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Homozygous variant p.Ser427Pro in PNPLA1 is a preventive factor from atopic dermatitis

Watanabe, Naoki Kono, Michihiro Suganuma, Mutsumi Tanahashi, Kana Akiyama, Masashi 名古屋大学

2020.01

概要

Journal of Dermatological Science

Homozygous variant p.Ser427Pro in PNPLA1 is a preventive
factor from atopic dermatitis
Journal: Journal of Dermatological Science
Manuscript ID JDermSci-2019-0610.R1
Article Type: Letter to the Editor

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Date Submitted by the
03-Dec-2019
Author:

Keywords:

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Complete List of Authors: Watanabe, Naoki; Nagoya University Graduate School of Medicine,
Department of Dermatology
Kono, Michihiro; Nagoya University Graduate School of Medicine,
Department of Dermatology
Suganuma, Mutsumi; Nagoya University Graduate School of Medicine,
Department of Dermatology
Tanahashi, Kana; Nagoya University Graduate School of Medicine,
Department of Dermatology; Nagoya University Graduate School of
Medicine, Department of Dermatology
Akiyama, Masashi; Nagoya University Graduate School of Medicine,
Department of Dermatology

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acylceramide, atopic eczema, ceramide, corneocyte lipid envelope, skin
barrier, stratum corneum

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Journal of Dermatological Science
Manuscript ID JDermSci-2019-0610 Revised Version
Letter to the Editor
Homozygous variant p.Ser427Pro in PNPLA1 is a preventive factor
from atopic dermatitis
Naoki Watanabe, Michihiro Kono, Mutsumi Suganuma, Kana Tanahashi,
Masashi Akiyama

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Department of Dermatology, Nagoya University Graduate School of Medicine,
Nagoya, Japan

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Corresponding Authors:
Michihiro Kono MD, PhD and Masashi Akiyama MD, PhD
Department of Dermatology
Nagoya University Graduate School of Medicine
65 Tsurumai-cho, Showa-ku, Nagoya
Aichi 466-8550, Japan
Tel: +81-52-744-2318, Fax: +81-52-744-2318
E-mail: miro@med.nagoya-u.ac.jp (MK) and makiyama@med.nagoya-u.ac.jp
(MA)

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Journal of Dermatological Science

Short title: PNPLA1 is a preventive factor from atopic dermatitis
Word, reference, table and figure counts: 982 words, 9 references, 1 table, 1
figure
Key words: acylceramide; atopic eczema; ceramide; corneocyte lipid
envelope; ichthyosis; skin barrier; stratum corneum

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Journal of Dermatological Science

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Main Text
To the Editor:
One of the genetic predisposing factors for atopic dermatitis (AD) is abnormal barrier
function in the stratum corneum. Mutations in the filaggrin gene (FLG) have become
apparent as a cause of this abnormal barrier function [1]. In addition, functional lipids in the

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epidermis, especially ω-O-esterified ultra-long-chain acylceramide (EOS), are important for
skin barrier function [2]. The corneocyte lipid envelope (CLE) is also an essential structure

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for proper stratum corneum barrier function [2]. CLE is a thin, single lipid layer located

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between the intercellular lipid layers and the cornified cell envelope (CCE). The CLE is

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mostly composed of ω-hydroxyceramide with ultra-long-chain (ULC) fatty acids derived
from EOS. A number of genes are involved in the formation of the CLE, including ELOVL

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family genes, CYP4F22, SLC27A4, and PNPLA1 [3, 4]. Few reports have addressed the
association between CLE formation and AD. Thus, to understand the association between
AD, and EOS synthesis and CLE formation, we analyzed polymorphisms of genes related to
EOS synthesis and CLE formation, and identified a significant association between the
PNPLA1 single-nucleotide polymorphism (SNP) rs4713956 and AD.

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In the genes involved in EOS synthesis and CLE formation, we first searched the Human
Genetic Variation Database for candidate SNPs that showed minor allele frequencies of
greater than 5% and that lead to missense, nonsense, or frameshift mutations
(http://www.hgvd.genome.med.kyoto-u.ac.jp/). Nine candidate SNPs in 5 genes (ALOXE3,
PNPLA1, SLC27A4, NIPAL4 and ELOVL4) were identified as the subjects of the present

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analysis (Supplementary Table 1). Then, we genotyped the SNPs in at least 142 healthy
controls and 109 AD patients (Supplementary Table 2). In the AD group, we performed a

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subgroup analysis on the presence/absence of FLG mutations, the absence or

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mild/moderate/severe serum IgE elevation (0-170, 171-10,000 or 10,000- UA/mL), the

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absence or mild/moderate/severe serum TARC elevation (0-450, 451-10,000 or 10,000IU/mL), and Investigator Global Assessment (IGA) scores (2-4) for AD severity at the first
physical examination.

