 × 10−6.
A GWAS for AD using an imputed data set consisting of more than 1.6 million variants was reported in 2015 [12]. The GWAS assessed 924 tertiary care cases and 5506 population-based controls, followed by an independent replication of 1383 cases and 1728 controls in the German population. Finally, two novel susceptibility loci were identified in the combined analysis: XIRP2 (2q24.3) and DMRTA1 (9p21.3). However, the functions of XIRP2 and DMRTA1 remain unknown.
5.6 Multi-ancestry Genome-Wide Association Study for Atopic Dermatitis
GWAS meta-analyses for common diseases using large sample sizes have recently been conducted. Collaborative studies consisting of a number of cohorts ensure sufficient statistical power and reveal disease susceptibility loci. A multi-ancestry genome-wide association study for AD using 21,000 cases and 95,000 controls of European, African, Japanese, and Latino ancestry was reported in 2015 [13]. A replication study of the GWAS was conducted using 32,059 cases and 228,628 controls from 18 studies, and a total of 11 novel loci of AD were finally identified.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