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Journal of Dermatological Science

One of the PNPLA1 SNPs, rs4713956 (T/C, p.Ser427Pro), showed that the incidence of the
CC genotype was significantly low in the AD patient group (AD, CC:CT+TT=26:84; control,
CC:CT+TT=54:88; p=0.015; Table 1). Furthermore, the tendency held true for the AD
group without FLG mutations (AD without FLG mutations, CC:CT+TT=20:67; control,
CC:CT+TT=54:88; p=0.018). The frequency of CC was also low in other subgroups, i.e. the

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AD subgroup showing moderate serum IgE elevation (171-10,000 UA/mL)
(CC:CT+TT=5:30; control, CC:CT+TT=54:88; p=0.008), the AD subgroup with moderate
serum TARC elevation (451-10,000 UA/mL) (CC:CT+TT=8:35, p=0.018), and the AD
subgroup with IGA score 3 (CC:CT+TT=2:15, p=0.032). All the results of SNP analysis
including data on other SNPs in other genes are shown in Supplementary Table 2.

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Then, we compared the thickness of the stratum corneum and the other layers of the

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epidermis (the basal, spinous and granular layers) of the skin lesions in the trunk, the arm or

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the leg of the patients with CC (n=3) and the patients with CT or TT (n=6) in the cohort of

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the AD group without FLG mutations. There was a tendency for the basal, spinous and
granular layers to be thicker in the patients with CC than in the patients with CT or TT.

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Conversely, there was a tendency for the stratum corneum to be thinner in the patients with
CC than in the patients with CT or TT (Supplementary Fig. 1).

PNPLA1 is a causative gene of autosomal recessive congenital ichthyosis (ARCI) [5]. From
a study of Pnpla1 knockout mice [6, 7], PNPLA1 was reported to have the function of
transferring linoleic acid to the terminal hydroxyl group of ω-hydroxide ceramide and
synthesize acylceramide (Fig. 1a). Acylceramide is then transported into the cell membrane

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Page 5 of 34

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zone or secreted to the intercellular space, where it forms CLE and the intercellular lipid
layers. Thus, PNPLA1 is thought to be extremely important for the skin barrier [6-8].

In the present study, the CC genotype at PNPLA1 rs4713956 was significantly less prevalent
in the AD group than in the control group. We regard homozygosity for PNPLA1 Pro427 as

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a strong factor in the prevention of AD, although PNPLA1 Pro427 deficiency is not
sufficient to cause the onset of AD, because a considerable number of individuals in the

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healthy group were homozygous for Ser427.

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In addition, the frequency of the CC genotype was low in some subgroups, including the AD
group with moderate serum IgE elevation (171-10,000 UA/mL), the AD group with

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moderate serum TARC elevation (451-10,000 UA/mL), and the AD group with IGA score 3.
Serum IgE and TARC concentrations are affected by previous treatment and environmental
factors. Unfortunately, we did not evaluate these factors in the present study. It is necessary
to increase the number of AD cases included in the study and to include more detailed
information of patients’ backgrounds in future study.

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PNPLA1 has a conserved catalytic domain called the patatin domain at the N-terminal side
and a proline-rich hydrophobic region at the C-terminal side (Fig. 1b). The causative
mutations of ARCI are mostly in the patatin domain, but there are a few mutations in other
areas, including proline-rich region [9]. Thus, the proline-rich region is presumed to have
some function, and rs4713956 (p.Ser427Pro) resides in that region.

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In our study, the stratum corneum of the lesional skin was thinner in the patients with the

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CC genotype than in the patients with the CT or TT genotypes. In cases of ichthyosis due to

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the loss-of-function of PNPLA1, marked hyperkeratosis was seen, compensating for the skin

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barrier dysfunction. These results suggest that the skin barrier function might be stronger in
the patients with the CC genotype than in the patients with the CT or TT genotypes.

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The present study is the first to propose the possibility that a gene associated with EOS
synthesis and CLE formation might be involved in the onset of AD. ...

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この論文で使われている画像

参考文献

[1] G.M. O'Regan, A. Sandilands, W.H.I. McLean, A.D. Irvine, Filaggrin in atopic

dermatitis, J. Allergy Clin. Immunol. 122 (2008) 689-693.

[2] M. Akiyama, Corneocyte lipid envelope (CLE), the key structure for skin barrier

function and ichthyosis pathogenesis, J. Dermatol. Sci. 88 (2017) 3-9.

[3] A. Kihara, Synthesis and degradation pathways, functions, and pathology of ceramides

and epidermal acylceramides, Prog. Lipid Res. 63 (2016) 50-69.

[4] Y. Ohno, S. Nakamichi, A. Ohkuni, N. Kamiyama, A. Naoe, H. Tsujimura, et al.,

Essential role of the cytochrome P450 CYP4F22 in the production of acylceramide, the

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key lipid for skin permeability barrier formation, Proc. Natl. Acad. Sci. U. S. A. 112

(2015) 7707-12.

Page 8 of 34

[5] A. Grall, E. Guaguere, S. Planchais, S. Grond, E. Bourrat, I. Hausser, et al., PNPLA1

mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and

humans, Nat. Genet. 44 (2012) 140-7.

[6] M. Pichery, A. Huchenq, R. Sandhoff, M. Severino-Freire, S. Zaafouri, L. Opalka, et al.,

PNPLA1 defects in patients with autosomal recessive congenital ichthyosis and KO

mice sustain PNPLA1 irreplaceable function in epidermal omega-O-acylceramide

synthesis and skin permeability barrier, Hum. Mol. Genet. 26 (2017) 1787-1800.

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[7] T. Hirabayashi, T. Anjo, A. Kaneko, Y. Senoo, A. Shibata, H. Takama, et al., PNPLA1

has a crucial role in skin barrier function by directing acylceramide biosynthesis, Nat

Commun 8 (2017) 14609.

[8] Y. Ohno, N. Kamiyama, S. Nakamichi, A. Kihara, PNPLA1 is a transacylase essential

for the generation of the skin barrier lipid omega-O-acylceramide, Nat Commun 8

(2017) 14610.

[9] T. Hirabayashi, M. Murakami, A. Kihara, The role of PNPLA1 in

omega-O-acylceramide synthesis and skin barrier function, Biochim Biophys Acta Mol

Cell Biol Lipids 1864 (2019) 869-879.

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Figure Legend

Fig. 1. The function and structure of PNPLA1. (A) Enzyme reaction catalyzed by PNPLA1.

PNPLA1 catalyzes the transacylation of linoleic acid from the TG molecule on to ULC

ω-hydroxyceramide to produce ω-O-acylceramide.[6-9] TG, triglyceride. (B) Schematic of

the primary structure of PNPLA1. Most mutations causative of ARCI are in the patatin

domain with the catalytic dyad Ser53 (S) and Asp172 (D). Ser427Pro (S427P) (red) is

located in the proline-rich hydrophobic region.

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Table 1. PNPLA1 rs4713956 genotype analysis in the AD patients and subgroups

Patient group

Control

Total AD

Subgroups by

IgE levels

absent/mild ↑

moderate ↑

severe ↑

Subgroups by

TARC levels

absent/mild ↑

moderate ↑

severe ↑

Subgroups by

IGA scores

Subgroups

with/without

FLG mutations

FLG

mutationpositive

FLG

mutationnegative

Total FLG

mutationnegative

Patient breakdown by

genotype

CT+TT

total

142

110

p value

0.018*

severe ↑

Subgroups

absent/mild ↑

by TARC

moderate ↑

levels

severe ↑

Subgroups

by IGA

scores

P values were obtained by statistical analysis between each subgroup and the control. *, statistically

significant.

Serum IgE (UA/ml); absent/mild ↑ 1-170, moderate ↑ 171-10,000, severe ↑ 10,000-.

Serum TARC (IU/ml); absent/mild ↑ 1-450, moderate ↑ 451-10,000, severe ↑ 10,000-.

Subgroups

by IgE

levels

absent/mild ↑

moderate ↑

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0.015*

0.612

0.008*

0.965

0.612

0.018*

0.799

0.177

0.032*

0.590

0.270

0.457

0.032*

0.607

0.976

0.016*

0.817

0.177

0.058

0.630

Journal of Dermatological Science

Fig. 1. The function and structure of PNPLA1. (A) Enzyme reaction catalyzed by PNPLA1. PNPLA1 catalyzes

the transacylation of linoleic acid from the TG molecule on to ULC ω-hydroxyceramide to produce ω-Oacylceramide.[6-9] TG, triglyceride. (B) Schematic of the primary structure of PNPLA1. Most mutations

causative of ARCI are in the patatin domain with the catalytic dyad Ser53 (S) and Asp172 (D). Ser427Pro

(S427P) (red) is located in the proline-rich hydrophobic region.

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199x108mm (300 x 300 DPI)

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Journal of Dermatological Science

Watanabe et al.

Supplementary Information

Homozygous variant p.Ser427Pro in PNPLA1 is a preventive factor

from atopic dermatitis

Naoki Watanabe, MD, Michihiro Kono, MD, PhD, Mutsumi Suganuma,

Kana Tanahashi, MD, PhD, Masashi Akiyama, MD, PhD

Department of Dermatology, Nagoya University Graduate School of

Medicine, Nagoya, Japan

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Watanabe et al.

SUPPLEMENTARY METHODS

Patients and control groups

This study was approved by the Ethics Committee of Nagoya University and was

performed in accordance with the Declaration of Helsinki. The diagnosis of atopic

dermatitis (AD) was based on the diagnostic criteria of Hanifin and Rajka [1], and

was made by consultant dermatologists. Blood samples for genetic analyses were

collected with written informed consent from AD patients and normal healthy controls

at Nagoya University Hospital and affiliated hospitals or clinics. Blood sampling other

than for genetic analysis, including for serum IgE, specific IgE antibodies, TARC and

LDH, and a questionnaire about medical history, family history, allergies, age of

onset and so on were performed on a voluntary basis.

Analysis of the genes associated with corneocyte lipid envelope (CLE)

formation

Based on the literature, we selected 20 genes that are involved in CLE formation.

The SNPs present in these genes were listed with reference to the Human Genetic

Variation Database provided by Kyoto University

<http://www.hgvd.genome.med.kyoto-u.ac.jp/> (accessed April 2018). This study

regards AD as a disease with a high incidence; therefore, SNPs with a minor allele

frequency of greater than 5% were targeted for analysis. SNP analysis was

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performed with two-color fluorescence probe methods (TaqMan® SNP Genotyping

Assay (Applied Biosystems Life Technologies, Foster City, California) and KASP™

genotyping assay (LGC Genomics, Hoddeson, United Kingdom)) using LightCycler®

480 II (Roche Diagnostics, Mannheim, Germany).

Journal of Dermatological Science

Statistical analyses

Statistical analyses were performed using SPSS Statistics 20 (IBM, Armonk, NY).

The correlation between genotypes and AD was examined by Chi-squared test.

Values of p<0.05 were considered to be significant.

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Watanabe et al.

SUPPLEMENTARY FIGURE

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Supplementary Fig. 1. Histopathological samples (tissue sections of skin biopsy specimens

stained with hematoxylin-eosin) from lesional skin in the trunk, the arm or the leg of 3

Page 20 of 34

CC-genotyped and 6 CT- or TT-genotyped AD patients were collected, and the thicknesses of

the stratum corneum and the other epidermal layers (the basal, spinous and granular layers)

were measured. To evaluate the thickness of the stratum corneum, the distance between the top

of the stratum corneum and the top of the uppermost granular layer was measured in each tissue

section. In addition, to evaluate the thickness of the other layers of the epidermis (the basal,

spinous and granular layers), the distance between the top of the uppermost granular layer and

the top of the dermal papilla was measured in each tissue section. The average of values

measured at 3 points was defined as the thickness value of each specimen. The average

thickness of the stratum corneum in the patients with the genotype CC (n=3) and with the

genotypes CT or TT (n=6) was 12.78 µm and 16.25 µm, respectively. The average thicknesses

of the other layers of the epidermis (the basal, spinous and granular layers) in the patients with

the CC genotype and with the CT or TT genotypes was 86.67 µm and 62.92 µm, respectively.

The thicknesses of the stratum corneum and the other epidermal layers showed no significant

difference between CC and CT/TT.

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Watanabe et al.

SUPPLEMENTARY TABLE

Supplementary Table 1. SNPs involved in CLE-related genes

Gene

loci

rs ID

Ref/Alt

Function

ALOXE3

17p13.1

rs3027232

G/A

missense

p.Pro11Leu

PNPLA1

6p21.31

rs74946910 G/A

missense

p.Ala136Ser

rs34598813 A/G

missense

p.Glu193Gly

rs12199580 C/A

missense

p.Pro328His

rs12197079 C/T

missense

p.Thr395Met

rs4713956

T/C

missense

p.Ser427Pro

SLC27A4

9q34.11

rs2240953

G/A

missense

p.Gly209Ser

NIPAL4

5q33.3

rs6860507

A/G

missense

p.Arg194Gly

ELOVL4

6q14.1

rs3812153

T/C

missense

p.Met299Val

SNPs more than 5% allele frequency.

SNPs that cause missense, nonsense, or frameshift mutations are extracted.

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Watanabe et al.

Supplementary Table 2. CLE-related gene SNP genotyping

ALOXE3 rs3027232

Patient group

Control

total AD

absent/mild↑

subgroups

moderate↑

by IgE levels

severe↑

absent/mild↑

subgroups

by TARC

moderate↑

levels

severe↑

subgroups

by IGA

score

subgroups

FLG

with/without mutation-positive

FLG

mutation

FLG

mutation-negative

Total FLG

mutation-negative

subgroups by IgE

levels

subgroups by

TARC levels

absent/mild↑

moderate↑

severe↑

absent/mild↑

moderate↑

severe↑

subgroups by IGA

scores

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PNPLA1 rs74946910

absent/mild↑

subgroups

moderate↑

by IgE levels

severe↑

absent/mild↑

subgroups

by TARC

moderate↑

levels

severe↑

subgroups

by IGA

score

subgroups

FLG

with/without mutation-positive

FLG

mutation

FLG

mutation-negative

Total FLG

mutation-negative

subgroups by IgE

levels

subgroups by

TARC levels

subgroups by IGA

scores

absent/mild↑

moderate↑

severe↑

absent/mild↑

moderate↑

severe↑

value

total

142

109

0.711

0.255

0.25

0.662

0.209

0.651

0.466

0.276

0.058

0.854

0.687

0.696

0.466

0.172

0.306

0.366

0.14

0.556

0.276

0.108

0.923

Patient group

Control

total AD

Patient breakdown by

genotype

Patient breakdown by

genotype

111

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value

total

143

109

0.853

0.243

0.312

0.355

0.632

0.65

0.839

0.819

0.324

0.518

0.519

0.794

0.322

0.199

0.505

0.772

0.504

0.897

0.819

0.362

0.443

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Watanabe et al.

PNPLA1 rs12199580

Patient group

Patient breakdown by

genotype

Control

total AD

absent/mild↑

subgroups

moderate↑

by IgE levels

severe↑

absent/mild↑

subgroups

by TARC

moderate↑

levels

severe↑

subgroups

by IGA

score

subgroups

FLG

with/without mutation-positive

FLG

mutation

FLG

mutation-negative

Total FLG

mutation-negative

subgroups by IgE

levels

subgroups by

TARC levels

absent/mild↑

moderate↑

severe↑

absent/mild↑

moderate↑

severe↑

subgroups by IGA

scores

total

143

124

0.049*

0.637

0.167

0.155

0.056

0.948

0.282

0.265

0.82

0.275

0.648

0.192

0.275

0.412

0.293

0.056

0.898

0.723

absent/mild↑

subgroups

moderate↑

by IgE levels

severe↑

absent/mild↑

subgroups

by TARC

moderate↑

levels

severe↑

subgroups

by IGA

score

subgroups

FLG

with/without mutation-positive

FLG

mutation

FLG

mutation-negative

subgroups by

TARC levels

subgroups by IGA

scores

value

total

142

110

0.027*

0.962

0.729

0.06

0.967

0.364

0.094

0.463

0.475

0.056

0.69

0.099

0.577

0.981

0.053

0.972

0.364

0.165

0.884

Total FLG

mutation-negative

subgroups by IgE

levels

Patient breakdown by

genotype

0.427

0.683

0.637

Control

total AD

value

Patient group

PNPLA1 rs4713956

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Journal of Dermatological Science

absent/mild↑

moderate↑

severe↑

absent/mild↑

moderate↑

severe↑

https://mc.manuscriptcentral.com/jdermscience

0.051

0.729

Journal of Dermatological Science

Watanabe et al.

SLC27A4 rs2240953

Patient group

Patient breakdown by

genotype

Control

total AD

absent/mild↑

subgroups

moderate↑

by IgE levels

severe↑

absent/mild↑

subgroups

by TARC

moderate↑

levels

severe↑

subgroups

by IGA

score

subgroups

FLG

with/without mutation-positive

FLG

mutation

FLG

mutation-negative

Total FLG

mutation-negative

subgroups by IgE

levels

subgroups by

TARC levels

absent/mild↑

moderate↑

severe↑

absent/mild↑

moderate↑

severe↑

subgroups by IGA

scores

NIPAL4 rs6860507

iew

total

142

110

0.723

0.735

0.705

0.364

0.787

0.27

0.786

0.926

0.582

0.061

0.592

0.873

0.338

0.232

0.506

0.622

0.165

0.551

0.926

0.552

0.085

Patient group

Control

total AD

absent/mild↑

subgroups

moderate↑

by IgE levels

severe↑

absent/mild↑

subgroups

by TARC

moderate↑

levels

severe↑

subgroups

by IGA

score

subgroups

FLG

with/without mutation-positive

FLG

mutation

FLG

mutation-negative

Total FLG

mutation-negative

subgroups by IgE

levels

subgroups by

TARC levels

subgroups by IGA

scores

absent/mild↑

moderate↑

severe↑

absent/mild↑

moderate↑

severe↑

value

Patient breakdown by

genotype

Page 24 of 34

value

total

143

109

0.284

0.239

0.286

0.98

0.559

0.142

0.766

0.198

0.182

0.406

0.239

0.479

0.443

0.387

0.605

0.772

0.274

0.625

0.198

0.474

0.529

https://mc.manuscriptcentral.com/jdermscience

Page 25 of 34

Watanabe et al.

ELOLV4 rs3812153

Patient group

Control

total AD

absent/mild↑

subgroups

moderate↑

by IgE levels

severe↑

subgroups

absent/mild↑

by TARC

moderate↑

levels

severe↑

subgroups

by IGA

score

subgroups

FLG

with/without mutation-positive

FLG

mutation

FLG

mutation-negative

Total FLG

mutation-negative

subgroups by IgE

levels

subgroups by

TARC levels

absent/mild↑

moderate↑

severe↑

absent/mild↑

moderate↑

severe↑

subgroups by IGA

scores

ALOXE3 rs3027232

Patient group

Control

total AD

FLG

mutation-negative

Patient breakdown by

genotype

Total FLG

mutation-negative

subgroups by IgE

levels

subgroups by

TARC levels

subgroups by IGA

scores

absent/mild↑

moderate↑

severe↑

absent/mild↑

moderate↑

severe↑

value

total

143

115

0.926

0.114

0.637

0.684

0.066

0.298

0.766

0.417

0.72

0.858

0.498

0.672

0.274

0.828

0.718

Patient breakdown by

genotype

AG+GG total

142

109

absent/mild↑

subgroups

moderate↑

by IgE levels

severe↑

absent/mild↑

subgroups

by TARC

moderate↑

levels

severe↑

subgroups

by IGA

score

subgroups

FLG

with/without mutation-positive

FLG

mutation

iew

Journal of Dermatological Science

value

0.523

0.173

0.386

0.661

0.491

0.372

0.926

0.256

0.034*

0.716

0.885

0.417

0.281

0.154

0.258

0.751

https://mc.manuscriptcentral.com/jdermscience

0.048*

0.87

0.256

0.053

0.692

0.028*

0.417

0.877

0.417

0.741

0.977

Journal of Dermatological Science

Watanabe et al.

PNPLA1 rs74946910

Patient group

Patient breakdown by

genotype

AG+GG total

139

143

107

109

Control

total AD

absent/mild↑

subgroups

moderate↑

by IgE levels

severe↑

absent/mild↑

subgroups

by TARC

moderate↑

levels

severe↑

subgroups

by IGA

score

subgroups

FLG

with/without mutation-positive

FLG

mutation

FLG

mutation-negative

Total FLG

mutation-negative

subgroups by IgE

levels

subgroups by

TARC levels

absent/mild↑

moderate↑

severe↑

absent/mild↑

moderate↑

severe↑

subgroups by IGA

scores

PNPLA1 rs12199580

iew

Patient group

Control

total AD

absent/mild↑

subgroups

moderate↑

by IgE levels

severe↑

absent/mild↑

subgroups

by TARC

moderate↑

levels

severe↑

subgroups

by IGA

score

subgroups

FLG

with/without mutation-positive

FLG

mutation

FLG

mutation-negative

subgroups by

TARC levels

subgroups by IGA

scores

0.617

0.593

0.982

0.512

0.593

0.88

0.651

0.772

0.488

0.297

0.419

0.831

0.633

0.846

0.557

0.633

0.982

0.679

0.772

0.409

0.364

Patient breakdown by

genotype

value

AC+CC

137

115

total

143

124

0.11

0.634

0.276

0.853

0.081

0.276

0.31

0.61

Total FLG

mutation-negative

subgroups by IgE

levels

value

Page 26 of 34

absent/mild↑

moderate↑

severe↑

absent/mild↑

moderate↑

severe↑

https://mc.manuscriptcentral.com/jdermscience

0.279

0.399

0.695

0.017*

0.399

0.07

0.58

0.017*

0.744

0.14

0.017*

0.653

0.56

Page 27 of 34

Watanabe et al.

Patient breakdown by

genotype

value

AG+GG

135

103

total

142

110

0.622

0.473

0.85

0.819

0.492

0.942

0.547

0.699

0.349

0.08

0.457

0.788

0.522

0.668

0.411

0.358

0.577

0.58

0.699

0.379

0.088

Patient breakdown by

genotype

value

Patient group

SLC27A4 rs2240953

AG+GG

133

total

143

109

0.117

0.723

0.164

0.909

0.723

0.064

0.466

0.631

0.128

0.498

0.096

0.229

0.556

0.222

0.325

0.556

0.183

0.371

0.631

0.378

0.568

Control

total AD

absent/mild↑

subgroups

moderate↑

by IgE levels

severe↑

absent/mild↑

subgroups

by TARC

moderate↑

levels

severe↑

subgroups

by IGA

score

subgroups

FLG

with/without mutation-positive

FLG

mutation

FLG

mutation-negative

Total FLG

mutation-negative

subgroups by IgE

levels

subgroups by

TARC levels

absent/mild↑

moderate↑

severe↑

absent/mild↑

moderate↑

severe↑

subgroups by IGA

scores

NIPAL4 rs6860507

iew

Journal of Dermatological Science

Patient group

Control

total AD

absent/mild↑

subgroups

moderate↑

by IgE levels

severe↑

absent/mild↑

subgroups

by TARC

moderate↑

levels

severe↑

subgroups

by IGA

score

subgroups

FLG

with/without mutation-positive

FLG

mutation

FLG

mutation-negative

Total FLG

mutation-negative

subgroups by IgE

levels

subgroups by

TARC levels

subgroups by IGA

scores

absent/mild↑

moderate↑

severe↑

absent/mild↑

moderate↑

severe↑

https://mc.manuscriptcentral.com/jdermscience

Journal of Dermatological Science

Watanabe et al.

ELOLV4 rs3812153

Patient group

Patient breakdown by

genotype

TC+CC total

143

115

Control

total AD

absent/mild↑

subgroups

moderate↑

by IgE levels

severe↑

absent/mild↑

subgroups

by TARC

moderate↑

levels

severe↑

subgroups

by IGA

score

subgroups

FLG

with/without mutation-positive

FLG

mutation

FLG

mutation-negative

Total FLG

mutation-negative

subgroups by IgE

levels

subgroups by

TARC levels

absent/mild↑

moderate↑

severe↑

absent/mild↑

moderate↑

severe↑

iew

subgroups by IGA

scores

https://mc.manuscriptcentral.com/jdermscience

value

0.957

0.039*

0.346

0.974

0.15

0.411

0.755

0.186

0.422

0.872

0.78

0.951

0.149

0.539

0.919

0.149

0.467

0.856

0.186

0.467

0.967

Page 28 of 34

Page 29 of 34

Watanabe et al.

Patient group

ALOXE3 rs3027232

Patient breakdown by

genotype

AA+AG

total

119

142

109

Control

total AD

absent/mild

subgroups

moderate

by IgE levels

severe

subgroups

absent/mild

by TARC

moderate

levels

severe

subgroups

by IGA

score

subgroups

FLG

with/without mutation-positive

FLG

mutation

Total FLG

FLG

mutation-negative

absent/mild

subgroups by IgE

moderate

levels

severe

absent/mild

subgroups by

moderate

TARC levels

severe

subgroups by

IGA

scores

iew

https://mc.manuscriptcentral.com/jdermscience

value

0.741

0.603

0.254

0.373

0.168

0.989

0.247

0.445

0.637

0.607

0.389

0.982

0.781

0.424

0.183

0.215

0.643

0.284

0.445

0.772

0.948

Journal of Dermatological Science

Watanabe et al.

Patient group

PNPLA1 rs74946910

Patient breakdown by

genotype

AA+AG

total

111

143

109

Control

total AD

absent/mild

subgroups

moderate

by IgE levels

severe

subgroups absent/mild

by TARC

moderate

levels

severe

subgroups 2

by IGA

score

subgroups FLG

with/without mutation-positive

FLG

mutation

Total FLG

FLG

mutation-negative

absent/mild

subgroups by IgE

moderate

levels

severe

absent/mild

subgroups by

moderate

TARC levels

severe

subgroups by

IGA

scores

iew

https://mc.manuscriptcentral.com/jdermscience

value

0.915

0.093

0.143

0.155

0.356

0.407

0.614

0.656

0.313

0.865

0.308

0.58

0.131

0.078

0.255

0.51

0.263

0.741

0.656

0.417

0.544

Page 30 of 34

Page 31 of 34

Watanabe et al.

PNPLA1 rs12199580

Patient group

Patient breakdown by

genotype

Control

total AD

absent/mild↑

subgroups

moderate↑

by IgE levels

severe↑

absent/mild↑

subgroups

by TARC

moderate↑

levels

severe↑

subgroups

by IGA

score

subgroups

FLG

with/without mutation-positive

FLG

mutation

FLG

mutation-negative

Total FLG

mutation-negative

subgroups by IgE

levels

subgroups by

TARC levels

absent/mild↑

moderate↑

severe↑

absent/mild↑

moderate↑

severe↑

subgroups by IGA

scores

Patient group

PNPLA1 rs4713956

absent/mild↑

subgroups

moderate↑

by IgE levels

severe↑

absent/mild↑

subgroups

by TARC

moderate↑

levels

severe↑

subgroups

by IGA

score

subgroups

FLG

with/without mutation-positive

FLG

mutation

FLG

mutation-negative

subgroups by

TARC levels

subgroups by IGA

scores

AA+AC

total

143

124

0.314

0.995

0.349

0.207

0.995

0.295

0.097

0.347

0.917

0.321

0.446

0.6

0.4

0.401

0.325

0.4

0.27

0.192

0.347

0.991

0.49

Patient breakdown by

genotype

value

CC+CT

121

total

142

110

0.592

0.676

0.247

0.805

0.676

0.338

0.974

0.382

0.758

0.217

0.394

0.791

0.861

0.427

0.481

0.861

0.492

0.897

0.382

0.592

0.792

Total FLG

mutation-negative

subgroups by IgE

levels

value

Control

total AD

iew

Journal of Dermatological Science

absent/mild↑

moderate↑

severe↑

absent/mild↑

moderate↑

severe↑

https://mc.manuscriptcentral.com/jdermscience

Journal of Dermatological Science

Watanabe et al.

SLC27A4 rs2240953

Patient group

Patient breakdown by

genotype

Control

total AD

absent/mild↑

subgroups

moderate↑

by IgE levels

severe↑

absent/mild↑

subgroups

by TARC

moderate↑

levels

severe↑

subgroups

by IGA

score

subgroups

FLG

with/without mutation-positive

FLG

mutation

FLG

mutation-negative

Total FLG

mutation-negative

subgroups by IgE

levels

subgroups by

TARC levels

absent/mild↑

moderate↑

severe↑

absent/mild↑

moderate↑

severe↑

subgroups by IGA

scores

NIPAL4 rs6860507

iew

Patient group

Control

total AD

absent/mild↑

subgroups

moderate↑

by IgE levels

severe↑

absent/mild↑

subgroups

by TARC

moderate↑

levels

severe↑

subgroups

by IGA

score

subgroups

FLG

with/without mutation-positive

FLG

mutation

FLG

mutation-negative

Total FLG

mutation-negative

subgroups by IgE

levels

subgroups by

TARC levels

subgroups by IGA

scores

absent/mild↑

moderate↑

severe↑

absent/mild↑

moderate↑

severe↑

value

AA+AG

total

142

110

0.372

0.614

0.145

0.087

0.564

0.976

0.108

0.289

0.866

0.386

0.059

Patient breakdown by

genotype

AA+AG

total

143

109

Page 32 of 34

0.451

0.612

0.404

0.158

0.904

0.125

0.615

0.866

0.486

0.04*

value

0.822

0.133

0.739

0.895

0.372

0.903

0.895

0.116

0.557

0.352

0.86

0.852

...

参考文献をもっと見る

分野

大学

学位論文種類・取得年

言語

Homozygous variant p.Ser427Pro in PNPLA1 is a preventive factor from atopic dermatitis

概要

この論文で使われている画像

関連論文

A novel NCSTN missense mutation in the signal peptide domain causes hidradenitis suppurativa, which has features characteristic of an autoinflammatory keratinization disease

Unique reticular hyperkeratotic eruptions seen in a patient with Darier's disease and attention deficit hyperactivity disorder

Identification of a novel causative mutation in KRT1 in diffuse palmoplantar keratoderma, facilitated by whole-exome sequencing

Successful dupilumab treatment for ichthyotic and atopic features of Netherton syndrome

Hereditary Mucoepithelial Dysplasia and Autosomal-Dominant IFAP Syndrome Is a Clinical Spectrum Due to SREBF1 Variants

参考文献

分野

大学

学位論文種類・取得年

言語

コピーが完了しました

URLをコピーしました

Homozygous variant p.Ser427Pro in PNPLA1 is a preventive factor from atopic dermatitis

概要

この論文で使われている画像

関連論文

A novel NCSTN missense mutation in the signal peptide domain causes hidradenitis suppurativa, which has features characteristic of an autoinflammatory keratinization disease

Unique reticular hyperkeratotic eruptions seen in a patient with Darier's disease and attention deficit hyperactivity disorder

Identification of a novel causative mutation in KRT1 in diffuse palmoplantar keratoderma, facilitated by whole-exome sequencing

Successful dupilumab treatment for ichthyotic and atopic features of Netherton syndrome

Hereditary Mucoepithelial Dysplasia and Autosomal-Dominant IFAP Syndrome Is a Clinical Spectrum Due to SREBF1 Variants

参考文献